use of a composition comprising bile acid recycling inhibitors and pediatric cross-reference dosage

专利摘要:
BILE ACID RECYCLING INHIBITORS FOR THE TREATMENT OF PEDIATRIC CHOLESTATIC HEPATIC DISEASES. Pediatric dosage forms are provided herein for use in the treatment of pediatric cholestatic liver disease by non-systematically administering to an individual, in need thereof, a therapeutically effective amount of the pediatric dosage form comprising a bile acid-dependent transport inhibitor Apical sodium (ASBTI) or a pharmaceutically acceptable salt thereof. Said pediatric dosage forms are also provided for use in the treatment of pediatric liver disease, for use in lowering levels of bile acids or serum hepatic bile acids, for use in the treatment of pruritus, for use in reducing liver enzymes or bilirubin that comprise administering, unsystematically, to an individual in need of a therapeutically effective amount of a pediatric formulation comprising an ASBTI or a pharmaceutically acceptable salt thereof.
公开号:BR112014010223B1
申请号:R112014010223-6
申请日:2012-10-26
公开日:2020-11-10
发明作者:Bronislava Gedulin；Michael Grey；Niall O'Donnell
申请人:Lumena Pharmaceuticals Llc；
IPC主号:

专利说明:

[0001] This application claims the benefit of US Provisional Application No. 61 / 553,094 filed on October 28, 2011, US Provisional Application No. 61 / 607,487 filed on March 6, 2012, US Provisional Application No. £ 61 / 607,503 filed on March 6, 2012, which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION
[0002] Pediatric cholestatic liver diseases affect a small percentage of children, but medical treatment results in significant healthcare costs each year. Today, many of the pediatric cholestatic liver diseases require invasive and expensive treatments, such as surgery and liver transplantation. An effective and less invasive treatment, which is suitable for the pediatric population, is not available.
[0003] It is well understood and accepted that the therapeutic needs of children are sufficiently different from those aimed at adults in terms of the requirement for specific drug studies in children. For example, oral administration of a solid drug dosage form is efficient and simple for most adult patients, but for the pediatric patient population, swallowing a solid oral dosage form produced for adults can be problematic. In addition, drugs used in solid dosages often have an unpleasant taste. Most importantly, oral administration of adult medications for cholestatic liver disease can result in side effects such as diarrhea and intestinal discomfort. Such problems represent a fulfillment of security risks and affections. Effective and acceptable forms of pediatric drugs are needed for pediatric cholestatic liver diseases. SUMMARY OF THE INVENTION
[0004] Therapeutic compositions and methods for treating or ameliorating a pediatric cholestatic liver disease or pediatric cholestasis are provided here. In certain embodiments, methods are provided herein for the treatment or amelioration of a pediatric cholestatic liver disease comprising non-systemic administration to a pediatric patient, of a therapeutically effective amount of a composition comprising a sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for the treatment or amelioration of a pediatric cholestatic liver disease comprising administering to a subject in need of a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. . In certain embodiments, methods are provided herein for the treatment or amelioration of a pediatric cholestatic liver disease comprising non-systemic administration to a pediatric patient, of a therapeutically effective amount of a pediatric dosage form comprising a Bile Acid Transporter Inhibitor sodium-dependent (ASBTI) or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for the treatment or amelioration of a pediatric cholestatic liver disease comprising administering to a subject in need of a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or one thereof. pharmaceutically acceptable salt.
[0005] In certain embodiments, pediatric dosage forms comprising a pediatric dosage of a sodium-dependent bile acid carrier inhibitor (ASBTI) absorbed non-systemically or a pharmaceutically acceptable salt thereof are provided herein. In some embodiments, pediatric dosage forms comprising any non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof, described herein, are provided herein. In some embodiments, pediatric dosage forms comprising any non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof and a second agent described herein are provided herein.
[0006] Therapeutic compositions and methods for treating or ameliorating itching are provided here. In certain embodiments, methods are provided herein for the treatment or improvement of pruritus which comprises administering non-systemically, to a patient suffering from pediatric cholestatic liver disease, a therapeutically effective amount of a composition comprising an ASBTI or a pharmaceutically salt thereof. acceptable. In certain embodiments, methods are provided herein for treating or ameliorating itching comprising administering to a person in need thereof a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for the treatment or amelioration of pruritus which comprises administering non-systemically, to a pediatric patient suffering from a pediatric cholestatic liver disease, a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for treating or ameliorating itching comprising administering to a subject in need thereof a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
[0007] Therapeutic compositions and methods for treating or ameliorating pediatric hypercholemia are provided here. In certain embodiments, methods are provided herein for the treatment or amelioration of pediatric hypercholemia comprising the non-systemic administration to a pediatric patient of a therapeutically effective amount of a composition comprising an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for the treatment or amelioration of pediatric hypercholemia comprising administering to a subject in need of a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for the treatment or amelioration of pediatric hypercholemia comprising the non-systemic administration, to a pediatric patient, of a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for the treatment or amelioration of pediatric hypercholemia comprising administering to a subject in need of a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. .
[0008] Therapeutic compositions and methods for reducing serum bile acid concentrations or concentrations of hepatic bile acids are provided here. In certain embodiments, methods are provided herein to decrease serum levels or concentrations of bile acids or levels or concentrations of hepatic bile acids comprising non-systemic administration to a patient suffering from a pediatric cholestatic liver disease of a pediatric amount effectiveness of a composition comprising an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein to reduce serum levels of bile acids or hepatic bile acids, comprising administering to a subject in need of a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a salt thereof. pharmaceutically acceptable. In certain embodiments, methods are provided herein to decrease serum levels or concentrations of bile acids or levels or concentrations of hepatic bile acids comprising non-systemic administration to a patient suffering from a pediatric cholestatic liver disease of a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein to reduce serum levels of bile acids or hepatic bile acids comprising administering, to an individual in need thereof, a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
[0009] In some embodiments, the compositions and methods provided herein decrease the levels of serum or hepatic bile acids by at least 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15 %, or 10%, compared to levels prior to administration of the compositions of the invention or, compared to control subjects provided. In some embodiments, the methods provided herein decrease serum or hepatic bile acid levels by at least 30%. In some embodiments, the methods provided herein decrease serum or hepatic bile acid levels by at least 25%. In some embodiments, the methods provided herein decrease serum or hepatic bile acid levels by at least 20%. In some embodiments, the methods provided herein decrease serum or hepatic bile acid levels by at least 15%.
[0010] Therapeutic compositions and methods for the treatment or improvement of xanthoma are provided here. In certain embodiments, methods for the treatment or improvement of xanthoma are provided herein, comprising non-systemic administration to a pediatric patient suffering from a pediatric cholestatic liver disease of a therapeutically effective amount of a composition comprising an ASBTI or a salt thereof. pharmaceutically acceptable. In certain embodiments, methods for treating or ameliorating xanthoma are provided herein, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods for treating or ameliorating xanthoma are provided herein, comprising non-systemic administration to a pediatric patient suffering from a pediatric cholestatic liver disease of a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for the treatment or improvement of xanthoma, comprising administering to a subject in need thereof a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. .
[0011] In some embodiments, compositions and methods of decreasing serum lipoprotein X levels or concentrations comprising non-systemic administration to a patient suffering from pediatric xanthoma of a therapeutically effective amount of a composition comprising an ASBTI are provided herein. or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein to reduce levels of serum lipoprotein X comprising administering to a subject in need of a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein to decrease levels or concentrations of serum lipoproteins X comprising non-systemic administration to a patient suffering from pediatric xanthoma of a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or one thereof pharmaceutically acceptable salt. In certain embodiments, methods are provided herein to reduce levels of lipoprotein X serum which comprises administering to a subject in need of a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically salt thereof. acceptable.
[0012] In certain embodiments, methods and compositions for reducing serum levels of bilirubin, gamma-glutamyl transpeptidase or gamma-glutamyl transferase (GGT), or liver enzymes, such as alkaline phosphatase, ALT and AST, in an individual in need thereof, comprising the non-systemic administration of a therapeutically effective amount of an ASBTI composition or a pharmaceutically acceptable salt thereof. In some embodiments, the methods comprise administering a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods for reducing serum levels of bilirubin, gamma-glutamyl transpeptidase or gamma-glutamyl transferase (GGT), or liver enzymes, such as alkaline phosphatase, ALT and AST, are described herein. subject in need thereof, comprising the non-systemic administration of a therapeutically effective amount of a pediatric dosage form of an ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, the methods comprise administering a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
[0013] In certain embodiments, the methods provided herein comprise administration of compounds that inhibit ASBT or any recoverable bile salt transporter. In certain embodiments, the use of the compounds presented herein reduces or inhibits the recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided herein reduce intra-enterocyte bile acids / salts or reduce necrosis and / or damage to the intestinal or hepatocellular architecture.
[0014] In certain embodiments, the methods described here, treat or ameliorate a pediatric cholestatic liver disease, increasing the intraluminal concentrations of bile acids / salts, which are then excreted in the faeces, thereby reducing the overall burden of bile acid and serum bile acid or hepatic bile acid in an individual in need of it. In certain embodiments, the increase in intraluminal concentrations of bile acids according to the methods described herein provide protection and / or control of the liver and / or intestine integrity of an individual who has been injured by cholestasis and / or liver disease cholestatic.
[0015] In certain embodiments, the methods described herein, treat or ameliorate itching by increasing intraluminal concentrations, and / or reducing serum concentrations, or hepatic concentrations of bile acids / salts of an individual in need thereof. In certain embodiments, the increase in intraluminal concentrations of bile acids according to the methods described herein provide protection and / or control of the integrity of the liver and / or intestine of an individual who has been injured by a cholestatic liver disease.
[0016] In certain embodiments, the methods described herein decrease serum bile acid concentrations or hepatic bile acid concentrations, increasing the intraluminal concentrations of bile acids / salts in an individual in need thereof. In certain embodiments, the increase in intraluminal bile acid concentrations according to the methods described herein will provide protection and / or control of the liver and / or intestine integrity of an individual who has been injured by a cholestatic liver disease.
[0017] In certain embodiments, an ASBTI or a pharmaceutically acceptable salt thereof is provided herein for use in the treatment of a pediatric cholestatic liver disease, wherein the ASBTI is not absorbed systemically or is formulated to be absorbed non-systemically. In some embodiments, a pharmaceutical composition is provided herein for use in the treatment of pediatric cholestatic liver disease, where the composition comprises a pediatric dosage form of an ASBTI and a pharmaceutically acceptable excipient, in which ASBTI is absorbed non-systemically. or it is formulated to be absorbed non-systemically. In some embodiments, a composition provided herein is suitable for non-systemic administration to the distal ileum, colon and / or rectum.
[0018] In certain embodiments, an ASBTI or a pharmaceutically acceptable salt thereof is provided herein for use in the treatment of pruritus in a patient suffering from a pediatric cholestatic liver pediatric disease, in which the ASBTI is absorbed non-systemically or is formulated to be absorbed non-systemically. In some embodiments, a pharmaceutical composition for use in the treatment of pruritus is provided herein, which composition comprises a pediatric dosage form of an ASBTI and a pharmaceutically acceptable excipient, wherein the ASBTI is absorbed non-systemically or is formulated to be absorbed not systemically. In some embodiments, a composition provided herein is suitable for non-systemic administration to the distal ileum, colon and / or rectum.
[0019] In certain embodiments, an ASBTI or a pharmaceutically acceptable salt thereof is provided herein for use in reducing the concentration of serum bile acids or concentrations of hepatic bile acids in a pediatric patient suffering from pediatric cholestatic liver disease , in which ASBTI is absorbed non-systemically or is formulated to be absorbed non-systemically. In some embodiments, a pharmaceutical composition is provided herein for use in reducing the concentration of serum bile acids or the concentrations of hepatic bile acids, wherein the composition comprises a pediatric dosage form of an ASBTI and a pharmaceutically acceptable excipient, in that ASBTI is absorbed non-systemically or is formulated to be absorbed non-systemically. In some embodiments, a composition provided herein is suitable for non-systemic administration to the distal ileum, colon and / or rectum.
[0020] In some embodiments, an ASBTI provided here is minimally absorbed or formulated to be minimally absorbed. In some embodiments, a pediatric dosage form of an ASBTI is administered non-systemically to the distal ileum, colon and / or rectum of an individual in need of it. In some embodiments, an ASBTI is administered non-systemically to the ileum, colon or rectum, of an individual who needs it. In some embodiments, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the ASBTI is absorbed systemically. In a preferred embodiment, less than 10% of the ASBTI is absorbed systemically. In another preferred embodiment, less than 5% of the ASBTI is absorbed systemically. In another preferred embodiment, less than 1% of the ASBTI is absorbed systemically.
[0021] In one aspect, a method is provided herein for the treatment of a pediatric cholestatic liver disease in an individual in need thereof, which comprises non-systemic administration to the individual's distal gastrointestinal tract thereby requiring a therapeutically effective amount of a pediatric dosage form of an ASBTI or a pharmaceutically acceptable salt thereof. In one aspect, a method is provided herein for the treatment of itching in an individual in need thereof, comprising non-systemic administration to the distal gastrointestinal tract of the individual in need thereof of a therapeutically effective amount of a pediatric dosage form of an ASBTI or a pharmaceutically acceptable salt thereof. In one aspect, a method for reducing serum bile acid concentrations in an individual in need is provided herein, which comprises non-systemic administration to the individual's distal gastrointestinal tract thereby requiring a therapeutically effective amount of a dosage form. pediatric use of an ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, the distal gastrointestinal tract is jejunum, ileum, colon, or rectum. In some embodiments, the distal gastrointestinal tract is the ileum, colon or rectum. In some embodiments, the distal gastrointestinal tract is jejunum. In some embodiments, the distal gastrointestinal tract is ileum.
[0022] In certain embodiments, pediatric cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, post-Kasai biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, liver disease associated with post-liver transplantation, liver disease associated with intestinal failure, bile acid-mediated liver injury, pediatric primary sclerosing cholangitis, MRP2 deficiency syndrome, neonatal sclerosing cholangitis, pediatric obstructive cholestasis, pediatric non-obstructive cholestasis, pediatric extrahepatic cholestasis, pediatric intrahepatic cholestasis, pediatric primary intrahepatic cholestasis, pediatric secondary intrahepatic cholestasis , recurrent benign intrahepatic cholestasis (BRIC), BRIP type 1, BRIC type 2, BRIC type 3, cholestasis associated with parenter nutrition total al, paraneoplastic cholestasis, Stauffer's syndrome, drug-associated cholestasis, cholestasis associated with infection or gallstone disease. In some embodiments, pediatric cholestatic liver disease is a pediatric form of liver disease described herein.
[0023] In certain embodiments, a pediatric cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritus, cirrhosis, hypercholemia, neonatal respiratory distress syndrome, pulmonary pneumonia, increased serum bile acid concentration, increased concentration of hepatic bile acids, increased concentration of serum bilirubin, hepatocellular lesion, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, hemorrhage gastrointestinal, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, peculiar smell, dark urine, whitish stools, steatorrhea, growth deficit and / or renal failure.
[0024] In certain embodiments, the pediatric patient is a newborn, a premature newborn, a baby, a child, a preschool child, a school child, a prepubertal child, a post-pubertal child, a teenager or a teenager under the age of eighteen. In some embodiments, the pediatric patient is a newborn, a premature newborn, a baby, a child, a child of preschool age, or a school child. In some embodiments, the pediatric patient is a newborn, a premature newborn, a baby, a child, or a preschooler. In some embodiments, the pediatric patient is a newborn, a premature newborn, a baby, or a child. In some embodiments, the pediatric patient is a newborn, a premature newborn or a baby. In some embodiments, the pediatric patient is a newborn. In some embodiments, the pediatric patient is an infant. In some embodiments, the pediatric patient is a child.
[0025] In certain embodiments, the individual is a child under 2 years of age. In some cases, for any of the methods and / or compositions described here, the individual is a child between 0 and 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a child between 1 and 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a child between 2 and 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a child between 3 to 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a child between 4 and 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a child between 6 to 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a child between 18 and 24 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a child between 6 to 12 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is a child between about 2 and about 10 years old. In some cases, the individual is less than about 10 years old. In some cases, the individual is between about 10 to about 17 years old.
[0026] In some cases, for any of the methods and / or compositions described here, the individual is a child between 6 months to 12 years old.
[0027] Therapeutic methods and compositions using compounds that inhibit the apical sodium-dependent bile acid transporter (ASBT) or a pharmaceutically acceptable salt thereof, or any recoverable bile salt transporter for treatment are provided here in certain embodiments from a pediatric cholestatic liver disease or itching or to lower serum bile acid concentrations. In certain cases, the use of the compounds presented here reduces or inhibits the recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided herein reduce intra-enterocyte bile salts / acids and / or damage to the ileo or hepatocellular architecture caused by a pediatric cholestatic disease of the liver and / or allow the regeneration of the intestinal mucosa or liver. In some embodiments, bile acid transport inhibitors are non-systemic compounds. In other embodiments, bile acid transporter inhibitors are non-systemic compounds delivered systemically. In other embodiments, bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile acid transport inhibitors described herein increase the secretion of enteroendocrine peptide by intestinal L cells.
[0028] In some embodiments of the methods described above, ASBTI is a compound of Formula I or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula II or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula III or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula IV or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula V or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula VI or Formula VID or a pharmaceutically acceptable salt thereof, as described herein.
[0029] In some embodiments, a method is provided herein to treat or ameliorate a pediatric cholestatic liver disease comprising non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form of an ASBTI Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided herein to treat or ameliorate itching comprising non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula I or a pharmaceutically acceptable salt thereof. . In some embodiments, a method is provided herein to increase the levels of a peptide or enteroendocrine hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemic administration to the individual in need of it in a therapeutically effective amount. pediatric dosage form of an ASBTI of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, a method for reducing serum bile acid concentrations or the concentration of hepatic bile acids is provided herein which comprises non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form. of a Formula I ASBTI or a pharmaceutically acceptable salt thereof.
[0030] In some embodiments, a method is provided herein to treat or ameliorate a pediatric cholestatic liver disease comprising non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form of an ASBTI Formula II or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided herein to treat or ameliorate itching comprising non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric formulation of a Formula II ASBTI or a pharmaceutically acceptable salt thereof. . In some embodiments, a method is provided herein to increase the levels of a peptide or enteroendocrine hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemic administration to the individual in need of it in a therapeutically effective amount. pediatric dosage form of a Formula II ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method for reducing serum bile acid concentrations or the concentration of hepatic bile acids is provided here comprising the non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form a Formula II ASBTI or a pharmaceutically acceptable salt.
[0031] In some embodiments, a method is provided herein to treat or ameliorate a pediatric cholestatic liver disease comprising non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form of a Formula ASBTI III or a pharmaceutically acceptable salt. In some embodiments, a method is provided herein to treat or ameliorate itching comprising non-systemic administration to an individual in need thereof of a therapeutically effective amount of a pediatric formulation of a Formula III ASBTI or a pharmaceutically acceptable salt. . In some embodiments, a method is provided herein to increase the levels of a peptide or enteroendocrine hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemic administration to the individual in need of a therapeutically effective amount of a pediatric dosage form of a Formula III ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method for reducing serum bile acid concentrations or the concentration of hepatic bile acids is provided herein which comprises non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form. a Formula III ASBTI or a pharmaceutically acceptable salt.
[0032] In some embodiments, a method is provided here for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form of an ASBTI Formula. IV or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided herein to treat or ameliorate itching comprising non-systemic administration to an individual in need thereof of a therapeutically effective amount of a pediatric formulation of a Formula IV ASBTI or a pharmaceutically salt thereof. acceptable. In some embodiments, a method is provided herein to increase the levels of a peptide or enteroendocrine hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemic administration to the individual in need of a therapeutically effective amount of a pediatric dosage form of a Formula IV ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided herein to lower the concentration of serum bile acids or the concentration of liver bile acids which comprises the non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form of a Formula IV ASBTI or a pharmaceutically acceptable salt thereof.
[0033] In some embodiments, a method is provided herein to treat or ameliorate a pediatric cholestatic liver disease comprising non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form of an ASBTI Formula V or a pharmaceutically acceptable salt. In some embodiments, a method is provided herein to treat or ameliorate itching comprising non-systemic administration to an individual in need thereof of a therapeutically effective amount of a pediatric formulation of a Formula V ASBTI or a pharmaceutically salt thereof. acceptable. In some embodiments, a method is provided herein to increase the levels of a peptide or enteroendocrine hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemic administration to the individual in need of a therapeutically effective amount of a pediatric dosage form of a Formula V ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method for reducing serum bile acid concentrations or the concentration of hepatic bile acids is provided here comprising the non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form of a Formula V ASBTI or a pharmaceutically acceptable salt.
[0034] In some embodiments, a method is provided herein to treat or ameliorate a pediatric cholestatic liver disease comprising non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form of an ASBTI Formula VI or a pharmaceutically acceptable salt. In some embodiments, a method is provided herein to treat or ameliorate itching comprising non-systemic administration to an individual in need thereof of a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula VI or a pharmaceutically salt thereof. acceptable. In some embodiments, a method is provided herein to increase the levels of a peptide or enteroendocrine hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemic administration to the individual in need of a therapeutically effective amount of a pediatric dosage form of a Formula VI ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method for reducing serum bile acid concentrations or the concentration of hepatic bile acids is provided herein which comprises non-systemic administration to an individual in need of a therapeutically effective amount of a pediatric dosage form. of a Formula VI ASBTI or a pharmaceutically acceptable salt thereof.
[0035] In certain embodiments, an ASBTI is any compound described herein that inhibits the recycling of bile acids / salts in an individual's gastrointestinal tract. In certain embodiments, an ASBTI is (-) - (3R, 5R) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl -1,4-benzothiazepinal, 1-dioxide; ("Compound 100A") or any other salt or the like. In some of the above mentioned embodiments, an ASBTI is a sulfonate salt of 1- [4- [4- [(4R, 5R) -3,3-dibutyl-7- (dimethylamino) - 2,3,4 , 5-tetrahydro-4-hydroxy-1,1-dioxide-1-benzothiepine-5-yl] phenoxy] butyl] -4-aza-1-azoniabicyclo [2.2.2] octane methane ("Compound 100B") or any other salt or an analog thereof. In certain embodiments, an ASBTI is N, N-dimethylimido-dicarbonimidic diamide ("Compound 100C") or any salt thereof or the like. In certain embodiments, an ASBTI is any commercially available ASBTI, including, but not limited to SD-5613, A-3309, 264W94, S-8921, SAR-548304, BARI-1741, HMR-1453, TA- 7552, R-146224 or SC-435. In some embodiments, an ASBTI is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {((R) -a- [N - ((R) -l -carboxy-2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -a- [N- ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -a- [N- ((S) -1- carboxybutyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -a- [N- ((S) -1- carboxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3, 4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N- (2-sulphoethyl) carbamoyl] -4-hydroxy-benzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,2,5-benzothia-diazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -a- [N - ((S) -1-carboxyethyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N- ((R) -1-carboxy-2-methylthioethyl) carbamoyl] benzyl} carbamoyl-methoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - {(S) -l- [N - ((S) - 2-hydroxy-1-carboxyethyl) carbamoyl] propyl} carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N- ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoyl-methoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1- dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N - {(R) -α-carboxy4-hydroxybenzyl} carbamoylmethoxy] -2,3,4,5-tetrahydro-l , 2,5-benzothiadiazepine; or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3, 4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1'-phenyl-1 '- [N' - (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N '- ((S) -1-carboxy-propyl) carbamoyl] - 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1'-phenyl-1 '- [N' - (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N '- ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine, or a pharmaceutically acceptable salt thereof; 1 - [[5— [[3 - [(3S, 4R, 5R) -3-butyl-7- (dimethylamino) -3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-1 , 1-dioxido-1-benzothiepin-5yl] phenyl] amino] - 5-oxopentyl] amino] -1-deoxy-D-glucitol; or Potassium (((2R, 3R, 4S, 5R, 6R) -4-benzyloxy-6- {3- [3 - (((3S, 4R, 5R) - 3-butyl-7-dimethylamino-3-ethyl-4- hydroxy-l, l-dioxo-2,3,4,5-tetrahydro-lH-benzo [b] tiepin-5-yl) -phenyl] -ureido} -3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl ) ethanolate sulfate, hydrate. In certain embodiments, an ASBTI is 264W94 (Glaxo), SC-435 (Pfizer), SD-5613 (Pfizer) or A3309 (Astra-Zeneca).
[0036] In certain embodiments, the methods provided herein further comprise the administration of a second agent selected from ursodiol, UDCA, cholestyramine / resins, anti-histaminic agents (e.g., hydroxyzine, diphenidamine), rifampicin, nalaxone, Phenobarbital, dronabinol (CB1 agonist), methotrexate, corticosteroids, cyclosporine, colchicine, TPGS - vitamin A, D, E or K, optionally with polyethylene glycol, zinc, and a resin or scavenger for the absorption of bile acids or an analog thereof . In certain embodiments, the methods provided herein further comprise administration of a second agent selected from a bile acid or bile salt with reduced toxicity or a hydrophilic bile acid such as ursodiol, norursodiol, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic, glycodeoxycholic acid, taurodeoxycholic acid, taurocholate, glycoquenodeoxycholic acid or tauroursodeoxycholic acid.
[0037] In certain embodiments, available here are the pediatric dosage forms, such as a solution, syrup, suspension, elixir, powder for reconstitution of suspension or solution, dispersible / effervescent tablet, chewable tablet, gum, lollipop, popsicle, lozenges , thin oral strips, oral disintegrating tablets, sachet, soft gelatin capsule, and oral spray powder or granules.
[0038] In some embodiments, the pediatric dosage of an ASBTI is between about 1 pg / kg / day and about 10 mg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 5 pg / kg / day and about 1 mg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 pg / kg / day and about 300 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is any dosage between about 14 pg / kg / day and about 280 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is any dosage between about 14 pg / kg / day and about 140 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 5 pg / kg / day and about 200 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 pg / kg / day and about 200 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 pg / kg / day and about 175 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 pg / kg / day and about 150 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 pg / kg / day and about 140 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 25 pg / kg / day and about 140 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 50 pg / kg / day and about 140 pg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 70 gg / kg / day and about 140 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 gg / kg / day and about 100 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 10 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 20 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 30 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 35 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 40 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 50 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 60 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 70 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 80 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 90 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 100 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 110 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 120 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 130 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 140 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 150 gg / kg / day. In some embodiments, the pediatric dosage of an ASBTI is 175 gg / kg / day.
[0039] In some embodiments, pediatric ASBTI dosages between 14 pg / kg / day and 140 pg / kg / day, or between 14 mg / kg / day and 280 pg / kg / day are provided here.
[0040] In some embodiments, the pediatric dosage of an ASBTI is between about 0.5 mg / day and about 40 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 0.5 mg / day and about 30 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 1 mg / day and about 20 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 1 mg / day and about 10 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between about 1 mg / day and about 5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 1 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 10 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 20 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg / day and 5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg / day and 4.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg / day and 4 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg / day and 3.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg / day and 3 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg / day and 2.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg / day and 2 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg / day and 1.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg / day and 1 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg / day and 4.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg / day and 4 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg / day and 3.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg / day and 3 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg / day and 2.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg / day and 2 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 0.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 1 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 1.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 2 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 2.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 3 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 3.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 4 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 4.5 mg / day. In some embodiments, the pediatric dosage of an ASBTI is 5 mg / day. In some embodiments, the pediatric dosage described herein is the dosage of the total composition administered.
[0041] In some embodiments, the pediatric dosage form comprises 0.5 mg of ASBTI. In some embodiments, the pediatric dosage form comprises 1 mg of ASBTI. In some embodiments, the pediatric dosage form comprises 2.5 mg of ASBTI. In some embodiments, the pediatric dosage form comprises 5 mg of ASBTI. In some embodiments, the pediatric dosage form comprises 10 mg of ASBTI. In some embodiments, the pediatric dosage form comprises 20 mg of ASBTI.
[0042] In certain embodiments, the pediatric dosage of an ASBTI is given once a day. In some embodiments, the pediatric dosage of an ASBTI is given q.d. In some embodiments, the pediatric dosage of an ASBTI is given once a day, in the morning. In some embodiments, the pediatric dosage of an ASBTI is given once a day, at noon. In some embodiments, the pediatric dosage of an ASBTI is given once a day, at the end of the day or at night. In some embodiments, the pediatric dosage of an ASBTI is given twice a day. In some embodiments, the pediatric dosage of an ASBTI is b.i.d. In some embodiments, the pediatric dosage of an ASBTI is given twice a day, in the morning and at noon. In some embodiments, the pediatric dosage of an ASBTI is given twice a day, in the morning and at the end of the day. In some embodiments, the pediatric dosage of an ASBTI is given twice a day, in the morning and in the evening. In some embodiments, the pediatric dosage of an ASBTI is given twice a day, at noon and at the end of the day. In some embodiments, the pediatric dosage of an ASBTI is given twice a day, at noon and at night. In some embodiments, the pediatric dosage of an ASBTI is administered three times a day. In some embodiments, the pediatric dosage of an ASBTI is given t.i.d. In some embodiments, the pediatric dosage of an ASBTI is given four times a day. In some embodiments, the pediatric dosage of an ASBTI is given q.i.d. In some embodiments, the pediatric dosage of an ASBTI is given every four hours. In some embodiments, the pediatric dosage of an ASBTI is given q.q.h. In some embodiments, the pediatric dosage of an ASBTI is given on alternate days. In some embodiments, the pediatric dosage of an ASBTI is given q.o.d. In some embodiments, the pediatric dosage of an ASBTI is administered three times a week. In some embodiments, the pediatric dosage of an ASBTI is given t.i.w.
[0043] Here, in certain embodiments, methods and dosage forms (for example, the oral or rectal dosage form) are provided for use in the treatment of a pediatric cholestatic liver disease or itching, or decreased acid concentrations serum bile, comprising a therapeutically effective amount of an ASBTI, or a pharmaceutically acceptable salt thereof, and a carrier. In some embodiments, a method for the treatment of cholestasis and / or a cholestatic liver disease is provided herein comprising the oral administration of a therapeutically effective amount of a minimally absorbed ASBTI, or a pharmaceutically acceptable salt thereof, to an individual with need for it. In some embodiments, a method for the treatment of cholestasis and / or a cholestatic liver disease comprising oral administration of a therapeutically effective amount of a minimally absorbed ASBTI, or a pharmaceutically acceptable salt thereof, is provided here to an individual in need the same. In some embodiments, the ASBTI, or its salt, is a minimally absorbed ASBTI. In specific embodiments, the dosage form is an enteric formulation, an ileo pH sensitive release formulation, or a suppository or other appropriate form.
[0044] In some embodiments, a composition for use in the treatment of pediatric cholestatic liver disease or itching, or decreased serum bile acid concentrations comprises at least one of a dispersing agent or a wetting agent. In some embodiments, the composition comprises an absorption inhibitor. In some cases, an absorption inhibitor is a mucus-adhesive agent (for example, a mucus-adhesive polymer). In certain embodiments, the mucus-adhesive agent is selected from methyl cellulose, polycarbophil, polyvinylpyrrolidone, sodium carboxymethyl cellulose, and combinations thereof. In some embodiments, the agent that increases the secretion of enteroendocrine peptide is covalently linked to the absorption inhibitor. In certain embodiments, the pharmaceutical composition comprises an enteric coating. In some embodiments, a composition for use in the treatment of cholestasis, a cholestatic liver disease or itching described above comprises a vehicle. In certain embodiments, the vehicle is a rectally suitable vehicle. In certain embodiments, any pharmaceutical composition described herein is formulated as a suppository, enema solution, rectal foam, or rectal gel. In some embodiments, any pharmaceutical composition described herein comprises an orally suitable carrier.
[0045] In some embodiments, a pediatric dosage form comprising an ASBTI is administered orally. In some embodiments, ASBTI is administered as an ileal pH-sensitive release formulation that provides ASBTI to a person's terminal ileum, colon and / or rectum. In some embodiments, ASBTI is administered as an enteric coated formulation. In some embodiments, oral administration of an ASBTI provided herein may include formulations, as are well known in the art, to provide prolonged or sustained administration of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the pH change of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the intestinal tract mucosa, or enzymatic release of the active drug from the dosage form. The intended effect is to prolong the period of time during which the active drug molecule is administered to the site of action (the ileum) by manipulating the dosage form. Thus, enteric coated and enteric coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate and anionic polymers of methacrylic acid and methyl ester methacrylic acid.
[0046] In some embodiments, the methods and compositions provided here further comprise the administration of a scavenger or a bile acid binder to reduce gastrointestinal side effects. In some embodiments, the methods comprise administering a labile bile acid scavenger, wherein the labile bile acid scavenger has a low affinity in the individual's colon or rectum for at least one bile acid. In some embodiments, a labile bile acid scavenger provided herein releases bile acid into a human's colon or rectum. In some embodiments, a labile bile acid scavenger provided herein does not sequester a bile acid for excretion or excretion in the faeces. In some embodiments, a labile bile acid scavenger provided herein is a labile, non-systemic bile acid scavenger. In some embodiments, non-systemic labile bile acid scavenger is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% systemically absorbed. In some embodiments, the labile bile acid scavenger is lignin or modified lignin. In some embodiments, the labile bile acid scavenger is a polycationic polymer or copolymer. In certain embodiments, the labile bile acid scavenger is a polymer or copolymer that comprises one or more N-alkenyl-N-alkylamine residues; one or more residues of N, N, N-trialkyl-N- (N'-alkenylamino) alkyl-azanium; one or more residues of N, N, N-trialkyl-N-alkenyl-azanium; one or more alkenyl amine residues; cholestyramine, colestipol, or colesevelam or a combination thereof.
[0047] In some embodiments of the methods described above, a pediatric dosage form comprising an ASBTI is administered prior to eating food. In some embodiments of the methods described above, a pediatric dosage form comprising an ASBTI is administered with or after eating food.
[0048] In some embodiments, the methods provided herein further comprise the administration of vitamin supplements to compensate for reduced vitamin digestion, in particular fat-soluble vitamins, in an individual with pediatric cholestatic liver disease, itching, or levels or high concentrations of serum bile acids. In some embodiments, vitamin supplements comprise fat-soluble vitamins. In some embodiments, the fat-soluble vitamins are vitamin A, D, E or K.
[0049] In some cases, by any of the methods described above, the administration of an ASBTI reduces intra-enterocyte bile acids / salts of an individual in need of it. In some embodiments, the methods described herein reduce the accumulation of bile acids / salts in ileo enterocytes of an individual in need of it. In some cases, by any of the methods described above, the administration of an ASBTI inhibits the transport of ileal lumen bile acids / salts into enterocytes of an individual in need of it. In some cases, for any of the methods described above, administration of an ASBTI increases ileal bile acid / bile salts of an individual in need of it. In some cases, for any of the methods described above, administration of an ASBTI reduces damage to intestinal (eg ileo cells) or hepatocellular (eg liver cells) architecture associated with pediatric or elevated cholestatic liver disease concentrations of serum or liver bile acids in an individual who needs it. In some cases, for any of the methods described above, administration of an ASBTI regenerates the intestinal lining or liver cells that have been damaged by cholestasis and / or cholestatic liver disease in an individual suffering from cholestatic liver disease.
[0050] In some embodiments, methods are provided herein for the treatment of a pediatric cholestatic liver disease which comprises administering a therapeutically effective amount of a pediatric dosage form comprising a combination of an ASBTI and ursodiol to an individual in need for it. In some embodiments, methods are provided herein for the treatment of a pediatric cholestatic liver disease comprising administering a therapeutically effective amount of a combination of an ASBTI and a resin or scavenger for the absorption of bile acids to an individual in need thereof. . In some embodiments, an ASBTI is administered in combination with one or more agents selected from the group consisting of ursodiol, UDCA, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycolic acid, glycodesoxycholic acid, taurodeoxycholic, taurocholate, glycoquenodeoxycholic acid, tauroursodeoxycholic acid, cholestyramine / resins, antihistaminic agents (eg, hydroxyzine, diphenidamine), rifampicin, nalaxone, Phenobarbital, dronabinol (CB1 agonist), methotrexate, cyclohexine, corticosteroids, cyclohexine, corticosteroids, methotrexate, corticosteroids, methotrexate, cyclosporine TPGS - vitamin A, D, E or K, optionally with polyethylene glycol, zinc, a resin or scavenger to absorb bile acids.
[0051] In some embodiments, the methods provided herein further comprise partial external biliary bypass therapy (LDPE).
[0052] In some embodiments, a kit is provided herein comprising any composition described herein (for example, a pharmaceutical composition formulated for rectal administration) and a device for delivery located within the rectum or colon. In certain embodiments, the device is a syringe, bag or pressurized container. BRIEF DESCRIPTION OF THE DRAWINGS
[0053] Figure 1. Oral administration of 264W94 dose depends on increased bile acids in stool. Fecal bile acid concentrations were increased up to 6.5 times with an ED50 of 0.17 mg / kg, when compared to vehicle-treated rats. Fecal NEFA also increased slightly in mice treated with 264W94. Plasma bile acid concentrations were decreased dose-dependent in rats treated with 264W94.
[0054] Figure 2. Bile acid levels in the plasma of ZDF rats after administration of ascending doses of SC-435 and LUM002. Male ZDF rats (n = 4) were administered vehicles, SC-435 (1, 10 or 30 mg / kg) or LUM002 (0.3, 1, 3, 10 or 30 mg / kg) by oral probe, twice a day for 2 weeks. Plasma bile acid levels were determined at the end of the second week. The data are expressed as mean values ± SEM.
[0055] Figure 3. Analysis of serum bile acid (SBA) in healthy subjects after administration of multiple ascending oral doses of LUM001, a randomized, double-blind, placebo-controlled study. Data from 0.5 (n = 16), 1.0 groups (n = 8), 2.5 (n = 8), 5.0 (n = 8) and 10 (n = 8) are shown in the graphs ) mg dosage. On day 1, blood was drawn to the SBA baseline about 30 minutes before and after breakfast and 30 minutes after lunch and dinner. The samples were obtained on day 14.
[0056] Figure 4. Analysis of bile acids in the stool of healthy subjects after administration of multiple ascending oral doses of LUM001, a randomized, double-blind, placebo-controlled study. Stool samples were collected for all panels, except the dose titration panel, 2.5 (2) and 5 mg (2), on days 9 to 14 and 23 to 28.
[0057] Figure 5. Fasting serum bile acid levels and postprandial peak in the morning in children under the age of 12. LUM001 was administered once daily (QD) in the morning for 14 days. Placebo-treated patients had an average fasting bile acid level of 8.6 pmol / L and a peak postprandial serum bile acid level of 11.9 pmol / L. For patients treated with LUM001 the values were 6.5 pmol / L and 9.2, respectively, which represents a decrease of 24% and 23%. DETAILED DESCRIPTION OF THE INVENTION
[0058] Bile acids / salts play a critical role in the activation of digestive enzymes and solubilization of fats and fat-soluble vitamins and are involved in the liver, bile ducts and intestinal diseases. Bile acids are synthesized in the liver via a multiple-stage organelle pathway. The hydroxyl groups are added to specific sites on the steroid structure, the double bond of the cholesterol B ring is reduced and the hydrocarbon chain is shortened by three carbon atoms, resulting in a carboxyl group at the end of the chain. The most common bile acids are cholic acid and chenodeoxycholic acid (the "primary bile acids"). Before eliminating hepatocytes and forming bile, bile acids are conjugated with glycine (to produce glycolic acid or glycoquenodeoxycholic acid) or taurine (to produce taurocholic acid or tauroquenodeoxycholic acid). Conjugated bile acids are called bile salts and their amphipathic nature makes them more effective detergents than bile acids. Bile salts, not bile acids, are found in bile.
[0059] Bile salts are excreted by hepatocytes in canaliculi to form bile. The canaliculi drain into the right and left hepatic ducts and the bile flows into the gallbladder. Bile is released from the gallbladder and travels to the duodenum, where it contributes to fat metabolism and breakdown. The bile salts are reabsorbed in the terminal ileum and transported back to the liver through the portal vein. Bile salts often pass through several enterohepatic circulations before being excreted in the faeces. A small percentage of bile salts can be reabsorbed in the proximal intestine by passive or vehicle-mediated transport processes. Most bile salts are recovered in the distal ileum by an apically sodium-dependent bile acid carrier referred to as the sodium-dependent apical bile acid carrier (ASBT). On the basolateral surface of the enterocyte, a truncated version of ASBT is involved in the vectorial transfer of bile acids / salts to the portal circulation. The completion of the enterohepatic circulation occurs on the basolateral surface of hepatocytes through a transport process that is mediated mainly by a sodium-dependent bile acid transporter. The transport of intestinal bile acid plays a key role in the enterohepatic circulation of bile salts. The molecular analysis of this process has recently led to important advances in our understanding of the biology, physiology and pathophysiology of intestinal bile acid transport.
[0060] Within the intestinal lumen, bile acid concentrations vary, with most reuptake occurring in the distal intestine. Bile acids / salts alter the growth of bacterial flora in the intestine. Certain compositions and methods that control bile acid concentrations in the intestinal lumen are described herein, thereby controlling the hepatocellular damage caused by the accumulation of bile acid in the liver.
[0061] In another aspect, the compositions and methods provided here increase the concentrations of bile acids in the intestine. Increased concentrations of bile acids / salts stimulate the subsequent secretion of factors that protect and control the integrity of the intestine when it is injured by pediatric cholestasis and / or a pediatric cholestatic liver disease (eg, a pediatric cholestatic liver disease associated with pruritus , or a pediatric cholestatic liver disease associated with high concentrations of serum bile acids or concentrations of liver bile acids).
[0062] In yet another aspect, the compositions and methods described herein have an advantage over systemically absorbed agents. The compositions and methods described herein use ASBT inhibitors that are not absorbed systemically. Thus, the compositions are effective without leaving the lumen of the intestine, thus reducing any toxicity and / or side effects associated with systemic absorption. The pediatric formulations described here have an advantage over existing dosage forms and dosages for adults by reducing harmful side effects and increasing compliance.
[0063] In another aspect, the compositions and methods described here stimulate the release of enteroendocrine hormones GLP-2 and PYY. Increased secretion of GLP-2 or PYY allows the prevention or treatment of pediatric cholestasis and / or a pediatric cholestatic liver disease, controlling the adaptation process, attenuating intestinal damage, reducing bacterial translocation, inhibiting the release of free radicals from oxygen, inhibiting the production of pro-inflammatory cytokines, or any combination thereof.
[0064] The use of ASBT inhibitors or any recuperative bile salt transporter active in the gastrointestinal tract (GI) for the treatment or prevention of pediatric cholestasis and / or a pediatric cholestatic liver disease in an individual in need is described here the same. In certain embodiments, the use of ASBT inhibitors or any recuperative bile salt transporters active in the gastrointestinal tract (GI) for the treatment or prevention of itching in an individual in need is described herein. In certain embodiments, the use of ASBT inhibitors or any recuperative bile salt transporter that are active in the gastrointestinal tract (GI) to decrease serum bile acid concentrations or hepatic bile acid concentrations in an individual in need is described herein. the same. In certain embodiments, the methods provided herein comprise administering a therapeutically effective amount of an ASBTI to an individual in need thereof. In some embodiments, such ASBT inhibitors are absorbed non-systemically. In some of such embodiments, such bile salt transport inhibitors include a radical or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a part or group loaded in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption. In some other embodiments, these ASBT inhibitors are absorbed systemically. In some embodiments, the ASBTI provided here is formulated for non-systemic delivery to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some embodiments, an ASBTI is administered systemically to the colon or rectum of an individual in need of it.
[0065] In some embodiments, such ASBT inhibitors are absorbed non-systemically. In some of such embodiments, such bile salt transport inhibitors include a radical or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a part or group loaded in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption. In some other embodiments, these ASBT inhibitors are absorbed systemically. In some embodiments, ASBTI is formulated for non-systemic delivery to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some embodiments, an ASBTI is administered non-systemically to the colon or rectum of an individual in need.
[0066] In some embodiments, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 9%, less than 8% less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the ASBTI is absorbed systemically. In certain embodiments, the ASBTIs described herein inhibit the elimination of bile salts by the recovery bile acid salt transporters in the distal gastrointestinal tract (for example, the terminal ileum, the colon and / or the rectum).
[0067] In some cases, inhibition of bile salt recycling results in higher concentrations of bile salts in the distal lumen of the gastrointestinal tract, or portions thereof (e.g., the distal small intestine and / or colon and / or rectum) . As used herein, the distal gastrointestinal tract includes the region from the distal ileum to the anus. In some embodiments, the compounds described herein reduce intra-enterocyte bile acids / salts or their accumulation. In some embodiments, the compounds described herein reduce the damage to the hepatocellular or intestinal architecture associated with cholestasis and / or a cholestatic liver disease. Mammalian microbiome, bile acid pools and metabolic interactions
[0068] The integrated metabolism of bile acid pools in the intestinal lumen lends itself to complex biochemical interactions between the host and microbiome symbionts.
[0069] Bile acids / salts are synthesized from cholesterol in the liver, by a coordinated multi-enzyme process and are essential for the absorption of dietary fats and vitamins soluble in lipids in the intestine. Bile acids / salts play a role in maintaining the intestinal barrier function to prevent the overgrowth and translocation of intestinal bacteria, as well as the invasion of adjacent tissues by enteric bacteria.
[0070] Under normal conditions (that is, when an individual is not suffering from pediatric cholestasis and / or a pediatric cholestatic liver disease), the symbiotic intestine microorganisms (microbiome) interact closely with the host's metabolism and are important determinants of Cheers. Many species of bacteria in the intestine are able to modify and metabolize bile acids / salts and the intestinal flora affects systemic processes, such as metabolism and inflammation.
[0071] Bile acids / salts have strong antimicrobial and antiviral effects - deficiency leads to overgrowth of bacteria and increased disjugation, leading to less ileal reabsorption. In animals, feeding of conjugated bile acids abolishes bacterial overgrowth, decreases bacterial translocation to lymph nodes and reduces endotoxemia.
[0072] Thus, the methods and compositions described here allow the replacement, displacement, and / or redirection of acids / bile salts from different areas of the gastrointestinal tract, which affects (for example, inhibition or retardation) the growth of microorganisms that may cause infection associated with cholestasis and / or cholestatic liver disease. Classes of Pediatric Cholestatic Liver Diseases
[0073] As used herein, "cholestasis" means the disease or symptom comprising deficiency of bile formation and / or bile flow. As used herein, "cholestatic liver disease" means liver disease associated with cholestasis. Cholestatic liver diseases are often associated with jaundice, fatigue and itching. Cholestatic liver disease biomarkers include elevated serum bile acid concentrations, elevated serum alkaline phosphatase (PA), elevated gamma-glutamyltranspeptidease, elevated conjugated hyperbilirubinemia, and elevated serum cholesterol.
[0074] Cholestatic liver disease can be classified clinicopathologically between two main categories of obstruction, cholestasis, often extrahepatic, and non-obstructive, or intrahepatic cholestasis. In the first case, cholestasis results when the bile flow is blocked mechanically, as by gallstones or tumor, or as in extrahepatic biliary atresia.
[0075] The last group that has non-obstructive intrahepatic cholestasis, in turn, is divided into two main subgroups. In the first subgroup, cholestasis results when the processes of bile secretion and modification or synthesis of bile components are secondarily caught up with hepatocellular damage so severe that unspecified deficiency of many functions can be expected, including those that assist in bile formation. In the second subgroup, no probable cause of hepatocellular damage can be identified. Cholestasis in these patients appears to result when one of the steps in bile secretion or modification, or synthesis of bile components, is constitutively damaged. Such cholestasis is considered primary.
[0076] Thus, methods and compositions for stimulation of the proliferation and / or epithelial regeneration of the intestinal mucosa and / or the improvement of adaptive processes in the intestine in individuals with cholestasis and / or cholestatic liver disease are provided here. In some of such embodiments, the methods comprise increasing the concentration of bile acid and / or concentrations of GLP-2 in the intestinal lumen.
[0077] Hypercholemia, and high levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma GT (gamma-glutamyl transpeptidase) and 5'-nucleotidase are biochemical markers of cholestasis and cholestatic liver disease. Thus, methods and compositions are provided here for stimulating proliferation and / or epithelial regeneration of the intestinal mucosa and / or improving adaptive processes in the intestine in individuals with hypercholemia, and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase) ), gamma GT (gamma-glutamyl transpeptidase or GGT), and / or 5'-nucleotidase. In some embodiments, the methods comprise increasing the concentrations of bile acids in the intestinal lumen. Also provided here are methods and compositions for the reduction of hypercholemia, and elevated levels of AP (alkaline phosphatase), LAP (alkaline leukocyte phosphatase), gamma GT (gamma-glutamyl transpeptidase) and 5'-nucleotidase, including load reduction of bile acids by excreting bile acids in the stool.
[0078] Pruritus is often associated with pediatric cholestasis and pediatric cholestatic liver diseases. Itching has been suggested to result from bile salts that act under the afferent nerves of peripheral pain. The degree of itching varies with the individual (that is, some individuals are more sensitive to high levels of bile acids / salts). Administration of agents that reduce serum bile acid concentrations has been shown to reduce itching in some individuals. Consequently, methods and compositions for stimulating proliferation and / or regenerating the intestinal mucosa and / or improving adaptive processes in the intestine in individuals with epithelial pruritus are provided herein. In some of such embodiments, the methods comprise increasing the concentrations of bile acids in the intestinal lumen. In addition, methods and compositions for the treatment of pruritus which comprise reducing the overall bile acid load by excreting bile acids in the faeces are also provided herein.
[0079] Another symptom of pediatric cholestasis and pediatric cholestatic liver disease is an increase in the serum concentration of conjugated bilirubin. Elevated serum concentrations of conjugated bilirubin result in jaundice and dark urine. The magnitude of the elevation is not diagnostically important since no relationship has been established between serum levels of conjugated bilirubin and the severity of cholestasis and cholestatic liver disease. The conjugated bilirubin concentration rarely exceeds 30 mg / dL. Consequently, methods and compositions for stimulating proliferation and / or coating regeneration and / or enhancing adaptive processes in the intestine in individuals with elevated serum concentrations of conjugated bilirubin are provided herein. In some of such embodiments, the methods comprise increasing the concentrations of bile acid concentrations in the intestinal lumen. In addition, methods and compositions for treating high serum concentrations of conjugated bilirubin are further provided herein, comprising reducing the overall bile acid load by excreting bile acids in the faeces.
[0080] The increase in the serum concentration of conjugated bilirubin is also considered a diagnosis of cholestasis and cholestatic liver disease. Portions of bilirubin and covalently linked to albumin (bilirubin delta or biliprotein). This fraction may be responsible for a large proportion of total bilirubin in patients with jaundice. The presence of large amounts of delta bilirubin indicates long-term cholestasis. Delta bilirubin in umbilical cord blood or in the blood of a newborn is indicative of cholestasis / pediatric cholestatic liver disease that precedes birth. Consequently, methods and compositions are provided herein for the stimulation of epithelial proliferation and / or the regeneration of the intestinal mucosa and / or the improvement of adaptive processes in the intestine in individuals with high serum concentrations of unconjugated bilirubin or delta bilirubin. In some of such embodiments, the methods comprise increasing the concentrations of bile acid concentrations in the intestinal lumen. In addition, methods and compositions for the treatment of elevated serum concentrations of unconjugated bilirubin and delta bilirubin are further provided herein comprising reducing the overall bile acid load by excreting bile acids in the faeces.
[0081] Pediatric cholestasis and cholestatic liver disease results in hypercholemia. During metabolic cholestasis, hepatocytes retain bile salts. Bile salts are regurgitated from the serum hepatocyte, which results in an increase in the concentration of bile salts in the peripheral circulation. In addition, the absorption of bile salts that enter the liver into the blood portal of the vein is inefficient, which results in leakage of bile salts into the peripheral circulation. Consequently, methods and compositions are provided herein for stimulating proliferation and / or epithelial regeneration of the intestinal mucosa and / or improving adaptive processes in the intestine in individuals with hypercholemia. In some of such embodiments, the methods comprise increasing the concentrations of bile acid concentrations in the intestinal lumen. In addition, methods and compositions for the treatment of hypercholemia comprising reducing the overall bile acid load by excreting bile acids in the faeces are provided herein.
[0082] Hyperlipidemia is characteristic of some, but not all cholestatic diseases. Serum cholesterol is high in cholestasis due to the decrease in bile salts, which contribute to the metabolism and degradation of circulating cholesterol. Cholesterol retention is associated with an increase in the cholesterol content of the membrane and a reduction in membrane fluidity and membrane function. In addition, as bile salts are the metabolic products of cholesterol, the reduction in cholesterol metabolism results in a decrease in bile acid / salt synthesis. Serum cholesterol in children with cholestasis ranges from about 1,000 mg / dL to about 4000 mg / dL. Consequently, methods and compositions for stimulating the proliferation and / or epithelial regeneration of the intestinal mucosa and / or improving adaptive processes in the intestine in people with hyperlipidemia are provided herein. In some of such embodiments, the methods comprise increasing the concentrations of bile acid concentrations in the intestinal lumen. Additionally, methods and compositions for the treatment of hyperlipidemia comprising reducing the overall bile acid load by excreting bile acids in the stool are provided here.
[0083] In individuals with pediatric cholestasis and pediatric cholestatic liver diseases, xanthomas develop from the deposition of excess cholesterol that circulates in the dermis. The development of xanthoma is more characteristic of obstructive cholestasis than hepatocellular cholestasis. Planar xanthomas first occur around the eyes and then in the folds of the palms and soles, followed by the neck. Tuberous xanthomas are associated with chronic and long-term cholestasis. Consequently, methods and compositions are provided herein for stimulating proliferation and / or epithelial regeneration of the intestinal mucosa and / or improving adaptive processes in the intestine in individuals with xanthomas. In some of such embodiments, the methods comprise increasing the concentrations of bile acid concentrations in the intestinal lumen. Additionally, methods and compositions for the treatment of xanthomas are provided herein, comprising reducing the overall bile acid load by excreting bile acids in the faeces.
[0084] In children with chronic cholestasis, one of the main consequences of pediatric cholestasis and pediatric cholestatic liver disease is the inability to thrive. Growth deficit is a consequence of reduced delivery of bile salts to the intestine, which contributes to inefficient digestion and absorption of fats, and reduced vitamin absorption (vitamins E, D, K and A are all poorly absorbed in cholestasis). In addition, supplying fat to the colon can result in colon secretion and diarrhea. Treatment of growth deficit involves replacing the diet and supplementing with long chain triglycerides, medium chain triglycerides, and vitamins. Ursodeoxycholic acid, which is used to treat some cholestatic conditions, does not form mixed micelles and have no effect on fat absorption. Thus, methods and compositions are provided here to stimulate epithelial proliferation and / or regeneration of intestinal lining and / or enhancement of adaptive processes in the intestine in individuals (e.g., children) with growth deficit. In some of such embodiments, the methods comprise increasing the concentrations of bile acid concentrations in the intestinal lumen. In addition, methods and compositions for the treatment of growth deficit are included here, which comprise the reduction of the global bile acid load by excretion of bile acids in the faeces.
[0085] Symptoms of pediatric cholestasis and pediatric cholestatic liver disease have been treated with choleretic agents (eg, Ursodiol), phenobarbitols, corticosteroids (eg, prednisone and budesonide), immunosuppressive agents (eg, azathioprine, cyclosporine A, methotrexate , chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen and lamivudine. Therefore, in some embodiments, any of the methods described herein further comprise the administration of an additional active agent selected from: choleretic agents (eg, Ursodiol), phenobarbitols, corticosteroids (eg, prednisone and budesonide), agents immunosuppressants (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine and their combinations. In some embodiments, the methods are used to treat individuals who do not respond to treatment with choleretic agents (eg, Ursodiol), phenobarbitols, corticosteroids (eg, prednisone and budesonide), immunosuppressive agents (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine and their combinations. In some embodiments, the methods are used to treat individuals who do not respond to treatment with choleretic agents. In some embodiments, the methods are used to treat individuals who do not respond to ursodiol treatment. Progressive Familial Intrahepatic Cholestasis (PFIC) PFIC 1
[0086] PFIC 1 (also known as Bilisr FIC1 disease or deficiency) is associated with mutations in the ATP8B1 gene (also known as FIC1). This gene, which encodes a type P ATPase, is located on human chromosome 18, and is also mutated in the milder phenotype, benign recurrent type 1 intra-hepatic cholestasis (BRIC1) and in familial cholestasis in Greenland. The FIC1 protein is located in the canalicular membrane of the hepatocyte, but within the liver it is mainly expressed in cholangiocytes. Type P ATPase appears to be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phosphatidylethanolamine in the inner layer of the plasma membrane, compared to the outer layer. The asymmetric distribution of lipids in the membrane bilayer plays a protective role against high concentrations of bile salts in the canalicular lumen. The abnormal protein function can indirectly disrupt bile acid secretion. Abnormal secretion of bile acids / salts leads to overload of bile acid in hepatocytes.
[0087] PFIC-1 typically presents in children (for example, age 6-18 months). Children may show signs of itching, jaundice, bloating, diarrhea, malnutrition and reduced height. Biochemically, individuals with PFIC-1 have high serum transaminases, high bilirubin, high serum bile acid levels and low gammaGT levels. The individual may also have liver fibrosis. Individuals with PFIC-1 do not normally have bile duct proliferation. Most individuals with PFIC-1 will develop terminal liver disease by the age of 10. None of the medical treatments has proved beneficial for the long-term treatment of PFIC-1. In order to reduce extrahepatic symptoms (eg, malnutrition and growth deficit), children are often administered with medium chain triglycerides and fat-soluble vitamins. Ursodiol has not been shown to be effective in individuals with PFIC-1.
[0088] Methods of treating PFIC-1 in an individual who needs it are disclosed herein, in certain embodiments, comprising the non-systemic administration of a therapeutically effective amount of a sodium-dependent bile acid apical transport inhibitor ( ASBTI) or a pharmaceutically acceptable salt thereof. In some embodiments, such ASBT inhibitors are absorbed non-systemically. In some of such embodiments, such bile salt transport inhibitors include a radical or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a part or group loaded in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects, due to systemic absorption. In some other embodiments, these ASBT inhibitors are absorbed systemically. In some embodiments, ASBTI is formulated for non-systemic delivery to the distal ileo. In some embodiments, an ASBTI is minimally absorbed. In some embodiments, an ASBTI is administered non-systemically to the colon or rectum of an individual in need. In some embodiments, the methods further comprise administering a therapeutically effective amount of a bile acid derivative (eg, ursodiol), a corticosteroid (eg, prednisone and budesonide), an immunosuppressive agent (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination thereof. PFIC 2
[0089] PFIC 2 (also known as Bilisr syndrome or BSEP deficiency) is associated with mutations in the ABCB11 gene (also called BSEP). The ABCB11 gene encodes the ATP-dependent canalicular bile salt export pump (BSEP) from human liver and is located on human chromosome 2. The BSEP protein, expressed on the hepatocyte canalicular membrane, is the largest exporter of primary bile acids / salts against extreme concentration of gradients. Mutations in this protein are responsible for the secretion of decreased bile bile salts described in affected patients, leading to decreased bile flow and the accumulation of bile salts inside the hepatocyte with continuous severe hepatocellular damage.
[0090] PFIC-2 usually presents in children (for example, age 6-18 months). Children may show signs of itching. Biochemically, individuals with PFIC-2 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low gammaGT levels. The individual may also have portal inflammation and giant cell hepatitis. In addition, people often develop hepatocellular carcinoma. No medical treatment has proven beneficial for the long-term treatment of PFIC-1. In order to reduce extrahepatic symptoms (for example, malnutrition and growth deficit), children are often administered with medium chain triglycerides and fat-soluble vitamins. Ursodiol has not been shown to be effective in individuals with PFIC-2.
[0091] Here, in certain embodiments, methods of treating PFIC-2 in an individual in need are disclosed, comprising the non-systemic administration of a therapeutically effective amount of a sodium-dependent Apical Bile Acid Transport Inhibitor ( ASBTI) or a pharmaceutically acceptable salt thereof. In some embodiments, such ASBT inhibitors are absorbed non-systemically. In some of such embodiments, such bile salt transport inhibitors include a radical or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a part or group loaded in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects, due to systemic absorption. In some other embodiments, these ASBT inhibitors are absorbed systemically. In some embodiments, ASBTI is formulated for non-systemic delivery to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some embodiments, an ASBTI is administered non-systemically to the colon or rectum of an individual in need. In some embodiments, the methods further comprise administering a therapeutically effective amount of a bile acid derivative (eg, ursodiol), a corticosteroid (eg, prednisone and budesonide), an immunosuppressive agent (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination thereof. PFIC 3
[0092] PFIC3 (also known as MDR3 deficiency) is caused by a genetic defect in the ABCB4 gene (also called MDR3) located on chromosome 7. Class III multi-drug resistance glycoprotein P (P-gp) ( MDR3), is a translocating phospholipid involved in the biliary excretion of phospholipids (phosphatidylcholine) in the canlicular membrane of the hepatocyte. PFIC3 results from the toxicity of bile, in which detergent bile salts are not inactivated by phospholipids, leading to bile ducts and bile epithelial lesions.
[0093] PFIC-3 also appears in early childhood. Unlike PFIC-1 and PFIC-2, individuals have high gammaGT levels. Individuals also have portal inflammation, fibrosis, cirrhosis and proliferation of massive bile ducts. Individuals can also develop intrahepatic gallstone disease. Ursodiol has been effective in treating or improving PFIC-3.
[0094] Here, in certain embodiments, methods of treating PFIC-3 are disclosed in an individual in need thereof, which comprises the non-systemic administration of a therapeutically effective amount of a sodium-dependent Bile Acid Transport Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. In some embodiments, such ASBT inhibitors are absorbed non-systemically. In some of such embodiments, such bile salt transport inhibitors include a radical or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a part or group loaded in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects, due to systemic absorption. In some other embodiments, these ASBT inhibitors are absorbed systemically. In some embodiments, ASBTI is formulated for non-systemic delivery to the distal ileo. In some embodiments, an ASBTI is minimally absorbed. In some embodiments, an ASBTI is administered systemically to the colon or rectum of an individual in need of it. In some embodiments, the methods further comprise administering a therapeutically effective amount of a bile acid derivative (eg, ursodiol), a corticosteroid (eg, prednisone and budesonide), an immunosuppressive agent (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination thereof. Benign Recurrent Intrahepatic Cholestasis (BRIC) BRIC 1
[0095] BRIC1 is caused by a genetic defect of the FIC1 protein in the hepatocyte canalicular membrane. BRIC1 is typically associated with normal serum cholesterol and Y_glutamyltranspeptidasetranspeptidase levels, but elevated serum bile salts. Expression and function of residual FIC1 is associated with BRIC1. Despite recurrent attacks of cholestasis or cholestatic liver disease, there is no progression to chronic liver disease in most patients. During attacks, patients are severely attacked with jaundice and experience itching, steatorrhea and weight loss. Some patients also have kidney stones, pancreatitis and diabetes. BRIC 2
[0096] BRIC2 is caused by mutations in ABCB11, leading to defective BSEP expression and / or function in the hepatocyte canalicular membrane. BRIC 3
[0097] BRIC3 is related to the expression and / or defective function of MDR3 in the hepatocyte canalicular membrane. Patients with MDR3 deficiency typically exhibit high levels of serum Y-β-transamptidase in the presence of normal or slightly elevated bile acid levels. Dubin-Johnson syndrome (DJS)
[0098] DJS is characterized by conjugated hyperbilirubinemia due to hereditary MRP2 dysfunction. Liver function is preserved in affected patients. Several different mutations have been associated with this condition, resulting both in the complete absence of MRP2 detectable immunohistochemically in affected patients and in the maturation and screening of the altered protein. Acquired cholestatic disease Pediatric Primary Sclerosing Cholangitis (PSC)
[0099] Pediatric PSC is a chronic inflammatory liver disease, slowly progressing to terminal liver failure in most affected patients. In pediatric PSC inflammation, fibrosis and large and medium-sized intra and extrahepatic duct obstruction is predominant. Gallstone disease
[0100] Gallstone disease is one of the most common and costly of all diseases of the digestive system, with a prevalence of up to 17% in Caucasian women. Cholesterol containing gallstones are the main form of gallstones and supersaturation of bile with cholesterol is therefore a prerequisite for the formation of gallstones. ABCB4 mutations may be involved in the pathogenesis of cholesterol gallstone disease. Drug-induced cholestasis
[0101] Inhibition of BSEP function by drugs is an important mechanism of drug-induced cholestasis, leading to hepatic accumulation of bile salts and subsequent damage to liver cells. Several drugs have been implicated in the inhibition of BSEP. Most of these drugs, such as rifampicin, cyclosporine, glibenclamide or troglitazone, directly cis-inhibit the transport of ATP-dependent taurocholate in a competitive manner, while estrogen and progesterone metabolites indirectly trans-inhibit BSEP after secretion into the bile duct by MRP2 . Alternatively, drug-mediated stimulation of MRP2 can promote cholestasis or cholestatic liver disease, altering the composition of bile. Cholestasis Associated with Total Parenteral Nutrition
[0102] TPNAC is one of the most serious clinical situations where cholestasis or cholestatic liver disease occurs quickly and is highly linked to early death. Babies, who are usually premature and have had bowel resections, are dependent on TPN for growth and often develop cholestasis or cholestatic liver disease that progresses rapidly to fibrosis, cirrhosis and portal hypertension, usually before the age of 6 months. The degree of cholestasis or cholestatic liver disease and chance of survival in these children have been related to the number of septic episodes, probably started by recurrent bacterial translocation throughout their intestinal mucosa. Although there are also cholestatic effects of the intravenous formulation in these children, septic mediators probably contribute, at most, to the altered liver function. Alagille syndrome
[0103] Alagille syndrome is a genetic disease that affects the liver and other organs. Often presented during childhood (for example, age 6-18 months), through early childhood (for example, the age of 3-5 years) and may stabilize after the age of 10. Symptoms may include chronic progressive cholestasis , dutopenia, jaundice, pruritus, xanthomas, congenital heart problems, shortage of intrahepatic bile ducts, poor linear growth, hormone resistance, posterior embriotoxon, Axenfeld anomaly, pigmented retinitis, pupillary abnormalities, heart murmur, interatrial communication, septal defect ventricular, ductus arteriosus and Tetralogy of Fallot. Individuals diagnosed with Alagille syndrome were treated with ursodiol, hydroxyzine, cholestyramine, rifampicin and phenobarbital. Due to a reduced ability to absorb fat-soluble vitamins, individuals with Alagille Syndrome are still administered multivitamins at high doses.
[0104] Here, in certain embodiments, methods of treating Alagille syndrome are disclosed in an individual in need thereof, which comprises the non-systemic administration of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, such ASBT inhibitors are absorbed non-systemically. In some of such embodiments, such bile salt transport inhibitors include a radical or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a part or group loaded in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects, due to systemic absorption. In some other embodiments, these ASBT inhibitors are absorbed systemically. In some embodiments, ASBTI is formulated for non-systemic delivery to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some embodiments, an ASBTI is administered systemically to the colon or rectum of an individual in need of it. In some embodiments, the methods further comprise administering a therapeutically effective amount of a bile acid derivative (eg, ursodiol), a corticosteroid (eg, prednisone and budesonide), an immunosuppressive agent (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination thereof. Biliary Atresia
[0105] Biliary atresia is a life-threatening condition in newborns in which bile ducts inside or outside the liver do not have normal openings. With biliary atresia, bile gets stuck, accumulates, and damages the liver. The damage leads to scar formation, loss of liver tissue and cirrhosis. Without treatment, the liver eventually fails and the child needs a liver transplant to stay alive. The two types of biliary atresia are fetal and perinatal. Fetal biliary atresia appears while the baby is still in the womb. Perinatal biliary atresia is much more common, and does not become evident until 2 to 4 weeks after birth. Post-Kasai Biliary Atresia
[0106] Biliary atresia is treated with surgery called the Kasai procedure or a liver transplant. The Kasai procedure is usually the first treatment for biliary atresia. During a Kasai procedure, the pediatric surgeon removes damaged bile ducts from the child and brings a bowel around to replace them. Although the Kasai procedure can restore bile flow and correct many problems caused by biliary atresia, surgery does not cure biliary atresia. If the Kasai procedure is not successful, children will usually need a liver transplant within 1 to 2 years. Even after successful surgery, most children with biliary atresia slowly develop cirrhosis over the years and require liver transplantation in adulthood. Possible complications after the Kasai procedure include ascites, bacterial cholangitis, portal hypertension and itching. Biliary Atresia After Liver Transplantation
[0107] If the atresia is complete, liver transplantation is the only option. Although liver transplantation is generally successful in treating biliary atresia, liver transplantation can have complications, such as organ rejection. In addition, a donor liver may not become available. In addition, in some patients, liver transplantation may not be successful in curing biliary atresia. Xanthoma
[0108] Xanthoma is a hepatic cholestatic disease associated with a skin condition, in which certain fats are built under the surface of the skin. Cholestasis results in various disorders of lipid metabolism, resulting in the formation of an abnormal lipid particle in the blood called lipoprotein X. Lipoprotein X is formed by regurgitation of bile lipids in the blood from the liver and does not bind to the LDL receptor to stop deliver cholesterol to cells throughout the body as normal LDL does. Lipoprotein X increases the production of cholesterol in the liver five times and promotes the normal removal of lipoprotein particles from the blood by the liver. Compounds
[0109] In some embodiments, ASBT inhibitors are provided here that reduce or inhibit the recycling of bile acids in the distal gastrointestinal (GI) tract, including the terminal ileum, colon and / or rectum. In certain embodiments, ASBTIs are absorbed systemically. In certain embodiments, ASBTIs are absorbed non-systemically. In some embodiments, ASBTIs described herein are modified or replaced (for example, with an LK-group) to be non-systemic. In certain embodiments, any ASBT inhibitor is modified or replaced with one or more charged groups (for example, K) and, optionally, one or more linkers (for example, L), where L and K are as defined herein.
[0110] In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula I:
wherein: R1 is a single-chain C1-6 alkyl group; R2 is a single-chain C1-6 alkyl group; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is an optionally substituted pyridyl or phenyl or -Lz-Kz; where z is 1, 2 or 3; each L is independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a cycloalkyl substituted or unsubstituted, or a substituted or unsubstituted heterocycloalkyl; each K is a radical that prevents systemic absorption; R5, R6, R7 and R8 are the same or different and each is selected from hydrogen, halogen, cyano, R5-acetylide, OR15, optionally substituted C1-6 alkyl, COR15, CH (OH) R15, SÍOJnR1 ^, P ( O) (OR15) 2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15, CHO, (CH2) PCN, CONR12R13, (CH2) pCO2R15, (CH2) pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH = CHR15, O (CH2CH2O) nR15, O (CH2) pSOaR15, O (CH2) PNR12R13, O (CH2) pN + R12R13R14 and -W-R31, where W is O or NH and R31 is selected from
where p is an integer 1-4, n is an integer 0-3 and R12, R13, R14 and R15 are independently selected from hydrogen and optionally substituted C1-6 alkyl; or R6 and R7, are linked to form a group
wherein R12 and R13 are as previously defined in is 1 or 2; and R9 and R10 are the same or different and each is selected from hydrogen or C1-2 alkyl; and salts, solvates and physiologically functional derivatives thereof.
[0111] In some embodiments of the methods, the compound of Formula I is a compound wherein R1 is a single-chain C1-6 alkyl group; R2 is a single-chain C1-6 alkyl group; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is an optionally substituted phenyl group; R5, R6 and R8 are independently selected from hydrogen, C1-4 alkyl optionally substituted by fluorine, C1-4 alkoxy, halogen, or hydroxy; R7 is selected from halogen, cyano, R15-acetylide, OR15, optionally substituted C1-6 alkyl, COR15, CH (OH) R15, S (0) nR15, P (O) (OR15) 2, OCOR15, OCF3, OCN, SCN, HNCN, CH2OR15, CHO, (CH2) PCN, CONR12R13, (CH2) pCO2R15, (CH2) pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH = CHR15, 0 (CH2CH2O) pR15, 0 (CH2) , 0 (CH2) pNR12R13 and 0 (CH2) pN + R12R13R! 4; wherein n, p and R12 to R15 are as previously defined; with the proviso that at least two of R5 to R8 are not hydrogen; and salts, solvates and physiologically functional derivatives thereof.
[0112] In some embodiments of the methods described herein, the compound of Formula I is a compound in which R1 is a single-chain C1-6 alkyl group; R2 is a single-chain C2-6 alkyl group; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-4 alkylcarbonyl group; R4 is an unsubstituted phenyl group; R5 is hydrogen or halogen; R ° and R3 are independently selected from hydrogen, C1-4 alkyl optionally substituted by fluorine, C1-4 alkoxy, halogen, or hydroxy; R7 is selected from OR15, S (O) nR15, OCOR15, OCF3, OCN, SCN, CHO, OCH2OR15, OCH = CHR13, 0 (CH2CH2O) nR15, 0 (CH2) pSOaR15, 0 (CH2) pNR12R13 and 0 (CH2) pN + R12R12R14 where p is an integer from 1-4, n is an integer from 0-3, and R12, R13, R14, and R15 are independently selected from hydrogen and optionally substituted C1-6 alkyl; R9 and Rlu are the same or different and each is selected from hydrogen or C1-6 alkyl; and salts, solvates and physiologically functional derivatives thereof.
[0113] In some embodiments of the methods, wherein the compound of Formula I is a compound in which R1 is methyl, ethyl or n-propyl; R2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is unsubstituted phenyl; R5 is hydrogen; R6 and R ”are independently selected from hydrogen, C1-4 alkyl optionally substituted by fluorine, C1-1 alkoxy, halogen, or hydroxy; R7 is selected from OR15, S (O) nR25, OCOR15, OCRs, OCN, SCN, CHO, OCH2OR15, OCH = CHR15, O (CH2CH2O) NR15, 0 (CH2) pSOaR15, 0 (CH2) pNR12R13 and 0 ( CH2) PN + R12R13R14 where p is an integer from 1-4, n is an integer from 0-3, and R12, R13, R14, and R15 are independently selected from hydrogen and optionally substituted C1-6 alkyl; R9 and R10 are the same or different and each is selected from hydrogen or C1-6 alkyl; and salts, solvates and physiologically functional derivatives thereof.
[0114] In some embodiments of the methods, the compound of Formula I is a compound in which R1 is a methyl, ethyl or n-propyl; R2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is unsubstituted phenyl; R5 is hydrogen; Rb is C1-4 alkoxy, halogen, or hydroxy; R7 is OR15, where R15 is hydrogen or optionally substituted C1-6 alkyl; R8 is hydrogen or halogen; R9 and R10 are the same or different and each is selected from hydrogen or alkyl; and salts, solvates and physiologically functional derivatives thereof.
[0115] In some embodiments of the methods, the compound of Formula I is (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-dioxide , 8-dimethoxy-5-phenyl-1,4-benzothiazepine; (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4- 1,1-dioxide ol; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4- 1,1-dioxide ol; (3R, 5R) -7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (3R, 5R) -7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benxothiaxepin- 1,1-dioxide 4-ol; (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol 1,1-dioxide; (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-ol 1,1-dioxide; (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-thiol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5 - tetrahydro-5 - phenyl - 1,4 — benzothiazepin — 8 - sulfonic acid 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; 1,1 (3R, 5R) -3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine dioxide; (±) -Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±) -Trans-3-butyl-3-θyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzo-thiazepine dioxide hydrochloride; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-carbaldehyde 1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; 1.1 3.3 — diethyl — 2,3,4,5 — tetnahidno dioxide — 8 — methoxy-5-phenyl-1,4-benzothiazepine; 3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4,8-diol 1,1-dioxide; (RS) -3,3-diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±) -Trans-butyl-3-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepin-4- 1,1-dioxide ol; (3R, 5R) -3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4,7,8-triol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; 3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; (±) -Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulfate; or 3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogensulfate;
[0116] In some embodiments of the methods, the compound of Formula I is:


[0117] In some embodiments of the methods, the compound of Formula I is:

[0118] In some embodiments, the compound of Formula I is not a structure shown as:
where m represents an integer of 1 or 2, and R3 and R4, which can be mutually different, each represents an alkyl group having 1 to 5 carbon atoms.
[0119] In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula II:
where: q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, where alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9RinR «A-, SR9, S + R9R10A ~, P + R9R10RnA-, S (O) R9, SO2R9, SO3R9, CO2R9, CN, halogen, oxo and CONR9R10, where alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons substituted by 0, NR9, N + R9R10A-, S, SO, SO2, S + R9A ", R + R9R10A-, or phenylene, where R9, R10, and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S (O) R9, SO2R9, and SO3R9, where R9 and R10 are as defined above; or R3 and R4 together = 0, = NOR11, = S, = NNR41R12, = NR9, or = CR14R12, where R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (O) R9, SO2R9, SO3R9, CO2R9, CN, halogen, oxo and CONR9R10, where R9 and R10 are above, provided that both R3 and R4 cannot be OH, NH2, and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quaternary heteroaryl, OR9, SR9, S (O) R9, SO2R9, SO3R9, and - Lz -Kz; where z is 1, 2 or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted cycloalkyl or unsubstituted, or a substituted or unsubstituted heterocycloalkyl; each K is a radical that prevents systemic absorption; wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R15, OR13, OR13, R14, NR13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13 NR14 Ris, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C (O) NR13R14, C (O) OM, CR13, P (O) R13R14, P + R13R14R15A-, P (OR13) OR14, S + R13R14A-, and N + R9R31R12A-. where: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can further be substituted with one or more substituent groups selected from from the group consisting of OR7, NR7R8, S (O) R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N + R7R8R9A “, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R7R8, P + R7R8R9A ~, and P (0) (OR7) OR8e wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR7, N + R7R8, A ~, S, SO, S02, S + R7A “, PR7, P (O) R7, P + R7R8A ~, or phenylene, and R13, R14 and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, heterocycle quat ernary, quaternary heteroaryl, quaternary heteroarylalkyl, and -GTVW, where alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons substituted by 0, NR9, N + R9R10A-, S, SO, SO2, S + R9A_, PR, P + R9R10 -A, P (O) R9, phenylene, carbohydrate, C2-C7 polyol, amino acid, peptide, or polypeptide, and G, T and V are each, independently, a bond, - 0-, -S-, -N (H) -, substituted or unsubstituted alkyl, -0-alkyl, -N (H) -alkyl, -C (0) N (H) -, N (H) C ( O) -, -N (H) C (0) N (H) -, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl , substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl, and W is quaternary heterocycle, h quaternary etheraryl, quaternary heteroarylalkyl, N + R9R11R12A “, P + R9R1QR11A-, OS (O) 2OM, OR S + R9R10A-, and R13, R14 and R15, can optionally be replaced with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N1R'R11R12A “, SR9, S (O) R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO (OR16) OR P + R9R10R21A-, S + R 'R10A-, and 0 (0) OM, where R16 and R17 are independently selected from the substituents that constitute R9 and M; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl and arylalkyl; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more of Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heteroaryl, quaternary heteroaryl, OR13, NR13R14, SR13, S (O) R13, S (O) 2R13, SO3R13, S + R13R14A “, NR13OR14, NR13NR14R15, NO2, CO2R13 / CN, OM, SO2OM, SO2NR13R14, NR14C (O) R13, C (O ) NR13R14, NR14 C (O) R13, C (0) OM, COR13, OR18, S (O) nNR18, NR13R18, NR18R14, N + R9R11R12A “, P + R9RHR12A-, amino acid, peptide, polypeptide, and carbohydrate, in that alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle and quaternary heteroaryl can still be replaced with OR9, NR9R10, N + R9R31R12A ', SR9, S (O) R SO2R9, SO3R9, OXO, CO2R9, CN, halogen, CONR9R10, SO2MO, SO2NR9R10, PO (ORM OR17, P + R9RUR12A-, S + R9RI ° A-, OR C (0) M, and where R18 is selected from among the group consisting of acyl, aryl loxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10 + R9R11R12A “, SR9, S (O) R9, SO2R9, SO3R9, oxo, CO3R9, CN, halogen, CONR9R10, SO3R9, SO2OM, SO2NR9R10, PO (OR16) OR17e C (0) 0M, where in Rx, one or more carbons are optionally substituted by 0, NR13, N + R13R14A ~, S, SO, SO2, S + R13A ", PR13, P (O) R13, P + R13R14A", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether , or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally substituted by 0, NR9, R9R10A-, S, SO, SO2, S + R9A-, PR9, P + RSRiOA- or P (O) R9; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14 , SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14 R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C (O) NR13R14, C (O) OM, COR13, P (O) R13R] 4, P + R13R14R15A ", P (OR13) OR14, S + R13R14A" and N + R9R11R12A-, as long as both R5 and R6 are not hydrogen or SH; provided that when R5 or R6 is phenyl, only one of R1 or R2 is H; provided that when q = 1 and Rx is styryl, anilide, or anilinocarbonyl, only one of R5 or R6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0120] In some embodiments of the methods, the compound of Formula II is a compound in which q is an integer from 1 to 4; n is 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkoxy, dialkylamino and alkylthio, where alkyl, alkoxy, dialkylamino, alkylthio and are optionally substituted with one or more substituents selected from the group consisting of OR9 , NR9R10, SR9, SO2R9, CO2R9, CN, halogen, oxo, and CONR9R10; each R9 and R10 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, acyl, heterocycle and arylalkyl; R1 and R4 are independently selected from the group consisting of H, alkyl, acyloxy, OR9, NR9R10, SR9, and SO2R9, where R9 and R10 are as defined above; R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalcoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (O) R , SO2R9, SO3R9, CO2 R9, CN, halogen, oxo and CONR9R10, where R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, NH2, and SH, or R11 and R12 together with nitrogen or the carbon atom to which they are attached form a cyclical ring; R5 and R6 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, heterocycle, and -Lz-Kz; where z is 1 or 2; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a radical that prevents systemic absorption; wherein alkyl, aryl, cycloalkyl and heterocycle can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13 , OR13, R14, NR13R14, SR13, SO2R13, NR13NR14R15, NO2, CO2R13, CN, OM, and CR13, in which: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; R13, R14 and R13 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl and quaternary heteroarylalkyl, where R13, R14 and R15 can optionally be substituted with one or more groups selected from the group consisting of quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9R31R12A-, SR9, S (O) R9, SO2R9, SO3R9, oxo, CO2R9 , CN, halogen and CONR9R10; or R ^ 4 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl and arylalkyl; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, OR13, NR13R14, SR13, S (0) 2R13, NR13NR14R15, N02 , CO2 R13, CN, Sθ2NR13R14, NR14C (O) R13, C (O) NR13R14, NR14C (O) R13 and COR13; since both R5θ R6 cannot be hydrogen; since when R5 or Rb is phenyl, only one of R1 or R2 is H; provided that when q = 1 and Rx is styryl, anilide, or anilinocarbonyl, only one of R5 or R6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0121] In some embodiments, the compound of Formula II is a compound in which q is 1; n is 2; Rx is N (CH3) 2; R7 and R8 are independently H; R1 and R2 is alkyl; R3 is H, and R4 is OH; R5 is H, and R6 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quaternary heteroaryl, OR9, SR9, S (O) R9, SO2R9, SO3R9, and -Lz- Kz; where z is 1, 2 or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted cycloalkyl or unsubstituted, or a substituted or unsubstituted heterocycloalkyl; each K is a radical that prevents systemic absorption; wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl , cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R15, OR13, OR13R14, NRi3Ri4, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, OMROM , SO2 NR13R14, C (O) NR13R14, C (0) OM, CR13, P (O) R13R14, P + R13R14R45A-, P (OR13) OR14, S + R13R14A “, and N + R9R14R42A-. where A 'is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may further be substituted with one or more substituent groups selected from among group consisting of OR7, NR7R8, S (O) R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N + R7R8R9A “, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heteroaryl, heteroaryl P (O) R7R8, P + R7R8R9A-, and P (O) (OR7) OR8 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR7, N + R7R8A ~, S, SO, SO2, S + R7A ", PR7, P (O) R7, P + R7R8A ~ or phenylene, and R13, R14 and R15 are selected independently from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, and -GTVW, where alkyl, alkenyl, alkynyl, arylalkyl, heterocycle and polyalkyl optionally have one or more carbons substituted by 0, NR9, N + R9R10A-, S, SO, SO2, S + R9A “ , PR, P + R9R10A ", P (O) R9, phenylene, carbohydrate, C2-C7 polyol, amino acid, peptide or polypeptide, and G, T and V are each, independently, a bond, -0-, - S-, -N (H) -, substituted or unsubstituted alkyl, -0-alkyl, -N (H) -alkyl, -C (0) N (H) -, N (H) C (0) -, -N (H) C (0) N (H) -, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, substituted alkynylalkyl, heteroalkyl substituted or unsubstituted, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl, and W is quaternary heteroaryl, heteroaryl quaternary, heteroarylalkylquaternary, N + R9R11R12A ~, P + R9R1 ° R11A-, OS (O) 2OM, OR S + R9R10A-, and R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl , cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl and alkylammoniumalkyl; R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalcoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (O) R , SO2R9, SO3R9, CO2R9, CN, halogen, oxo and CONR9R10, where R9 and R10 are as defined above, since both R3 and R4 cannot be OH, NH2 and SH, or R11 and R12 together with nitrogen or the carbon atom to which they are attached form a cyclic ring; R13, R14 and R15 can optionally be substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9R11R12A “, SR9, S (O) R9, SO2R9 , SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2 NR9RI °, PO (OR16) OR17, P + R9R1OR11A-, S + R9R10A-, and C (O) OM, where R16 and R17 are independently selected between the substituents that make up R9 and M; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl and arylalkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0122] In some embodiments, the compound of Formula II is a compound in which q is 1; n is 2; Rz is N (CH3) 2; R7 and R8 are independently H; R1 and R9 is, independently, C1-C4 alkyl; R3 is H, and R4 is OH; R5 is H, and R6 is aryl substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R15, OR13, OR13, R14, NR13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, N02, CO2R13, CN, OM, SO2OM, S02 NR13R14, C (O) NR13R14, C (0) OM, CR73, P (O) R13R14, P + R13R14R15A-, P (OR13) OR14, S + R13R14A “and N + R9RHRi2A-. where A ~ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may further be substituted with one or more substituent groups selected from among group consisting of OR7, NR7R8, S (O) R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N + R7R8R9A “, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heteroaryl, heteroaryl P (O) R7R8, P + R7R8R9A-, and P (O) (OR7) OR8 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle can optionally have one or more carbons replaced by 0, NR7, N + R7RδA ", S, SO, S02, S + R7A", PR7, P (O) R7, P + R7R8A ", OR phenylene, and R13, R14 and R15 are selected independently from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, and -GTVW, where alkyl, alkenyl, alkynyl, arylalkyl, heterocycle and polyalkyl optionally have one or more carbons substituted by 0, NR9, N + R9R10A “, S, SO, SO2, S + R9A ~ , PR, P + R9R10A ~, P (O) R9, phenylene, carbohydrate, C2-C7 polyol, amino acid, peptide or polypeptide, and G, T and V are each, independently, a bond, -0-, - S-, -N (H) -, substituted or unsubstituted alkyl, -0-alkyl, -N (H) -alkyl, -C (0) N (H) -, N (H) C (0) -, -N (H) C (0) N (H) -, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, substituted alkynylalkyl, heteroalkyl substituted or unsubstituted, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl, and W represents a quaternary heterocycle , quaternary heteroaryl, quaternary heteroaryl, N + R9R11R12A-, P + R9R10R11A-, OS (O) 2OM, OR S + R9R10A-, and R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl , cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl and alkylammoniumalkyl; R11 and R19 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalcoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (O) R , SO2R9, SO3R9, CO2R9, CN, halogen, oxo and CONR9R10, where R9 and R10 are as defined above, since both R3 and R4 cannot be OH, NH2, and SH, or R11 and R12 together with nitrogen or the carbon atom to which they are attached form a cyclic ring; R13, R14 and R15 can optionally be substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9R14R12A_, SR9, S (O) R9, SO2R9, SO3R9 , oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO (OR16) OR17, P + R9R10R11A “, S + R9R10A- and 0 (0) OM, where R16 and R17 are independently selected from the substituents that constitute R9 and M; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl and arylalkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0123] In some embodiments of the methods, the compound of Formula II is a compound in which R5 and R6 are independently selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle and quaternary heteroaryl in which aryl, heteroaryl , quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, OR13, R14, NR13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14 R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C (O) NR13R14, C (0) 0M, COR13, P (O ) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A ~, N + R9R11R12A" and -Lz-Kz.
[0124] In some embodiments of the methods, the compound of Formula II is a compound in which R5 or R6 is -Ar- (Rv) t t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolil, isoxazolyl, pyrimidyl, triazole, triazole indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzoisothiazolyl e; and one or more Ry are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, OR13, R14, NR13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2MO, SO2NR13R14, C (O) NR13R14, C (O) OM, COR13, P (O) R13R14, P + R13R14R15A “, P (OR13) OR14, S + R13R14A ', N + R9RnR12A- and - L - K-; wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may further be substituted with one or more substituent groups selected from the group consisting of OR13, NR13R14, SR13, S (O) R13, SO2R13, SOsR13, NR13 OR14, NR13NR14 R15, NO2, CO2R13, CN, oxo, CONR7R8, N + R7R8R9A “, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, heteroaryl Quaternary, P (R) 7 , P + R7R8A-, and P (O) (OR7) OR8, and or phenylene; wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons substituted by 0, NR7, N + R7R8, A “, S, SO, S02, S + R7A ", PR7, P (O) R7, P + R7R8A", OUphenylene.
[0125] In some embodiments of the methods, the compound of Formula II is a compound in which R5 or R6 is

[0126] In some embodiments of the methods, the compound of Formula II is a compound in which n is 1 or 2. In some embodiments of the methods, the compound of Formula II is a compound in which R1 and R2 are independently H or C1-7 alkyl. In some embodiments of the methods, the compound of Formula II is a compound in which each C1-7alkyl is, independently, ethyl, n-propyl, n-butyl or isobutyl. In some embodiments of the methods, the compound of Formula II is a compound in which R3 and R4 are independently, H or OR9. In some embodiments of the methods, the compound of Formula II is a compound in which R9 is H.
[0127] In some embodiments of the methods, the compound of Formula II is a compound in which one or more of R1: is in the 7-, 8-, or 9- position of the benzene ring of General Formula II. In some embodiments of the methods, the compound of Formula II is a compound in which R : is at the 7- position of the benzene ring of General Formula II. In some embodiments of the methods, the compound of Formula II is a compound in which one or more of Rx are independently selected from OR13 and NR13R14.
[0128] In some embodiments of the methods, the compound of Formula II is a compound in which: q is 1 or 2; n is 2; R1 and R2 are each alkyl; R is hydroxy; R4 and R6 are hydrogen; R5 has the formula
where t is an integer from 0 to 5; one or more Rvs are OR13or OR13R14; R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl; wherein said alkyl, alkenyl, alkynyl, arylalkyl, heterocycle and polyalkyl optionally have one or more carbons substituted by O, NR9, N + R9R10A ~, S, SO, SO2, S + R9A ", PR9, P + R9R10A", P (O) R9, phenylene, carbohydrate, amino acid, peptide or polypeptide; R13 and R14, can optionally be substituted with one or more groups selected independently from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9R1] -R12A-, SR9, S (O) R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO (OR16) OR17, P + R9R10R11A ", S + R9R10A" and 0 (O) OM, where A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl and alkylammoniumalkyl; R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxy alkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (O) R , SO2R9, SO3R9, CO2R9, CN, halogen, oxo and CONR9R10, where R9 and R10 are as defined above, since both R3 and R4 cannot be OH, NH2 and SH, or R11e R12 together with nitrogen or carbon atom to which they are attached form a cyclic ring; and R16 and R17 are independently selected from the substituents that constitute R9 and M; R7 and R8 are hydrogen; and one or more of R ;: are independently selected from the group consisting of alkoxy, alkylamino and dialkylammon and -W-R31, where W is 0 or NH and R31 is selected from
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0129] In some embodiments of the methods, the compound of Formula II is:

[0130] In some embodiments of the methods the compound of Formula II is:

[0131] In certain embodiments, ASBTIs suitable for the methods described herein are non-systemic analogues of Compound 100C. Certain compounds provided herein are analogues of Compound 100C modified or substituted to comprise a charged group. In specific embodiments, the analogs of Compound 100C are modified or replaced with a charged group which is an ammonium group (for example, a cyclic arcyclic ammonium group). In certain embodiments, the ammonium group is a non-protic ammonium group, which contains a quaternary nitrogen atom.
[0132] In some embodiments, a Formula II compound is:

[0133] In some embodiments, a compound of Formula II is 1 - [[5- [[3- [(3S, 4R, 5R) -3-butyl-7- (dimethylamino) -3-ethyl-2, 3,4,5-tetrahydro-4-hydroxy-1,1-dioxide-1-benzothiepin-5-yl] phenyl] amino] -5-oxopentyl] amino] - 1-deoxy-D-glucitol or SA HMR1741 (aka Bari-1741).
[0134] In some embodiments, a Formula II compound is:

[0135] In some embodiments, a compound of Formula II is potassium ethanolate ((2R, 3R, 4S, 5R, 6R) -4-benzyloxy-6- {3- [3 - ((3S, 4R, 5R ) - 3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] thienpin-5-yl) -phenyl] - ureido} -3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl) sulfate, hydrate or SAR548304B (aka SAR-548304).
[0136] In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula III:
where: each R1, R2 is, independently, H, hydroxyl, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted aryl or unsubstituted, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl , or -LK; or R1 and R2, together with the nitrogen to which they are attached, form a 3- to 8-membered ring that is optionally substituted with R8; each R3, R4 is, independently, H, hydroxyl, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl or -LK ; R5 represents H, hydroxy, alkyl, alkoxy, C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl aryl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, each R6, R7 is, independently , H, hydroxyl, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, cycloalkyl substituted unsubstituted, substituted or unsubstituted alkyl cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl heteroaryl, substituted or unsubstituted heterocycloalkyl substituted or unsubstituted alkylheterocycloalkyl, or -LK; or R6 and R7 taken together form a bond; each X is, independently, NH, S, or O; each Y is, independently, NH, S or O; R8 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl cycloalkyl, substituted or unsubstituted heteroaryl, alkyl- substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, or -LK; L is An, where each A is, independently, NR1, S (O) m, O, C (= X) Y, Y (C = X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted aryl or unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; where each m is independently 0-2; n is 0 - 7; K is a radical that prevents systemic absorption; provided that at least one of R1, R2, R2 or R4 is -LK; or a pharmaceutically acceptable prodrug thereof.
[0137] In some embodiments of a compound of Formula III, R1 and R3 are -L-K. In some embodiments, R1, R2 and R3 are -L-K.
[0138] In some embodiments, at least one of R1, R2, R3, R4, R5, R6 and R7 is H. In certain embodiments, R5, R6 and R7 are H and R1, R2, R3 and R4 are alkyl, aryl, alkyl-aryl or heteroalkyl. In some embodiments, R1 and R2 are H. In some embodiments, R1, R2, R2, R6 and R7 are H. In some embodiments, R6 and R7 together form a bond. In certain embodiments, R5, R6 and R7 are H, alkyl or O-alkyl.
[0139] In some embodiments, R1 and R3 are -L-K. In some embodiments, R1, R2 and R3 are - L-K. In some embodiments, R3 and R4 are -L-K. In some embodiments, R1 and R2, together with the nitrogen to which they are attached, form a 3-8 membered ring and the ring is replaced with -L-K. In some embodiments, R1 or R2 or R3 or R4 are aryl, optionally substituted with -L-K. In some embodiments, R1 or R2 or R2 or R4 are alkyl optionally substituted with -L-K. In some embodiments, R1 or R- or RJ or R4 are alkyl-aryl optionally substituted with -L-K. In some embodiments, R1 or R2 or R2 or R4 are heteroalkyl optionally substituted with -L-K.
[0140] In some embodiments, L is C1-C7 alkyl. In some embodiments, L is heteroalkyl. In certain embodiments, L is C1-C7 alkylaryl. In some embodiments, L is C 1 -C 7 alkyl-aryl-C 1 -C 7 alkyl.
[0141] In certain embodiments, K is a charged, non-protic group. In some specific embodiments, each K is an ammonium group. In some embodiments, each K is a non-protic cyclic ammonium group. In some embodiments, each K is a non-protic acyclic ammonium group.
[0142] In certain embodiments, each K is a cyclic non-protic ammonium group of structure:

[0143] In certain embodiments, K is an acyclic non-protic ammonium group with a structure:
where p, q, R9, R10 and Z are as defined above. In certain embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3. In some embodiments, q is 0. In other embodiments, q is 1. In some other embodiments, q is 2.
[0144] The compounds still comprise 1, 2, 3 or 4 anionic counterions, selected from Cl ', Br', I-, R11SO3 “, (SO3 - R11-SO3 '), R11CO2-, (CO2 '-Rn-CO2-), (R11) 2 (P = O) 0 “and (R11) (P = O) O22-, where R11 is as defined above. In some embodiments, the counterion is Cl-, Br-, I-, CH2CO2-, CH3SO3-, or CeHsSOs- or CO2-- (CH2) 2-CO2-. In some embodiments, the Formula III compound has a K group and a counterion. In other embodiments, the Formula III compound has a K group, and two molecules of the Formula III compound have a counterion. In yet other embodiments, the Formula III compound has two K groups and two counterions. In some other embodiments, the Formula III compound has a K group, comprising two ammonium groups and two counterions.
[0145] Also described here are compounds with Formula IIIA:
where: each R1, R2 is, independently, H, substituted or unsubstituted alkyl, or -LK; or R1 and R2, together with the nitrogen to which they are attached, form a 3- to 8-membered ring that is optionally substituted with R8; and R3, R4, R8, L and K are as defined above.
[0146] In some embodiments of the compounds of Formula III, L is An, where each A is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and n is 0-7. In certain specific embodiments of the compound of Formula III, R1 is H. In some embodiments of Formula III, R1 and R2, together with the nitrogen to which they are attached, form a 3-8 membered ring which is optionally replaced with -LK.
[0147] Also described here are compounds that have Formula IIIB:
where: each R3, R4 is, independently, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, or -LK; and R1, R2, L and K are as defined above.
[0148] In certain embodiments of Formula IIIB, R3 is H. In certain embodiments, R3 and R4 are each -L-K. In some embodiments, R 3 is H and R 4 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl aryl containing one or two groups -L-K.
[0149] In some embodiments, an ASBTI suitable for the methods described here is a compound of general formula IIIC
where: each R1, R2 is, independently, H, hydroxyl, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted aryl or unsubstituted, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocyclo-alkyl, substituted or substituted alkyl-heterocycloalkyl unsubstituted, or -LK; or R1 and R2, together with the nitrogen to which they are attached, form a 3- to 8-membered ring that is optionally substituted with R8; each R3, R4 is, independently, H, hydroxyl, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl or -LK ; R5 is H, hydroxy, alkyl, alkoxy, -C (= X) YR8, YC (= X) R8, substituted or unsubstituted alkyl, unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl aryl, cycloalkyl substituted or unsubstituted, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, each R6, R7 is, independently, H , hydroxyl, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted cycloalkyl or unsubstituted, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, alkylheter substituted or unsubstituted ocycloalkyl, or -LK; or R6 and R7 taken together form a bond; each X is, independently, NH, S or O; each Y is, independently, NH, S or O; R8 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl cycloalkyl, substituted or unsubstituted heteroaryl, alkyl- substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, or -LK; L is An, where each A is independently NR1, S (0) m, O, C (= X) Y, Y (C = X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted cycloalkyl or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl; where each m is independently 0-2; n is 0 - 7; K is a radical that prevents systemic absorption; or a pharmaceutically acceptable thereof.
[0150] In some specific embodiments of Formulas I, II or III, K is selected from:

[0151] In some embodiments, an ASBTI suitable for the methods described here is a Formula IV compound:
Where: R1 is a straight chain C1-6 alkyl group; R2 is a straight chain C1-6 alkyl group; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is pyridyl or optionally substituted phenyl; R5, R6 and R8 are the same or different and each is selected from: hydrogen, halogen, cyano, R15-acetylide, OR15, optionally substituted C1-6 alkyl, COR15, CH (OH) R15, S (O) nR15, P (O) (OR15) 2, OCOR15, OCF3, OCN, SON, NHCN, CH2OR15, CHO, (CH2) PCN, CONR12R13, (CH2) PCO2R15, (CH2) PNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH = CHR15, O (CH2CH2O) nR15, O (CH2) PSO3R15, O (CH2) PNR12R13 and O (CH2) PN + R12R13R14 where p is an integer 1-4, n is an integer 0-3 and R12, R13, R14 and R15 are independently selected from hydrogen and optionally substituted C1-6 alkyl, R7 is a group of the formula
wherein the hydroxyl groups can be substituted with acetyl, benzyl, or (C1-Cg) -alkyl-R17, where the alkyl group can be substituted with one or more hydroxyl groups; R16 is -COOH, -CH2-OH, -CH2-O-Acetyl, -COOMe or COOEt; R17 is H, -OH, -NH2, -COOH or COOR18; R18 is (C1-Cg-alkyl or -NH- (C1-C4) -alkyl; X is -NH- or -O-; and R9 and R10 are the same or different and each is hydrogen or C1-C6 alkyl; salts.
[0152] In some embodiments, a compound of general formula IV has the structure of Formula IV or Formula IVB:

[0153] In some embodiments, a compound of General Formula IV has the structure of Formula IVC:

[0154] In some embodiments of Formula IV, X is O and R7 is selected from

[0155] In some embodiments, a Formula IV compound is:

[0156] In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula V:
Where: Rv is selected from hydrogen or C1-6 alkyl; One from R1 and R2 is selected from hydrogen or C1-6 alkyl and the other is selected from C1-6 alkyl; Rx and Rv are independently selected from hydrogen, hydroxy, amino, mercapto, C1-6 alkyl, C1-6 alkoxy, N- (C1-6 alkyl) amino, N, N- (C1-6 alkylHino, alkyl C1-6-S (O) a where a is 0 to 2; Rz is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-6 alkyl, alkenyl Co- e, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkanoyl, C1-6 alkanoyloxy, N- (C1-6 alkyl) amino, N, N- (C1-6 alkyl) 2 amino, C1-6 alkanoylamino, N- (C1-6 alkyl) carbamoyl, N, N- (C1-6alkyl) 2carbamoyl, C1-6 alkyl S (O) a where a is 0 to 2, C1-6 alkoxycarbonyl, N- (C1-) e-alkyl) -sulfamoyl and N, N- (C1-alkyl) 2-sulfamoyl; n is 0 - 5; one of R4 and R5 is a group of formula (VA):
R3 and R6 and the other from R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 alkoxy, C1-6 alkanoyl, C1-6 alkanoyloxy, N- (C1-6 alkyl) amino, N, N- (C1-6 alkyl) 2-amino, C1-6 alkanoylamino, N- (C1-6 alkyl) ) carbamoyl, N, N- (C1-6 alkyl) 2carbamoyl, C1-6 alkyl S (0) a where a is 0 to 2, C1-6 alkoxycarbonyl, N- (C1-6 alkyl) sulfamoyl and N, N- (C1-alkyl) 2 sulfamoyl; wherein R3 and R6 and the other of R4 and R5 can be optionally substituted on carbon by one or more R17; X is -0-, - N (Ra) -, -S (O) b- or -CH (Ra) -; where Ra is hydrogen or C1-6 alkyl and b is 0-2; ring A is aryl or heteroaryl; wherein Ring A is optionally substituted on carbon by one or more substituents selected from R18; R7 is hydrogen, C1-6 alkyl, carbocyclyl or heterocyclyl; wherein R7 is optionally substituted on carbon by one or more substituents selected from R19; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R20; R8 is hydrogen or C1-6 alkyl; R9 is hydrogen or Ci-e-alkyl; R10 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 alkanoyl, C1-6 alkanoyloxy 10, N- (C1-10-alkyl) amino, N, N- (C1-10-alkyl) 2amino, N, N, N- (C1-10 alkyl) sammonium, C1-10 alkanoylamino, N- (C1-6 alkyl) -10) carbamoyl, N N- (C 1-10 alkyl) 2carbamoyl, C 1-10 alkyl S (0) a where a is 0 to 2, N- (C 1-10 alkyl) sulfamoyl, N, N (alkyl C1-10) 2-sulfamoyl, N- (C1-10 alkyl) sulfamoylamino, N, N- (C1-10 alkyl) 2sulfamoyl amino, C1-10 alkoxycarbonylamino, carbocyclyl, carbocyclyl C1-10 alkyl, heterocyclyl, heterocyclyl C1-6 alkyl -10, carbocyclyl (C1-10 alkyl) P-R21- (C1-10 alkyl) q- or heterocyclyl- (C1-10 alkyl) r-R22- (C1-10 alkyl) s-; wherein R10 is optionally substituted on carbon by one or more substituents selected from R23; and wherein if said heterocyclyl contains an NH-group, that nitrogen can be optionally substituted by a group selected from R24; or R10 represents a group of formula (VB):
where: R11 is hydrogen or Ci-e-alkyl; R12 and R13 are independently selected from hydrogen, halogen, carbamoyl, sulfamoyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkanoyl, N- (C1-10 alkyl) carbamoyl, N, N- ( C1-10 alkyl) 2carbamoyl, C1-1 alkyl-S (0) a where a is 0 to 2, N- (C1-10 alkyl) sulfamoyl, N N- (C1-10 alkyl) 2-sulfamoyl, N - (C1-10 alkyl) sulfamoylamino, N, N- (C1-10 alkyl) sulfamoylamino, carbocyclyl or heterocyclyl; wherein R14θ R13 can optionally be independently substituted on carbon by one or more substituents selected from R25; and wherein if said heterocyclyl contains an -NH- group, the nitrogen can optionally be further substituted by a group selected from R26; R14 sub selected from hydrogen, halogen, carbamoyl, sulfamoyl, hydroxyminocarbonyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkanoyl, N- (C1-10 alkyl) carbamoyl, N, N- (C1-10 alkyl) 2carbamoyl, C1-3 alkyl (O) a where a is 0 to 2, N- (C1-10 alkyl) sulfamoyl, N, N- (C1-10 alkyl) 2-sulfamoyl , N- (C1-10 alkyl) sulfamoylamino, N, N- (C1-10 alkyl) 2sulfamoylamino, carbocyclyl, carbocyclyl-C1-10 alkyl, heterocyclyl, heterocyclyl-C1-10 alkyl, carbocyclyl- (C1-10 alkylene) P -R27- (C1-10 alkylene) cyclic heterocyclyl- (C1-10 alkylene) r-R28- (C1-10 alkylene) s-; wherein R14 can be optionally substituted on carbon with one or more substituents selected from R29; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R30; or R14 is a formula group (VC):
R15 is hydrogen or C1-6 alkyl; and R16 is hydrogen or C1-6 alkyl; wherein R16 can be optionally substituted on carbon by one or more groups selected from R31; or R15 and R16 together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl can be optionally substituted on carbon by one or more R37; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R38; m is 1-3; wherein the values of R7 can be the same or different; R17, R18, R29, R23, R35, R39, R31 and R37 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, C1-10 alkyl, C2-10 alkenyl, alkynyl C2-10, C1-10 alkoxy, C1-10 alkanoyl, C1-10 alkanoyloxy, N- (C1-10alkyl) amino, N, N- (C1-1o-alkyl) 2amino, N, N, N- (C1-10 alkyl, C1-10 alkanoylamino, N- (C1-10 alkyl) carbamoyl, N N- (C1-10 alkyl) 2carbamoyl, C1-10 alkyl (0) where a is 0 to 2, N- (C1-10 alkyl) sulfamoyl, N, N (C1-10 alkyl) 2-sulfamoyl, N- (C1-10 alkyl) sulfamoylamino, N, N- (C1-10 alkyl) 2sulfamoyl 1 amino, Ci-10 alkoxycarbonylamino, carbocyclyl, carbocyclyl C1-10 alkyl, heterocyclyl, heterocyclyl C1-10 alkyl, carbocyclyl- (C1-10 alkylene) p-R32- (C1-10 alkylene) q- or heterocyclyl (C1-10 alkylene) r-R33 - (C1-10 alkylene) 5-, wherein R17, R18, R19, R23, R25, R29, R31 and R37 can be independently optionally substituted on carbon by one or more R34; and in which said heterocycle ilo contains a group -NH-, this nitrogen can be optionally substituted by a group selected from R35; R21, R22, R27, R28, R32 or R33 are independently selected from -O-, -NR36-, -S (O) x-, -NR36 C (O) NR36-, - NR36C (S) NR36-, -OC (O) N = C-, -NR36C (O) - or - C (O) NR36-; wherein R36 is selected from hydrogen or C1-6alkyl, ex is 0-2; p, q, res are independently selected from 0-2; R34is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, alii, ethinyl, formyl, acetyl, formed, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N, N-dimethylsulfamoyl, N-methylsulfamoylamino and N, N-dimethylsulfamoylamino; R30, R34, R36, R30, R35 and R33 are independently selected from C1-6 alkyl, C1-8 alkanoyl, C1-8 alkylsulfonyl, carbamoyl, N- (C1-8 alkyl) carbamoyl, N, N- (C1-6 alkyl ) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; and where a "heteroaryl" is a totally unsaturated, mono- or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulfur and oxygen, which heteroaryl can, unless otherwise specified, be bonded to carbon or nitrogen; where a "heterocyclyl" is a saturated, partially saturated or unsaturated ring, a mono or bicyclic containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulfur and oxygen, which heterocyclyl can be saved specification to the contrary, carbon or nitrogen bond, in which a -CH2- group can be optionally substituted by a -C (0) - group, and a sulfur atom in the ring can be optionally oxidized to form an S oxide; and wherein a "carbocyclyl" is a saturated, partially saturated or unsaturated, mono- or bicyclic carbon ring containing 3-12 atoms; wherein a -CH2- group can be optionally substituted by a -C (0) group; or a pharmaceutically acceptable salt or hydrolyzable ester in vivo or amide formed in a carboxyl or hydroxyl group available therefrom.
[0157] In some embodiments, the compound of Formula V is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N- ((R) -1-carboxy-2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio -8- (N - {(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] carbamoylmethoxy} -4-hydroxybenzyl) -2,3,4,5-tetrahydro -1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -l -carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1, 1-dioxo-3,3-dibutyl -5-phenyl-7-methylthio-8- (N-; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R)) - «- [N - (((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1, 1-dioxo-3, 3- dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -a- [N- ((S) -1-carboxy-but11) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2, 3,4,5- tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - (((S) -1-carboxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-2,5-benzothiadiazepine; 1, 1-dioxo-3,3-dibutyl-5-phenyl -7 - methylthio-8- (N - {(R) -α- [N - ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5- benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((S) -l-carboxy-2- (R) - hydroxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3, 4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N- (2-sulphoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((S) -1-carboxyethyl) carbamoyl] -4-hydroxybenzyljcarbamoylmethoxy ) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methyl-thio-8- (N - {(R) -α- [N - ((R) -l-carboxy-2-methylthioethyl) carbamoyl] benzyl (carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -α- [N - {(S) -1- [N - ((S) - 2-hydroxy-1-carboxyethyl) carbamoyl] propyl} carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((S) -1-carboxy-2-methyl-propyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N - {(R) -α-carboxy-4-hydroxybenzyl} carbamoylmethoxy] -2,3,4,5-tetrahydro -1, 2,5-benzothiadiazepine or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a_ [N_ (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a salt thereof.
[0158] In some embodiments, the Formula V compound is:

[0159] In some embodiments, an ASBTI suitable for the methods described here is a Formula VI compound:
where: Rve Rw are independently selected from hydrogen or C1-6 alkyl and one of R1 and R2 is selected from hydrogen or and the other is selected from Cl-6 alkyl Rze R7 are independently selected from hydrogen or C 1 -alkyl or one of R;: and Ry is hydrogen or C 1 -alkyl and the other is hydroxy or C 1 -alkyl R = is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl , mercapto, sulfamoyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, N- (C1-6 alkyl) amino, N, N- (CI-6 alkyl) 2amino, N- (C1-6 alkyl) carbamoyl, N, N- (C1-alkyl) 2carbamoyl, C1-eS (O) a where a is 0 to 2, C1-alkoxycarbonyl, N- (C1-6 alkyl) sulfamoyl and N, N- ( C1-6 alkyl) 2-sulfamoyl; n is 0 - 5; one of R4 and R5 is a group of formula (VIA):
R3 and R6 and the other from R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy C1-alkanoyloxy, C1-alkanoyloxy, N- (C1-alkyl) amino, N, N- (C1-alkyl) 2amino, C1-alkanoylamino, N, (C1-alkyl carbamoyl, N, N- (C1-6 alkyl) 2Carbamoyl, C1-8 alkyl (0) a where a is 0-2, C1-6 alkoxycarbonyl, N- (C1-6 alkyl) - sulfamoyl and N, N- ( C1-6 alkyl) 2-sulfamoyl; where R3 and R6 and the other of R4 and R5 can be optionally substituted on carbon by one or more R17; X is -0-, -N (Ra) -, -S (O) b- or -CH (Ra) -; where R one is hydrogen or C1-6 alkyl and b is 0 - 2; Ring A is aryl or heteroaryl; where Ring A is optionally substituted on carbon by one or more selected substituents from R18, R7 is hydrogen, C1-6alkyl, carbocyclyl or heterocyclyl, where R7 is optionally substituted on carbon by one or more substituents selected from R19; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R20; R8 is hydrogen or C1-6 alkyl; R9 is hydrogen or C1-6 alkyl; R10 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkanoyl, N- (C1-10 alkyl) carbamoyl, N, N- (C1-10 alkyl) 2carbamoyl, C1-10 alkyl (S) a where a is 0 to 2, N- (C1-10 alkyl) sulfamoyl, N, N- (C1-6 alkyl) -10) 2-sulfamoyl, N- (C1-10 alkyl) sulfamoylamino, N, N- (C1-10 alkyl) 2sulfamoyl amino, carbocyclyl, carbocyclyl-C1-10 alkyl, heterocyclyl, heterocyclyl-C1-10 alkyl, carbocyclyl - (C1-10 alkylene) P-R21- (C1-10 alkylene) q- or heterocyclyl- (C1-10 alkylene) r-R22- (C1-10 alkylene) s-; wherein R10 is optionally substituted on carbon by one or more substituents selected from R23; and wherein said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R24; or R10 is a group of formula (VIB):
where: R11 is hydrogen or C1-8 alkyl R12 and R13 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, C1-10 alkyl, C2-10 alkenyl, C2 alkynyl -10, C1-10 alkoxy, C1-10 alkanoyl, C1-10 alkanoyloxy, N- (C1-10 alkyl) amino, N, N- (C1-6 alkyl) 2amino, C1-6 alkanoylamino, N, (C1-6 alkyl) -10) carbamoyl, N, N- (C1-10 alkyl) 2carbamoyl, C1-10-S alkyl (0) a where a is 0-2, N- (C1-10 alkyl) - sulfamoyl, N, N - (C1-10 alkyl) 2-sulfamoyl, N- (C1-10alkyl) -sulfamoylamino, N, N- (C1-10 alkyl) 2sulfamoylamino, carbocyclyl or heterocyclyl; wherein R12 and R13 can optionally be independently substituted on carbon by one or more substituents selected from R25; and wherein if said heterocyclyl contains an -NH- group, the nitrogen can be optionally substituted by a group selected from R26; R14 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkanyl, N- (alkyl C1-10) carbamoyl, N, N- (C1-10 alkyl) 2carbamoyl, C1-10 alkyl (S) where a is 0 to 2, N- (C1-10 alkyl) sulfamoyl, N, N- (C1-10 alkyl) 2-sulfamoyl, N- (C1-10 alkyl) sulfamoylamino, N, N- (C10-alkyl) 2sulfamoyl amino, carbocyclyl, carbocyclyl-C1-10 alkyl, heterocyclyl, heterocyclyl-C1- alkyl 10, carbocyclyl- (C1-10 alkylene) P-R27- (C1-10 alkylene) q- or heterocyclyl- (C1-10 alkylene) r-R28- (C1-10 alkylene) 3-; wherein R14 can be optionally substituted on carbon with one or more substituents selected from R29; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R30; or R14 is a group of formula (VIC):
R15 is hydrogen or C1-6 alkyl; R16 is hydrogen or C1-6 alkyl; wherein R16 may be optionally substituted on carbon by one or more groups selected from R31; n is 1-3; wherein the values of R7 can be the same or different; R17, R18, R19, R23, R25, R29 or R31 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, amidino, C1-10 alkyl, C2-10 alkenyl, alkynyl C2-10, C1-10 alkoxy, C1-10 alkanoyl, C1-10 alkanoyloxy, (C1-10 alkyl) 3SÜÍI, N- (C1-10 alkyl) amino, N, N- (Cylamino alkyl, N, N , N- (C1-10 alkyl) sammonium, C1-10 alkanoylamino, N- (C1-10 alkyl) carbamoyl, N, N- (C1-10 alkyl) 2carbamoyl, C1-10 alkyl-S (0) to a is 0 to 2, N- (C1-10 alkyl) sulfamoyl, N, N- (C1-10 alkyl) 2-sulfamoyl, N- (C1-10 alkyl) sulfamoylamino, N, N- (C1-10 alkyl) 2-sulfamoylamino, C1-10 alkoxycarbonylamino, carbocyclyl, C1-10 carbocyclylalkyl, heterocyclyl, C1-10 heterocyclylalkyl, carbocyclyl- (C1-10 alkylene) p-R32- (C1-10 alkylene) q- or heterocyclyl- (alkylene C1-10) r- R33- (C1-10 alkylene) s_; wherein R17, R18, R19, R23, R25, R29 or R31 can be independently optionally substituted on carbon by One or more θm quo so or "heterocyclyl acid" contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R35; R21, R22, R27, R28, R32 or R33 are independently selected from -O-, - NR36-, -S (O) x-, - NR36C (O) NR36-, -NR36C (S) NR36-, - OC (O) N = C-, -NR36C (O) - or - C (O) NR36-; wherein R36 is selected from hydrogen or C1-6alkyl, ex is 0-2; p, q, res are independently selected from 0-2; R34 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, ally, ethinyl, formyl, acetyl, formamide, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N, N-dimethyl-sulfamoyl, N-methylsulfamoylamino and N, N-dimethylsulfamoylamino; R30, R24, R26, R3 & or R35 are independently selected from C1-6 alkyl, C1-6 alkanoyl, C1-6 alkylsulfonyl, C1-4 alkoxycarbonyl, carbamoyl, N- (C1-8 alkyl) carbamoyl, N, N - (C1-6 alkyl) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; or a salt, solvate or solvate of such a pharmaceutically acceptable salt or an in vivo hydrolyzable ester formed in an available carboxyl or hydroxyl thereof, or an in vivo hydrolyzable amide formed in an available carboxyl of these.
[0160] In some embodiments, a Formula VI compound has the Formula VID structure:
wherein: R1 and R2 are independently selected from C1-6 alkyl; one of R4 and R5 is a group of formula (VIE):
R3 and R6 and the other of R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl C1-4, C1-4 alkanoyl, N- (C1-4alkyl) amino, N, N- (C1-4alkyl) 2amino, C1-4alkanoylamino, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) 2 carbamoyl, C1-4alkyl (O) a where a is 0 to 2, C1-4 alkoxycarbonyl, N- (C1-4alkyl) sulfamoyl and N, N- (C1alkyl) -4) 2-sulfamoyl; wherein R3 and R6 and the other of R4 and R5 can be optionally substituted on carbon by one or more R14; R7 is carboxy, sulpho, sulfine, phosphono, P (O) (ORa) (ORb), P (O) (OH) (ORa), -P (O) (OH) (Ra) or P (O) (ORa ) (Rb), where Ra and Rb are independently selected from C1-6 alkyl; or R7is a formula group (VIF):
R8 and R9 are independently hydrogen, C1-4 alkyl or a saturated cyclic group, or R8 and R9 together form C2-6 alkylene; wherein R8 and R9, or R8 and R9 together, can optionally be independently substituted on carbon by one or more substituents selected from R15; and wherein if said saturated cyclic group contains an -NH- radical, that nitrogen can be optionally substituted by one or more R20; R10 is hydrogen or C1-4alkyl; wherein R10 is optionally substituted on carbon by one or more substituents selected from R24; R11 is hydrogen, C1-4alkyl, carbocyclyl or heterocyclyl; wherein R11 is optionally substituted on carbon by one or more substituents selected from R16; and wherein if said heterocyclyl has an -NH- group, that nitrogen can be optionally substituted by one or more R'1; R12 is hydrogen or C1-4alkyl, carbocyclyl or heterocyclyl; wherein R12 is optionally substituted on carbon by one or more substituents selected from R17; and wherein if said heterocyclyl has an -NH- group, that nitrogen can be optionally substituted by one or more R22; R12 is carboxy, sulfo, sulfine, phosphono, P (0) (0Rc) (0Rd), -P (0) (OH) (0Rc), -P (0) (OH) (Rc), or P (0) (0R-) (Rd) where R (~ and Rd are independently selected from C 1 -G alkyl; m is 1-3; where the values of R8 and R9 can be the same or different; n is 1 -3; where R11 values can be the same or different; p is 1-3; where R12 values can be the same or different; R14 and R16 are independently selected from halo, nitro, cyano, hydroxy , amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-4 alkanoyloxy, N- (C1-4 alkyl) amino , N, N- (C1-4 alkyl) 2amino, C1-4 alkanoylamino, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) 2carbamoyl, C1-4alkyl (0) a where a is 0 to 2, C1-4 alkoxycarbonyl, N- (C1-4alkyl) sulfamoyl and N, N- (C1-4alkyl) 2-sulfamoyl; where R14 and R16 can independently be optionally substituted on carbon by one or more R18; R15 and R17 are selected are independently from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 alkanoyloxy -4, N- (C1-4alkyl) amino, N, N- (C1-4alkyl) 2amino, C1-4 alkanoylamino, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) 2carbamoyl, C1-4-S (0) alkyl a where 0 to 2, C1-4-alkoxycarbonyl, N- (C1-4alkyl) sulfamoyl and N, N- (C1-4alkyl) 2-sulfamoyl, carbocyclyl, heterocyclyl, sulpho, sulfine, amidino, phosphono, -P (0) (0Re) (0Rf), -P (0) (OH) (ORθ), -P (0) (OH) (Rθ) or P (0) (0Re) (Rf), where Re and Rf are independently selected from C1-6 alkyl, where R15 and R17 can independently be optionally substituted on carbon by one or more R19; and wherein if said heterocyclyl has an -NH- group, that nitrogen can be optionally substituted by one or more R23; R16, R19 and R25 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido-amino nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, ally, ethynyl, methoxycarbonyl, formyl, acetyl, formamide, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl; R20, R21, R22, R2 'and R26 are independently C1-4 alkyl, C1-4alkanyl, C1-4alkylsulfonyl, sulfamoyl, N- (C1-4alkyl) sulfamoyl, N, N- (C1-4alkyl) 2 -sulfamoyl, C1-4 alkoxycarbonyl, carbamoyl, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) 2-carbamoyl, benzyl, phenethyl, benzoyl, phenylsulfonyl or phenyl; R24 is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 alkanoyloxy C1-4, N- (C1-4alkyl) amino, N, N- (C1-4alkyl> 2amino, C1-4alkanoylamino, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) ) 2carbamoyl, C1-4 alkyl (O) a where a is 0 to 2, C1-4 alkoxycarbonyl, N- (C1-4alkyl) sulfamoyl and N, N- (C1-4alkyl) 2-sulfamoyl , carbocyclyl, heterocyclyl; wherein R24 can independently be optionally substituted on carbon by one or more R25; and wherein if said heterocyclyl has an -NH- group, that nitrogen can be optionally substituted by one or more R26; saturated cyclic group is a mono or bicyclic ring, fully or partially saturated containing 3-12 atoms of which 0-4 atoms are selected from nitrogen, sulfur or oxygen, which may be carbon or nitrogen bound; a heterocyclic is a satur ring partially saturated or unsaturated, mono- or bicyclic containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which may be carbon or nitrogen bond, in which a group -CH2- group may be optionally substituted by a -C (O) - or a ring sulfur atom may be optionally oxidized to form the oxides of S; and wherein any carbocyclyl is a saturated, partially saturated or unsaturated mono or bicyclic carbon ring, containing 3-12 atoms, where a group - CH2 - can be optionally substituted by a -C (O) -; or a pharmaceutically acceptable salt thereof.
[0161] In some embodiments, a compound of Formula IV is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -l'-phenyl- 1 '- [N' - (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzoythiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -a- [N '- ((S) -1-carboxypropyl) carbamoyl] -4- hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1'-phenyl- [N '- (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy) -2 , 3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N '- ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy ) -2,3, 4,5-tetrahydro-1,5-benzothiazepine; or your salt.
[0162] In some embodiments, any compound described herein is covalently conjugated to a bile acid using any suitable method. In some embodiments, the compounds described herein are covalently linked to a cyclodextrin or a biodegradable polymer (for example, a polysaccharide).
[0163] In certain embodiments, the compounds described herein are absorbed non-systemically. In addition, compounds are provided here that inhibit the recycling of bile salt in an individual's gastrointestinal tract. In some embodiments, the compounds described herein, cannot be transported from the intestinal lumen and / or do not interact with ASBT. In some embodiments, the compounds described herein do not affect, or minimally affect, the digestion and / or absorption of fat. In certain embodiments, administration of a therapeutically effective amount of any compound described herein does not result in gastrointestinal disorders or lactic acidosis in an individual. In certain embodiments, the compounds described herein are administered orally. In some embodiments, an ASBTI is released at the terminal ileum. An ASBTI compatible with the methods described herein can be a direct inhibitor, an allosteric inhibitor, or a partial inhibitor of the sodium-dependent apical bile acid carrier.
[0164] In certain embodiments, compounds that inhibit ASBT or any carriers of the recovering bile acids are compounds that are described in EP1810689, US Patents 6,458,851, 7,413,536, 7,514,421, US Order Publication Nos 2002/0147184, 2003/0119809, 2003/0149010, 2004/0014806, 2004/0092500, 2004/0180861, 2004/0180860, 2005/0031651, 2006/0069080, 2006/0199797, 2006/0241121, 2007/0065428, 2007/0065428, 2007 / 0066644, 2007/0161578, 2007/0197628, 2007/0203183, 2007/0254952, 2008/0070888, 2008/0070892, 2008/0070889, 2008/0070984, 2008/0070984, 2008/0089858, 2008/0096921, 2008/0161400, 2008/0167356 , 2008/0194598, 2008/0255202, 2008/0261990, WO 2002/50027, WO2005 / 046797, WO2006 / 017257, WO2006 / 105913, WO2006 / 105912, WO2006 / 116499, WO2006 / 117076, WO2006 / 121861, WO2006 / 122186, WO2006 / 122186, WO2006 / 124713, WO2007 / 050628, WO2007 / 101531, WO2007 / 134862, WO2007 / 140934, WO2007 / 140894, WO2008 / 028590, WO2008 / 033431, WO2008 / 033464, WO2008 / 031501, WO2008 / 031500, WO2008 / 01500, WO2008 / 0 034534, WO2008 / 039829, W O2008 / 064788, WO2008 / 064789, WO2008 / 088836, WO2008 / 104306, WO2008 / 124505 and WO2008 / 130616; the compounds described herein that inhibit the recovery of recoverable bile acid are incorporated herein by reference.
[0165] In certain embodiments, compounds that inhibit ASBT or any recooperative bile acid transporters are compounds described in WO93 / 16055, W094 / 18183, W094 / 18184, WO96 / 05188, WO96 / 08484, WO96 / 16051, W097 / 33882, W098 / 38182, W099 / 35135, WO98 / 40375, WO99 / 64409, WO99 / 64410, WO00 / 01687, WOOO / 47568, WOOO / 61568, DE 19825804, WOOO / 38725, WOOO / 38726, WOOO / 38727 ( including those compounds with a 1,2,3,4,5-tetrahydro-benzothiepine 1,1-dioxide structure), WOOO / 38728, WOOl / 66533, W002 / 50051, EP0864582 (e.g. (3R, 5R) -3-butyl-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl), β-D-glycopyranosidurδnic acid, WO94 / 24087 , WO98 / 07749, W098 / 56757, W099 / 32478, W099 / 35135, WOOO / 20392, WOOO / 20393, WO00 / 20410, WO00 / 20437, W001 / 34570, WOOO / 35889, WOOl / 68637, W001 / 68096, WO02 / 08211, W003 / 020710, WO03 / 022825, W003 / 022830, WO03 / 0222861, JP10072371, US Patents NA 5,910,494; 5,723,458; 5,817,652; 5,663,165; 5,998,400; 6,465,451, 5,994,391; 6,107,494; 6,387,924; 6,784,201; 6,875,877; 6,740,663; 6,852,753; 5,070,103, 6,114,322, 6,020,330, 7,179,792, EP251315, EP417725, EP489-423, EP549967, EP573848, EP624593, EP624594, EP624595, EP869121, EP1070703, W004 / 005247, the compounds disclosed to have IBAT activity in Drugs of the Future, 24, 425-430 (1999), Journal of Medicinal Chemistry (Revista de Quimica Medicinal), 48, 5837-5852, (2005) and Current Medicinal Chemistry (13 Quimica Medicinal Atual), 13 , 997-1016, (2006); the compounds disclosed therein that inhibit the recovery of recoverable bile acid are incorporated herein by reference.
[0166] In some embodiments, the compounds that inhibit ASBT or any recooperative bile acid transporter are benzothiepines, benzothiazepines (including 1,2-benzothiazepines; 1,4-benzothiazepines, 1,5-benzothiazepines, and / or 1, 2,5-benzothiadiazepines). In some embodiments, compounds that inhibit ASBT or any reciprocal bile acid transporter include, but are not limited to, S-8921 (described in EP597107, WO 93/08155), 264W94 (GSK), disclosed in WO 96/05188; SC-435 (1- [4- [4- [(4R, 5R) -3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1 methanesulfonate salt , 1-dioxido-1-benzothiepin-5-yl] phenoxy] butyl] -4-aza-1-azoniabicyclo [2.2.2] octane), SC-635 (Searle); 2164U90 (3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide); BARI-1741 (Aventis SA), AZD 7508 (Astra Zeneca); barixibat (11- (D-gluconamido) -N- {2 - [(1S, 2R, 3S) -3-hydroxy-3-phenyl-2- (2-pyridyl) -1- (2-pyridylamino) propyl] phenylJundecanamide ) or similar, or combinations thereof. In some embodiments, an ASBTI is:

[0167] In certain embodiments, the compounds described herein have one or more chiral centers. As such, all stereoisomers are provided for here. In various embodiments, the compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds of the present invention encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof, which have the useful therapeutic properties described herein. The preparation of the optically active forms is achieved in any appropriate manner, including by means of a non-limiting example, by resolving the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. In some embodiments, mixtures of one or more isomers are used as the therapeutic compound described herein. In certain embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including the synthesis and / or separation of a mixture of enantiomers and / or enantioselective diastereomers. The resolution of compounds and their isomers is achieved by any means, including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like.
[0168] The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, ADVANCED ORGANIC CHEMISTRY 4r Ed., (Wiley 1992) .; Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4r Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). The general methods for preparing the compound as described herein are modified through the use of reagents and suitable conditions, for the introduction of the various radicals found in the formulas as provided herein. As a guide, the following synthesis methods are used. Formation of covalent bonds by reaction of an electrophile with a nucleophile
[0169] The compounds described herein are modified using various electrophiles and / or nucleophiles to form new functional or substituent groups. Table A, entitled "Examples of covalent bonds and their precursors", lists selected non-limiting examples of covalent bonds and functional precursor groups that produce covalent bonds. Table A is used as a guide for the variety of combinations of electrophiles and nucleophiles available that provide covalent bonds. The precursor functional groups are shown as electrophilic groups and nucleophilic groups. Table A: Examples of covalent bonds and their precursors

Use of protection groups
[0170] In the reactions described, it is necessary to protect functional reactive groups, for example hydroxy, amino, imino, uncle or carboxyl, when these are desired in the final product, to avoid their unwanted participation in the reactions. Protective groups are used to block some or all reactive units and prevent these groups from participating in chemical reactions, until the protective group is removed. In some embodiments, it is contemplated that each protecting group is removed by a different means. Protection groups that are cleaved under totally different reaction conditions fulfill the requirement for differential removal.
[0171] In some embodiments, protecting groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are labile acids and are used to protect the carboxyl and hydroxyl reactive units in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are of labile bases. The reactive carboxylic acid and hydroxyl groups are blocked with basic labile groups, such as, but not limited to, methyl, ethyl and acetyl in the presence of amines blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.
[0172] In some embodiments, the reactive carboxylic acid and hydroxyl groups are blocked with hydrolytically removable protecting groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with basic labile groups, such as like Fmoc. The reactive portions of carboxylic acid are protected by conversion to simple ester compounds as exemplified herein, which include the conversion of alkyl esters, or are blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while the coexisting amino groups are blocked with fluoride labile silyl carbamates.
[0173] Alyl blocking groups are useful in the presence of base and acid protecting groups, since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, a blocked allyl carboxylic acid is deprotected with a reaction catalyzed by Pd ° in the presence of t-butyl carbamate acid protecting groups or basic labile acetate amine. Yet another form of protecting group is a resin to which a compound or intermediate is bonded. While the residue is attached to the resin, the functional group is blocked and does not react. Once released from the resin, the functional group is available to react.
[0174] protection / blocking groups are typically selected from:


[0175] The other protection groups, in addition to a detailed description of the techniques applicable to the creation of protection groups and their removal, are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, Nova York, NY, 1999, and Kocienski, Protective Groups, Tieme Verlag, New York, NY, 1994, which are hereby incorporated by reference for such disclosure.
[0176] In some embodiments, the ASBTIs described herein are synthesized as described in, for example, WO 96/05188, U.S. Patent No. 5,994,391; 7238684; 6906058; 6020330; and 6114322. In some embodiments, the ASBTIs described herein are synthesized from compounds that are available from commercial sources or that are prepared using the procedures described herein. In some embodiments, the compounds described herein are prepared according to the process shown in Scheme 1: Scheme 1:

[0177] In certain embodiments, the synthesis begins with a reaction of 1,4-diazabicyclo [2.2.2] octane with 4-iodo-1-chlorobutane to provide a compound with structure 1-1. These compounds are prepared in any suitable manner, for example, as established in Tremont, SJ et. al., J. Med. Chem. 2005, 48, 5837-5852. The compound having structure 1-1 is then subjected to a reaction with phenethylamine to obtain a compound having structure 1- II. The compound of structure l-II is then allowed to react with dicyandiamide to provide a compound of Formula I.
[0178] In some embodiments, a first Formula III compound is subjected to an additional reaction to provide a second Formula III compound, as shown in Scheme 2 below. Scheme 2:

[0179] A first Formula III compound, 1-IA, is alkylated with iodomethane to provide a second Formula III compound, 1-IB. Alkylation of 1-IB with a compound of structure 2-II provides a new compound of Formula III, IC. In an alternative embodiment, a first compound of Formula III, 1-IA, is alkylated with a compound of structure 2-I to provide a second compound of Formula III, 1-IC.
[0180] In some embodiments, the compounds described here are prepared according to the process shown in Scheme 3: Scheme 3:

GENERAL DEFINITIONS
[0181] The term "bile acid", as used herein, includes steroid acids (and / or the carboxylate anion thereof), and their salts, found in the bile of an animal (for example, a human), including, by way of non-limiting example, cholic acid, cholate, deoxycholic acid, deoxycholate, hyiodesoxycholic acid, hyiodesoxycholate, glycolic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, ursodeoxycholic acid, ursodiol, a tauroursodeoxycholic acid, a glycodesodeoxycholic acid, 7-B-methyl cholic acid, methyl lithocholic acid, kenodeoxycholate, lithocholic acid, lithocolate and the like. Taurocholic acid and / or taurocholate are referred to herein as TCA. Any reference to a bile acid used herein includes the reference to a bile acid, one and only one bile acid, one or more bile acids, or at least one bile acid. Therefore, the terms "bile acid", "bile salt", "bile acid / salt", "bile acids", "bile salts" and "bile acids / salts" are, unless otherwise stated, used here indiscriminately. Any reference to a bile acid used herein includes the reference to a bile acid or a salt thereof. In addition, pharmaceutically acceptable bile acid esters are optionally used as "bile acids" described herein, for example, bile acids / salts of conjugates with an amino acid (for example, glycine or taurine). Others of bile acids include, for example, substituted or unsubstituted alkyl ester, substituted or unsubstituted heteroalkyl ester, substituted or unsubstituted aryl ester, substituted or unsubstituted heteroaryl ester, or the like. For example, the term "bile acid" includes cholic acid conjugated to glycine or taurine: glycocholate and taurocholate, respectively, (and their salts). Any reference to a bile acid used herein includes reference to an identical compound naturally or synthetically prepared. Furthermore, it is to be understood that any reference to a component in the singular (bile acid or otherwise) used herein includes the reference to one and only one, one or more, or at least one of these components. Likewise, any reference to a plural component used herein includes reference to one and only one, one or more, or at least one of such components, unless otherwise indicated. In addition, as used herein, bile acid / salt mimetics or mimetics described herein are compounds that mimic the agonist signaling bile acid / salt properties, especially in TGR5 receptors (GPBAR1, BG37, Axorl09). Examples include those described in WO 2010/014836, which is incorporated herein by this disclosure. In some embodiments, bile acid mimetics include triterpenoids, such as oleanic acid, ursolic acid, or the like.
[0182] The term "subject", "patient" or "individual" is used interchangeably here and refers to mammals and non-mammals, for example, who suffer from a disorder described herein. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees and other simians and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In an embodiment of the methods and compositions provided herein, the mammal is a human being.
[0183] Unless otherwise specified, the following terms used in this application, including the specification and claims, have the definitions given below with respect to "pediatric" or "pediatric patients" include Neonatal (children aged 0 to 4 weeks), Babies ( ages 4 weeks to 2 years), children (aged 2 to 5 years), children (aged 6 to 11 years) and adolescents (12 to 18 years).
[0184] The term "about," as used herein, includes any value that is within 10% of the value described.
[0185] The term "between", as used herein, is included in the lower and upper number of the range.
[0186] The term "colon", as used herein, includes the cecum, ascending colon, hepatic flexure, splenic flexure, descending colon and sigmoid.
[0187] The term "composition", as used herein, includes the disclosure of both a composition and a composition administered in a method as described herein. In addition, in some embodiments, the composition of the present invention is or comprises a "formulation", an oral dosage form or a rectal dosage form, as described herein.
[0188] The terms "treat", "treating" or "treatment" and other grammatical equivalents as used herein, include relieving, inhibiting or reducing symptoms, reducing or inhibiting the severity of, reducing the incidence of, reducing or inhibiting recurrence of, delay the onset of, delay the recurrence of, decrease or ameliorate a disease or condition symptoms, improvement of the symptoms of the underlying causes, inhibition of the disease or condition, for example, stopping the development of the disease or condition, alleviation of the disease or condition , cause the disease or condition to regress, alleviate a condition caused by a disease or condition, or stop the symptoms of the disease or condition. The terms further include achieving a therapeutic benefit. Therapeutic benefit is intended to eradicate or ameliorate the underlying disease to be treated, and / or to eliminate or ameliorate one or more of the physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient.
[0189] The terms "prevent", "preventing" or "prevention", and other grammatical equivalents as used herein, include preventing additional symptoms, avoiding the underlying causes of symptoms, inhibiting the disease or condition, for example, by stopping development disease or condition and are intended to include prophylaxis. The terms further include achieving a prophylactic benefit. For prophylactic benefit, the compositions are optionally administered to a patient at risk of developing a particular disease, to a patient showing one or more of the physiological symptoms of a disease, or to a patient at risk of disease recurrence.
[0190] Where combination treatments or prevention methods are contemplated, the agents described herein are not intended to be limited by the particular nature of the combination. For example, the agents described herein are optionally administered in combination as simple mixtures, as well as chemical hybrids. An example of the latter is that the agent is covalently linked to a vehicle or to an active pharmaceutical target. Covalent bonding can be achieved in a number of ways, such as, although not limited to, the use of a commercially available crosslinking agent. In addition, combination treatments are optionally administered separately or simultaneously.
[0191] As used herein, the terms "pharmaceutical combination", "administration of an additional therapy", "administration of an additional therapeutic agent" and the like refer to a pharmaceutical therapy resulting from mixing or combining more than one ingredient active and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that at least one of the agents described herein and at least one co-agent are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that at least one of the agents described herein and at least one co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with varying intervening periods, at which that administration provides levels of two or more agents in the patient's body. In some cases, the co-agent is administered once or over a period of time after which the agent is administered once or over a period of time. In other cases, the co-agent is administered over a period of time, after which a therapy involving the administration of both co-agent and the agent is administered. In still other embodiments, the agent is administered once or over a period of time, after which the co-agent is administered once or over a period of time. These also apply to cocktail therapies, for example, the administration of three or more active ingredients.
[0192] As used herein, the terms "co-administration", "administered in combination with" and their grammatical equivalents are intended to encompass the administration of selected therapeutic agents to a single patient and are intended to include treatment regimes in which agents are administered by the same or different routes of administration or at the same time or different times. In some embodiments, the agents described herein will be co-administered with other agents. These terms include the administration of two or more agents to an animal so that both agents and / or their metabolites are present in the animal at the same time. They include simultaneous administration, in separate compositions, administration at different times in separate compositions, and / or administration of a composition in which both agents are present. Thus, in some embodiments, the agents described herein and the other agent (s) are administered in a single composition. In some embodiments, the agents described herein and the other agent (s) are mixed into the composition.
[0193] The term "effective amount" or "therapeutically effective amount", as used herein, refers to a sufficient amount of at least one agent to be administered, which achieves a desired result, for example, to relieve to a certain extent measure one or more symptoms of a disease or condition to be treated. In certain cases, the result is a reduction and / or alleviation of the signs, symptoms, or causes of an illness, or any other desired change to a biological system. In certain cases, an "effective amount" for therapeutic purposes is the amount of the composition comprising an agent as set forth herein necessary to provide a clinically significant decrease in disease. An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.
[0194] The terms "administer", "administering", "administration" and the like, as used herein, refer to methods that can be used to allow the administration of agents or compositions to the desired site of biological action. These methods include, but are not limited to, oral, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Administration techniques that are optionally used with the agents and methods described herein are found in sources, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, (current ed.); Pergamon; and Remington, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In certain embodiments, the agents and compositions described herein are administered orally.
[0195] The term "pharmaceutically acceptable", as used herein, refers to a material that does not negate the biological activity or properties of the agents described herein, and is relatively non-toxic (that is, the toxicity of the material significantly exceeds the benefit of the material). In some cases, a pharmaceutically acceptable material can be administered to an individual, without causing significant undesirable biological effects or interacting in a significantly detrimental way with any of the components of the composition in which it is contained.
[0196] The term "carrier", as used herein, refers to relatively non-toxic chemical agents that, in certain cases, facilitate the incorporation of an agent into cells or tissues.
[0197] The term "non-systemic" or "minimally absorbed" as used herein refers to the low bioavailability and / or systemic absorption of an administered compound. In some cases, a non-systemic compound is a compound that is not substantially absorbed systemically. In some embodiments, the ASBTI compositions described herein deliver the ASBTI to the distal ileo, colon and / or rectum and not systemically (for example, a substantial portion of the ASBTI is not absorbed systemically). In some embodiments, the systemic absorption of a non-systemic compound is <0.1%, <0.3% <0.5% <0.6% <0.7% <0.8% <0, 9% <1%, <1.5%, <2%, <3%, or <5% of the administered dose (% by weight or% by mol). In some embodiments, the systemic absorption of a non-systemic compound is <10% of the administered dose. In some embodiments, the systemic absorption of a non-systemic compound is <15% of the administered dose. In some embodiments, the systemic absorption of a non-systemic compound is <25% of the administered dose. In an alternative embodiment, a non-systemic ASBTI is a compound that has low systemic bioavailability compared to the systemic bioavailability of a systemic ASBTI (for example, compound 100A, 100C). In some embodiments, the bioavailability of a non-systemic ASBTI described herein is <30%, <40%, <50%, <60%, or <70% of the bioavailability of a systemic ASBTI (for example, compound 100A, 100C).
[0198] In another alternative approach, the compositions described here are formulated to deliver <10% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <20% of the administered dose of the ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <30% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <40% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <50% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <60% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <70% of the administered dose of ASBTI systemically. In some embodiments, systemic absorption is determined in any suitable manner, including the total amount in circulation, the amount cleared after administration, or the like.
[0199] The term "ASBT inhibitor" refers to a compound that inhibits apical transport of sodium-dependent bliar acid, or salt of any recuperative bile acid transport. The term apical sodium bile acid carrier (ASBT) is used interchangeably with the term ileal bile acid carrier (IBAT).
[0200] The term "increase secretion of enteroendocrine peptides" refers to a sufficient increase in the level of the enteroendocrine peptide agent, for example, for the treatment of any disease or disorder described herein. In some embodiments, the increased secretion of enteroendocrine peptides reverses or alleviates the symptoms of cholestasis or a cholestatic liver disease.
[0201] In various embodiments, the pharmaceutically acceptable salts described herein include, by way of non-limiting example, a nitrate, chloride, bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butyrate, subsalicylate , maleate, laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate, p-tolunenesulfonate, mesylate and the like. In addition, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (for example, calcium or magnesium), alkali metal salts (for example, potassium or sodium-dependent), ammonium salts and the like.
[0202] The term "optionally substituted" or "substituted" means that the referenced group has been replaced with one or more additional group (s). In certain embodiments, the one or more additional group (s) is individually and independently selected from amide, ester, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, arylxi, alkylthio , arylthio, alkylsulfoxide, arylsulfoxide, ester, alkylsulfone, arylsulfone, cyano, halo, alcohol, alkoyloxo, isocyanate, thiocyanate, isothiocyanate, nitro, haloalkyl, haloalkoxy, fluoroalkyl, amino, alkyl-amino, dialkyl-amino, starch.
[0203] An "alkyl" group refers to an aliphatic hydrocarbon group. Reference to an alkyl group includes "saturated alkyl" and / or "unsaturated alkyl". The alkyl group, whether saturated or unsaturated, includes branched, straight-chain or cyclic groups. By way of example only, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl, iso-pentyl, neo-pentyl and hexyl. In some embodiments, the alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, and the like. A "lower alkyl" is C 1 -C 6 alkyl. A "heteroalkyl" group replaces any of the carbon atoms in the alkyl group with a heteroatom having the appropriate number of hydrogen atoms attached (for example, a CH2 group for an NH group or a group 0).
[0204] The term "alkylene" refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above can be alkylene by abstraction of a second hydrogen atom from the alkyl group. In one aspect, an alkenene is C1-C10 alkylene. In another aspect, an alkylene group is a C 1 -C alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH (CH3) -, -C (CH3) 2-, -CH2CH2-, - CH2CH (CH3) -, -CH2C (CH3) 2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2- and the like.
[0205] An "alkoxy" group refers to a (alkyl) 0- group, where alkyl is as defined herein.
[0206] The term "alkylamine" refers to the group -N (alkyl) zHy, where alkyl is as defined herein, and y and y are selected from the group x = l, y = lex = 2 ry = 0. When x = 2, the alkyl groups, taken together with the nitrogen to which they are attached, optionally form a cyclic ring system.
[0207] An "amide" is a chemical moiety with the formula -C (O) NHR or -NHC (O) R, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached via a ring carbon ) and heteroalicyclyl (linked via a ring carbon).
[0208] The term "ester" refers to a chemical part with the formula -C (= 0) OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic.
[0209] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms that form the ring is a carbon atom. Aryl rings described herein include rings having five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups are optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl.
[0210] The term "aromatic" refers to a flat ring with a delocalized n electron system containing 4n +2 n electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, ten, or more than ten atoms. Aromatics can optionally be replaced. The term "aromatic" includes carbocyclic aryl ("aryl", for example, phenyl) and heterocyclic aryl groups (or "heteroaromatics" or "heteroaryl") (e.g., pyridine). The term includes monocyclic or fused ring polycyclic groups (i.e., rings that share adjacent pairs of carbon atoms).
[0211] The term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic radical, in which each of the atoms that make up the ring (that is, the atoms
of the skeleton) is a carbon atom. In several embodiments, cycloalkyls are saturated, or partially unsaturated. In some embodiments, cycloalkyls are fused with an aromatic ring. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following radicals: and the like. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0212] The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups containing 1-4 ring heteroatoms, each selected from O, Se N. In certain cases, each heterocyclic group has 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl (derived from aziridine). An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidine, morpholine, thiomorphine, toxanil, piperazinyl, oxiperyl, tylanilil, tiperidyl, aziperyl, tylanyl, tylanilyl, tyridine, , diazepinil, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanil, 1,3-dioxolanil, pyrazolinyl, dithianyl, dithiolanil, dihydro-pyridine, dihydro , dihydrofuranil, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0 hexanil, 3-azabicyclo [4.1.0] heptanil, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, indininyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolil, quinazolinyl, quinoxalinyl, and naphyriridinin.
[0213] The terms "heteroaryl" or, alternatively, "heteroaromatic" refer to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An "heteroaromatic" or "heteroaryl" portion containing N refers to an aromatic group in which at least one of the atoms in the ring skeleton is a nitrogen atom. In certain embodiments, the heteroaryl groups are monocyclic or polycyclic. Glossy examples of heteroaryl groups include the following radicals:
and the like.
[0214] A "heteroalicyclic" group or a "heterocycle" group refers to a cycloalkyl group, in which at least one skeleton ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. In various embodiments, the radicals are with an aryl or heteroaryl. Illustrative examples of heterocyclic groups, also referred to as non-aromatic heterocycles and which include:
and the like. The term heteroalicyclic also includes all forms of carbohydrate ring, including, but not limited to, monosaccharides, disaccharides and oigosaccharides.
[0215] The term "halo" or, alternatively, "halogen" means fluorine, chlorine, bromine and iodine.
[0216] The terms "haloalkyl" and "haloalkoxy" include alkyl and alkoxy structures that are replaced with one or more halogens. In embodiments, in which more than one halogen is included in the group, the halogens are the same or are different. The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halogen is fluorine.
[0217] The term "heteroalkyl" includes optionally substituted alkyl, alkenyl and alkynyl radicals that have one or more atoms in the backbone selected from an atom other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, silicon, or their combinations. In certain embodiments, the heteroatom (s) is placed in any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, - CH2-N (CH3) -CH3 , -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S- CH2-CH3, -CH2-CH2, -S (O) -CH3, -CH2-CH2-S (O) 2-CH3, -CH = CH-O-CH3, -Si (CH3) 3, -CH2-CH = N-OCH3, and -CH = CH-N (CH3) -CH3. In some embodiments, up to two heteroatoms are consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-SY (CH3) 3.
[0218] A "cyan" group refers to a group - CN.
[0219] An "isocyanate" group refers to an -NCO group.
[0220] A "thiocyanate" group refers to a -CNS group.
[0221] An "isothiocyanate" group refers to an -NCS group.
[0222] "Alkoyloxy" refers to an RC (= 0) 0- group.
[0223] "Alcohil" refers to an RC (= O) - group.
[0224] The term "modular" as used herein refers to having an effect on (for example, increasing, improving or maintaining a certain level).
[0225] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group (s) individually and independently selected from C 1 -C 6 alkyl, Ct-Cs cycloalkyl, aryl, heteroaryl, C2-C6 heteroalicyclyl, hydroxy, C1-Ce alkoxy, aryloxy, arylalkoxy, aralkyloxy, arylalkyloxy, C1-Ce alkylthio, arylthio, Ci-Ce alkyl sulfoxide, aryl sulfoxide, Ci-Ce alkyl sulfone, aryl sulfone, cyano, halo C2-C8, C2-C8 acyloxy, nitro, C1-C haloalkyl, C1-Cs fluoroalkyl, and amino, including C1-C alkylamino and its protected derivatives. For example, an optional substituent can be LSRS, where each Ls is independently selected from a bond, -0-, -C (= 0) -, -S-, -S (= 0) -, - S (= O) 2-, -NH-, -NHC (= O) -, -C (= O) NH-, S (= O) 2NH-, -NHS (= O) 2-, OC (= O ) NH-, -NHC (= O) O-, - (C 1 -C 6 alkyl) - or - (C 2 -C alkenyl) -; and each Rs is independently selected from H, (C 1 -C 4 alkyl), (C 1 -C 6 cycloalkyl), heteroaryl, aryl, and C 1 -C heteroalkyl. Optionally substituted non-aromatic groups can be substituted with one or more oxo (= 0). The protecting groups that can form the protective derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts, above. In some embodiments, the alkyl groups described herein are optionally substituted with a 0 that is attached to two adjacent carbon atoms (i.e., forming an epoxide).
[0226] The term "therapeutically effective amount" or an "effective amount", as used herein, refers to a sufficient amount of a therapeutically active agent to provide a desired effect on a patient or individual. In some embodiments, a "therapeutically effective amount" or an "effective amount" of an ASBTI refers to a sufficient amount of an ASBTI to treat cholestasis or cholestatic liver disease in a subject or individual. L cells
[0227] The inventors found that enteroendocrine L cells play a repair role. The epithelial barrier is also a key component in the defense of the host. Another pre-proglicagon splicing product, GLP-2, is secreted by L-enteroendocrine cells in the distal small intestine and has been shown to improve intestinal wound healing in a TGF-B (anti-inflammatory TGF-B cytokines), mediation process, small intestine responding better than the large intestine. GLP-2 has also been shown to alleviate barrier dysfunction induced by experimental stress and food allergy. Once again, L-cells are activated by luminal nutrients, and the impairment of the barrier observed in TPN may reflect, in part, its hyposecretion in the absence of enteral stimuli. In addition, GLP-2 is also responsible, at least in part, for the growth and adaptation seen in short bowel models. Therefore, the function of abnormal enteroendocrine cells (EEC) may predispose GI to inflammatory diseases, and the underlying EEC-vagal-nutrient pathways are targets in the injured intestine as contemplated in current achievements.
[0228] L-cells are spread throughout the epithelial layer of the intestine from the duodenum to the rectum, with the highest numbers occurring in the ileum, colon and rectum. They are characterized by an open cell morphology, with apical microvilli facing the lumen of the intestine and secretory vesicles located adjacent to the basolateral membrane, and are therefore in direct contact with nutrients in the intestinal lumen. In addition, L cells are located in the vicinity of both neurons and the microvasculature of the intestine, thus allowing the L cell to be affected by both neural and hormonal signals. As well as Peptide 1 of the glucagon type (GLP-1) and Peptide 2 of the glucagon type (GLP-2), L cells, also secrete peptide YY (PYY), and glutamate. The cells are just one member of a much larger family of enteroendocrine cells that secrete a range of hormones, including ghrelin, GIP, cholecystokinin, somatostatin and secretin, which are involved in the local coordination of the intestine's physiology, as well as playing roles broader in controlling cytokine release and / or controlling the adaptation process, attenuating intestinal damage, reducing bacterial translocation, inhibiting the release of oxygen free radicals, or any combination thereof. L cells are unevenly distributed in the gastrointestinal tract, with higher concentrations in the distal portion of the gastrointestinal tract (for example, in the distal ileum, colon and rectum). Bile acid
[0229] Bile contains water, electrolytes and numerous organic molecules, including bile acids, cholesterol, phospholipids and bilirubin. The bile is secreted from the liver and stored in the gallbladder, and upon the contraction of the gallbladder, due to the ingestion of a high fat meal, the bile passes through the bile duct into the intestine. Bile acids / salts are critical for the digestion and absorption of fat and fat-soluble vitamins in the small intestine. Adult humans produce 400 to 800 mL of bile per day. Bile secretion can be considered to occur in two stages. Initially, hepatocytes secrete bile into canaliculi, from which it flows into bile ducts and this liver bile contains large amounts of bile acids, cholesterol and other organic molecules. Then, as bile flows through the bile ducts, it is modified by adding a secretion rich in aqueous bicarbonate from epithelial cells in the ducts. Bile is concentrated, typically five times, during storage in the gallbladder.
[0230] Bile flow is less during fasting, and a majority of it is diverted to the gallbladder for concentration. When chyme of an ingested meal enters the small intestine, acid and partially digested fats and proteins stimulate the secretion of cholecystokinin and secretin, both of which are important for secretion and bile flow. Cholecystokinin (cholecyst = gallbladder and kinin = movement) is a hormone that stimulates the contractions of the gallbladder and the common bile duct, resulting in the delivery of bile to the intestine. The most potent stimulus for the release of cholecystokinin is the presence of fat in the duodenum. Secretin is a hormone secreted in response to acid in the duodenum, which simulates bile duct cells to secrete bicarbonate and water, which expands the volume of bile and increases its flow from the outside into the intestine.
[0231] Bile acids / salts are derived from cholesterol. Cholesterol, taken as part of the diet or derived from liver synthesis, is converted into bile acids / salts in the hepatocyte. Examples of such bile acids / salts include cholic and deoxycholic acids, which are then conjugated to an amino acid (such as glycine or taurine), to obtain the conjugated form that is actively secreted by the canaliculi. The most abundant of bile salts in humans are cholate and deoxycholate, and they are normally conjugated with glycine or taurine to give glycocholate or taurocholate respectively.
[0232] Free cholesterol is practically insoluble in aqueous solutions, however, in bile it is made soluble by the presence of bile acids / salts and lipids. Liver synthesis of bile acids / salts accounts for most of the breakdown of cholesterol in the body. In humans, about 500 mg of cholesterol is converted to bile acids / salts and eliminated each day. Therefore, bile secretion is an important route for the elimination of cholesterol. Large amounts of bile acids / salts are secreted into the intestine each day, but only relatively small amounts are lost from the body. This is because about 95% of the acids / bile salts delivering to the duodenum are absorbed back into the blood within the ileum, by a process known as "enterohepatic recirculation".
[0233] The venous blood of the ileo goes directly to the portal vein, and therefore through the sinusoid of the liver. Hepatocytes extract bile acids / salts very efficiently from sinusoidal blood, and little escapes from the healthy liver to the systemic circulation. Bile acids / salts are then transported through hepatocytes to be resected in canaliculi. The net effect of this enterohepatic recirculation is that each bile salt molecule is reused about 20 times, often two or three times during a single digestive phase. Bile biosynthesis represents the main metabolic destination of cholesterol, being responsible for more than half of the approximately 800 mg / day of cholesterol that an average adult uses in metabolic processes. In comparison, steroid hormone biosynthesis consumes only about 50 mg of cholesterol per day. Much more than 400 mg of bile salts are needed and secreted into the intestine per day, and this is achieved by recycling the bile salts. Most of the bile salts secreted into the upper region of the small intestine are absorbed together with the dietary lipids that have been emulsified at the lower end of the small intestine. They are separated from the food lipid and returned to the liver for reuse. Recycling thus allows 20-30g of bile salts to be secreted into the small intestine each day.
[0234] Bile acids / salts are amphipathic, with the cholesterol derivative portion, containing both hydrophobic (lipid-soluble) and hydrophilic (polar) portions while the amino acid conjugate is generally polar and hydrophilic. This amphipathic nature allows bile acids / salts to perform two important functions: emulsification of lipid aggregates and the solubilization and transport of lipids in an aqueous medium. Bile acids / salts have a detergent action on fat particles in the diet that causes fat globules to break or be emulsified. Emulsification is important as it greatly increases the surface area of the fat available for digestion by lipases that cannot access the interior of lipid droplets. In addition, bile acids / salts are lipid carriers and are capable of solubilizing many lipids, forming micelles and are essential for the transport and absorption of fat-soluble vitamins. Pharmaceutical Compositions and Methods of Use
[0235] In some embodiments, the compositions described herein are administered to deliver enteroendocrine peptide secretion-enhancing agents to a subject or individual. In certain embodiments, any compositions described herein are formulated for ileal, rectal and / or colonic delivery. In more specific embodiments, the composition is formulated for non-systemic or local delivery to the rectum and / or colon. It is to be understood that, as used herein, delivery to the colon includes delivery of sigmoid colon, transverse colon, and / or ascending colon. In even more specific embodiments, the composition formulated for non-systemic or local delivery to the rectum and / or colon is administered rectally. In other specific embodiments, the composition formulated for non-systemic or local delivery to the rectum and / or colon is administered orally.
[0236] In some embodiments, a composition comprising an enteroendocrine peptide secretion enhancing agent and, optionally, a pharmaceutically acceptable carrier for alleviating the symptoms of pediatric cholestasis or a pediatric cholestatic liver disease in an individual is provided in this document.
[0237] In certain embodiments, the composition comprises an agent that increases the secretion of enteroendocrine peptide and an absorption inhibitor. In specific embodiments, the absorption inhibitor is an inhibitor that inhibits the absorption of (or at least one of) the specific enteroendocrine peptide-enhancing agent with which it is combined. In some embodiments, the composition comprises an agent that increases the secretion of enteroendocrine peptide, an absorption inhibitor and a vehicle (for example, an orally suitable vehicle or a rectally suitable vehicle, depending on the intended mode of administration). In certain embodiments, the composition comprises an agent that increases the secretion of enteroendocrine peptide, an absorption inhibitor, a carrier and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, an dispersion and a wetting agent.
[0238] In other embodiments, the compositions described herein are administered orally for the non-systemic delivery of the active bile salt component to the rectum and / or colon, including the sigmoid colon, transverse colon, and / or the colon ascending. In specific embodiments, compositions formulated for oral administration are, by way of non-limiting example, enterically coated or formulated oral dosage forms, such as tablets and / or capsules. It is to be understood that the terms "subject" and "individual" are used interchangeably here and include, for example, humans and human patients in need of treatment. Absorption inhibitors
[0239] In certain embodiments, the composition described herein as being formulated for the non-systemic administration of ASBTI further includes an absorption inhibitor. As used herein, an absorption inhibitor includes an agent or set of agents that inhibit the absorption of a bile acid / salt.
[0240] Suitable bile acid absorption inhibitors (also described herein as inhibiting absorption agents) include, by way of non-limiting example, anion exchange matrices, polyamines, polymers containing quaternary amine, quaternary ammonium salts, polymers and polyalylamine copolymers, colesevelam, colesevelam hydrochloride, Colestagel (polymer of N, N, N-trimethyl-6- (2-propenylamino) - 1-hexanaminium with (chloromethyl) oxirane, 2 - propen-l-amine hydrochloride and N-2-propenyl-1-decanamine), cyclodextrins, chitosan derivatives, chitosan, carbohydrates that bile bile acids, lipids that bile bile acids, proteins and proteinaceous materials that bile bile acids, and antibodies and albumins that bind bile acids. Suitable cyclodextrins include those that bind bile acids / salts, such as, by way of non-limiting example, β-cyclodextrin and hydroxypropyl-β-cyclodextrin. Suitable proteins include those that bind bile acids / salts, such as, by way of non-limiting example, bovine serum albumin, egg albumin, casein, acid α-glycoprotein, gelatin, soy proteins, peanut proteins, almond, and vegetable wheat proteins.
[0241] In certain embodiments, the absorption inhibitor is cholestyramine. In specific embodiments, cholestyramine is combined with a bile acid. Cholestyramine, an ion exchange resin, is a polymer of styrene, containing quaternary ammonium groups cross-linked by divinylbenzene. In other embodiments, the absorption inhibitor is colestipol. In specific embodiments, colestipol is combined with a bile acid. Colestipol, an ion exchange resin, is a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane.
[0242] In certain embodiments of the compositions and methods described herein, ASBTI is linked to an absorption inhibitor, while in other embodiments, ASBTI and absorption inhibitors are separate molecular entities. In specific embodiments, bile acid, bile acid mimic or modified bile acid is linked to an inhibitor of bile acid absorption described herein. Cholesterol absorption inhibitors
[0243] In certain embodiments, a composition described herein optionally includes at least one cholesterol absorption inhibitor. Suitable cholesterol absorption inhibitors include, by way of non-limiting example, ezetimibe (SCH 58235), ezetimibe analogs, ACT inhibitors, stigmastanil phosphorylcholine, stigmastanyl phosphorylcholine analogs, p-lactam cholesterol absorption inhibitors, polysaccharides, sulfate neomycin, plant sponins, plant sterols, FM-VP4 preparation of phytostanol, sitostanol, β-sitosterol, acyl-CoA: cholesterol-O-acyltransferase (ACAT) inhibitors, avasimib, implitapide, steroidal glycosides and the like. Suitable enzetimib analogs include, by way of non-limiting example, SCH 48461, SCH 58053 and the like. Suitable ACT inhibitors include, by way of non-limiting example, trimethoxy fatty acid anilides such as Cl-976, 3- [decyldimethylsilyl] -N- [2- (4-methylphenyl) -1- phenylethyl] -propanamide, melinamide and similar. Inhibitors of β-lactam cholesterol include, by way of non-limiting example, (3R-4S) -1,4-bis- (4-methoxyphenyl) -3- (3-phenylpropyl) -2-azetidinone and the like. Peptidase inhibitors
[0244] In some embodiments, the compositions described herein optionally include at least one peptidase inhibitor. Such peptidase inhibitors include, but are not limited to, dipeptidyl-peptidase-4 (DPP-4) inhibitors, neutral endopeptidase inhibitors, and conversion enzyme inhibitors. Suitable dipeptidyl-peptidase-4 (DPP-4) inhibitors include, by way of non-limiting example, Vildaglipti, 2S) -l- {2- [(3-hydroxy-1-adamantyl) amino] acetyl} -pyrrolidine-2 - carbonitrile, sitagliptin, (3R) -3-amino-1- [9- (trifluoromethyl) -1, 4,7,8-tetrazabicyclo [4.3.0] nona-6, 8-dien-4-yl] -4 - (2,4,5-tri-fluorophenyl) butan-l-one, saxagliptin, and (IS, 3S, 5S) -2 - [(2S) -2-amino-2- (3-hydroxy-l-adamantyl ) acetyl] -2-azabicyclo [3.1.0] hexane-3-carbonitrile. Such neutral endopeptidase inhibitors include, but are not limited to, Candoxatrilat and Ecadotril. Dispersing agents / wetting agents
[0245] In certain embodiments, the composition described herein optionally comprises a dispersing agent. In some embodiments, a dispersing agent is used to improve the dispersion of the composition in the colon and / or rectum. Suitable dispersing agents include, by way of non-limiting example, hydroxyethylcellulose, hydroxypropylmethyl cellulose, polyethylene glycol, colloidal silicon dioxide, propylene glycol, cyclodextrins, microcrystalline cellulose, polyvinylpyrrolidone, polyoxyethylated glycerides, polycarbonate and polycarbonate; ™ OE, polyalkylene glycol fatty alcohol ethers, Aethoxal ™ B), 2-ethylhexyl palmitate, CEGESOFT ™ C24), and isopropyl fatty acid esters.
[0246] In some embodiments, the compositions described herein optionally comprise a wetting agent. In some embodiments, a wetting agent is used to improve the wettability of the composition in the colon and rectum. Suitable wetting agents include, by way of non-limiting example, ionic or nonionic surfactants. In some embodiments, surfactants are selected from, by way of non-limiting example, SLS, poloxamers (for example, poloxamer 188), polysorbate (for example, 20 or 80), stearic hetanoate, fatty acid esters of caprylic / capric acids of C12-C18 chain length saturated fatty alcohols, isostearyl diglycerol isoteearic acid, sodium dodecyl sulfate, isopropyl myristate, isopropyl palmitate, and isopropyl myristate / isopropyl stearate / isopropyl stearate. I saw tamines
[0247] In some embodiments, the methods provided here still comprise the administration of one or more vitamins.
[0248] In some embodiments, the vitamin is vitamin A, Bl, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine , retinol, beta-carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherols, phylloquinone, menaquinone.
[0249] In some embodiments, the vitamin is a fat-soluble vitamin, such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherols, phylloquinone. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS). Bile acid sequestrants / binders
[0250] In some embodiments, in labile bile acid scavenger is an enzyme-dependent bile acid scavenger. In certain embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in high concentrations in the human colon or rectum in relation to the concentration found in the small intestine. Examples of activated micro-flora systems include dosage forms comprising pectin, galactomannan, and / or azo hydrogels and / or glycoside conjugates (e.g., D-galactoside, β-D-xylopyranoside conjugates or the like) of the active agent. Examples of micro-flora gastrointestinal enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glycosidase, α-L-arabinofuranosidase, β-D-xylopyranidasidase or the like.
[0251] In certain embodiments, a labile bile acid scavenger is a time-dependent bile acid scavenger. In some embodiments, a labile bile acid scavenger releases bile acid or is degraded after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds of kidnapping. In some embodiments, a labile bile acid scavenger releases bile acid or is degraded after 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds of kidnapping. In some embodiments, a labile bile acid scavenger releases bile acid or is degraded after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of sequestration. In some embodiments, a labile bile acid scavenger releases a bile acid or is degraded after about 15, 20, 25, 30, 35, 45, 50, or 55 minutes of kidnapping. In some embodiments, a labile bile acid scavenger releases a bile acid or is degraded after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours of kidnapping. In some embodiments, a labile bile acid scavenger releases bile acid or is degraded after 1, 2, or 3 days after the scavenging.
[0252] In some embodiments, the labile bile acid scavenger has a low affinity for bile acid. In certain embodiments, the labile bile acid scavenger has a high affinity for a primary bile acid and a low affinity for a secondary bile acid.
[0253] In some embodiments, the labile bile acid scavenger is a pH-dependent bile acid scavenger. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 6 or below and a low affinity for bile acids at a pH of above 6. In certain embodiments, the scavenger pH-dependent bile acid has a high affinity for bile acids at a pH of 6.5 or less and a low affinity for bile acids at a pH above 6.5. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 7 or below, and a low affinity for bile acids at a pH above 7. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 7.1 or less and a low affinity for bile acids at a pH above 7.1. In certain embodiments, pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 7.2 or lower and a low affinity for bile acids at a pH above 7.2. In certain embodiments, pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 7.3 or below and a low affinity for bile acids at a pH above 7.3. In certain embodiments, pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 7.4 or lower and a low affinity for bile acids at a pH above 7.4. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 7.5 or below and a low affinity for bile acids at a pH above 7.5. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 7.6 or less and a low affinity for bile acids at a pH above 7.6. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 7.7 or less and a low affinity for bile acids at a pH above 7.7. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 7.8 or less and a low affinity for bile acids at a pH above 7.8. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH greater than 6. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 6.5. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.1. In some embodiments, the pH-dependent bile acid scavenger degrades to a pH above 7.2. In some embodiments, the pH-dependent bile acid scavenger degrades to a pH above 7.3. In some embodiments, the pH-dependent bile acid scavenger degrades to a pH above 7.4. In some embodiments, the pH-dependent bile acid scavenger degrades to a pH above 7.5. In some embodiments, the pH-dependent bile acid scavenger degrades to a pH greater than 7.6. In some embodiments, the pH-dependent bile acid scavenger degrades to a pH above 7.7. In some embodiments, the pH-dependent bile acid scavenger degrades to a pH above 7.8. In some embodiments, the pH-dependent bile acid scavenger degrades to a pH above 7.9.
[0254] In certain embodiments, the labile bile acid scavenger is lignin or modified lignin. In some embodiments, the labile bile acid scavenger is a polycationic polymer or copolymer. In certain embodiments, the labile bile acid scavenger is a polymer or copolymer that comprises one or more residues of N-alkenyl-N-alkylamine; one or more residues of N, N, N-trialkyl-N- (N'-alkenylamino) alkyl-azanium; one or more residues of N, N, N-trialkyl-N-alkenyl-azanium; one or more alkenyl amine residues; or a combination of them.
[0255] In some embodiments, the bile acid binder is cholestyramine, and various compositions including cholestyramine, which are described, for example, in U.S. Patent Nos. 3,383,281; 3,308,020; 3,769,399; 3,846,541; 3,974,272; 4,172,120; 4,252,790; 4,340,585; 4,814,354; 4,874,744; 4,895,723; 5,695,749; and 6,066,336. In some embodiments, the bile acid binder is colestipol or cholesevelam. METHODS
[0256] Here, in certain embodiments, methods are provided for the treatment of pediatric cholestasis or a pediatric cholestatic liver disease comprising the non-systemic administration of a therapeutically effective amount of an ASBTI. Here, in certain embodiments, methods are provided for the treatment of pediatric cholestasis or pediatric cholestatic liver disease comprising contacting the gastrointestinal tract, including the distal ileum and / or the colon and / or rectum, of an individual in need of it , with an ASBTI. Also provided here are methods for reducing intra-enterocyte bile acids, reducing damage to hepatocellular or intestinal architecture caused by cholestasis or cholestatic liver disease, from an individual who comprises administering a therapeutically effective amount of an ASBTI to a individual in need of it.
[0257] In some embodiments, a method of treating pediatric cholestasis or a pediatric cholestatic liver disease in an individual is provided here, comprising delivering the individual's ileum or colon with a therapeutically effective amount of any ASBTI described herein. In some embodiments, methods are provided herein to reduce damage to hepatocellular or intestinal architecture or cholestasis cells or a cholestatic liver disease comprising administering a therapeutically effective amount of an ASBTI. In certain embodiments, methods are provided herein for reducing intra-enterocyte bile acids / salts which comprise administering a therapeutically effective amount of an ASBTI to an individual in need thereof.
[0258] In some embodiments, the methods provide for the inhibition of bile salt recycling by administering any of the compounds described herein to an individual. In some embodiments, an ASBTI described herein is absorbed systemically by administration. In some embodiments, an ASBTI described herein is not absorbed systemically. In some embodiments, an ASBTI here is administered to the individual orally. In some embodiments, an ASBTI described herein is delivered and / or released to an individual's terminal ileum.
[0259] In certain cases, contact of a pediatric individual's distal ileum with an ASBTI (for example, any ASBTI described here) inhibits bile acid reuptake and increases the concentration of bile acids / salts in the vicinity of L-cells in the distal ileo and / or colon and / or rectum, thereby reducing intra-enterocyte bile acids, reducing serum and / or hepatic bile acid levels, reducing the total bile acid load, and / or reducing the damage caused to the ileal architecture caused cholestasis or cholestatic liver disease. Without being limited to any particular theory, reducing serum and / or hepatic bile acid levels improves cholestasis and / or cholestatic disease.
[0260] Administration of a compound described herein is accomplished in any suitable manner, including, by way of non-limiting example, orally, enteral, parenteral (e.g., intravenous, subcutaneous, intramuscular), nasal, buccal, topical , rectal, or transdermal routes of administration. Any compound or composition described herein is administered by a method or formulation suitable for the treatment of a newborn or child. Any compound or composition described herein is administered in an oral formulation (for example, solid or liquid) for the treatment of a newborn or child. In some embodiments, the pediatric dosage form is selected from a solution, syrup, suspension, elixir, powder for reconstitution as a suspension or solution, dispersible / effervescent tablet, chewable tablet, lollipop, popsicles, pastilles, strips oral fines, tablets that disintegrate orally, strips that disintegrate orally, and oral powder or granules. In some embodiments, a compound or composition described herein is administered by a pediatric dosage formulation method or form suitable for treating children. In some embodiments, a compound or composition described herein is administered by a method or form of pediatric dosage formulation suitable for the treatment of adolescents. In some embodiments, a compound or composition described herein is administered by a method or form of pediatric dosage formulation suitable for the treatment of a newborn or child. In some embodiments, a compound or composition described herein is administered in an oral formulation (for example, solid or liquid) for the treatment of a newborn or child. In some embodiments, the pediatric dosage form described herein is administered before eating, with food or after eating.
[0261] In certain embodiments, a compound or composition comprising a compound described herein, is administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to an individual who is already suffering from a disease or condition, in an amount sufficient to cure or at least partially stop the symptoms of the disease or condition. In several cases, the effective amounts for this use depend on the severity and course of the disease or condition, previous therapy, the individual's health status, weight, and response to drugs, and the judgment of the attending physician.
[0262] In prophylactic applications, the compounds or compositions containing the compounds described herein are administered to an individual susceptible to, or otherwise at risk for, a particular disease, disorder or condition. In certain embodiments of this use, the exact amount of compound administered will depend on the individual's state of health, weight, and the like. In addition, in some cases, when a compound or composition described herein is administered to an individual, the effective amounts for this use depend on the severity and course of the disease, disorder or condition, prior therapy, the individual's state of health and response to medication and the judgment of the attending physician.
[0263] In certain cases, where, after administration of a selected dose of a compound or composition described herein, the condition of an individual does not improve, at the physician's discretion, the administration of a compound or composition described herein is optionally administered chronically, that is, over an extended period of time, including over the duration of the individual's life, in order to improve or otherwise control or limit the symptoms of the individual's disorder, disease or condition.
[0264] In certain embodiments, an effective amount of a particular agent varies, depending on one or more of a number of factors such as the particular compound, the disease or condition and its severity, identity (e.g., weight ) of the subject or host in need of treatment, and is determined according to the particular circumstances surrounding the case, including, for example, the specific agent to be administered, the route of administration, the condition to be treated, and the subject or host to be treated. In some embodiments, the doses administered include those up to the maximum tolerable dose. In some embodiments, the doses administered include those up to the maximum dose tolerable by a newborn or child.
[0265] In certain embodiments, about 0.001-5000 mg per day, from about 0.001-1500 mg per day, about 0.001 to about 100 mg / day, about 0.001 to about 50 mg / day, or about 0.001 to about 30 mg / day, or about 0.001 to about 10 mg / day of a compound described herein, is administered to an individual in need thereof. In various embodiments, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses. doses per day. In various embodiments, a single dose is from about 0.001 mg / kg to about 500 mg / kg. In various embodiments, a single dose is about 0.001, 0.01, 0.1, 1, or 10 mg / kg to about 10, 50, 100, or 250 mg / kg. In various embodiments, a single dose of an ASBTI is from about 0.001 mg / kg to about 100 mg / kg. In various embodiments, a single dose of an ASBTI is from about 0.001 mg / kg to about 50 mg / kg. In various embodiments, a single dose of an ASBTI is from about 0.001 mg / kg to about 10 mg / kg. In various embodiments, a single dose of an ASBTI is administered every 6 hours, every 12 hours, every 24 hours, every 48 hours, every 72 hours, every 96 hours, every 5 days, every 6 days, or once a week.
[0266] In the event that the patient's condition does not improve, at the doctor's discretion, an ASBTI is optionally administered continuously; alternatively, the dose of medication to be administered is temporarily reduced or temporarily suspended for a certain period of time (i.e., a "drug vacation"). The length of the drug vacation optionally varies between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reduction during drug holidays includes 10% - 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the total dose of ASBTI is in the range described above.
[0267] Once the patient's condition has improved, a maintenance dose is administered, if necessary. Subsequently, the dosage or frequency of administration, or both, is reduced, depending on the symptoms, to a level where the disease, disorder or improved condition is maintained. In some embodiments, patients require intermittent treatment on a long-term basis after any recurrence of symptoms.
[0268] In certain cases, there are a large number of variables with respect to an individual treatment regime, and considerable excursions from these recommended values are considered within the scope described here. The dosages described here are optionally changed depending on a number of variables, such as, by way of non-limiting example, the activity of the compound used, the disease or condition to be treated, the mode of administration, the conditions of the individual subject, the severity of the disease or condition to be treated, and the practitioner's judgment.
[0269] The toxicity and therapeutic efficacy of such therapeutic regimes are optionally determined by pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of LDso (the lethal dose for 50% of the population) and EDso (the therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between LDso and EDso. Compounds that exhibit high therapeutic indexes are preferred. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a dosage range for use in humans. In specific embodiments, the dosage of the compounds described herein is within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending on the dosage form employed and the route of administration used.
[0270] In some embodiments, the systemic exposure of a therapeutically effective amount of any non-systemic ASBTI described herein (for example, an ASBTI comprising a non-systemic portion such as LK or other groups described herein) is reduced when compared to systemic exposure of a therapeutically effective amount of any systemically absorbed ASBTI (e.g., compounds 100A, 100C). In some embodiments, the AUC of a therapeutically effective amount of any non-systemic ASBTI described herein (for example, an ASBTI comprising a non-systemic portion such as LK or other groups described herein) is at least 10%, at least 20 %, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% reduced when compared to the AUC of any ASBTI absorbed systemically (for example , compounds 100A, 100C).
[0271] In some embodiments, systemic exposure of a therapeutically effective amount of a Formula I compound, which is not systemically absorbed (for example, a Formula I compound, which comprises a non-systemic portion such as LK or others groups described herein) is reduced when compared to the systemic exposure of a therapeutically effective amount of the compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula I compound, which is not absorbed systemically (for example, a Formula I compound, which comprises a non-systemic portion such as LK or other groups described herein) is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula I compound, which is not absorbed systemically (for example, a Formula I compound, which comprises a non-systemic portion such as LK or other groups described herein) it is about 50% reduced when compared to the AUC of a therapeutically effective amount of compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula I compound, which is not systemically absorbed (for example, a Formula I compound, which comprises a non-systemic portion such as LK or other groups described herein) it is about 75% reduced when compared to the AUC of a therapeutically effective amount of compound 100A.
[0272] In some embodiments, systemic exposure of a therapeutically effective amount of a Formula II compound that is not systemically absorbed (for example, a Formula II compound, which comprises a non-systemic portion such as LK or other groups described herein) is reduced when compared to the systemic exposure of a therapeutically effective amount of the compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula II compound that is not systemically absorbed (for example, a Formula II compound, which comprises a non-systemic portion such as LK or other groups described herein) about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to AUC of a therapeutically effective amount of compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula II compound that is not systemically absorbed (for example, a Formula II compound, which comprises a non-systemic portion such as LK or other groups described herein) about 50% reduced when compared to the AUC of a therapeutically effective amount of compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula II compound that is not systemically absorbed (for example, a Formula II compound, which comprises a non-systemic portion such as LK or other groups described herein) about 75% reduced when compared to the AUC of a therapeutically effective amount of compound 100A.
[0273] In some embodiments, the systemic exposure of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is reduced when compared to the systemic exposure of a therapeutically effective amount of Compound 100C. In some embodiments, the AUC of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is about 10%, about 20%, about 30%, about 40%, about 50 %, about 60%, about 70%, about 80% or about 90% reduced, when compared to the AUC of a therapeutically effective amount of Compound 100C. In some embodiments, the AUC of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100C. In other embodiments, the AUC of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100C.
[0274] In some embodiments, systemic exposure of a therapeutically effective amount of a Formula IV compound, which is not systemically absorbed (for example, a Formula IV compound, which comprises a non-systemic portion such as LK or others groups described herein) is reduced when compared to the systemic exposure of a therapeutically effective amount of compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula IV compound, which is not systemically absorbed (for example, a Formula I compound, which comprises a non-systemic portion such as LK or other groups described herein) is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula IV compound, which is not systemically absorbed (for example, a Formula IV compound, which comprises a non-systemic portion such as LK or other groups described herein) it is about 50% reduced when compared to the AUC of a therapeutically effective amount of compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula IV compound, which is not systemically absorbed (for example, a Formula IV compound, which comprises a non-systemic portion such as LK or other groups described herein) it is about 75% reduced when compared to the AUC of a therapeutically effective amount of compound 100A.
[0275] In some embodiments, systemic exposure of a therapeutically effective amount of a Formula V compound, which is not systemically absorbed (for example, a Formula V compound, which comprises a non-systemic portion such as LK or others groups described herein) is reduced when compared to the systemic exposure of a therapeutically effective amount of compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula V compound, which is not systemically absorbed (for example, a Formula V compound, which comprises a non-systemic portion such as LK or other groups described herein) is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%) reduced when compared to the AUC of a therapeutically effective amount of compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula I compound, which is not systemically absorbed (for example, a Formula V compound, which comprises a non-systemic portion such as LK or other groups described herein) it is about 50% reduced when compared to the AUC of a therapeutically effective amount of compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula I compound, which is not systemically absorbed (for example, a Formula V compound, which comprises a non-systemic portion such as LK or other groups described herein) it is about 75% reduced when compared to the AUC of a therapeutically effective amount of compound 100A.
[0276] In some embodiments, systemic exposure of a therapeutically effective amount of a Formula VI or VID compound that is not systemically absorbed (for example, a Formula VI or VID compound that comprises a non-systemic portion such as LK or other groups described herein) is reduced when compared to the systemic exposure of a therapeutically effective amount of compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula VI or VID compound that is not systemically absorbed (for example, a Formula VI or VID compound that comprises a non-systemic portion such as LK or other groups here described) is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared with AUC a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula VI or VID compound that is not systemically absorbed (for example, a Formula VI or VID compound that comprises a non-systemic portion such as LK or other groups here described) is about 50% reduced when compared to the AUC of a therapeutically effective amount of compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula I compound, which is not systemically absorbed (for example, a Formula VI or VID compound comprising a non-systemic portion such as LK or other groups described herein ) is about 75% reduced when compared to the AUC of a therapeutically effective amount of compound 100A.
[0277] In certain embodiments, the Cmax of a therapeutically effective amount of any non-systemic ASBTI described herein (for example, an ASBTI comprising a non-systemic portion such as LK or other groups described herein) is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% less when compared to the Cmax of any systemically absorbed ASBTI (e.g., Compound 100A).
[0278] By way of example, the Cmax of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% reduced, when compared to the Cmax of a therapeutically effective amount of Compound 100C. In some embodiments, the Cmax of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is about 25% reduced when compared to the Cmax of a therapeutically effective amount of Compound 100C. In certain embodiments, the Cmax of a therapeutically effective amount of a compound of III, IIIA or IIIB is about 50% reduced when compared to the Cmax of a therapeutically effective amount of Compound 100C. In other embodiments, the Cmax of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is about 75% reduced when compared to the Cmax of a therapeutically effective amount of Compound 100C.
[0279] In certain embodiments, the pharmaceutical composition administered includes a therapeutically effective amount of a bile salt, a bile acid mimic, or a bile salt mimic, an absorption inhibitor and a vehicle (For example, an orally vehicle or a rectally suitable vehicle, depending on the intended mode of administration). In certain embodiments, the pharmaceutical composition used or administered comprises a bile salt, a bile acid mimic, or a bile salt mimic, an absorption inhibitor, a vehicle and one or more of a cholesterol absorption inhibitor, a enteroendocrine peptide, a peptidase inhibitor, a dispersing agent and a wetting agent.
[0280] In a specific embodiment, the pharmaceutical composition used to prepare a rectal dosage form or administered rectally comprises a bile salt, a bile acid mimic, or a bile salt mimic, an absorption inhibitor, a rectally appropriate vehicle, an optional cholesterol absorption inhibitor, an optional enteroendocrine peptide, an optional peptidase inhibitor, an optional dispersing agent, and an optional wetting agent. In certain embodiments, compositions administered rectally evoke a perianal response. In specific embodiments, the perianal response is an increase in the secretion of one or more enteroendocrine cells (for example, L-cells) in the colon and / or rectum (for example, in the epithelial layer of the colon and / or rectum) . In some embodiments, the anorectal response persists for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23 or 24 hours. In other embodiments, the anorectal response persists for a period between 24 hours and 48 hours, while in other embodiments the anorectal response persists for a period greater than 48 hours.
[0281] In another specific embodiment, the pharmaceutical composition used to prepare an oral dosage form, or administered orally comprises a bile salt, a bile acid mimic, or a bile salt mimic, an absorption inhibitor , an orally suitable vehicle, an optional cholesterol absorption inhibitor, an optional enteroendocrine peptide, an optional peptidase inhibitor, an optional dispersing agent and an optional wetting agent. In certain embodiments, compositions administered orally evoke a perianal response. In specific embodiments, the perianal response is an increase in the secretion of one or more enteroendocrine cells from the colon and / or rectum (for example, in L cells of the epithelial layer of the colon and / or rectum). In some embodiments, the anorectal response persists for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23 or 24 hours. In other embodiments, the anorectal response persists for a period between 24 hours and 48 hours, while in other embodiments the anorectal response persists for a period greater than 48 hours. Routes of Administration and Dosage
[0282] In some embodiments, the compositions described herein and the compositions administered in the methods described herein are formulated to inhibit bile acid reuptake, or to reduce serum or hepatic bile acid levels. In certain embodiments, the compositions described herein are formulated for administration rectally or orally. In some embodiments, these formulations are administered rectally or orally, respectively. In some embodiments, the compositions described herein are combined with a device for the local delivery of compositions to the rectum and / or colon (sigmoid colon, transverse colon or ascending colon). In certain embodiments, for rectal administration, the composition described herein is formulated as enemas, rectal gels, rectal foams, aerosols, rectal suppositories, suppositories, jelly or retention enemas. In some embodiments, for oral administration, the compositions described herein are formulated for oral administration and enteral delivery to the colon.
[0283] In certain embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein, deliver the ASBTI to the distal ileum, colon and / or rectum and non-systemically (for example, a substantial portion of the enteroendocrine peptide secretion-enhancing agent is absorbed non-systemically). In some embodiments, the oral compositions described herein deliver ASBTI to the distal ileum, colon and / or rectum and non-systemically (for example, a substantial portion of the enteroendocrine peptide secretion-enhancing agent is absorbed non-systemically). In some embodiments, the rectal compositions described herein deliver ASBTI to the distal ileum, colon and / or rectum and non-systemically (e.g., a substantial portion of the enteroendocrine peptide secretion-enhancing agent is absorbed non-systemically). In certain embodiments, the non-systemic compositions described herein offer less than 90% w / w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein provide less than 80% w / w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein provide less than 70% w / w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein provide less than 60% w / w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein, provide less than 50% w / w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein provide less than 40% w / w systemic ASBTI. In certain embodiments, the non-systemic compositions described herein provide less than 30% w / w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein provide less than 25% w / w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein provide less than 20% w / w ASBTI systemically. In certain embodiments, the compositions described herein, do not systemically provide less than 15% w / w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein provide less than 10% w / w systemic ASBTI. In certain embodiments, the non-systemic compositions described herein provide less than 5% w / w ASBTI systemically. In some embodiments, systemic absorption is determined in any suitable manner, including the total amount in circulation, the amount cleared after administration, or the like.
[0284] In certain embodiments, the compositions and / or formulations described herein are administered at least once a day. In certain embodiments, formulations containing ASBTI are administered at least twice a day, while in other embodiments formulations containing ASBTI are administered at least three times a day. In certain embodiments, formulations containing ASBTI are administered up to five times a day. It is to be understood that in certain embodiments, the dosage regimen of the composition containing the ASBTI described herein is determined by considering various factors such as the patient's age, sex and diet.
[0285] The concentration of ASBTI administered in the formulations described here varies between about 1 mM to about 1 M. In certain embodiments, the concentration of ASBTI administered in the formulations described here varies between about 1 mM to about 750 mM . In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 5 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 10 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 25 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 50 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 100 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 200 mM to about 500 mM.
[0286] In certain embodiments, any composition described herein, comprises a therapeutically effective amount (for example, to treat cholestasis or a cholestatic liver disease) of ursodiol. In some embodiments, ursodiol can be replaced by any other therapeutic acid or bile salt. In some embodiments, the compositions described herein comprise or methods described herein comprise administering about 0.01 mg to about 10 g of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.1 mg to about 500 mg of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.1 mg to about 100 mg of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.1 mg to about 50 mg of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.1 mg to about 10 mg of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.5 mg to about 10 mg of ursodiol. In some embodiments, the compositions described herein comprise or methods described herein, comprising administering from about 0.1 mmol to about 1 mol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.01 mmol to about 500 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.1 mmol to about 100 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.5 mmol to about 30 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.5 mmol to about 20 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 1 mmol to about 10 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.01 mmol to about 5 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering from about 0.1 mmol to about 1 mmol of ursodiol. In various embodiments, certain bile acids / salts have different potencies and the dosage is optionally adjusted accordingly. For example, research on CHO cells transfected with TGR5 potency of natural bile acid / bile salts TGR5 agonist indicates the following potency post: lithocholic acid (LCA)> deoxycholic acid (DCA)> murocholic acid (Muro-CA)> lagodeoxycholic acid (lago- DCA)> kenodeoxycholic (CDCA)> cholic acid (CA)> hyodesoxycholic acid (HDCA> ursodeoxycholic acid (UDCA), and assays in TGR5 transfected CHO cells demonstrate that EC50 (in pM) for UDCA was 3 6 , 4, TauroCA (TCA) 4.95 and 0.58 LCA.
[0287] In certain embodiments, by directing the distal gastrointestinal tract (for example, the distal ileum, colon and / or rectum), compositions and methods described herein provide an efficacy (for example, in reducing microbial growth and / or relieve symptoms of cholestasis or cholestatic liver disease) with a reduced dose of enteroendocrine peptide secretion-enhancing agent (for example, compared to an oral dose that does not target the distal gastrointestinal tract). Rectal Administration Formulations
[0288] The pharmaceutical compositions described herein for the non-systemic delivery of a compound described herein to the rectum and / or colon are formulated for rectal administration as rectal enemas, rectal foams, rectal gels and rectal suppositories. The components of these formulations are described here. It is to be understood that as used herein, the pharmaceutical compositions and compositions are or comprise the formulations, as described herein. In some embodiments, rectal formulations comprise rectal enemas, foams, gels or suppositories.
[0289] In certain embodiments, liquid or co-solvent carrier vehicles in the compositions and / or formulations described herein include, as a non-limiting example, purified water, propylene glycol, PEG200, PEG300, PEG400, PEG600, polyethylene glycol, ethanol , 1-propanol, 2-propanol, 1-propen-3-ol (allyl alcohol), propylene glycol, glycerol, 2-methyl-2-propanol, formamide, methyl-formamide, dimethyl-formamide, ethyl-formamide, diethyl-formamide , acetamide, methyl-acetamide, dimethyl-acetamide, ethyl-acetamide, diethyl-acetamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, tetramethylurea, 1,3-dimethyl-2-imidazolidinone , propylene carbonate, 1,2-butylene carbonate, 2,3-butylene carbonate, dimethyl sulfoxide, diethyl sulfoxide, hexamethylphosphoramide, pyruvic dimethylacetal aldehyde, dimethylisorbide and their combinations.
[0290] In some embodiments, the stabilizers used in the compositions and / or formulations described herein include, but are not limited to, partial glycerides of polyoxyethylene saturated fatty acids.
[0291] In certain embodiments, surfactants / emulsifiers used in the compositions and / or formulations described herein include, as a non-limiting example, mixtures of cetostearyl alcohol with sorbitan esterified with polyoxyethylene fatty acids, polyoxyethylene fatty ethers, esters of polyoxyethylene, fatty acids, sulfated fatty acids, phosphate fatty acids, sulfosuccinates, amphoteric surfactants, nonionic poloxamers, nonionic meroxapols, petroleum derivatives, aliphatic amines, polysiloxane derivatives, fatty acid sorbitan esters, laureth-4 , PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, sodium dioctylsulfosuccinate, cocoamphopropionate, poloxamer 188, meroxapol 258, triethanolamine, dimethicone, polysorbate 60, sorbitan monostearate, pharmaceutically acceptable salts, and combinations thereof.
[0292] In some embodiments, the non-ionic surfactants used in the compositions and / or formulations described herein include, as a non-limiting example, phospholipids, alkyl poly (ethylene oxide), poloxamers (For example, poloxamer 188), polysorbates, sodium dioctylsulfosuccinate, Brij ™ -30 (Laureth-4), Brij ™ -58 (Ceteth-20) and Brij ™ -78 (stearide-20), Brij ™ -721 (stearide-21), CRILLET-1 ( Polysorbate 20), CRILLET-2 (Polysorbate 40), CRILLET-3 (Polysorbate 60), CRILLET 45 (Polysorbate 80), Myrj-52 (PEG-40 stearate), Myrj-53 (PEG-stearate 50), Pluronic ™ F77 (Poloxamer 217), Pluronic ™ F87 (Poloxamer 237), Pluronic ™ F98 (Poloxamer 288), Pluronic ™ L62 (Poloxamer 182), Pluronic ™ L64 (Poloxamer 184), Pluronic ™ F68 (Poloxamer 188), Pluronic ™ L81 (Poloxamer 231), Pluronic ™ L92 (poloxamer 282), Pluronic ™ L101 (Poloxamer 331), Pluronic ™ P103 (Poloxamer 333), Pluracare ™ F 108 NF (Poloxamer 338), and Pluracare ™ F 127 NF (Poloxamer 407) and their combinations s. Pluronic ™ polymers are commercially available from BASF, USA and Germany.
[0293] In certain embodiments, the anionic surfactants used in the compositions and / or formulations described herein include, as a non-limiting example, sodium lauryl sulfate, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, salts of alkyl sulfate, alkyl benzene sulfonate and combinations thereof.
[0294] In some embodiments, the cationic surfactants used in the compositions and / or formulations described herein include, as a non-limiting example, benzalkonium chloride, benzethonium chloride, cetyl trimethylammonium, hexadecyl trimethyl ammonium bromide, other salts of alkyltrimethylammonium, cetylpyridinium chloride, polyethoxylated tallow and their combinations.
[0295] In certain embodiments, the thickening agents used in the compositions and / or formulations described herein include, as a non-limiting example, natural polysaccharides, semi-synthetic polymers, synthetic polymers, and combinations thereof. Natural polysaccharides include, by way of non-limiting example, acacia, agar, alginates, carrageenan, guar, arabica, tragacanth gum, pectin, dextran, xanthan and gellan gums. Semi-synthetic polymers include, by way of non-limiting example, cellulose esters, modified starches, modified celluloses, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. Synthetic polymers include, by way of non-limiting example, polyoxyalkylenes, polyvinyl alcohol, polyacrylamide, polyacrylates, carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidones), polyvinyl acetate, polyethylene glycols and poloxamers. Other thickeners include, by way of non-limiting example, polyoxyethylene glycol isostearate, cetyl alcohol, polyglycol 300 isostearate, propylene glycol, collagen acids, gelatin, and fatty acids (eg lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, oleic acid and the like).
[0296] In some embodiments, the chelating agents used in the compositions and / or formulations described herein include, as a non-limiting example, ethylene diaminetetraacetic acid (EDTA) or its salts, phosphates and combinations thereof.
[0297] In some embodiments, the concentration of the chelating agent or agents used in the rectal formulations described herein is an appropriate concentration, for example, about 0.1%, 0.15%, 0.2%, 0.25 %, 0.3%, 0.4%, or 0.5% (w / v).
[0298] In some embodiments, preservatives used in the compositions and / or formulations described herein include, as a non-limiting example, parabens, ascorbyl palmitate, benzoic acid, butylated hydroxyanisol, butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben, methylparaben, butylparaben, propylparaben, monothioglycerol, phenol, phenylethyl alcohol, propylparaben, sodium benzoate, sodium propionate, sodium sulfoxylate formaldehyde, sodium metabisulfite, sorbic acid, sulfur dioxide, maleic acid, propyl gallate, benzal chloride benzethonium chloride, benzyl alcohol, chlorhexidine acetate, chlorhexidine gluconate, sorbic acid, potassium sorbitol, chlorobutanol, phenoxyethanol, cetylpyridinium chloride, phenylmercury nitrate, thimerosal, and combinations thereof.
[0299] In certain embodiments, the antioxidants used in the compositions and / or formulations described herein include, as a non-limiting example, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisol, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate , sodium ascorbate, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, potassium metabisulfite, sodium metabisulfite, oxygen, quinones, t-butyl hydroquinone, erythorbic acid, olive oil (Olea eurpaea), pentassodic acid pentetic, tocopherol, tocopherol acetate and their combinations.
[0300] Pharmaceutically acceptable preservatives include quaternary ammonium salts, such as benzalkonium chloride, alcohols such as benzyl alcohol, organic acids or their salts and derivatives, such as benzoic acid, sodium benzoate, sorbic acid, potassium sorbate , propionic acid, sodium propionate, parabens, such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, ethyl parahydroxybenzoate or butyl parahydroxybenzoate, aqueous preservatives; chlorhexidine diacetate, digluconate. Given the use for which the present composition is intended, preservatives are preferably suitable for pediatric use. Preferred preservatives are parabens, such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, ethyl parahydroxybenzoate or butyl parahydroxybenzoate, in particular, methyl or propyl parahydroxybenzoate. Preservatives are present in a composition in a concentration in order to provide sufficient antimicrobial activity in the pre-concentrated composition or in the liquid composition after reconstitution. Preferably, the concentration of preservatives in a resulting reconstituted liquid composition varies up to about 3% (w / w), more preferably up to about 2.5% (w / w), more preferably up to about 2% (w / w) ), depending on the preservative present to be used.
[0301] The composition of the present invention may also contain one or more antioxidants, such as, for example, sodium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, BHA (butylhydroxyanisole), BHT ( butylhydroxytoluene), vitamin E, propylgalate, ascorbyl palmitate, or complexing agents, such as EDTA (ethylene diaminetetraacetic acid), citric acid, tartaric acid, sodium hexametaphosphate and the like. Given the use for which the present composition is intended, anti-oxidants or complexing agents are preferably suitable for pediatric use. Preferred antioxidants are BHA, BHT, vitamin E or propylgalate. In some embodiments, the concentration of anti-oxidant or anti-oxidants used in the rectal formulations described here is sufficient to achieve a desired result, for example, about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% (w / v).
[0302] Lubricating agents used in the compositions and / or formulations described herein include, as a non-limiting example, natural or synthetic fat or petroleum fat (for example, a tris-fatty acid glycerate and the like). In some embodiments, lubricating agents include, by way of non-limiting example, glycerin (also called glycerin, glycerol, 1,2,3-propanotriol, and trihydroxypropane), polyethylene glycols (PEG), polypropylene glycol, polyisobutene, oxide of polyethylene, behenic acid, beenyl alcohol, sorbitol, mannitol, lactose, polydimethylsiloxane and their combinations.
[0303] In certain embodiments, mucoadhesive and / or bioadhesive polymers are used in the compositions and / or formulations described herein as agents for inhibiting the absorption of the enteroendocrine peptide secretion-enhancing agent through the rectal mucosa or the colon . Bioadhesive or mucoadhesive polymers include, by way of non-limiting example, hydroxypropylcellulose, polyethylene oxide homopolymers, maleic acid polyvinyl ether copolymers, methylcellulose, ethylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose. carbopol, polyurethanes, polyethylene oxide-polypropylene oxide copolymers, sodium carboxymethylcellulose, polyethylene, polypropylene, lectins, xanthan gum, alginates, sodium alginate, polyacrylic acid, chitosan, hyaluronic acid and its vinyl acetate homopolymer esters , calcium polycarbophil, gelatin, natural gums, karaya, tragacanth, algin, chitosan, starches, pectins and their combinations.
[0304] In some embodiments, buffering / adjusting and pH agents used in the compositions and / or formulations described herein include, as a non-limiting example, phosphoric acid, sodium monobasic phosphate or potassium phosphate, triethanolamine (TRIS ), Bicina, HEBES, Trizma, glycine, histidine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, carbonate, bicarbonate, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, acetic acid, acetate, citric acid , anhydrous sodium citrate, sodium citrate dihydrate and their combinations. In certain embodiments, an acid or base is added to adjust the pH. Suitable acids or bases include, by way of non-limiting example, HCL, NaOH and KOH.
[0305] In certain embodiments, the concentration of the buffering agent or agents used in the rectal formulations described herein is sufficient to achieve or maintain a physiologically desirable pH, for example, about 0.1%, 0.2%, 0, 3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, or 1.0% (w / w).
[0306] Tonicity modifiers used in compositions and / or formulations described herein include, as a non-limiting example, sodium chloride, potassium chloride, sodium phosphate, mannitol, sorbitol or glucose. Pediatric Dosage Formulations and Compositions
[0307] A pediatric dosage formulation or composition comprising a therapeutically effective amount of any compound described herein is provided in certain embodiments herein. In certain cases, the pharmaceutical composition comprises an ASBT inhibitor (for example, any ASBTI described herein).
[0308] In certain embodiments, suitable dosage forms include, by way of non-limiting example, aqueous or non-aqueous oral dispersions, liquids, gels, syrups, elixirs, pastes, suspensions, solutions, controlled release formulations, formulations quick-melting, effervescent formulations, lyophilized formulations, chewable tablets, gums, oral disintegrating tablets, powder for reconstitution as suspension or solution, oral spray powder or granules, dragees, delayed release formulations, prolonged release formulations, release formulations pulsatile, multiparticulate formulations and mixtures of immediate and controlled release formulations. In some embodiments, a pharmaceutical composition is provided in this document in which the pediatric dosage form is selected from a solution, syrup, suspension, elixir, powder for reconstitution as a suspension or solution, dispersible / effervescent tablet, compressed chewable, gum, lollipop, popsicle, lozenges, oral thin strips, oral disintegrating tablet, oral disintegrating strips, sachet, and oral spray powder or granules.
[0309] In another aspect, a pharmaceutical composition is provided here, wherein at least one excipient is a flavoring or sweetening agent. In some embodiments, a coating is provided here. In some embodiments, a taste masking technology selected from coating drug particles with a neutral flavor polymer by spray drying, wet granulation, fluidized bed, and microencapsulation is provided herein; coating with molten waxes of a mixture of molten waxes and other pharmaceutical adjuvants; entrapment of drug particles by complexing, flocculating or coagulating an aqueous polymeric dispersion; adsorption of drug particles on resin and inorganic supports; and wherein the solid drug dispersion and one or more neutral flavor compounds are melted and cooled, or co-precipitated by evaporation of the solvent. In some embodiments, a delayed or sustained release formulation comprising drug particles or granules in a rate control polymer or matrix is provided herein.
[0310] Suitable sweeteners include sucrose, glucose, fructose or intense sweeteners, that is, agents with a high sweetening power when compared to sucrose (for example, at least 10 times sweeter than sucrose). Suitable intense sweeteners include aspartame, saccharin, sodium or potassium or calcium saccharin, potassium acesulfame, sucralose, alitame, xylitol, cyclamate, neomato, neo-hesperidin dihydrochalcone or mixtures thereof, thaumatin, palatinite, stevioside, rebaudide Magnasweet (R). The total concentration of sweeteners can vary effectively from zero to about 300 mg / mL, based on the liquid composition after reconstitution.
[0311] In order to increase the palatability of the liquid composition by reconstitution with an aqueous medium, one or more flavoring agents can be added to the composition in order to mask the taste of the ASBT inhibitor. A flavor masking agent can be a sweetener, a flavoring agent or a combination thereof. Flavor masking agents typically provide up to about 0.1% or 5% by weight of the total pharmaceutical composition. In a preferred embodiment of the present invention, the composition contains both sweetener (s) and flavor (s).
[0312] A flavoring agent here is a substance capable of improving the taste or aroma of a composition. Suitable natural or synthetic flavoring agents can be selected from reference books, for example, Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of flavoring and / or sweetening agents useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, blackcurrant, butter candy, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, gum, citrus fruits, citrus fruit punch, citrus cream, cotton candy, cocoa, cola, fresh cherry, fresh citrus, cyclamate, cyclamate, dextrose , eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza syrup (licorice), grapes, grapefruit, honey, isomalt, lemon, lemon cream, monoammon glirrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow , menthol, mint, mixed berry, neo-hesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® powder, raspberry, beer, rum, saccharin, safrole, sorbitol, mint , mint cream, strawberry, strawberry cream, stevia, suc Ralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, Tallinn, silitol, sucralose, sorbitol, swiss cream, tagatose, mandarin, thaumatin, tutti fruitti, vanilla, nuts, watermelon, wild cherry, gualtéria, xilitol , or any combination of these flavoring ingredients, for example, anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lime-lemon, lemon-mint, menthol, eucalyptus, orange-cream , mint vanilla and their mixtures. Flavoring agents can be used individually or in combinations of two or more. In some embodiments, the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a concentration ranging from about 0.001% to about 5.0% of the volume of the aqueous dispersion. In one embodiment, the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a concentration ranging from about 0.001% to about 1.0% of the volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a concentration ranging from about 0.005% to about 0.5% of the volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a concentration ranging from about 0.01%. about 1.0% of the volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a concentration ranging from about 0.01% to about 0.5% of the volume of the aqueous dispersion.
[0313] In certain embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including, for example, excipients and auxiliaries that facilitate the processing of active compounds in preparations that are suitable for pharmaceutical use. In certain embodiments, the appropriate formulation is dependent on the chosen route of administration. A summary of the pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, nineteenth Ed. (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsilvania, 1975; Liberman, H.A. and Lachman, L., Eds. Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).
[0314] A pharmaceutical composition, as used herein, refers to a mixture of a compound described herein, such as, for example, a compound of Formula I to VI, with other chemical components, such as vehicles, stabilizers, diluents , dispersing agents, suspending agents, thickening agents and / or excipients. In certain cases, the pharmaceutical composition facilitates the administration of the compound to an individual or cell. In certain embodiments of the practice of the methods of treatment or use provided herein, the therapeutically effective amounts of the compounds described herein are administered in a pharmaceutical composition to an individual who has a disease, disorder or condition to be treated. In specific embodiments, the individual is a human being. As discussed herein, the compounds described herein are used either alone or in combination with one or more additional therapeutic agents.
[0315] In certain embodiments, the pharmaceutical formulations described herein are administered to an individual in any form, including one or more of several routes of administration, such as, by way of non-limiting example, orally, parenterally (eg example, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration.
[0316] In certain embodiments, a pharmaceutical composition described herein, includes one or more compounds described herein as an active ingredient in the form of free acid or free base, or in a pharmaceutically acceptable salt form. In some embodiments, the compounds described herein are used as an N-oxide or in a crystalline or amorphous form (i.e., a polymorph). In some situations, a compound described here, exists as tautomers. All tautomers are included within the scope of the compounds presented here. In certain embodiments, a compound described herein, exists in an unsolvated or solvated form, wherein the solvated forms comprise any pharmaceutically acceptable solvent, for example, water, ethanol, and the like. Also considered are the solvated forms of the compounds presented herein to be described herein.
[0317] A "carrier" includes, in some embodiments, a pharmaceutically acceptable excipient and is selected based on compatibility with the compounds described herein, such as compounds of any Formula I-VI, and the properties of the profile of release of the desired dosage form. Exemplary support materials include, for example, binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, for example, Remington: The Science and Practice of Pharmacy, nineteenth Ed. (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, H.A. and Lachman, L., Eds. Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).
[0318] In addition, in certain embodiments, the pharmaceutical compositions described herein are formulated as a dosage form. As such, in some embodiments, a dosage form is provided herein comprising a compound described herein, suitable for administration to an individual. In certain embodiments, suitable dosage forms include, by way of non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, pastes, suspensions, solid oral dosage forms, aerosols, controlled release formulations, quick-melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed-release formulations, prolonged-release formulations, pulsatile-release formulations, multiparticulate formulations, and a mixture of immediate-release and controlled-release formulations .
[0319] In certain respects, the composition or formulation containing one or more compounds described herein is administered orally for the local delivery of an ASBTI, or a compound described here to the colon and / or rectum. Unit dosage forms of such compositions include a tablet, lozenge or capsules formulated for enteral delivery to the colon. In certain embodiments, such pills, tablets or capsules contain the compositions described herein, imprisoned or embedded in microspheres. In some embodiments, microspheres include, by way of non-limiting example, chitosan microcolor HPMC capsules and cellulose acetate butyrate (CAB) microspheres. In certain embodiments, oral dosage forms are prepared using conventional methods known to those skilled in the pharmaceutical formulation. For example, in certain embodiments, tablets are manufactured using standard tablet processing processes and equipment. An exemplary method for forming tablets by direct compression is a powder, crystalline or granular composition, which contains the active agent (s), alone or in combination with one or more vehicles, additives , or the like. In alternative embodiments, the tablets are prepared by wet granulation or dry granulation processes. In some embodiments, the tablets are molded instead of tablets, from a moist or otherwise treatable material.
[0320] In certain embodiments, tablets prepared for oral administration contain various excipients, including, by way of non-limiting example, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, coloring agents, agents flavorings and the like. In some embodiments, binders are used to impart cohesive qualities to a tablet, ensuring that the tablet remains intact after compression. Suitable binder materials include, by way of non-limiting example, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene glycol, waxes and natural and synthetic gums , for example, acacia, sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose and the like), Veegum, and combinations thereof. In certain embodiments, diluents are used to increase the mass of the tablet, so that a practical tablet size is provided. Suitable diluents include, by way of non-limiting example, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and combinations thereof. In certain embodiments, lubricants are used to facilitate the manufacture of the tablet. Examples of suitable lubricants include, by way of non-limiting example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil, glycerin, magnesium stearate, stearate calcium, stearic acid and combinations. In some embodiments, disintegrants are used to facilitate the disintegration of the tablet, and include, by way of non-limiting example, starches, clays, celluloses, algins, gums, crosslinked polymers and combinations thereof. Fillers include, by way of non-limiting example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. In certain embodiments, stabilizers are used to inhibit or delay drug decomposition reactions, which include, by way of example, oxidative reactions. In certain embodiments, surfactants are anionic, cationic, amphoteric or non-ionic surface active agents.
[0321] In some embodiments, ASBTIs, or other compounds described herein are administered orally in association with a vehicle suitable for delivery to the distal gastrointestinal tract (for example, the distal ileum, colon and / or rectum).
[0322] In certain embodiments, a composition described herein comprises an ASBTI, or other compounds described herein, in association with a matrix (for example, a matrix comprising hypermellosis) that allows for the controlled release of an active agent in the distal part of the ileum and / or colon. In some embodiments, a composition comprises a polymer that is sensitive to pH (for example, an MMX ™ matrix from Cosmo Pharmaceuticals) and allows for the controlled release of an active agent in the distal part of the ileum. Examples of such pH sensitive polymers suitable for controlled release include and are not limited to polyacrylic polymers (for example, anionic polymers of methacrylic acid and / or esters of methacrylic acid, for example, Carbopol® polymers) which comprise acid groups (for example example, -COOH, -SO3H) and swell at the basic pH of the intestine (for example, pH about 7 to about 8). In some embodiments, a composition suitable for controlled release in the distal ileum comprises microparticles of active agent (e.g., micronized active agent). In some embodiments, a non-enzymatically degrading poly (dl-lactide-co-glycolide) (PLGA) nucleus is suitable for delivering an enteroendocrine peptide secretion-enhancing agent (e.g., bile acids) to the distal ileum . In some embodiments, a dosage form comprising an enteroendocrine peptide secretion-enhancing agent (for example, bile acids) is coated with an enteric polymer (for example, Eudragit® S-100, cellulose acetate, phthalate polyvinylacetate, hydroxypropylmethylcellulose phthalate, anionic methacrylic acid polymers, methacrylic acid esters, or the like) for specific local delivery to the distal ileum and / or colon. In some embodiments, the bacteria-activated systems are suitable for targeted delivery to the distal part of the ileum. Examples of micro-flora activated systems include dosage forms comprising pectin, galactomannan, and / or azo hydrogels and / or glycoside conjugates (e.g., D-galactoside, β-D-xylopyranoside conjugates or the like) of the active agent. Examples of gastrointestinal micro-flora enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranidasidase or the like.
[0323] The pharmaceutical composition described herein optionally includes an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetening agent, disintegration, dispersing agent, surfactant, lubricant, dye, diluent, solubilizing agent, wetting agent, plasticizing agent, a stabilizer, a penetration enhancer, wetting agent, antifoam, antioxidant, preservative, or one or more of its combinations. In some respects, using conventional coating procedures, such as those described in Remington Pharmaceutical Sciences, 20th Edition (2000), a coating film is provided around the formulation of the Formula I compound. In one embodiment, a compound described herein is in the form of a particle and some or all particles of the compound are coated. In certain embodiments, some or all of the particles of a compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.
[0324] According to other embodiments, a tablet or capsule comprising an ASBTI or other compounds described herein is coated with film for delivery to target sites in the gastrointestinal tract. Examples of enteric coating films include and are not limited to hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudo ethylcellulose, amylopectin and the like. Solid dosage forms for Pediatric administration
[0325] The solid dosage forms for pediatric administration of the present invention can be manufactured by standard manufacturing techniques. Non-limiting examples of solid oral dosage forms for pediatric administration are described below. Effervescent Compositions
[0326] The effervescent compositions of the invention can be prepared according to techniques well known in the art of pharmacy.
[0327] Effervescent formulations contain an effervescent pair of a base component and an acid component, which components penetrate, in the presence of water, to generate a gas. In some embodiments, the base component may comprise, for example, an alkali metal or alkaline earth metal of carbonate, or bicarbonate. The acid component can comprise, for example, an aliphatic carboxylic acid or a salt thereof, such as citric acid. The basic and acidic components can each independently constitute, for example, 25% to 55% (w / w) of the effervescent composition. The ratio of acidic component and base component can be within the range of 1: 2 to 2: 1.
[0328] The effervescent compositions of the invention can be formulated using pharmaceutically acceptable vehicles or additional excipients as appropriate. For example, one or more flavor masking agents can be used. Dyes can also be used, as pediatric patients often prefer colored pharmaceutical combinations. The compositions can take the form of, for example, tablets, granules or powders, granules or powders presented in envelopes. Chewable tablets
[0329] The chewable tablets of the invention can be prepared according to techniques well known in the art of pharmacy.
[0330] Chewable tablets are tablets that are intended to disintegrate in the mouth under the action of chewing or sucking and where, as a result, the active ingredient has a greater opportunity to come into contact with the bitter taste receptors on the tongue.
[0331] One method of overcoming this problem is to absorb the active ingredient in a suitable substrate. This approach is described in U.S. Patent No. 4,647,459.
[0332] Another approach involves the formation of the active ingredient in an aggregate, along with a substantially anhydrous pre-swollen hydrocolloid. The hydrocolloid absorbs saliva and acquires a slippery texture which allows it to lubricate the aggregate particles and mask the flavor of the active ingredient. This approach is described in European patent application 0190826.
[0333] Another approach involves the use of a hygroscopic excipient, insoluble in water, such as microcrystalline cellulose. This approach is described in U.S. Patent No. 5,275,823.
[0334] In addition to the above methods, the chewable tablets of the present invention may also contain other excipients for forming support tablets such as a disintegrant and a flavor masking agent. Orodispersible tablets
[0335] The orodispersible tablets of the invention can be prepared according to techniques well known in the art of pharmacy.
[0336] In orodispersible tablets of the invention, the mixture of excipients is such that it provides it with a disintegration speed, so that its disintegration in the oral cavity occurs in an extremely short time, and especially less than sixty seconds. In some embodiments, the excipient mixture is characterized by the fact that the active substance is in the form of coated microcrystals or uncoated microgranules. In some embodiments, the orodispersible tablet comprises one or more disintegrating agents of the carboxymethyl cellulose type or of the insoluble crosslinked PVP type, one or more swelling agents which may include a carboxymethyl cellulose, a starch, a modified starch, or a microcrystalline cellulose, or, optionally, a direct compression sugar. Reconstitution powders
[0337] The powder for reconstitution pharmaceutical compositions of the invention can be prepared according to techniques well known in the art of pharmacy.
[0338] In some embodiments, the powder for reconstitution compositions of the invention comprises an effective amount of at least one internal dehydrant. The internal dehydrator can increase the stability of the powder. In some embodiments, the internal dehydrating agent is magnesium citrate or disodium carbonate. In some embodiments, the powder composition comprises a pharmaceutically acceptable diluent, such as sucrose, dextrose, mannitol, xylitol or lactose.
[0339] The powdered compositions of the invention can be placed in envelopes or bottles of simultaneous dissolution or, for short term storage, in liquid form (for example, 7 days). Gum candy
[0340] The gummy candies of the present invention can be prepared according to techniques well known in the art of pharmacy.
[0341] Traditional gum candies are made from a gelatin base. Gelatin gives the candy its elasticity, the desired rubber consistency, and a longer shelf life. In some embodiments, the gummy candy pharmaceutical composition of the invention includes a binding agent, a sweetener, and an active ingredient.
[0342] In some embodiments, the binding agent is a pectin gel, gelatin, food starch, or any combination thereof.
[0343] In some embodiments, gum candies comprise sweeteners, a binding agent, natural and / or artificial flavors, and colors and preservatives. In some embodiments, gum candies comprise glucose syrup, natural cane juice, gelatin, citric acid, lactic acid, natural colors, natural flavors, fractionated coconut oil, and carnauba wax. Liquid dosage forms
[0344] The liquid pharmaceutical dosage forms of the invention can be prepared according to techniques well known in the art of pharmacy.
[0345] A solution refers to a liquid pharmaceutical formulation in which the active ingredient is dissolved in the liquid. The pharmaceutical solutions of the present invention include syrups and elixirs. A suspension refers to a liquid pharmaceutical formulation in which the active ingredient is a precipitate in the liquid.
[0346] In a liquid dosage form, it is desirable to have a certain pH and / or to be kept within a specific pH range. In order to control the pH, a suitable buffer system can be used. In addition, the buffer system must have sufficient capacity to maintain the desired pH range. Examples of the buffer system useful in the present invention include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art. Preferably the buffer system includes sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium phosphate and potassium dihydrogen phosphate, etc. The concentration of the buffer system in the final suspension varies according to factors such as the strength of the buffer system and the pH / pH ranges required for the liquid dosage form. In one embodiment, the concentration is within the range of 0.005 to 0.5 w / v%, in the form of final liquid dosage.
[0347] The pharmaceutical composition comprising the liquid dosage form of the present invention can also include a suspending / stabilizing agent to prevent sedimentation of the active material. Over time, the settlement can lead to the formation of agglomerates of the asset for the inner walls of the product packaging, leading to difficulties with redispersion and precise dosing. Suitable stabilizing agents include, but are not limited to, polysaccharide stabilizers, such as xanthan gum, guar and tragacanth, as well as HPMC cellulose derivatives (Hydroxypropylmethylcellulose), methylcellulose and Avicel RC-591 (microcrystalline cellulose / carboxymethyl cellulose) sodium). In another embodiment, polyvinylpyrrolidone (PVP) can also be used as a stabilizing agent.
[0348] In addition to the aforementioned components, the ASBTI oral suspension form may also optionally contain other excipients commonly found in pharmaceutical compositions, such as alternative solvents, tastemasking agents, antioxidants, fillers, flavor masking agents, enzyme inhibitors and other components, as described in the Handbook of Pharmaceutical Excipients, Rowe et al., Eds., 4th edition, Pharmaceutical Press (2003), which is incorporated herein by reference.
[0349] The addition of an alternative solvent can help to increase the solubility of an active ingredient in liquid dosage form, and consequently, the absorption and bioavailability within a subject's body. Preferably the alternative solvents include methanol, ethanol or propylene glycol and the like.
[0350] In another aspect, the present invention provides a process for preparing the liquid dosage form. The process comprises the steps of bringing ASBTI or its pharmaceutically acceptable salts into a mixture with the components including glycerol or syrup, or a mixture thereof, a preservative, a buffer system and a suspending / stabilizing agent, etc., in a liquid medium . In general, the liquid dosage form is prepared by mixing uniformly and intimately these various components in the liquid medium. For example, components, such as glycerol or syrup, or a mixture thereof, a preservative, a buffer system and a suspending / stabilizing agent, etc., can be dissolved in water to form the aqueous solution, then the active ingredient it can then be dispersed in the aqueous solution to form a suspension.
[0351] In some embodiments, the liquid dosage form provided herein can have a volume of between 5 ml and 50 ml. In some embodiments, the liquid dosage form provided herein can have a volume of between 5 ml and 40 ml. In some embodiments, the liquid dosage form provided herein can have a volume of between 5 ml and 30 ml. In some embodiments, the liquid dosage form provided herein can have a volume of between 5 ml and 20 ml. In some embodiments, the liquid dosage form provided herein can have a volume of between 10 ml and 30 ml. In some embodiments, the ASBTI can be in an amount ranging from about 0.001% to 90% of the total volume. In some embodiments, ASBTI can be in an amount ranging from about 0.01% to 80% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 0.1% to 70% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 1% to 60% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 1% to 50% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 1% to 40% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 1% to 30% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 1% to 20% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 1% to 10% of the total volume. of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 5% to 70% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 5% to 60% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 5% to 50% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 5% to 40% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 5% to 30% of the total volume. of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 5% to 20% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 5% to 10% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 10% to 50% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 10% to 40% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 10% to 30% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 10% to 20% of the total volume. In one embodiment, the resulting liquid dosage form can be in a liquid volume of 10 ml to 30 ml, preferably 20 ml, and the active ingredient can be in an amount ranging from about 0.001 mg / ml to about 16 mg / ml, or from about 0.025 mg / ml to about 8 mg / ml, or between about 0.1 mg / ml to about 4 mg / ml, or about 0.25 mg / ml, or about 0.5 mg / ml, or about 1 mg / ml, or about 2 mg / ml, or about 4 mg / ml, or about 5 mg / ml, or about 8 mg / ml, or about 10 mg / ml, or about 12 mg / ml, or about 14 mg / ml or about 16 mg / ml. Bile acid scavenger
[0352] In certain embodiments, an oral formulation for using any method described herein is, for example, an ASBTI in association with a labile bile acid scavenger. A labile bile acid scavenger is a bile acid scavenger with a labile affinity for bile acids. In certain embodiments, a bile acid scavenger described herein is an agent that scavenges (e.g., absorbs or is charged with) bile acid, and / or its salts.
[0353] In specific embodiments, the labile bile acid scavenger is an agent that sequesters (for example, absorbs or is charged with) bile acid, and / or its salts, and releases at least a portion of bile acid absorbed or charged, and / or its salts in the distal gastrointestinal tract (for example, colon, ascending colon, sigmoid colon, distal colon, rectum, or any combination thereof). In certain embodiments, the labile bile acid scavenger is an enzyme-dependent bile acid scavenger. In specific embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in high concentrations in the human colon or rectum in relation to the concentration found in the small intestine. Examples of activated micro-flora systems include dosage forms comprising pectin, galactomannan, and / or azo hydrogels and / or glycoside conjugates (e.g., D-galactoside, β-D-xylopyranoside conjugates or the like) of the active agent. Examples of gastrointestinal micro-flora enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase or the like. In some embodiments, the labile bile acid scavenger is a time-dependent scavenger of bile acid (i.e. bile acid scavenges bile acid and / or its salts, and after a time at least releases a portion of the bile acid and / or its salts). In some embodiments, a time-dependent bile acid scavenger is an agent that degrades in an aqueous environment over time. In certain embodiments, a labile bile acid scavenger described herein is a bile acid scavenger that has a low affinity for bile acids and / or their salts, thus allowing the bile acid scavenger to continue to sequester bile acids and / or their salts in an environment where bile acids / salts and / or their salts are present in a higher concentration and release them in an environment where bile acids / salts and / or their salts are present in a relatively low concentration . In some embodiments, the labile bile acid scavenger has a high affinity for a primary bile acid and a low affinity for a secondary bile acid, allowing the bile acid scavenger to sequester a primary bile acid or its salt, and subsequently release a secondary bile acid or its salt, since the primary bile acid or its salt is converted (for example, metabolized) to the bile acid derivative or a salt thereof. In some embodiments, the labile bile acid scavenger is a pH-dependent bile acid scavenger. In some embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acids at a pH of 6 or below and a low affinity for bile acids at a pH of above 6. In certain embodiments, the scavenger pH-dependent bile acid degrades at a pH greater than 6.
[0354] In some embodiments, the labile bile acid scavengers described herein include any compound, for example, a macrostructured compound, which can sequester bile acids / salts and / or their salts, by any suitable mechanism . For example, in certain embodiments, bile acid scavengers sequester bile acids / salts and / or their salts, through ionic interactions, polar interactions, static interactions, hydrophobic interactions, lipophilic interactions, hydrophilic interactions, spherical interactions, or the like . In certain embodiments, macrostructured compounds sequester bile acids / salts and / or scavengers by trapping bile acids / salts and / or their salts in the pockets of macrostructured compounds and, optionally, other interactions, such as those described above. In some embodiments, bile acid scavengers (e.g. labile bile acid scavengers) include, by way of non-limiting example, lignin, modified lignin, polymers, polycationic polymers and copolymers, polymers and / or copolymers any one or more of N-alkenyl-N-alkylamine residues; one or more N, N, N-trialkyl-N- (N'-alkenylamino) alkyl-azanium residues; one or more residues of N, N, N-trialkyl-N-alkenyl-azanium; one or more alkenylamine residues; or a combination of them, or any combination of them. The covalent connection of the drug with a vehicle
[0355] In some embodiments, the strategies used for targeted delivery to the colon include, by way of non-limiting example, covalent attachment of the ASBTI or other compounds described herein to a vehicle, coating the dosage form with a polymer sensitive to pH for delivery upon reaching the colon pH environment, use of sensitive redox polymers, use of time-released formulation, use of coatings that are specifically degraded by colon bacteria, use of bioadhesive system and use of osmotically drug delivery systems controlled.
[0356] In certain embodiments of such an oral administration of a composition containing an ASBTI or other compounds described herein involves covalent attachment to a vehicle, where after oral administration, the bound fraction remains intact in the stomach and intestine slender. Upon entering the colon, the covalent bond is divided by changes in pH, enzymes, and / or degradation by the intestinal microflora. In certain embodiments, the covalent bond between the ASBTI and the vehicle includes, by way of non-limiting example, azo bond, glycosidic conjugates, glucuronic acid conjugates, cyclodextrin, dextran conjugates, and amino acid conjugate conjugates (high hydrophilicity and long chain length of the vehicle amino acid). Polymer coating: pH sensitive polymers
[0357] In some embodiments, the oral dosage forms described herein are coated with an enteric coating, to facilitate the delivery of an ASBTI or other compounds described herein to the colon and / or rectum. In certain embodiments, an enteric coating is one that remains intact in the low pH environment of the stomach, but readily dissolves when the optimum dissolution pH of the particular coating is reached, which depends on the chemical composition of the enteric coating. The thickness of the coating will depend on the solubility characteristics of the coating material. In certain embodiments, the coating thicknesses used in such formulations described herein vary from about 25 pm to about 200 pm.
[0358] In certain embodiments, the compositions or formulations described herein are coated so that an ASBTI or other compounds described herein from the composition or formulation is delivered to the colon and / or rectum without absorbing in the upper part of the intestine. In a specific embodiment, specific distribution to the colon and / or rectum is achieved by coating the dosage form with polymers that degrade only in the colon's pH environment. In alternative embodiments, the composition is coated with an enteric coating that dissolves at the pH of the intestine and an outer layer matrix that slowly corrodes in the intestine. In some of such embodiments, the matrix slowly erodes, until only a core composition comprising an enteroendocrine peptide secretion-enhancing agent (and, in some embodiments, an agent absorption inhibitor) is left and the nucleus is delivered to the colon and / or rectum.
[0359] In certain embodiments, pH-dependent systems use the pH which increases progressively throughout the human gastrointestinal tract (GIT) from the stomach (pH 1-2, which increases to 4 during digestion), intestine thin (pH 6-7), to the digestion site and 7-8 in the distal ileum. In certain embodiments, dosage forms for oral administration of the compositions described herein are coated with pH sensitive polymer (s) to provide delayed release and protect the enteroendocrine peptide secretion-enhancing agents from gastric fluid. In certain embodiments, such polymers are able to withstand lower pH values in the stomach and in the proximal part of the small intestine, but disintegrate at a neutral or slightly alkaline pH of the terminal ileum and / or ileocecal junction. Thus, in certain embodiments, an oral dosage form comprising a coating, the coating comprising a pH sensitive polymer, is provided in this document. In some embodiments, the polymers used for targeting the colon and / or rectum include, by way of non-limiting example, methacrylic acid copolymers, methacrylic acid and methyl methacrylate copolymers, Eudragit L100, Eudragit S100, Eudragit L -30D, Eudragit FS-30D, Eudragit L100-55, polyvinyl acetate phthalate, hydroxypropyl acetate phthalate, hydroxypropyl cellulose phthalate 50, hydroxypropyl cellulose phthalate 55, cellulose trimethyl acetate, cellulose acetate phthalate and combinations thereof.
[0360] In certain embodiments, oral dosage forms suitable for delivery to the colon and / or rectum comprise a coating that has a biodegradable degradable polymer and / or bacteria or polymers that are degraded by the microflora (bacteria) in the colon. In such biodegradable systems, suitable polymers include, by way of non-limiting example, azo polymers, segmented linear polyurethanes containing azo groups, polygalactomannans, pectin, dextran crosslinked glutaraldehyde, polysaccharides, amylose, guar gum, pectin, chitosan, inulin, cyclodextrin , chondroitin sulfate, dextran, locust bean gum, chondroitin sulfate, chitosan, poly (caprolactone), polylactic acid and poly (lactic-co-glycolic) acid.
[0361] In certain embodiments of such oral administration of compositions containing one or more ASBTIs or other compounds described herein, the compositions are delivered to the colon, without absorbing into the upper part of the small intestine by coating the dosage forms with polymers sensitive to redox that are degraded by the microflora (bacteria) in the colon. In such biodegradable systems, such polymers include, by way of non-limiting example, redox sensitive polymers containing an azo and / or a disulfide bond in the structure.
[0362] In some embodiments, compositions formulated for delivery to the colon and / or rectum are formulated for release over time. In some embodiments, the extended release formulations resist the acidic environment of the stomach, thereby delaying the release of the enteroendocrine peptide secretion-enhancing agent until the dosage form enters the colon and / or rectum.
[0363] In certain embodiments, the time release formulations disclosed herein comprise a capsule (comprising an enteroendocrine peptide secretion-enhancing agent and an optional absorption inhibitor) with hydrogel buffer. In certain embodiments, the hydrogel plug and capsule are covered by a water-soluble layer and the entire unit is coated with an enteric polymer. When the capsule enters the small intestine, the enteric coating dissolves and the hydrogel plug swells and dislodges from the capsule after a period of time and the composition is released from the capsule. The amount of hydrogel is used to adjust the time period for releasing the contents.
[0364] In some embodiments, an oral dosage form is provided in this document which comprises a multilayer coating, in which the coating consists of several layers of polymers with different pH sensitivities. As the coated dosage forms move along the GIT the different layers dissolve depending on the pH found. The polymers used in such formulations include, by way of non-limiting example, polymethacrylates with suitable pH dissolving characteristics, Eudragit® RL and Eudragit® RS (inner layer) and Eudragit® ES (outer layer). In other embodiments, the dosage form is an enteric-coated tablet with an outer layer of hydroxypropyl cellulose or hydroxypropyl methyl cellulose acetate succinate (HPMCAS).
[0365] In some embodiments, an oral dosage form is provided which comprises coating with cellulose phthalate butyrate, cellulose acid phthalate, cellulose propionate, polyvinyl acetate phthalate, cellulose acetate phthalate, trimellitate cellulose acetate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, polymers and copolymers formed from acrylic acid, their methacrylic acid and their combinations. Combination therapy
[0366] In certain cases, provided herein are compositions and / or combination therapies comprising any compound described herein and an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an L cell endocrine peptide enhancer. In some cases, the L cell endocrine peptide enhancer is a GLP-2 enhancer. In some embodiments, the GLP-2 enhancer is GLP-2, a GLP-2 secretion enhancer, a similar inhibitor of GLP-2 degradation, or a combination thereof. In certain cases, the increased GLP-2 concentration provides regeneration of the intestinal mucosa and / or wound healing for gastrointestinal structures and / or reduces the induction of cytokines and / or improves the adaptation process, mitigates intestinal damage, decreases bacterial translocation, inhibits the release of oxygen free radicals, or any combination thereof. In some cases, the L-cell endocrine peptide enhancer is a PYY enhancer. In some cases, the endocrine L-cell peptide enhancer is an oxintomodulin enhancer. In some cases, increased PYY or oxintomodulin secretion cures bowel injuries caused by cholestasis or cholestatic liver disease. TGR5 receiver modulators
[0367] In some cases, the additional therapeutic agent modulates bile acid receptors in the gastrointestinal lumen. In some embodiments, the additional therapeutic agent agonizes or partially agonizes bile acid receptors (for example, TGR5 receptors or Farnesoid-X receptors) in the gastrointestinal tract. In some embodiments, the additional therapeutic agent is a bile acid analogue. In certain cases, the additional therapeutic agent is a TGR5 agonist. In certain cases, administration of a TGR5 agonist in combination with any of the compounds described herein increases the secretion of L cell enteroendocrine peptides (eg, TGR5 modulators) include, but are not limited to, the compounds described in WO 2008/091540, WO 2008/067219 and U.S. Application No. 2008/0221161. Enteroendocrine Peptides
[0368] In some embodiments, the additional therapeutic agent is an enteroendocrine peptide. In some embodiments, enteroendocrine peptides heal injuries to the intestine or liver due to cholestatic liver disease. Examples of enteroendocrine peptides that are administered as additional therapeutic agents include but are not limited to GLP-1 or GLP-1 analogs such as taspoglutide® (Ipsen), or the like. Combined therapy with fat-soluble vitamins
[0369] In some embodiments, the methods provided here still comprise the administration of one or more vitamins. In some embodiments, the vitamin is vitamin A, Bl, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta-carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherols, phylloquinone, menaquinone.
[0370] In some embodiments, the vitamin is a fat-soluble vitamin, such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherols, phylloquinone. In a preferred embodiment, the fat-soluble vitamin is polyethylene glycol tocopherol (TPGS). Combination therapy with partial external biliary bypass (LDPE)
[0371] In some embodiments, the methods provided here further include the use of partial external biliary bypass as a treatment for patients who have not yet developed cirrhosis. This treatment helps to reduce the circulation of bile acids / salts in the liver in order to reduce complications and avoid the need for early transplantation in many patients.
[0372] The surgical technique involves isolating a 10 cm long intestine segment for use as a bile duct (a channel for the passage of bile) from the rest of the intestine. One end of the conduit is attached to the gallbladder and the other end is brought into the skin to form a stoma (an opening surgically constructed to allow for the passage of residues). The partial external biliary bypass can be used for patients who do not respond to all medical therapies, especially older, older patients. This procedure cannot be of help to young patients, such as children. The partial external biliary bypass can decrease the intensity of the itching and abnormally lower the blood cholesterol levels. Combination therapy with ASBTI and ursodiol
[0373] In some embodiments, an ASBTI is administered in combination with ursodiol or ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocolic acid, glycocholic acid, glycodesoxycholic acid, taurodeoxy cholic acid, taurocholate, glycoquenodeoxycholic acid, tauroursodesoxic acid . In some cases, an increase in the concentration of bile acids / salts in the distal intestine induces intestinal regeneration, attenuating intestinal damage, reducing bacterial translocation, inhibiting the release of oxygen free radicals, inhibiting the production of pro-inflammatory cytokines, or any combination thereof, or any combination.
[0374] An ASBTI and a second active ingredient are used in such a way that the combination is present in a therapeutically effective amount. That therapeutically effective amount arises from the use of a combination of an ASBTI and the other active ingredient (for example, ursodiol), each of which is used in a therapeutically effective amount, or because of the additive or synergistic effects arising from the combined use, each can also be used in a therapeutically effective subclinical amount, i.e., an amount which, if used alone, provides reduced efficacy, for the therapeutic purposes mentioned herein, provided that the combined use is therapeutically effective. In some embodiments, the use of a combination of an ASBTI and any other active ingredient, as described herein, encompasses combinations where the ASBTI or the other active ingredient is present in a therapeutically effective amount, and the other is present in an amount subclinical therapeutically effective, provided the combined use is therapeutically effective due to its additive or synergistic effects. As used herein, the term "additive effect" describes the combined effect of two (or more) pharmaceutically active agents that is equal to the sum of the effect of each agent administered alone. A synergistic effect is one in which the combined effect of two (or more) pharmaceutically active agents is greater than the sum of the effect of each agent administered alone. Any suitable combination of an ASBIT with one or more of the other active ingredients mentioned above and, optionally, with one or more other pharmacologically active substances is contemplated as being within the scope of the methods described herein.
[0375] In some embodiments, the particular choice of compounds depends on the diagnosis of the attending physicians and the judgment of the individual's condition and the appropriate treatment protocol. The compounds are optionally administered simultaneously (for example, at the same time, essentially, at the same time or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder or condition, the individual's condition, and the actual choice of drugs. compounds used. In certain cases, the determination of the end of administration, and the number of repetitions of administration of each therapeutic agent, during a treatment protocol, is based on the assessment of the disease to be treated and the condition of the individual.
[0376] In some embodiments, therapeutically effective doses vary when drugs are used in combination treatments. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature.
[0377] In some embodiments of the combination therapies described herein, the dosages of the co-administered compounds vary depending on the type of co-drug employed, the specific drug employed, the disease or condition to be treated and so on. In addition, when co-administered with one or more biologically active agents, the compound provided herein is optionally administered either simultaneously with the biologically active agent (s), or sequentially. In certain cases, if administered sequentially, the attending physician will decide on the appropriate sequence of therapeutic compound described herein, in combination with the additional therapeutic agent.
[0378] Multiple therapeutic agents (at least one of which is a therapeutic compound described herein) are optionally administered in any order or even simultaneously. If simultaneously, multiple therapeutic agents are optionally supplied in a single, unified form, or in several forms (by way of example only, either as a single tablet or as two separate tablets). In certain cases, one of the therapeutic agents is optionally given in multiple doses. In other cases, both are optionally given in multiple doses. If it is not simultaneous, the interval between multiple doses is any suitable time, for example, from more than zero weeks to less than four weeks. In addition, combination methods, compositions and formulations should not be limited to the use of just two agents; the use of multiple therapeutic combinations is also considered (including two or more compounds described herein).
[0379] In certain embodiments, a dosage regimen to treat, prevent, or improve the condition (s) for which relief is required is modified according to a variety of factors. These factors include the disorder from which the subject suffers, as well as the subject's age, weight, sex, diet and medical condition. Thus, in various embodiments, the dosage regimen employed varies and deviates from the dosage regimens defined herein.
[0380] In some embodiments, the pharmaceutical agents that perform the combination therapy described herein are provided in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. In certain embodiments, the pharmaceutical agents that perform the combination therapy are administered sequentially, with any therapeutic compound being administered by a two-stage so-called administration regime. In some embodiments, the two-stage administration regime requires sequential administration of the active agents or spaced administration of the separate active agents. In certain embodiments, the time between multiple administration steps varies, by way of non-limiting example, from a few minutes to several hours, depending on the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, time half-life and kinetic profile of the pharmaceutical agent.
[0381] In certain embodiments, combination therapies are provided here. In certain embodiments, the compositions described herein comprise an additional therapeutic agent. In some embodiments, the methods described herein, comprise administering a second dosage form comprising an additional therapeutic agent. In certain embodiments of the combined treatment, the compositions described herein are administered as part of a therapeutic regimen. Therefore, additional therapeutic agents and / or additional pharmaceutical dosage form can be applied to a patient, either directly or indirectly, and, concomitantly or sequentially, with the compositions and formulations described herein. Kits
[0382] In another aspect, kits containing a device for pre-filled rectal administration of a pharmaceutical composition described herein are provided herein. In certain embodiments, the kits contain a device for oral administration and a pharmaceutical composition as described herein. In certain embodiments the kit includes a pre-filled envelope or bottle for oral administration, while in other embodiments the kits include pre-filled bags for administration of rectal gels. In certain embodiments the kit includes pre-filled syringes for administration of oral enemas, while in other embodiments the kits include pre-filled syringes for administration of rectal gels. In certain embodiments, the kit includes pre-filled pressurized cans for administration of rectal foams. Release in the distal ileo and / or colon
[0383] In certain embodiments, a dosage form comprises a matrix (e.g., a matrix comprising hypermellosis) that allows for the controlled release of an active agent in the distal jejunum, proximal ileum and distal ileo and / or the colon. In some embodiments, a dosage form comprises a polymer that is sensitive to pH (for example, an MMX ™ matrix from Cosmo Pharmaceuticals) and allows for the controlled release of an active agent in the ileum and / or colon. Examples of such pH sensitive polymers suitable for controlled release include and are not limited to polyacrylic polymers (for example, anionic polymers of methacrylic acid and / or esters of methacrylic acid, for example, Carbopol® polymers) which comprise acid groups (for example example, - COOH, - SO3H) and swell at basic intestinal pH (for example, pH about 7 to about 8). In some embodiments, a suitable dosage form for controlled release in the distal ileum comprises microparticles of active agent (e.g., micronized active agent). In some embodiments, a non-enzymatically degrading poly (dl-lactide-co-glycolide) (PLGA) nucleus is suitable for delivering an ASBTI to the distal ileum. In some embodiments, a dosage form comprising an ASBTI is coated with an enteric polymer (for example, Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic methacrylic acid polymers , methacrylic acid esters, or the like) for site-specific delivery to the ileum and / or colon. In some embodiments, the activated bacteria systems are suitable for targeted delivery to the ileo. Examples of activated micro-flora systems include dosage forms comprising pectin, galactomannan, and / or azo hydrogels and / or glycoside conjugates (e.g., D-galactoside, β-D-xylopyranoside conjugates or the like) of the active agent. Examples of gastrointestinal micro-flora enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase or the like.
[0384] The solid pharmaceutical dosage forms described herein optionally include an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetening agent , disintegrating agent, dispersing agent, surfactant, lubricant, dye, diluent, solubilizing agent, wetting agent, plasticizing agent, stabilizer, penetration promoter, wetting agent, defoaming agent, antioxidant, preservative, or one or more combinations . In some aspects, using conventional coating procedures, such as those described in Remington Pharmaceutical Sciences, 20th Edition (2000), a coating film is provided around the formulation of the Formula I-VI compound. In one embodiment, a compound described herein is in the form of a particle and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of a compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.
[0385] An ASBT inhibitor (for example, a compound of Formula I-VI) is used in the preparation of drugs for the prophylactic and / or therapeutic treatment of cholestasis or a cholestatic liver disease. A method for treating any of the diseases or conditions described herein in an individual in need of such treatment, involves administering pharmaceutical compositions containing at least one ASBT inhibitor described herein, or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable N-oxide , pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in amounts therapeutically effective for said individual. Screening Process
[0386] In certain embodiments, processes and kits for the identification of compounds suitable for the treatment of cholestasis or cholestatic liver disease are provided in certain embodiments. In certain embodiments, assays are provided herein for the identification of compounds that selectively inhibit ASBT by: a. provide cells that are a model of intestinal cells; B. contacting the cells with a compound (for example, a compound as described herein); ç. detect or measure the effect of the compound on inhibiting ASBT activity.
[0387] In certain embodiments, assays are provided here for identifying compounds that are non-systemic compounds by: a. providing cells that are a model of intestinal permeability (for example, Caco-2 cells); B. cell culture as a monolayer on semi-permeable plastic supports that are mounted in the wells of multi-well culture plates; ç. contacting the apical or basolateral surface of the cells with a compound (for example, a compound as described herein) and incubate for an appropriate period of time; d. detect or measure the concentration of the compound on both sides of the monolayer by liquid chromatography-mass spectrometry (LC-MS) and compute the intestinal permeability of the compound.
[0388] In certain embodiments, non-systemic compounds are identified by means of suitable parallel artificial membrane permeability tests (PAMPA).
[0389] In certain embodiments, non-systemic compounds are identified by the use of isolated vascular perfused intestinal preparations.
[0390] In certain embodiments, assays are provided here for the identification of compounds that inhibit the recycling of bile acid salts by: a. providing cells that are a model of intestinal cells with apical bile acid transporters (eg, BHK cells, CHO cells); B. incubating the cells with a compound (for example, a compound as described herein) and / or a radiolabeled bile acid (for example, 14C taurocholate) for an appropriate period of time; ç. washing the cells with an appropriate buffer (for example, buffered saline phosphate); d. detection or measurement of residual radiolabeled bile acid concentration in cells. EXAMPLES Example 1: Synthesis of 1-phenethyl-1 - ((1,4-diazabicyclo [2.2.2] octanyl) pentyl) diamide imidodicarbonimidic diamica, iodide salt

[0391] Step 1: Synthesis of 5- (1,4-diazabicyclo [2.2.2] octanyl) -1- iodo-pentane, iodide salt

[0392] 1,4-diazabicyclo [2.2.2] octane is suspended in THF. Diiodopentane is added dropwise and the mixture is refluxed overnight. The reaction mixture is filtered.
[0393] Step 2: Synthesis of N-phenethyl-5- (1,4-diazabicyclo [2.2.2] octanyl) -1-iodine pentane, iodide salt.

[0394] 5- (1,4-diazabicyclo [2.2.2] octanyl) -1-iodo-pentane, iodide salt is suspended in acetonitrile. Phenethylamine is added dropwise and the mixture is refluxed overnight. The reaction mixture is filtered.
[0395] Step 3: Synthesis of 1-phenethyl-1- ((1,4 diazabicyclo [2.2.2] octanyl) pentyl) imidodicarbonimidic diamide, iodide salt.
[0396] N-phenethi1-5- (1,4-diazabicyclo [2.2.2] octanyl) pentane-1-iodine, iodide salt is heated with dicyandiamide in n-butanol for 4 h. The reaction mixture is concentrated under reduced pressure.
[0397] The compounds of Table 1 are prepared using the methods as described herein, and using appropriate starting materials. Table 1

Example 2: In vitro assay for inhibition of ASBT-mediated bile acid absorption
[0398] Baby hamster kidney (BHK) cells are transfected with human ASBT cDNA. The cells are seeded in 96-well tissue culture plates of 60,000 cells / well. The tests are carried out within 24 hours after sowing.
[0399] On the day of the test the cell monolayer is washed with 100 ml of assay buffer. The test compound is added to each well, along with 6 mM [14C] taurocholate in assay buffer (final concentration of 3 mM [14C] taurocholate in each well). Cell cultures are incubated for 2 hours at 37 ° C. The wells are washed with BBS. Scintillation counting fluid is added to each well, the cells are shaken for 30 minutes before measuring the amount of radioactivity in each well. A test compound that has significant ASBT inhibitory activity provides an assay in which low levels of radioactivity are observed in the cells. Example 3: Glass test for GLP-2 secretion
[0400] Human cells NCI-H716 are used as a template for L cells. Two days before each test experiment, cells are seeded in 12-well culture plates coated with Matrigel® to induce cell adhesion. On the day of the test, the cells are washed with buffer. The cells are incubated for 2 hours with medium alone, or with test compound. The extracellular medium is assayed for the presence of GLP-2. Peptides in the medium are collected by reverse phase adsorption and the extracts are stored until analyzed. The presence of GLP-2 is assayed using the ELISA method. Detection of increased levels of GLP-2 in a well containing a test compound identifies the test compound as a compound that can increase the secretion of GLP-2 from L-cells. Example 4: In vivo bioavailability test
[0401] The test compounds are dissolved in saline. Sprague Dawley rats were dosed at 2-10 mg / kg of body weight intravenously and orally. Peripheral blood samples are taken from the femoral artery at selected time intervals of up to 8 hours. The plasma concentrations of the compounds are determined by means of quantitative HPLC and / or mass spectrometry. Release and AUC values are determined for the compounds.
[0402] For oral administration, bioavailability is also calculated by taking plasma samples from the portal vein. Cannulas are inserted into the femoral artery and hepatic portal vein to obtain estimates of total drug absorption without first-pass clearance in the liver. The absorbed fraction (F) is calculated by F = AUC po / AUC iv Example 5: Assay to determine levels of ileal and luminal intra-enterocyte bile acid
[0403] The levels of ileal luminal bile acids in SD rats are determined by the blushing of a 3 cm section of terminal ileum with cold sterile PBS. After additional washing with PBS, the same section of the ileo is weighed and then homogenized in fresh PBS for the determination of interenterocyte bile acid levels. The LC / MS / MS system is used to assess the levels of cholic acid, DCA, ACV, chnodeoxycholic acid, and ursodeoxycholic acid. Example 6: Animal to determine the effect of therapy on cholestasis or a cholestatic liver disease
[0404] The Knock MdR2 mouse model of mice induced with cholestasis or cholestatic liver disease (by carbon tetrachloride / phenobarbital) is used to test compositions described herein. The animals are administered orally, a composition comprising an ASBTI such as 100B, 264W94; SD5613; SAR548304B; SA HMR1741; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N- (2-sulphoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio- 8- (N - [(R) -a- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4 -hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1- carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoyl -methoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or 1,1-dioxo- 3,3-dibutyl-5-phenyl-7-methylthio-8- [N - ((R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine.
[0405] Cholestasis or cholestatic liver disease is quantified by the total bile acid and bilirubin in serum versus that of control rats / rats administered with placebo. Serum bile acids / salts are determined by ELISA with antibodies specific for colic and CCDCA. Serum bilirubin levels are determined by means of automated routine tests. Alternatively, rat livers can be harvested and the pathology of hepatocellular damage can be measured. Example 7: Investigation of LUM001 and 1- [4- [4- [(4R, 5R) -3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4- methanesulfonate hydroxy-l, l-dioxide-l-benzothiepin-5-yl] phenoxy] 4-aza -1-azanobicyclo [2.2.2] octane (Compound 100B) orally delivered at the plasma GLP-2 levels in normal rats
[0406] Male 12-week-old HSD rats are fasted for 16 h and given an oral dose of 0, 3, 30, 100 mg / kg of ASBTIs LUM001 or methanesulfonate (Synthesized by Nanosyn Inc., CA, USA) in a mixture of valine-pyrrolidine in water (n = 5 per group). Blood samples of 0.6 mL volume for each time point are taken from the caudal vein, with a heparinized capillary tube 0, 1, 3 and 5 hours after administration of the compounds and the GLP-2 levels of plasma are determined. Aprotinin and 10 pL of DPP-IV inhibitor per ml of blood are used to preserve blood samples for 10 minutes of centrifugation and for storage at -70 ° C or below. GLP-2 (pM Active) is tested by any commercially available ELISA kit. Example 8: Tablet formulation
[0407] 10 kg of a compound of Formula I-VI is first sieved through a suitable sieve (for example, 500 microns). 25 kg of lactose monohydrate, 8 kg of hydroxypropylmethylcellulose, the sieved compounds of Formula I-VI and 5 kg of hydrogen calcium phosphate (anhydrous) are then added to a suitable mixer (for example, a drum mixer) ) and mixed. The mixture is sieved through a suitable sieve (eg 500 microns) and remixed. About 50% of the lubricant (2.5 kg, magnesium stearate) is sieved, added to the mixture and mixed briefly. The remaining lubricant (2 kg, magnesium stearate) is sieved, added to the mixture and mixed briefly. The granules are sieved (for example, 200 microns), to obtain granulation particles of the desired size. In some embodiments, the granules are optionally coated with a drug release control polymer, such as polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or a methacrylic acid copolymer, to provide an extended release formulation. The granules are filled in gelatin capsules. Example 9: Pediatric formulation
[0408] Disintegration tablet formulation
[0409] The following example describes a large-scale preparation (100 kg) of an ASBTI compound of Formula I-VI (for example, LUM-001 or LUM-002).

[0410] Passage of ASBTI (2.5 kg), lactose monohydrate NF (47.5 kg), pregelatinized starch NF (18 kg), microcrystalline cellulose NF (17 kg), croscarmellose sodium NF (6 , 5 kg) and USP K29 / 32 (8.5 kg) through a # 10 mesh sieve. Add the sieved material to a Collette 600 mixer. Mix for 6 minutes at low speed, without chopping. Add the direct blended mixture from the previous step to a 20 cubic foot PK V-shell mixer (Model C266200). Pass the NF magnesium stearate (0.5-1 kg) through a 10 mesh sieve into a properly prepared container. Add approximately half of the magnesium stearate on each side of the PK mixer and mix for 5 minutes. Add the mixed mixture from the previous step to Kikusui tablet press for tablet compression. Compaction equipment can be equipped to make tools for 50 mg, 75 mg and 100 mg tablets. Example 10: Effervescent tablet
[0411] The active ingredient, anhydrous monosodium citrate, sodium bicarbonate and aspartame are mixed and granulated by adding a solution of polyvinylpyrrolidone in alcohol. The granules obtained after mixing are dried and passed through a calibrator, and the resulting granules are then mixed with sodium benzoate and flavorings. The granulated material is compressed into tablets using an alternative machine equipped with 20 mm punches.
[0412] A rotary machine equipped with 20 mm punches can also be used for the preparation of tablets.
Example 11: Chewable tablet
[0413] A 40% (w / w) solution of Eudragit E100 in ethanol was added, with mixing, to the active ingredient and mixed until the granules were formed. The resulting granules were dried and then sieved through a 16 mesh screen.


[0414] The granules of active ingredients and extragranular excipients were placed in a cone mixer and mixed well. The resulting mixture was discharged from the mixer and compressed in a suitable rotary tablet press equipped with the appropriate punches. Example 12: Orodispersible tablet
[0415] The active ingredient is introduced into a fluidized air bed installation and a solution of ethyl cellulose in ethanol is sprayed on it.
[0416] The excipients are sieved and the coated active ingredient is homogenized with the excipients in a mixing apparatus, in dry conditions.
[0417] The distribution and formation of tablets are carried out in a compression machine equipped with punches with a diameter equal to 16 mm and a radius of curvature equal to 20 mm.
[0418] The pressure is 15 kNewtons ± 1. The hardness of the tablets obtained in this way is 50 ± 5 Newtons. The disintegration time in the mouth is 15 to 20 seconds.

Example 13: Powder formulation
[0419] A powdery mixture of active ingredient and polyvivone (5 parts by weight) is granulated with 7% purified water (weight / weight).
[0420] The premix is prepared with the following components. calcium carbasalate (amount corresponding to parts by weight of acetylsalicylic acid); anhydrous citric acid (168 parts by weight); sodium bicarbonate (232 parts by weight); lactose (1500 parts by weight); magnesium citrate (180 parts by weight); potassium benzoate (250 parts by weight). The premix is then compacted dry.
[0421] The mixture of the powdery active ingredient and the dry-compacted premix, and the following compounds: aspartame and artificial vanilla flavor, which are in powder form, are mixed.
[0422] The powder mixture can be packaged directly in envelopes.

Example 14: Gum Jam
[0423] About 50 pounds of hot water is mixed with about 50 pounds of gelatin in the mixing tank, to form 100 lbs of gelling compound having a homogeneous 50/50 mixture of water and gelatin. About 0.1% to 10% sodium bisulfate, by weight, is added to the gelling compound to reduce the pH of the gelling compound to about 3.5.
[0424] In the mixing weight container, the gelling compound is mixed with about 6 pounds of water, 38.3 lbs of sucrose, and 50 lbs of corn syrup to form the candy paste. If the active ingredient is not a heat-sensitive drug, the active ingredient is added to the paste before cooking sweets. About 0.1% by weight sodium citrate is added to the candy paste to maintain the paste's pH at about 3.0 to 3.5.
[0425] The candy paste is then heated to a temperature of about 180 ° C before being passed through the buffer storage tank to the static cooker. In the static cooker, the sweet paste is heated to a temperature of about 240 ° F to 245 ° F, dehydrated the paste to a brix of about 78.
[0426] After the candy is prepared, the cooked candy is sent to the vacuum chamber, where the candy is further dehydrated for a brix of about 80. After leaving the vacuum, the cooked candy is placed in the Dosier where about 1.5/5 strawberry flavor, by weight, and about 1% red cabbage color, by weight, are added to the baked sweets. To balance the flavor, about 0.1% citric acid by weight and about 0.1% lactic acid by weight are added to the baked sweets.
[0427] After adding the flavoring and coloring, the baked candy is deposited in the leading machine and then cured. After the candies are cured, they are added to a falling drum to break up any starch that is left in the candies. As the sweets are being dropped, about 1% of coconut oil fractionated by weight, and about 1% by weight of carnauba wax is poured into the drum to coat the sweets to prevent them from breaking.
Example 15: Liquid flavor masking formulations
[0428] An aqueous pharmaceutical composition of the present invention is formulated by preparing a mixture of hydroxyethyl cellulose dissolved in 50 ml of purified water with 0.5 ml of orange flavoring agent, with dibasic potassium phosphate and monobasic potassium phosphate added ( from a mixture of hot water). 4.0 mg of active ingredient is then added and mixed until it dissolves. Sodium hydroxide is added to adjust the pH to between about 6.7 to about 6.9.

[0429] Alternative liquid oral formulations are provided below. For each of the formulations below, a sweetener from 0.5% to 2%, such as sucralose, mannitol, sucrose and / or a flavoring agent from 0.5% to 2%, such as grape, cherry, bubble gum, orange , lemon, strawberry can be added. Polypropylene glycol can be replaced with one of the PEGs.




Example 16: Envelope formulation
[0430] The following formulation is used to produce an envelope for pediatric use. A sweetener of 0.5% to 2%, such as sucralose, mannitol, sucrose and / or a flavoring agent of 0.5% to 2%, such as grape, cherry, bubble gum, orange, lemon, strawberry can be added. Sugar and sodium lauryl sulfate can be exchanged with other surfactants.
Example 17: Animal study
[0431] Animal Preparation. Fat male diabetic rats Zucker (ZDF / GmiCrl-fa / fa) were purchased from Charles River (Raleigh, NC) and housed in controlled conditions (12:12 light-dark cycle, 24 ° C and 50% relative humidity) , with free access to rodent food (Purina 5008, Harlan Teklad, Indianapolis, IN). All rats reached seven weeks of age (± 3 days). After a one-week acclimatization period, the rats were anesthetized with isoflurane (Abbott Laboratories, IL) and blood samples from the tail veins were collected at 9 am, without fasting. Blood glucose levels were measured using a glucometer (Bayer, Leverkusen, Germany). In order to ensure balanced treatment groups, ZDF rats were assigned to six treatment groups based on base glucose: vehicle (0.5% HPMC, 0.1% Tween80) and five doses of 264W94 (0.001, 0, 01, 0.1, 1, 10 mg / kg). All treatments were administered by oral tube, twice a day and the animals were followed for two weeks, with blood samples collected from the tail vein, at the end of each week at 9 am without fasting. Stool samples were collected for 24 hours during the second week of treatment.
[0432] Measurement of clinical chemistry parameters. Non-esterified fatty acids (NEFA), bile acids, and bile acids in fecal extraction were measured using the Olympus AU640 clinical chemistry analyzer (Beckman Coulter, Irving, TX).
[0433] Changes in the fecal excretion of bile acids and the concentration of bile acid in the plasma. Oral administration of 264W94 dose depends on increased bile acids in the stool. Fecal bile acid concentrations were increased up to 6.5 times with an EDso of 0.17 mg / kg when compared to vehicle treated rats. Fecal NEFA also increased slightly in rats treated with 264W94. In contrast, plasma bile acid concentrations were reduced in rats treated with 264W94 dose dependent. See Figure 1.
[0434] Bile acid levels in the plasma of ZDF rats after administration of ascending doses of SC-435 and LUM002. Male ZDF rats (n = 4) were administered with vehicle, SC-435 (1, 10 or 30 mg / kg) or LUM002 (0.3, 1, 3, 10 or 30 mg / kg) by oral tube, twice per day for 2 weeks. Plasma bile acid levels were determined at the end of the second week. Plasma bile acid levels were reduced for all doses of SC-435 and LUM002. The data are expressed as mean values ± SEM. See Figure 2. Example 18 Animal study on duration of action and time to start ASBTI activity for a single oral dose of LUM001 in total postprandial serum bile acids in Beagle dogs
[0435] Test compound: LUM001 - Form I
[0436] Dosage preparation and administration: LUM001 was dissolved in water at concentrations that required the administration of 0.2 ml / kg of solution. The solutions were placed in gelatin capsules, Torpac Inc., 13 batch size 594, East Hanover NJ, and administered orally.
[0437] Dogs: Male beagle dogs were obtained from Covance Research Products, Cumberland VA or Marshall Farms USA, Inc., North Rose NY. A total of 20 dogs, from 1 to 5 years old, 6.8-15.6 kg of body weight, were used in these experiments. The dogs were conditioned on a 12-hour light / dark cycle and kept on a 1-hour food restriction per day of access to food (Richman Standard Certified Canine Diet # 5007, PMI Nutrition, Inc., St. Louis MO) of 7 to 8 in the morning. They were trained to eat a special meal promptly within 20 minutes when presented (1 can. 397g, Evanger 100% Dog Meat, Evanger's Dog and Cat Food Co., Inc., Wheeling IL, mixed with 50g of cheese chedar).
[0438] Measurement of total bile acid in serum (SBA): SBA was measured by an enzymatic assay. SBA values are expressed as pg of total bile acids / ml of serum.
[0439] Control experiments to estimate the rise and duration of elevation in systemic serum bile acid: previous work has shown that the SBA of beagle dogs rises to a maximum level of one hour after the feed meal described above, and remains at a plateau 4 hours and then decreases. To estimate the details of this level, six dogs were given a test meal and blood samples for SBA measurement were taken at -30, 0, 30, 60, 65, 70, 80, 90, 120, 180, 240, 360 , 480, 720, 1410 and 1440 minutes from the moment of feeding. Any remaining food was removed 20 minutes after it was first presented to the dogs. To establish a method to extend the high SBA level, six dogs received the meal at 0 hours and an additional 1/2 meal size again 4 hours after the first meal. Blood samples were taken at 0, 1, 2, 3, 4, 4,5, 6, 7 and 8 hours. The curves for SBA level vs time obtained in these experiments were used as a reference to determine the blood collection times in experiments with LUM001. Whenever possible, the experimental design allowing, in experiments with test compound, each dog served as its own simultaneous control, and the mean SBA value of 1 hour served as a reference to which all other mean values were compared.
[0440] Experiments to measure the time of onset of LUM001 activity: LUM001 was administered at 0, 0.01, 0.05, 0.2 and 1 mg / kg, powder for dogs, n = 6, 1 hour after feeding the standard experimental meal. Blood samples for SBA measurement were taken at - 30, 0, 30, 60, 65, 70, 80, 90, 120 and 180 minutes from the time of feeding. Each dog served as its own control, and the average SBA levels were compared with the average SBA level of 60 minutes. Table 1. Beginning of LUM001 activity in canine serum bile acids
All animals were fed at 0 minutes and dosed at 60 minutes. * = p <0.05 compared to the value of 60 minutes on the same curve by testing two paired double samples.
[0441] Experiments to measure the duration of Action of LUMOOl: In dogs, a single experimental meal produces a postprandial increase in SBA that is raised to a peak in one hour after feeding and constant for another 3 hours. Previous experiments (2) indicate that LUMOOl remains active for more than 4.5 hours. To measure the duration of action of an ASBT inhibitor using postprandial SBA levels requires that, in the control situation, SBA levels remain high and constant throughout the period of action of the compound, or that the compound is administered long before the postprandial increase occurs, and remain active in the empty digestive system for long periods before feeding. Therefore, two alternative methods were used to provide a constant SBA elevation window that can be used to measure the duration of action of ASBT inhibitors.
[0442] Method 1: two meals for Extended SBA Elevation: LUMOOl was administered at 0.05 and 0.2 mg / kg, for 6 dogs 1 hour after feeding them a meal. At 4 hours after the meal was offered, a second meal of 1/2 the size of the first meal was offered. It was also consumed more quickly and completely as the first meal, and provided an extended, steady SBA plateau. Blood samples for SBA measurement were taken at 0, 1, 1.5, 2, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours after time to offer the first meal. The average levels of SBA were compared with the average level of SBA in 1 hour, each dog serves as its own control. The end of the activity is considered to occur at the point in time when the average value of SBA is not significantly less than the average value of 1 hour. Table 2. Duration of Action of LUM001 in Canine Serum Bile Acids I

[0443] All animals were fed a meal at 0 am, dosed orally with the compound in 1 hour and then fed by a single additional 4-hour feeding medium. * = p <0.05 compared to the mean value of the same 1-hour two-tailed paired t-test curve.
[0444] Method 2: One meal and extended interval between Dosing and Feeding: Alternatively, six dogs were dosed with water or LUM001, at 0.05 mg / kg, po in 1.5 hours before being fed, or 0.05 , or 0.2 mg / kg, 2 hours before feeding. This changed the high level of SBA instead of the dose point. Blood samples for SBA measurement were taken immediately before dosing (0 or 0.5 hr), during feeding (2 hours), 2.5, 3, 4 and 5 hours after feeding. This allowed the detection of activity outside 5.5 and 6 hours after administration, without feeding the dogs a second time. Average SBA levels were compared with the corresponding average SBA values in treated water controls. The end of activity is considered to occur at the first point in time when the mean SBA value is not significantly lower than the corresponding mean control value. Table 3. Duration of Action of LUMOOl in Canine Serum Bile Acids II
* = p <0.05 vs water treatment by two-pair paired t-test without assuming equal variances.
[0445] Conclusion: In the canine SBA model, the ED50 dose (0.2 mg / kg) of LUMOOl administered orally 1 hour after feeding significantly reduced serum bile acid levels up to 30 minutes after dosing and these levels remained significantly reduced for at least 6 hours. By comparison, a limit dose of 0.05 mg / kg significantly reduced SBA levels within approximately 1 to 2 hours after dosing, but the significant decrease was not maintained beyond 3 hours after dosing. Increasing the dose above the ED50 level of 1 mg / kg does not shorten the latency time for SBA by decreasing and still maintaining maximum suppression for 2 hours after dosing. When LUM001 was administered 2 hours before feeding, a dose of 0.2 mg / kg, it was necessary to produce a significant effect that was maintained for at least 2-3 hours after feeding. The results of these studies indicate that the presence of food in the gastrointestinal tract has a significant impact on the pharmacodynamic activity of the ASBT inhibitor, most likely by altering the residence time of the drug in the small intestine. Example 19 A randomized, double-blind, placebo-controlled, safe, tolerability, pharmacokinetic and pharmacodynamic study of ascending multiple oral doses of LUM001 in healthy subjects
[0446] This Phase 1 study was a double-blind, randomized, placebo-controlled study of ancestry of multiple oral doses of LUM001 in healthy, adult subjects. This study was conducted at a single center. There were 13 LUM001 dosing panels: 10, 20, 60, 100, and 20 mg every morning (qAM) (2) (ie, the regimen was tested a second time in the study), 5 mg every night (qPM ), 0.5, 1, 2.5, 5, 2.5 (2), 5 (2), and 0.5 to 5 mg qAM dose titration. Most dosing panels included subjects treated with placebo. Dosing group data is shown in the graphs 0.5 (n = 16), 1.0 (n = 8), 2.5 (n = 8), 5.0 (n = 8) and elO (n = 8) mg.
[0447] For the qAM, LUM001 or placebo dosing panels, it was administered each day of the treatment period (28 days), just before the morning meal at about 8:00 am and afterwards any necessary blood work was taken.
[0448] Serum bile acid analysis (SBA): On day -1, blood was drawn to SBA baseline about 30 minutes before and after lunch and 30 minutes after lunch and dinner. During the treatment period, samples were obtained on days 2, 14 and 28 (results for 14 days are shown in Figure 3), at -30, 30, 60 120, and 240 minutes after each of the three daily meals for analyze. For each sample, about 3 mL of venous blood were collected by venipuncture or saline block.
[0449] SBA were analyzed as part of the routine clinical analysis of the serum samples collected at each moment.
[0450] Fecal Bile Acid Analysis: Stool samples were collected for all panels except the dose titration panel, 2.5 (2) and 5 mg (2), on days 9 to 14 and 23 to 28 (data shown in Figure 4). Twenty-four hour FBA excretions were quantified by Farmacia for days 9 to 14 and 23 to 28. The feces were collected in a 24-hour recipient collection beginning at 8:00 am and ending 24 hours later. This procedure was followed on days 9 to 14 and 23 to 28, with new emission collection containers for each 24-hour period. The weight of each 24-hour fecal collection was recorded on the CRFs. The samples were stored in 24-hour containers, frozen at about -80 ° C before analysis.
[0451] An aliquot of each 24-hour stool sample collected in 23 days to 28 was combined, homogenized, and analyzed for concentrations of bile acid species by ANAPHARM. The species of fecal bile acids evaluated include chenodeoxycholic acid, cholic acid, deoxycholic acid and lithocholic acid.
[0452] Conclusion: The results show a significant reduction in serum bile acids and a significant increase in fecal bile acids. Example 20 Pediatric study to test the effectiveness of ASBTI in reducing serum bile acids in pediatric patients
[0453] LUM001 has been administered to forty patients under the age of 18 years. The following table shows the exemplary characteristics of five children who received LUM001. The drug was administered once daily (QD) in the morning for 14 days. Systemic exposure levels of LUM001 were measured on day eight and the drug was confirmed to be minimally absorbed by children. These doses are similar to those used to treat children with cholestatic diseases.
[0454] Table 4. Pharmacokinetics of LUM001 in pediatric subjects (study NB-00-02-014)


[0455] The effectiveness of LUMOOl was determined by measuring the total serum bile acids after eight days of administration to children and adolescents under the age of eighteen. Thirty minutes before the next administration of the drug, at about 8 am, serum bile acid levels were measured. The child had to abstain from food for 12 hours before this sample, thus providing a fasting level of serum bile acids. After lunch, serum bile acids were measured for up to the next 4 hours (8 am at noon) and the peak serum bile acid concentration observed. LUMOOl has been shown to generally decrease both fasting and peak postprandial serum bile acid levels (see table). In the table below, patients treated with placebo had an average fasting bile acid level of 8.6 m mol / L and a peak postprandial serum bile acid level of 11.9 m mol / L. For patients treated with LUMOOl the values were 6.5 m mol / L and 9.2, respectively, representing a decrease of 24% and 23% (see Figure 5).
[0456] Table 5. SBA fasting and morning postprandial peak in pediatric patients

Example 21 Clinical trial to test the effectiveness of ASBTI in treating and / or relieving symptoms of pediatric cholestasis or a pediatric cholestatic liver disease
[0457] This study will determine the effectiveness of ASBTI treatment in patients afflicted with pediatric cholestasis or a pediatric cholestatic liver disease.
[0458] Individuals under 12 years of age with a clinical diagnosis of cholestasis or cholestatic liver disease will be enrolled. Individuals can be diagnosed by symptoms such as jaundice, chronic itching, elevated serum bile acids / bilirubin.
[0459] Individuals who have fatal kidney disease, cardiovascular disease, or congenital anomalies will be excluded.
[0460] Individuals will be administered a daily oral dose of compound LUM001 formulated for release into the distal ileo. Alternatively, any of the following compounds can be the subject of a clinical trial: 264W94; SAR548304B; SA HMR1741; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -α- [N - ((S) -1-carboxy-2-methyl-propyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N- ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N- ( (R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.
[0461] The primary objective is the proportion of individuals who show resolution or improvement of the initial signs and symptoms, for example, jaundice, serum bile acid / salt levels and / or bilirubin, itching. Example 22 Clinical trial to test the effectiveness of ASBTI in treating and / or relieving symptoms of progressive familial intrahepatic cholestasis 1 (PFIC-1)
[0462] This study will determine the effectiveness of an ASBTI for treatment in pediatric patients suffering from PFIC1.
[0463] Patients diagnosed with anomalies genetically in the ATP8B1, ABCB11, or ABCB4 gene and who present with PFIC-1 are eligible for enrollment.
[0464] Inclusion criteria include severe itching (greater than grade II); non-responsive to ursodiol; native liver; genetic or immunohistochemistry findings consistent with PFIC1 or Alagille syndrome; informed consent; 12 months of age or older.
[0465] Exclusion criteria include chronic diarrhea requiring IV fluids or nutritional interventions; surgical interruption of enterohepatic circulation; or decompensated cirrhosis (PT> 16s, alb <3.0 gr / dl, ascites, diuretic therapy, variceal haemorrhage, encephalopathy).
[0466] Individuals will be administered a daily oral dose of LUMOOl formulated for release into the distal ileo. Alternatively, any of the following compounds can be the subject of a clinical trial: 264W94; SAR548304B; SA HMR1741; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2-methyl-propyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N- ( (R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.
[0467] Phase 1 will be a 4-week dose escalation study to determine the minimum dose tolerated by the patient. Dose 1: 14 pg / kg / day for 7 days; dose 2, 35 pg / kg / day for 7 days; dose 3; 70 gg / kg / day for 7 days; dose 4: 140 gg / kg / day for 7 days.
[0468] Phase 2 will be a double-blind, placebo-controlled crossover study. Individuals will be randomized to maximum tolerated dose or placebo for 8 weeks, followed by 2 weeks of drug vacation and crossover to receive the alternative regimen for eight weeks.
[0469] The primary objective is the proportion of individuals who show resolution or improvement of the initial signs and symptoms, for example, jaundice, serum levels of bile acid / salts and / or bilirubin, pruritus. Example 23 Clinical trial to test the effectiveness of ASBTI in treating and / or relieving symptoms of recurrent benign intrahepatic cholestasis or a cholestatic liver disease (BRIC)
[0470] The purpose of this study is to determine the effect of a non-systemic ASBTI suspension on the treatment of BRIC. A suspension of the enteric ileal pH released from an ASBTI can also be administered to an individual once a day.
[0471] Pediatric patients genetically diagnosed with abnormalities in the ATP8B1, ABCB11, or ABCB4 genes and have non-chronic but recurrent cholestasis or symptoms of cholestatic liver disease will be enrolled.
[0472] Individuals will be administered a daily oral dose of compound LUM001 formulated for release into the distal ileum. Alternatively, any of the following compounds may be the subject of a clinical trial: 264W94; SAR548304B; SA HMR1741; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -α- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -α- [N - ((S) -l-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -α- [N - ((S) -1-carboxy-2-methyl-propyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -α- [N- ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N- ( (R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine. The primary objective is the proportion of individuals who show resolution or improvement of the initial signs and symptoms, for example, jaundice, serum bile acid / salt levels and / or bilirubin, itching. Example 24 Clinical trial to test the effectiveness of ASBTI in treating and / or relieving symptoms of cholestasis associated with total parenteral nutrition (TPN-AC) or a cholestatic liver disease
[0473] The purpose of this study is to determine the effect of a non-systemic ASBTI suspension on the treatment of TPN-AC. An ileal enteric pH release suspension from an ASBTI can also be administered to a subject once a day.
[0474] Pediatric patients with clinical diagnosis of TPN-AC and associated symptoms will be enrolled.
[0475] Individuals will be administered a daily oral dose of LUMOOl compound formulated for release into the distal ileum. Alternatively, any of the following compounds can be the subject of a clinical trial: 264W94; SAR548304B; SA HMR1741; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2-methyl-propyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N- ( (R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine. The primary objective is the proportion of individuals who show resolution or improvement of the initial signs and symptoms, for example, jaundice, levels of bile acid / salts and / or serum bilirubin, itching. Example 25 Clinical trial to test the effectiveness of LUM-001 in the treatment and / or relief of symptoms of FIC1 disease and Alagille syndrome
[0476] Pediatric patients suffering from FICl disease (n = 15) and Alagille syndrome (n = 20) aged 12 months and older will be tested.
[0477] Inclusion criteria include (1) severe itching (> grade II) that does not respond to routine pharmacological therapy, (2) native liver, (3) genetic or clinical findings compatible with FICl disease or genetic findings of the syndrome Alagille, and (4) informed consent and approval, as appropriate.
[0478] The exclusion criteria will include (1) chronic diarrhea requiring specific intravenous fluids or nutritional intervention for diarrhea and / or its sequelae or (2) surgical interruption of enterohepatic circulation, (3) decompensated cirrhosis (PT> 16s, alb <3.0 gr / dl, ascites, diuretic therapy, variceal haemorrhage, encephalopathy).
[0479] Phase 1: increasing the 4-week dose of LUM-001 (doses based on adolescent / adult doses) to determine the maximum tolerated dose per patient. Doses of 1- 14 gg / kg / day for seven days; Doses of 2-35 gg / kg / day for seven days; Doses of 3-70 gg / kg / day for seven days; Doses of 4-140 gg / kg / day for seven days.
[0480] Phase 2: double-blind placebo controlled cross-over study. Randomized to maximum tolerated dose or placebo, for 8 weeks, followed by two weeks to wash, and cossed-on to receive the alternative regimen, for 8 weeks.
[0481] Possible Phase 3 with open label therapy.
[0482] Primary objectives: safety and tolerability of LUM-001.
[0483] Secondary objectives: changes in the itching scales, clinical laboratories, fecal bile acid secretion, serum bile acids and serum 7-a-hydroxy-4 colesten-3-one (7aC4).
[0484] Induction baseline assessment: FICl or Jagged 1 genotyping, complete history and physics, comprehensive clinical laboratory profile, 72 hour fecal bile acid collection, serum bile acid levels, bile acid synthesis marker (7aC4 ).
[0485] Phase 1 baseline assessments (except genotyping, history and physics) will be repeated at the end of each 7-day treatment period. The pruritus score will be assessed by the parents, child (if possible) and the doctor (s) at the beginning and at the end of each dose.
[0486] Phase 2 baseline assessments (except genotyping, history and physics) will be repeated at the end of each 8-week treatment period.
[0487] LUM-001 was well tolerated in a pediatric multiple dose study: 2 weeks daily up to 5 mg q.d. (39 individuals treated aged 10-17).
[0488] Although preferred embodiments of the present invention have been presented and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will now occur for those skilled in the art without departing from the invention. It is to be understood that various alternatives to the embodiments of the invention described herein can be employed in the practice of the invention. It is intended that the following claims define the scope of the invention and that the methods and structures within the scope of these claims and their equivalents are thus covered.

权利要求:
Claims (15)
[0001]
1. Use of a composition characterized in that it is in the preparation of a medicament for the treatment of pediatric cholestatic liver disease which comprises administering non-systematically to a pediatric patient a therapeutically effective amount of the composition comprising an Apical Bile Acid Transporter Inhibitor dependent on Sodium (ASBTI), where ASBTI is a compound of Formula:
[0002]
2. Use, according to claim 1, characterized by the fact of treating itching or hypercholemia in pediatric patients.
[0003]
3. Use, according to claim 1, characterized by the fact that the composition is a pediatric dosage form selected from a solution, syrup, suspension, elixir, powder for reconstitution as a suspension or solution, dispersible / effervescent tablet, chewable tablet, gum, lollipop, popsicle, lozenges, oral thin strips, oral disintegrating tablets, sachet, soft gelatin capsule, and oral spray powder or granules.
[0004]
4. Use, according to claim 1, characterized by the fact that the dosage comprises between 0.1 to 20 mg of ASBTI.
[0005]
5. Use according to claim 1, characterized by the fact that pediatric cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), type 1 PFIC, type 2 PFIC, type 3 PFIC, Alagille syndrome , Dubin-Johnson syndrome, biliary atresia, post-Kasai biliary atresia, biliary atresia after liver transplantation, cholestasis after liver transplantation, liver disease associated with post-liver transplantation, intestinal failure associated with liver disease, bile acid mediated liver, pediatric primary sclerosing cholangitis, MRP2 deficiency syndrome, neonatal sclerosing cholangitis, pediatric obstructive cholestasis, pediatric non-obstructive cholestasis, pediatric extrahepatic cholestasis, pediatric intrahepatic cholestasis, pediatric primary intrahepatic cholestasis, cholestasis secondary pediatric intrahepatic, benign periodic intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, cholestasis as combined with total parenteral nutrition, paraneoplastic cholestasis, Stauffer's syndrome, drug-associated cholestasis, infection-associated cholestasis, or gallstone disease.
[0006]
6. Use according to claim 1, characterized by the fact that pediatric cholestatic liver disease is defined by one or more symptoms of jaundice, pruritus, cirrhosis, hypercholemia, neonatal respiratory distress syndrome, pulmonary pneumonia, increased concentration of serum bile acids, increased concentration of hepatic bile acids, increased concentration of serum bilirubin, hepatocellular lesion, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation , hepatocellular carcinoma, gastrointestinal hemorrhage, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, peculiar smell, dark urine, whitish stools, steatorrhea, growth deficit, and kidney failure.
[0007]
7. Use, according to claim 1, characterized by the fact that ASBTI is:
[0008]
8. Use, according to claim 1, characterized by the fact that the ASBTI is:
[0009]
9. Use according to claim 1, characterized by the fact that the composition still comprises a scavenger or bile acid binder.
[0010]
10. Pediatric dosage form characterized by comprising a pediatric dosage of a Sodium-dependent Apical Bile Acid Transporter Inhibitor (ASBTI) absorbed non-systemically, where ASBTI is:
[0011]
11. Pediatric dosage form according to claim 10, characterized by the fact that the pediatric dosage form is selected from a solution, syrup, suspension, elixir, powder for reconstitution as a suspension or solution, dispersible / effervescent tablet, compressed chewable, gum, lollipop, popsicle, lozenges, oral thin strips, oral disintegrating tablets, sachet, soft gelatin capsule, and oral spray powder or granules.
[0012]
12. Pediatric dosage form, according to claim 10, characterized by the fact that ASBTI is:
[0013]
13. Pediatric dosage form, according to claim 10, characterized by the fact that ASBTI is:
[0014]
14. Use according to claim 1, characterized by the fact that ASBTI is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - ({[(1 - carboxypropyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a pharmaceutically acceptable salt thereof.
[0015]
15. Use according to claim 14, characterized by the fact that ASBTI is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - ({[(1-carboxypropyl) carbamoyl ] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a pharmaceutically acceptable salt thereof.

类似技术:

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-20| B25D| Requested change of name of applicant approved|Owner name: LUMENA PHARMACEUTICALS LLC (US) |

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-07-31| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2019-02-12| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-11-26| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-05-19| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-10| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 26/10/2012, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-02-23| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: REF. RPI 2601 DE 10/11/2020 QUANTO AO TITULO. |

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2021-08-17| B25A| Requested transfer of rights approved|Owner name: SHIRE HUMAN GENETIC THERAPIES, INC. (US) |

优先权:

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申请号 | 申请日 | 专利标题

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US201161553094P| true| 2011-10-28|2011-10-28|

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US61/553.094|2011-10-28|

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US201261607503P| true| 2012-03-06|2012-03-06|

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US201261607487P| true| 2012-03-06|2012-03-06|

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US61/607.487|2012-03-06|

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US61/607.503|2012-03-06|

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PCT/US2012/062284|WO2013063512A1|2011-10-28|2012-10-26|Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases|

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