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    • 专利摘要:
    The present invention provides methods and compositions that can slow gastrointestinal tract migration and prolong residence time, thereby optimizing the presence and absorption of the ingested nutrients and / or pharmacologically active agents in the small intestine. The present invention also provides methods and compositions that can enhance the bioavailability and therapeutic efficiency of pharmacologically active agents.
    公开号:KR19990014865A
    申请号:KR1019970708210
    申请日:1996-05-16
    公开日:1999-02-25
    发明作者:린헨리씨.
    申请人:피터 이. 브래이브맨；세다르스-신나이메디칼센터；
    IPC主号:
    专利说明:

    Compositions containing fatty acids for enhancing digestion and absorption in the small intestine
    The main function of the gastrointestinal tract is to process and absorb food. The stomach is a storage and digestive organ and works to optimize conditions for digestion and absorption of food in the small intestine. The small intestine is located above and before the large bowel (colon) and includes three areas: the duodenum, jejunum, and ileum. The main function of the small intestine is to absorb digested nutrients.
    The pathways to digestion and absorption of nutrients through the gastrointestinal tract of the food are controlled by a complex system of inhibitory and stimulatory motility mechanisms, which are influenced by the composition of the ingested food. Receive. Specific sensors in the small intestine respond to fat, protein, carbohydrates, osmolality acidity and food size. These detectors activate palpatory and inhibitory locomotor activity, regulate intestinal transit, thereby shortening or extending material residence time in the small intestine. Since digestion and absorption are both time-dependent processes, the rate of passage through the small intestine is very important for the rate, extent (size) and location (duodenum, jejunum, ileum or colon) of digestion and absorption in the gastrointestinal tract.
    The contact time of the substances with the mucous membrane of the small intestine is crucial for digestion and absorption. Thus, control of digestive tract movement and transit time through which the substance passes through the gastrointestinal tract will not only ensure optimal digestion and utilization of the absorbent surface, but will also prevent overloading of the absorption mechanism, resulting in intraluminal contents. It will prevent it from flowing into the colon (this can often happen if the substrates pass too quickly and exceed the absorption capacity of the epidermis already loaded in the small intestine).
    Important steps in the absorption of dietary lipids begin by controlling gastric emptying in the stomach, thereby placing a system of suppression and promotion mechanisms for controlling the movement of the digestive tract. Once food enters the small intestine and brakes the nutrient-sensitization deterrent sensors, these devices prevent the contents of the stomach from emptying into the duodenum prematurely, and this premature emptying overturns the absorption of lipids. It may be. However, at the beginning of a meal, before the nutrition-braking suppressors are sufficiently activated and depending on the load, fat may pour out of control from the stomach. Thus, after eating a large amount of fat, the fat will pour into the small intestine, overturn the proximal small intestine, and flow into distant factories and ileums. Appropriate action of the gastric emptying regulators prevents these events from occurring and enhances maximum contact with the water insoluble lipids and the soluble contents of the intestinal tract.
    Thus, depending on the extent to which fat is poured into the small intestine, that is, after ingesting a small amount of fat, only the proximal small intestine (the duodenum and proximal plant) will provide fat. In the duodenum, jejunum and / or ileum, fats released from the stomach meet with bile acids and enzymes of the pancreas. The function of the bile acids is to act as a surfactant that draws insoluble triglyceride molecules into solution, allowing digestion by the enzymes of the pancreas and uptake by the cells of the small intestinal mucosa.
    By controlling the rate of movement (the longer the residence time in the small intestine, the more fat-containing food is completely digested and absorbed), the intestinal absorption of lipids is normally effective for a wide range of dietary fat intake. Normally, normal people absorb approximately 95% to 98% of their dietary lipids. However, malabsorption syndrome often occurs when normal digestion and absorption processes or control of intestinal migration are impaired. For example, it usually takes two to four hours for food to reach the colon. This is a time sufficient for complete digestion and absorption. However, if gastrointestinal movement is abnormally promoted, it is not enough time for complete digestion and absorption.
    In addition to nutrients, water, vitamins, minerals and electrolytes, the small intestine is also an important place for the absorption of drugs or drugs. The proximal part of the small intestine has a maximum dose for the absorption of drugs. Intestinal absorption of drugs is greatly influenced by many of the same basic factors that affect digestion and absorption of nutrients, water and electrolytes.
    In order for drug absorption to proceed effectively, the drug must first reach a normal absorptive surface in a form suitable for absorption; Dwell for a sufficient time in a form and concentration that facilitates absorption; Normal epithelial cells must be absorbed, not digested by these cells. In addition, if the drug is delivered in the solid phase, the drug must dissolve before being absorbed. Therefore, the residence time in the gastrointestinal tract should be sufficient to allow complete dissolution and absorption of the drug. By doing so, significant advantages can be obtained if the dosage form of the medicament can be maintained in the stomach and / or in the small intestine for a long time so that proper absorption can occur.
    Absorption of drugs in the gastrointestinal tract depends not only on the properties of the gastrointestinal tract, but also on the properties of the drug, for example the molecular structure of the drug. The rate of absorption of certain drugs that are slowly and usually incompletely absorbed varies with the time of travel in the small intestine. Normally short (2-4 hours) intestinal transit time is an important and limiting factor in drug absorption, but the optimal absorption site of the drug is only a specific segment of the gastrointestinal tract, mostly proximal small intestine (duodenum and proximal Factory), the travel time is very important. This phenomenon is referred to as an absorption window (Davis, Small Intestine Transit, Ch. 4, pp. 57-58, in Drug Delivery to the Gastrointestinal Tract, Hardy et al. (Eds.), Ellis Horwood Ltd (1989). The passage of this site is so fast that complete dissolution and absorption of the drug cannot occur there.
    The methods currently used to increase the contact time of drugs with absorbed blood in the small intestine have not been so successful. Examples of these methods include prescriptions that delay the release of the active drug (eg, sustained-release formulations), bioadhesives that adhere to the intestinal mucosa (eg, polycarbophil (polycarbophil) and methods associated with maintenance of the dosage form in the stomach (e.g., tablets based on alginate and hydroxypropylmethylcellulose or gastric contents using swellable devices that swell in the stomach to form large drug-containing pills). Flotation at the top of the plane. The Stomach: Its Role in Oral Drug Delivery and Small Intestine: Transit and Absorption of Drugs, Ch. 4 and 5 in Physiological Pharmaceutics: Biological Barriers to Drug Absorption, Wilson and Worthington (Eds.), Ellis Horwood Ltd. (1989).
    An enormous amount of research has been done to identify adverse effects on nutrient intake and absorption in gastrointestinal diseases (Cerda, Med. Clin. N. Am. , 77: 881-87 (1993); Meyer, Gastro. Clin. N. Am. , 23: 227-60 (1994); Thompson, Gastro. Clin.N. Am. , 23: 403-20 (1994); Farrugia et al., Gastro.Clin.N . Am. , 25: 225-46 (1996)). Despite these studies, there are currently few standardized therapies to correct abnormal nutrition and enhance digestion and absorption in most of these diseases.
    The rate at which food passes through the gastrointestinal tract is an important factor influencing absorptive efficiency (how completely nutrients are absorbed) and the consequences of gastric surgery and / or bowel resection. A wide range of intestinal resections and the loss of absorbent blood in place of the diseased small intestinal mucosa can lead to specific malabsorption syndromes as well as loss of absorption capacity. Excessive loss of the small intestine may prevent successful food feeding through the digestive tract. Excessive ileal excision or disease is also known to cause vitamin B 12 and bile acid deficiencies, which can lead to less absorption of fats and other fat soluble compounds, such as vitamins. Strictures or intestinal transplant loops caused by surgery or the formation of fistulas may lead to blind loop syndrome with bacterial overgrowth and subsequent malabsorption. Even after treatment with antibiotics for bacterial overgrowth, the degree of malabsorption of fat is often more severe than expected from loss of absorbed blood. Abnormal rapid transits resulting from the loss of mobility control mechanisms provide another explanation for the indigestion and absorption in this state. By shortening the time required for digestion and absorption, the contact of nutrients with the already reduced absorbed blood is further limited.
    After intestinal surgical procedures, the most important treatment goal is to restore nutrition to maintain the patient's nutritional status. If necessary, this is often accomplished by parenteral nutrition in the early postoperative period. Intestinal nutrient intake can begin early after surgery. Maximization of the intestinal absorption of nutrients is important for successful intestinal food intake. In general, in order to maximize this in postoperative patients with impaired digestion and absorption, the intestinal intake needs to significantly exceed the normal nutritional needs necessary to ensure that the nutritional requirements are met. .
    Disruption of the normal digestion and absorption process results in various lesions such as weight loss, malnutrition, diarrhea, thirst, steatorrhea, vitamin deficiency, electrolyte imbalance, and the like.
    Absorption syndromes are associated with a wide variety of gastrointestinal disorders with common characteristics that do not normally assimilate the ingested substances. This defect degrades or damages the functions of most of the digestive system, including the stomach and intestines, as well as the liver, bile tract, pancreas, and lymphatic system. Clinical symptoms range from the complex severity of rapid bowel movements, dumping syndrome, diarrhea, thirst, weight loss, distension, lipectomy, and asthenia to deficiency of certain nutrients (eg malnutrition). And vitamin deficiency).
    Examples of gastrointestinal disorders that frequently manifest as one or more indigestion or malabsorption symptoms include inflammatory bowel disease, gastrectomy symptoms, rapid movement syndrome, chronic diarrhea associated with AIDS, diarrhea associated with diabetes, and postvagotomydiarrhea after vagus nerve resection Diarrhea associated with bariatric surgery-associated (including obesity operations: gastric bypass, gastroplasties, intestinal bypass), and short bowel syndromes (including intestinal resection due to trauma, radiation-induced complications, Crohn's disease and infarction due to vascular occlusion), diarrhea associated with tube-feeding, chronic secretion Diarrhea, carcinoid-related diarrhea, gastrointestinal peptide tumors, endrine tumors, chronic diarrhea associated with thyroid disease, bacterial overload Chronic diarrhea associated with multiple gastrinomas, chronic diarrhea associated with multiple gastrinomas, cholera diarrhea, chronic diarrhea associated with giardiasis, chronic diarrhea associated with antibiotics, diarrhea-predominant irritable bowel disease, indigestion and Chronic diarrhea associated with malabsorption, chronic diarrhea associated with idiopathic primary gastrointestinal motility disorders, chronic diarrhea associated with collagenos colitis, acute diarrhea associated with surgery, acute diarrhea associated with antibiotics, acute and chronic infectious Diarrhea, cirrhosis, chronic alcoholism, pancreatic insufficiency, pancreatic resection, cholestatic liver disease, celiac sprue, long-term parenteral nutrition, gastrointestinal bypass surgery, Whipple's disease, anorexia nervosa, bulimia (and other appetite-related disorders), AIDs intestinal disease, thyrotoxicosis, and hypothyroidism (hypopara) endoroid diseases such as thyroidism, protein-losing gastroenteropathies, and the like.
    In general, short bowel syndrome is associated with a condition in which the remaining small intestine is less than 150 cm in size and at the same time a large loss of absorbability. Short bowel is characterized by severe diarrhea or poor absorption. Patients with this disease often do not absorb water, electrolytes, vitamins, proteins, carbohydrates, and fats, resulting in chronic thirst, electrolyte depletion, vitamin deficiency, diarrhea, fecal incontinence, calorie depletion, fatty stool and Causes weight loss.
    Pancreatic insufficiency can also lead to fatty degeneration after gastrectomy. Lipodialysis is the presence of excess fat in the stool. This is usually caused by deficiencies in gastrointestinal digestion and / or absorption. Lipodialysis is due to poor absorption of other substances. For example, conditions such as osteomalacia associated with calcium and vitamin D deficiency or anemia due to iron deficiency or B 12 deficiency are often associated with poor malabsorption in lipodialysis. Weight loss is caused by loss of nutrients and calories. Diarrhea and chronic thirst are other major symptoms associated with lipectomy. This was seen in 80-97% of patients with malabsorption.
    Rapid movement syndrome is one of the most common causes of morbidity after gastric surgery. This syndrome is characterized by gastrointestinal syndrome and vasomotor syndrome. Gastrointestinal syndromes include postprandial fullness, crampy abdominal pain, nausea, vomiting and explosive diarrhea. Vasomotor syndrome includes diaphoresis, weakness, dizziness, flushing, palpitation, and a strong desire to lie down. These syndromes are caused as a direct result of rapid migration and abnormal supply of nutrients to the small intestine. Poorly regulated food supply results in abnormally overloaded nutrients or abnormally large chunks (badly broken) of food into the small intestine. This spilling extends the length of the nutrient spread through the digestive tract. Patients with severe dystonia may limit their food intake to weaken the syndrome, resulting in weight loss and poor nutrition. In severe cases, surgical treatment of rapid movement syndrome has been used as a last resort.
    Current pharmaceutical treatments for rapid movement syndrome include octootide acetate (Sandoz), a long-acting somatostatin homologue, and have been used to some extent. Octreotide is administered subcutaneously, slows gastric emptying, inhibits insulin release, and indiscriminately reduces intestinal peptide secretion. Unfortunately, because normal digestive function requires the release of some digestive tract peptides (which appear in the normal supply of nutrients), the use of octreotide may induce injection site pain, tachyphylaxis, iatrogenic diabetes, It involves a number of complications, including malabsorption and cholelithiasis.
    Diarrhea is a common problem associated with many gastrointestinal disorders and abdominal operations. Current treatments include simple dietary changes, combinations of opiate and / or opioid drugs such as diphenoxylate hydrochloride and atropine sulfate from Lomotil ™. Commercially available), loperamide hydrochloride (commercially available from Janssen as an Imodium TM product), opium camphorated tincture (commercially available from Lilly as a Paregoric ™ product), and opiates Camphor tincture of opiate with opiate, pectin and kaolin (commercially available as Parepectolin ™ from Rhone-Poulenc Rorer); Preparations for inhibiting intestinal motility, such as attapulgite (commercially available as Diasorb ™ from Key, or Kaopectate ™ from UpJohn), kaolin, hyoscyamine sulfate and atropine sulfate And complexes with scopolamine hydrobromide (commercially available from Robins as Donnagel ™ ), opiates in Donnagel ™ (commercially available from Robins as Donnagel-PG ™ product), difenoxin hydrochloride And complexes with atropine sulfate (commercially available from Carnick as the Motofen ™ product), and bismuth subsalicylate (commercially available from Proctor Gamble as the Pepto-Bismol ™ product). However, each treatment modality has been limited in success and has the side effects of use, with the exception of dietary changes. Because many diarrhea patients complain of abdominal cramps (due to abnormal movements and resulting dilatation of the dilated digestive tract), various antispasmodics have also been described, as described above, for phenobarbital and thiosucciamine sulfate. and composites of the persulfate atropine and hydrobromic acid Hi agarose chiahmin (from that commercially available as Donnatal TM product Robins), hydrochloric acid di cycloalkyl Min (dicyclomine hydrochloride) (available commercially as Bentyl TM product from Marion Merrell Dow), sulfate Hi agarose chiahmin (Commercially available from Schwarz Pharma as the Levsin ™ product), and propanetheline bromide (commercially available from Seale as the Pro-banthine ™ product). Unfortunately, these drugs are associated with serious side effects.
    Diarrhea is also a common complication associated with intestinal food intake. The hypoallergenic pathogenesis of diarrhea has been assumed, the occurrence of which may be a multifactorial process (Edes et al., Am. J. Med . 88: 91-93 (1990)). Examples of etiology include simultaneous use of antibiotics or other diarrhea-induced drugs, altered bacterial phase, excessive dominant effects on nutrient-braking suppression feedback in the composition of the formulation, rate of infusion, rate of intestinal migration, hypoalbuminemia ) And clouding of bowel prescriptions. In addition, the composition of the prescription may affect the occurrence of diarrhea. The fiber-containing regimen used to suppress diarrhea associated with tube feeding causes upset stomach (Frankenfield et al., Am. J. Clin. Nutr. , 50: 553-558 (1989)).
    Malnutrition is a common problem in patients with inflammatory bowel diseases such as Crohn's disease or ulcerative colitis. Weight loss was found in 70-80% of people with Crohn's disease and 18-62% of patients with ulcerative colitis. The role of nutrient intake as the primary treatment for inflammatory bowel disease is not well established. In inflammatory bowel disease with congenital history, frequent recurrences and natural healings, difficulty in quantifying the degree of disease, many changes, and difficulty in planning clinical trials have led to the identification of nutritional intake as the primary treatment for inflammatory bowel disease. Insufficient. In addition, the use of elemental diets as the primary treatment for inflammatory bowel disease has been demonstrated. Parenteral nutrition and a basic diet seem to limit the long-term use of patients with inflammatory bowel disease.
    Many drugs and formulations suppress gut inflammation associated with inflammatory bowel disease and physiological and physicochemical limitations associated with drug delivery (eg, instability, short half-life on biologics, inefficient absorption and poor biomarkers). It has been developed and continues to be developed because it is necessary to eliminate the utilization rate. Many patients have abnormally promoted intestinal migration (retention in the small intestine is less than one hour). In this state, techniques for controlling release have been applied in order to be able to control the absorption of the drug by slowing down the release of the active drug from the formulation containing the drug. This simply exacerbated the mismatch between the time required for the release of the active drug and the time at which the drug could be absorbed (short intestinal transit time). As a result, many drugs are not absorbed and enter the colon or toilet. Patients do not respond to oral drugs because the drugs are not delivered to the site of absorption, not because of the ineffectiveness of the drug, but due to altered digestive motility and intestinal migration rates. Recent pharmaceutical attempts to alter gastric emptying and intestinal transit time have not been so successful, including the use of bioadhesives (Khosla and Davis, J. Pharm. Pharmacol. 39: 47-49 (1987) Davis et al., Pharm. Res. 3: 208-213 (1986); Davis, p. 58, in Drug Delivery to the Gastrointestinal Tract (1989)).
    Thus, there is a need to adjust the gastrointestinal tract migration, that is, the time at which digestion and absorption of nutrients is possible and / or the time at which dissolution and absorption of oral drugs is possible. In order to optimize the absorption of the ingested nutrients and / or pharmacologically active agents in the small intestine, there is a need for an effective way to control the movement in the digestive tract, thereby preventing and / or reducing the invalidation of these substances by poor absorption. Do.
    Most drugs have a short half-life in biologics. Thus, frequent dosing is necessary to maintain therapeutic blood levels of these drugs. Frequent dosing has a problem of weakening patient compliance (it is difficult to take the drug four times daily for long periods of time). Due to the rapid rise and fall of the plasma drug content (a sharp vibrating drug peak and valley effect), which is characteristic of drugs with short half-lives, plasma drugs within a range of treatment times long enough that the next dose is not required immediately. It is necessary to dose a significant amount to maintain the content. For drugs with a narrow range of therapeutic plasma contents, these high doses may be associated with a risk of toxicity. In addition, this wide amplitude may be dangerous and undesirable for the treatment of many diseases. For example, wide amplitudes of bronchodilators in asthma patients can cause disease recurrence. Organ rejection may be the result of a very temporary drop in the content of the immune response inhibitor below the therapeutic content range. Dosing the drug at frequent intervals can also cause undesirable and unexpected accumulation of drug in the body. For example, the following doses can be added to the remainder of the previous doses to increase the plasma content even higher.
    There is strong evidence of the usefulness of controlled drug delivery. For example, in the case of sustained-release prescriptions of nitroglycerin, there is a need for lower doses (financial benefit plus fewer side effects) and reduced incidence of chest pain (Winsor et al., Chest , 62: 407 (1972)). I have met. In the case of procainamide, an anti-arrhythmic agent, the sustained release regimen extended the dosing interval from 3 to 6 hours (Graffner et al., Clin. Pharmacol. Ther ., 17: 414). (1975). It has been suggested that all drugs with a half-life of less than 4 hours benefit from controlled controlled release (Heimlick et al., J. Pharm. Sci ., 50: 232 (1961)). Drugs with long half-lives on biologics (e.g., bishydroxycoumarin, chlordiazepoxide, chlorphenteramine, chloropropamine, diazepam, etchlorby Lee and Robinson Drug Properties Influencing the Design of etchlorvynol, digitoxin, digoxin, meprobamate, phenytoin, and warfarin Sustained or Controlled Release Drug Delivery System in Sustained and Controlled Drug Delivery System, JR Robinson (Ed.) Marcel Dekker (1978)), The number of drugs that can benefit from a controlled supply to the gastrointestinal tract is enormous. In the case of drugs with a narrow therapeutic window, for example cyclosporin (an immunosuppressive agent used to prevent rejection of transplanted organs), the drug content is increased, resulting in a high peak ( It may slow the plasma profile of sharp peaks so that they can be maintained within the therapeutic content range, which may be associated with toxicity) or low valleys (which may be associated with rejection complications). Prescription is very desirable.
    To date, the pharmaceutical industry's efforts to achieve this objective have not been so successful. Most of these efforts have focused on changing the physicochemical properties of drug prescriptions. In other words, all efforts have focused on drug delivery systems rather than on the organ where the drug is absorbed and targeted by the drug. These efforts can be divided into physical, chemical and biological modifications (Lee and Robinson (1978)). Physical modifications used in the art include: 1. Dissolution time of active agents and through enteric coatings, microencapsulation, polymer coatings, multiparticulate systems, and other release delay products. Delaying release of the active drug (Healey, JNC, Enteric Coating and Delayed Release in Drug Delivery to the Gastrointestinal Tract, Davis and Wilson (Eds.), Pp. 97-110, Ellis Horwood Ltd. (1989)); 2. slowing the spread of drugs; 3. Using osmotic pumps (eg Osmet TM , Oros TM , and Alzet TM (Alza Corp.)) which release the active ingredient using the driving force by osmotic equilibrium through the semipermeable membrane (Davis and Fara, Osmotic Pumps in Drug Delivery to the Gastrointestinal Tract, Davis and Wilson (Eds.), pp. 97-110, Ellis Horwood Ltd. (1989)); 4. using mechanical pumps; 5. using ion exchange; 6. using hydraulically balanced capsules (Sheth and Taussounian, US Pat. No. 4,167,558 (1979)); 7. using hollow capsules / solid foams (Watanabe et al., US Pat. No. 3,976,764 (1976)); 8. using an inflatable balloon (Michaels et al., US Pat. No. 3,901,232 (1975)); 9. using a swellable polymer matrix (Mamajek and Moyer, US Pat. No. 4,207,890 (1980)); And 10. using bioadhesive polymers (Ch'ng et al., Proc. Amer. Pharm. Assoc. Acad. Pharm. Sci., 13: 137 (1983)). Chemical modifications used in the art include: 1. the use of homologues; And 2. Use of prodrugs. Biological modifications used in the art include the use of inhibitory enzymes that delay metabolism of the active drug.
    Except for the use of enzyme inhibitors to slow the metabolism of the drug, all of the above efforts are related to oral drug prescription and have not been so successful. No effort was involved in controlling the movement of drug prescription through the gastrointestinal tract. To date, Dressman says that in humans, no reproducible way of prolonging residence time in the small intestine has been demonstrated (Kinetics of Drug Absorption from the Gut in Drug Delivery to the Gastrointestinal Tract, Davis and Wilson). (Eds.), Pp. 195-219, Ellis Horwood Ltd. (1989). Despite all efforts by those skilled in the art, it is not surprising that the purpose of sustained release drug delivery has not been achieved.
    The widespread variability in drug bioavailability is not surprising. For example, it is known that food increases the bioavailability of certain drugs while decreasing the bioavailability of other drugs (this effect is also nutrient and load dependent; Wilson, Relationship between Pharmacokinetics and Gastrointestinal Transit in Drug Delivery to the Gastrointestinal Tract, Davis and Wilson (Eds.), pp. 161-178, Ellis Horwood Ltd. (1989)). The small and proximal small intestine (duodenum and proximal jejunum) are the main sites of drug absorption. Still, those skilled in the art are mostly focused on producing drug release delayed prescriptions. This regimen is likely to be successful for patients with rapid movement of diarrhea (for example, patients with dissected distal ileum), because the residence time in the small intestine is almost 15-30 minutes. not. Even in patients with a normal speed of movement (about 2-4 hours), full absorption may hardly occur because the drug passes through the absorption window too quickly. Therefore, the effectiveness of the delayed release regimen only slows the release of the active drug into the colon or toilet, rather than truly controlling the supply of pharmacologically active agents to the small intestine.
    Therefore, there is a need for a method that can enhance the bioavailability and efficiency of pharmacologically active agents by controlling the rate of movement through the small intestine. The present invention fulfills these needs, as well as providing related advantages.
    Summary of the Invention
    The present invention provides methods and compositions that can slow gastrointestinal tract migration, prolong the residence time in the small intestine, and optimize digestion of the nutrients or dissolution of pharmacologically active agents, as well as absorption in their small intestine. The methods of the present invention prevent and / or reduce the inefficiency of nutrients and / or pharmacologically active agents due to poor absorption. In general, the methods of the present invention comprise administering to a patient a composition containing an amount of active lipids sufficient to slow gastrointestinal tract migration and / or prolong the residence time of a substance in the small intestine.
    The present invention also provides methods and compositions that can enhance the bioavailability and therapeutic efficiency of pharmacologically active agents. The present invention also provides methods and compositions that can treat diarrhea, reduce atherogenic serum lipids, and reduce the inhibitory effects of nicotine on gastrointestinal motility machinery.
    The present invention relates to methods and pharmaceutical compositions for regulating the supply of luminal content to the gastrointestinal tract.
    FIG. 1 includes two parts, each of which is a graph showing slow bowel movement when treated with inflammatory bowel disease patients suffering from diarrhea as a result of rapid movement according to the method of the present invention (FIG. 1A and FIG. 1B).
    FIG. 2 is a graph showing improvement in bioavailability when acetaminophen, a marker drug, is ingested in dogs after administration of the composition according to the present invention. FIG.
    According to the present invention, there is provided a method of slowing gastrointestinal tract migration to extend the residence time of a substance in the small intestine of a patient for a time sufficient to cause digestion and absorption of the substance. The method of the present invention comprises administering to the patient a composition containing an amount of active lipids sufficient to slow the small intestine migration of the substance for a time sufficient to allow absorption of the substance. In a preferred embodiment, the active lipid is administered in the form of a premeal or pretreatment, about 0-24 hours prior to ingestion of the substance, and the substance moves the gastrointestinal tract for an optimal time.
    The composition of the present invention comprises active lipids and a pharmaceutically acceptable carrier. In a preferred embodiment, the compositions of the present invention comprise active lipids administered as a pre-medication or therapeutic agent. One function of the compositions of the present invention is to slow gastrointestinal tract migration and control the gastrointestinal tract residence time of the material, substantially making work in the lumen and mucosa necessary for absorption of the material in the small intestine. Another function of the compositions of the present invention is to control the supply of material to a predetermined site of the small intestine for absorption. In a preferred embodiment, the compositions of the present invention substantially prolong the residence time of material in the proximal (duodenum and proximal jejunum) of the small intestine.
    The present invention also provides methods and compositions for treating diarrhea in a patient, said methods comprising administering to the patient a composition containing an amount of active lipids sufficient to prolong the residence time in the small intestine of the luminal contents. Include. This allows the liquid to be absorbed better, thus reducing the amount of feces (less diarrhea).
    The present invention also provides pharmaceutical oral and intestinal formulations that slow gastrointestinal tract migration and prolong the residence time of the substance. The compositions of the present invention enhance the dissolution, absorption and thus bioavailability of the pharmacologically active agent ingested simultaneously or successively.
    Without wishing to be bound by any theory, the most important physiological functions by the compositions of the present invention are: Read et al., Gastro. , 86 (2): 274-80 (1984); Spiller et al., Gut , 29 (8): 1042-51 (1988); Spiller et al., Gut , 25 (4): 365-74 (1984)) and the braking of the plant in the proximal intestine ( Lin et al., Dig.Dis.Sci. , 41 (2): 326-329 (1996)). These nutrient-braking mechanisms are braked by the presence of a sufficient number of nutrient detectors in the intestine (eg, the end product of digestion). The degree of inhibition of intestinal migration depends on the number of nutrient detectors supplemented to generate feedback signals of inhibition.
    These mechanisms that slow the movement can be significantly damaged in gastrointestinal diseases such as inflammatory bowel disease. Spiller et al. (1988) can be damaged by an active disease in the ileum, or completely lost in IBD patients undergoing ilectomy. When nutrient-braking in the proximal gut is effective (Lin et al., (1996)), it is less effective than ileal braking (Zhao et al., Gastro., 108 (4): A714 (1995)). When the disease is active, factory braking is because the movement through the proximal digestive tract is too fast and the presence of the end product of digestion is insufficient and the contact time with the small intestine is not sufficient to activate this brake mechanism sufficiently. , Don't get involved.
    The present invention contemplates a range of optimal residence times depending on the nature of the material to be delivered. Substances as used herein include those ingested or located in the lumen of the gastrointestinal tract. Examples include electrolytes containing digested and partially digested foods and nutrients, pharmacologically active agents, fluids, and the like.
    Digestion, as used herein, involves the destruction of large molecules into their smaller components by enzymes and other processes in the gastrointestinal tract, so that nutrients become solutions as well as insoluble substances (eg pharmacologically active agents). Disintegration (large particles break down into their smaller constituents) and dissolution (eg, the active drug is released into solution).
    Absorption as used herein includes the transport of material from the intestinal lumen through the epithelial barrier of the mucosa and into the blood and / or lymphatic system.
    As used herein, the active lipid has a structure substantially similar to that of the end product of fat digestion, and includes molecules capable of activating the system of suppression and promotion of the gastrointestinal tract. Examples of end products of fat digestion are molecules such as glycerol and fatty acids.
    In a preferred embodiment, the active lipids comprise saturated or unsaturated fatty acids, mono- or di-glycerides, glycerol, and mixtures of two or more thereof. Fatty acids in the present invention typically have 4 to 24 carbon atoms. Examples of fatty acids used in practicing the present invention include caprolic acid, caprulic acid, capric acid, lauric acid, and myristic acid. ), oleic acid (oleic acid), palmitic acid (palmitic acid), stearic acid (stearic acid), palmitoleic acid rain (palmitoleic acid), linoleic acid (linoleic acid), linolenic acid (linolenic acid), trans-hexadecanoic acid (trans -hexadecanoic acid), elaidic acid, columbinic acid, arachidic acid, behenic acid, eicosenoic acid, erucic acid, bre Bressidic acid, cetoleic acid, nervonic acid, mead acid, mead acid, arachidonic acid, timnodonic acid, sardine acid, clupanodonic acid, Docosahexaenoic acid, structured lipids, and mixtures of two or more thereof. In a preferred embodiment, the active lipid comprises oleic acid.
    The active lipids of the present invention are preferably formulated in well dispersed form in a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers used herein include all standard pharmaceutical carriers known to those skilled in the art. Dispersion can be accomplished in a variety of ways, for example as a solution. Lipids can be prepared in a variety of ways, for example, if the solution has bile properties (e.g., with micelles mixed with added bile salts), by means of a detergent (e.g. a twin solution) or by a solvent. Can be.
    Alternatively, the dispersion may be in the form of a two-phase emulsion in which one liquid is dispersed in the form of droplets throughout the other liquid that do not mix with the liquid (Swinyard and Lowenthal, Pharmaceutical Necessities , p. 1296, REMINGTON'S PHARMACEUTICAL SCIENCES). , 17th ed., AR Gennaro (Ed.), Philadelphia College of Pharmacy and Science (1985)).
    Alternatively, the dispersion may be in the form of a suspension with dispersed solids (eg microcrystalline suspension). In addition, emulsifiers and suspending agents for human consumption may be used as excipients for the dispersion of the composition. For example, beeswax, glycowaxes, castor waxes, carnauba wax, 1,6-hexanediamine, starch, polyvinyl chloride, polyvinylpyrrolidone, gelatin coacervate, styrene- Maleic acid copolymer, shellacs, nylon, acrylic resins, silicones, 2-hydroxymethacrylate, 1,3-butyleneglycol dimethacrylate, ethylene glycol dimethacrylate, tween, acetylated Monoglycerides, hydroxypropylmethyl cellulose, gum acacias, agar, sodium alginate, bentonite, carbomers, carboxymethylcellulose, sodium carboxymethylcellulose, carrageenans, Powdered Cellulose, Cholesterol, Gelatin, Glycerol Palmitostearate, Glycerol Monostearate, Ethylcellulose, Cellulose Acetate, Cellulose Acetate Phthalay Acids, cellulose acetate butyrate acids, methacrylate hydrogels (hydrogels), polyethylene glycols, poly (dl - lactic acids), hydroxy ethyl cellulose acids, hydroxypropylcellulose acids, hydroxypropyl methylcellulose acids, methyl cellulose, Octooxynol 9, oleyl alcohol, polyvinyl alcohol, povidones, propylene glycol monostearate, sodium lauryl sulfate, sorbitan esters, stearyl alcohol, tragacanths Xanthan gum, chondrus, glycerin, trolamine, coconut oil, propylene glycol, ethyl alcohol, malts, malt extract, and the like may be used. All of these solutions, emulsions or suspensions may be combined to form capsules or microspheres or particles (coated or uncoated) contained in the capsules, or coated particles to form capsules, tablets or caplets. It may be.
    The pharmaceutical compositions of the present invention can be used in various forms, for example in the form of solids, solutions, emulsions, dispersions, micelles, liposomes, and the like, wherein the composition obtained is an active ingredient, and at least one active according to the present invention. The lipids are contained in the form of a combination with an organic or inorganic carrier or excipient suitable for enteric or parenteral preparations. The active ingredient is, for example, tablets, caplets, pills, lozenges, pellets, capsules, dispersible powders or particulates, solutions, emulsions, suspensions, syrups, elixirs, intestinal prescriptions, sustained release Formulated in a pharmaceutically acceptable non-toxic carrier for sexual systems and the like. Those skilled in the art will appreciate glucose, lactose, calcium carbonate, calcium phosphate, sodium phosphate, alginic acid, tragacanth gum, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, magnesium stearate, stearic acid, talc, corn starch, keratin, It will be appreciated that various carriers can be used, including colloidal silica, potato starch, urea, medium chain length triglycerides, dextran, vegetable oils, liquid paraffin, and the like. The pharmaceutical compositions of the present invention may be solid, semisolid or liquid.
    Oral compositions can be prepared according to various methods known in the art. Such compositions may be used as sweeteners (e.g. sucrose, lactose, aspartame or saccharin), flavorings (e.g. peppermint, wintergreen oil or cherries) to provide pharmaceutical formulated preparations. It may contain one or more agents selected from the group consisting of stabilizers, thickening agents, colorants, flavors, preservatives and the like.
    Fluids that can disperse active lipids, for example, shake-type beverages such as Carnation Instant Breakfast ™ , protein supplements such as high nitrogen-containing Vivonex Plus (Ross), non-dietary coffee creams such as Coffeemate ™ , Heinz ™ Instant Juicy, such as gravy, and other dietary solutions, emulsions or suspensions can all be used in the present invention. In a particularly preferred embodiment, the active lipid is mixed with a nutrient-rich beverage, such as Ensure ™ brand beverage (Ross), and taken about 0-24 hours before meals.
    Pharmaceutical oral medications may not be coated, or may be coated according to known techniques to delay catabolism and absorption in the gastrointestinal tract, thus maintaining drug action for longer periods of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. In addition, a sustained-release tablet for osmotic treatment is prepared by coating the pharmaceutical oral medicines using the techniques described in US Pat. Nos. 4,256,108, 4,167,558, 4,160,452 and 4,265,874, which are incorporated herein by reference. It may be formed. In addition, sustained-release compositions that can be used in the formulation of pharmaceutical compositions of the present invention are described in U.S. Pat.Nos. 4,193,985, 4,690,822, 3,976,764, 3,901,232, 4,207,890, which are incorporated herein by reference. And other techniques described in US Pat. No. 4,572,833.
    Without wishing to be bound by any theory, it is believed that at the beginning of the emptying of the stomach, before suppression feedback is activated, the load of fat entering the small intestine will vary depending on the weight of fat in the meal. Thus, exposure to fat is limited to the proximal small intestine after a small amount of meal, while a large amount of meal will flow further along the small intestine beyond the proximal absorption and expose the peripheral small intestine to fat. Thus, the small intestine's response to fat limits the dispersal of fat by decreasing the rate of migration, so that more absorption is complete in the proximal small intestine and less in the peripheral small intestine. In this case, the intestinal movement is suppressed load dependent by fat. Thus, whether the site of exposure to fat is limited to the proximal digestive tract or extended to the peripheral digestive tract, theoretically, the intestinal movement can be more precisely controlled.
    According to the present invention, it was observed that inhibition of intestinal migration by fat depends on the load of fat entering the small intestine. More specifically, intestinal migration is load-dependently inhibited by fat, whether nutrients are confined to the proximal segments of the small intestine or allowed to enter the entire digestive tract.
    In modern society, the gastrointestinal tract not only acts as an absorption site for nutrients, but also as a drug absorption site. Oral pharmaceutical formulations are applied for at least 80% of all the aforementioned drugs. Therefore, there is a need to maximize the therapeutic efficiency by controlling the multiple factors that affect the intestinal absorption of drugs.
    The drug must be dissolved before it can be absorbed into the gastrointestinal tract. Drugs taken in solid form must first be dissolved in gastrointestinal fluid before being absorbed, and tablets must first be destroyed before dissolving. Dissolution of drugs in the gastrointestinal tract is often a rate limiting step in determining their bioavailability. For some drugs, there is a 2 to 5 fold difference in rate or extent of gastrointestinal uptake depending on their dosage or formulation. Therefore, the method of the present invention is particularly useful for improving the bioavailability of solid drug formulations which require longer intestinal residence time compared to liquid drug formulations.
    The rate of gastric emptying directly affects the absorption of the ingested drugs and their bioavailability. Some drugs are metabolized or degraded in the stomach, and delayed stomach emptying reduces the amount of active drug absorbable. Because the methods and compositions of the present invention can also delay gastric emptying (Davis, pp. 55 and 57, in Drug Delivery to the Gastrointestinal Tract (1989)), the use of certain drugs in the stomach with increased consumption time in the stomach Protective coatings may be needed to prevent activation.
    The pharmaceutical industry has politely developed slow and / or sustained-release technology. These efforts have focused on delaying gastric emptying and slowing the release of active drug using controlled or delayed release systems. Sustained release formulations utilize several methods. Commonly a tablet containing mostly insoluble cores; Drugs applied to the outer layer are released soon after the drug is ingested, while drugs trapped inside the core are released much more slowly. Capsules contain multiparticulate units of the drug in a coating material that dissolves at different rates, which are also designed to provide a sustained release effect. However, the basic problem with sustained-release drugs is their considerable variability in their absorption because they cannot control the gastrointestinal tract.
    In fasting, the sustained release formulation moves rapidly from the stomach through the gastrointestinal tract. On an empty stomach, the exercise circulates into the intestine from the stomach to phase III of the major migratory complex (MMC), a potent lumen atrophic atrophy. Stage III of the MMC is responsible for the migration of the solid drug formulation. Since the MMC duration varies significantly (90-120 minutes), the migration of solid dosage forms (and uptake by them) depends on the time from ingestion to stage III of the next MMC. Since it is not known whether fasting exercise is in stage III, II or I upon drug intake, drug migration and bioavailability may be unpredictable (e.g., when stage III of MMC begins as soon as drug is ingested) It only takes a few minutes to move through the digestive tract, or several hours to move to the absorption site, unless the III of the next MMC returns for hundreds of minutes. After eating, the exercise pattern is converted into an acyclic pattern known as fed motility. In the fed state, the movement of the colon branch from the mouth takes 2-4 hours on average. Thus, slowing the release of the drug (eg, over several hours) without slowing the movement in the digestive tract maximizes the drug's bioavailability and extends the drug's residence time within the therapeutic range. To no avail.
    More dangerous problems can arise if a doctor over-prescribes oral medications to achieve the desired medical results. If a patient, such as an IBD patient, suffers from rapid movement, a large amount of drug needs to be administered at the same time so that an effective amount of the drug can be absorbed by the intestinal mucosa. Obviously, this is a waste of drugs. This problem is dangerous if the rapid movement of the substance through the patient's organs for some reason ends. If this happens, the patient may suddenly be able to absorb all of the excess drug, resulting in toxic problems. This is particularly dangerous in the case of drugs with narrow therapeutic windows (eg, toxicity occurs at concentrations near the effective concentration range). In the case of these drugs, over-prescription can be too dangerous, and instead the patient does not get full efficacy.
    The present invention solves the bioavailability problem described above. The methods and compositions of the present invention make it possible to control the balance of catabolism, dissolution and gastrointestinal tract migration by increasing the gastrointestinal retention time.
    In order to facilitate the absorption of drugs in the proximal small intestine, the present invention provides a method of extending the residence time in the gastrointestinal tract, allowing all dosage forms of drugs to be more completely dissolved into solution and absorbed. have. Because the compositions of the present invention slow down gastrointestinal tract migration (i.e., delay both gastric emptying and small intestine migration), it is easy to handle relatively slow dissolving dosage forms, and faster dissolving dosage forms are also a method of the present invention. And the bioavailability of the drug primarily controlled by the composition.
    The methods and compositions of the present invention are beneficial for pharmacologically active agents having slow dissolving properties. Since the active agent is released slowly, for example in formulations coated with enteric skin or packaged in sustained release formulations, the drug is likely to enter the colon with incomplete absorption. One object of the present invention is to increase the residence time in the gastrointestinal tract so that slowly dissolving drugs can be sufficiently absorbed. The advantages of the methods and compositions of the present invention are useful, even in the case of pharmacologically active agents with fast dissolution properties, because these agents can remain in contact with the site of absorption for an extended period of time to control migration and absorption.
    The methods and compositions of the present invention may also affect the synthesis of serum lipids. Postprandial serum lipids are derived from the migration of cholesterol, triglycerides and other lipids from the intestinal lumen into the mesenteric, lymphatic and finally circulatory system. Since cholesterol and triglycerides are insoluble in lymphatics and plasma, the migration of these lipids occurs using a glycoprotein-containing carrier called chylomicron. Absorption of fat from the lumen is rate-limiting for the proximal 1/2 intestine. On the other hand, E. coli synthesis or release is rate-limiting for the distal small intestine. As a result, the chylomicron formed by the peripheral small intestine is larger than that formed from the proximal small intestine (Wu et al., J. Lipid Res., 16: 251-57 (1975)). Glycoprotein lipase enzymes in the capillaries of the peripheral circulation system hydrolyze and remove most triglycerides from chylomicrons. The remaining glycoproteins are rich in cholesterol esters, potentially atherosogenic, and called chylomicron remnants. Postprandial glycoproteins are then removed from the circulatory system by the liver (Zilversmit, Circulation , 60 (3): 473 (1979)). Increasing the content of atherogenic serum lipids is directly related to atherosclerosis (Keinke et al., QJ Exp. Physiol ., 69: 781-795 (1984)).
    The present invention provides a new method of minimizing atherosclerosis postprandial lipemia by maximizing fat absorption in the proximal gut. In other words, the present invention provides a novel method by which the small intestine kinetic response to luminal fat can be regulated prior to absorption of atherogenic postprandial serum lipids.
    Preabsorptive control relies on braking specific patterns of the proximal intestinal kinetic system that can slow migration and minimize the inflow of fat into the peripheral digestive tract. After a small intake of fatty foods containing cholesterol, the small intestine restricts the fat absorption site to the proximal small intestine by activating a nonpropagated exercise to slow intestinal migration. Since the coarse grains produced by the proximal small intestine are small in size, the size distribution of postprandial glycoproteins is shifted to minimize postprandial fatemia. However, while eating high cholesterol, high fat diets, the ability to optimize the proximal fat absorption of the small intestine is reduced, as the effect of fat on non-developmental exercise decreases in time dependent. As a result, after the first one to two hours, faster intestinal migration shifts the lumen fat to the peripheral small intestine, where large cholesterol-rich, atherosclerosis is formed and released into the circulation.
    Limiting the distribution of fat to the proximal small intestine also slows down the inflow of fat into the circulation between postprandial meals. The formation of chylomicrons depends on the effectiveness of lipoproteins (apo-A IV) and because the synthesis of apo-A IV by the proximal small intestine is stimulated by exposure to fat in the peripheral small intestine (Kalogeris et al., Gastro ., 108: A732 (1995)), the present invention reduces serum lipids by reducing the stimulation of the peripheral digestive tract for apo-A IV synthesis of the proximal gut. By slowing intestinal migration, the methods and compositions of the present invention increase fat absorption by the proximal small intestine, thereby reducing the inflow of fat into the peripheral small intestine. The lower amount of fat comes into contact with the peripheral digestive tract, resulting in less stimulation of the production of apo-A IV by the proximal small intestine, and slower entry of the chylomicron into the circulatory system. Reduces the risk of food atherosclerosis).
    The present invention also provides novel methods and compositions for reducing the rate of intestinal movement in smokers. Studies have reported nicotine to inhibit intestinal motility (Carlson et al., J. Pharm. Exp. Ther. , 172: 367-76 and 377-383 (1970); Weissbrodt et al., Eur. J. Pharmacol ., 12: 310-319 (1970). In the postprandial state, this nicotine-related inhibitory action potentially reduces the movement of protective, braking, or non-development patterns normally braked by fat. As a result, nicotine may promote the influx of ingested lipids into the peripheral small intestine and impair pre-absorption regulation exerted by the lipids. The method of the present invention provides a means for minimizing nicotine-related inhibitory effects on post-prandial nutrient-braking motor responses. In addition, the methods of the present invention provide a means of maximizing fat absorption of the proximal digestive tract by reducing the rate of migration in the gastrointestinal tract and reducing the influx of ingested lipids into the peripheral small intestine.
    The methods and compositions of the present invention require an effective amount of active lipids. An effective amount of active lipid is an amount that is effective in slowing gastrointestinal tract migration and regulating the supply of substances to certain areas of the small intestine. For example, the effective amount of active lipids contemplated in the present invention is the amount of active lipids capable of braking all of the following reflexes: intestinal-lower esophageal sphincter (relaxation of low esophageal sphincter); Gut-gastric feedback (stomach emptying inhibitory action); Intestinal-intestinal feedback (President-factory feedback / chair braking, factory-factory feedback / factory braking (for control of movement and movement, as well as for intestinal-to-field reflexes to enhance intestinal absorption), intestinal-CNS feedback (E.g., potentiating intestinal signals for satiety)); Intestinal-pancreatic feedback (regulating secretion of exocrine enzymes); Intestinal-biliary feedback (biliary outflow control); Intestinal-mesenteric blood flow feedback (for control of red blood mucosa); Intestinal-colon feedback (so-called gastric-colon reflexes, whereby the colon contracts in response to nutrients in the proximal small intestine).
    In a preferred embodiment, the compositions of the present invention are administered in such a way that the active lipid dispersion can be supplied to the small intestine of a predetermined length. For example, it may be supplied to the small intestine of the battlefield. This distribution of active lipids will dampen the maximum response of the reflexes described above. Since low content damps weak reactions (i.e., delays migration less), it is desirable to administer the active lipids in an amount in which a desired effect can be obtained. In a preferred embodiment, the amount of active lipid administered to an adult patient is about 0.25 g to about 20.0 g per serving. In a more preferred embodiment, the amount of active lipid administered to an adult patient is about 0.5 g to about 6.0 g per serving.
    As used herein, a premeal contains an effective amount of active lipids that can substantially increase the retention time of a substance in the small intestine, and is a solid or liquid that is administered to the patient about 0 to 24 hours before ingesting the substance. Formulations of In another embodiment, the pre meal preparation is administered about 0-2 hours before ingesting the substance. In a preferred embodiment, the pre-medication is administered about 15-45 minutes before ingesting the substance. Therefore, the important point in pre-medication preparations is to control the time of administration so that the active lipid component can activate the system of suppression and promotion of the gastrointestinal tract and optimize the residence time of the substance in the small intestine.
    The use of the composition for enteral feeding of the present invention may be contemplated by adding the composition directly to the feeding regimen, in addition to pre-medication preparation. The compositions of the present invention can be formulated into the intestinal regimen required by the user if the delivery rate of the formulation is known (i.e., adding a composition capable of delivering only a predetermined amount of active lipid). Alternatively, the compositions of the present invention may be formulated in a factory where an intestinal prescription is prepared to have different concentrations of active lipid composition, and may be used according to the delivery rate of the prescription (ie, high concentration of active lipid when the delivery rate is low).
    The residence time in the small intestine for optimal absorption of digested food and nutrients can be calculated using the average orocecal (mouth to cecum) travel time as a reference. Normal buccal shift time is about 1 hour to about 6 hours on an empty stomach and 2 hours to about 4 hours when fed. The composition of the present invention, when used to promote absorption of ingested nutrients, aims to set the intestinal residence time within or above an average time frame of preferably approximately 2-4 hours.
    The pharmaceutical industry has published a great deal of information on dissolution times for individual pharmacologically active agents and compounds. This information is found in numerous pharmacological publications, and these publications are already available. For example, if the dissolution and release time of drug X in the in vitro model is 4 hours, the residence time for optimal absorption of drug X in the small intestine should be at least 4 hours, and additionally the gastric emptying may occur in vivo. It may also include the time it takes. Thus, in the case of pharmacologically active agents, the appropriate residence time depends on the time required for the release of the active agent. The present invention provides the opportunity to simultaneously control two variables, gastrointestinal transit time and release time of the active agent. There are many potential variables in creating a bioavailability profile of an ideal drug for each drug and for each disease.
    In order to extend the biological activity to have a simple daily dosage regimen, the present invention provides a composition of the invention as a premeal, i.e. before ingesting food, nutritional and / or pharmacologically active agents to be delivered. To administer. In a preferred embodiment, the compositions of the present invention are administered up to 24 hours prior to ingesting the food, nutrition and / or pharmacologically active agent (depending on the formulation). When delivered as a pre-medication, active lipids are consumed about 0-24 hours before ingesting the targeted food or pharmacologically active agent (0-2 hours before in other embodiments, 15-45 minutes before in more preferred embodiments). do. The time period before ingestion is determined according to the exact formulation of the composition of the present invention and the targeted pharmacologically active drug. For example, if the active lipid formulation itself is included in the release control system, the time and duration of release required for release of the active lipid will determine the time of administration of the composition. Sustained release formulations of the composition are useful because they can prolong intestinal exposure to active lipids, thereby maintaining the intestinal feedback effect.
    If the composition of the present invention is added to an intestinal prescription and the prescription is continuously delivered to the small intestine, the composition initially present in the nutritional formula will slow the movement of the delivered nutrition then and thereafter. With the exception of the beginning of feeding (when the migration is too fast because the inhibitory feedback from the composition has not yet been sufficiently active), once equilibrium is established, logically, no more, the physiological system, even though the physiological principles are still the same There is no need to deliver the composition as.
    Methods of administration are known to those skilled in the art and include, but are not limited to, oral administration, tube administration and intestinal administration.
    In one embodiment of the invention, the active lipid may be prescribed in enteric skin or sustained release formulation so that intestinal migration can be delayed for an extended time. In addition, pharmacologically active agents can be packaged in enteric skin or sustained release formulations so that they can be released slowly. This combination will have the longest biological activity, which is good if it is undesirable to have a high initial drug plasma peak.
    In another embodiment, the pharmaceutical agents of the present invention are formulated to allow controlled release of active lipids (enteric or sustained release formulations) and formulations for rapid release of pharmacologically active agents (tablets or capsules with rapid dissolution properties, Or a liquid composition). This convenient treatment can be used to retain the active agent in the proximal small intestine for a time sufficient to allow full absorption of the drug at any time when a high initial peak of the drug is required.
    In another embodiment of the invention, the composition of the invention may be prescribed in a rapid release formulation. This formulation may be administered in conjunction with or successively with pharmacologically active agents prescribed in enteric or sustained release formulations.
    In addition, according to the present invention, it is also possible to mix a formulation which allows the composition of the invention to be rapidly released and a formulation which allows the pharmacologically active agent to be released rapidly.
    Thus, the methods and compositions of the present invention, in combination with current pharmaceutical sustained release techniques, can control not only the movement in the gastrointestinal tract and the residence time of the pharmacologically active agent, but also the release time of the active agent. More specifically, the mixing of the methods and compositions of the present invention with existing sustained release techniques can control the double alleles that affect the intestinal absorption of the pharmacologically active agent. Control over these factors can maximize the bioavailability of all pharmacologically active agents and maximize the therapeutic efficacy.
    The following examples are intended to illustrate the invention and are not intended to limit the invention.
    Example I
    The application of oleate in the proximal field shows the presence of a factory braking system.
    Fat absorption has long been thought to be a unique function of the proximal small intestine (Borgstrom et al., Gastro. , 45 (2): 229-38 (1963)), but it has recently been found to be flawed in this concept (Lin et al. , Gastro ., 107: 1238a (1994); Lin et al., Am. J. Physiol ., In press (1996b). Instead, during a typical meal (fat load 60 g), both the proximal and peripheral small intestines participate in the absorption of these nutrients. The idea that fat is normally provided in the peripheral small intestine is important not only for normal control of gut movement but also for understanding the rapid movements seen in IBD patients. Injecting fat directly into the ileum slows gastric emptying and intestinal migration by the action of ileal braking (Read et al., (1984); Spiller et al., (1984)). In particular, this reaction is determined by the availability of fatty acids, the end products of fat digestion. Since the early reports of ileal braking, this peripheral gut response has been considered the only nutrient-braking control mechanism that governs intestinal migration.
    However, in short bowel patients without ileum, fat absorption was still increased in a load-dependent manner (Woolf et al., Gastro ., 84 (4): 823-828 (1993)). For these patients, it is impossible for ileal braking to occur and the absorbable epidermal area is fixed, suggesting that there is an inhibitory mechanism in the proximal gut. Recently, such a mechanism has been discovered, ie a jejunal brake that reacts to oleic acid, the product of fat digestion (Lin et al., (1996)).
    Therefore, in six dogs with duodenum (10 cm from the pylorus) and midgut (160 cm from the pylorus) fistula, 0, 15, 30 or 60 mM oleate was added in phosphate buffer at pH 7.0. Foley for occlusion in the peripheral limb of each fistula during delivery to the proximal ½ digestive tract (between fistulas) at a rate of 2 ml / min for 90 minutes, at a rate of 2 ml / min for 90 minutes. Intestinal migration through a test segment (between fistulas) of 150 cm was compared). 60 minutes after the start of perfusion, ~ 20 μCi of 99m Tc-DTPA (diethylenetriamine pentaacetic acid) was delivered to the test segment as a bolus. Then, every 5 minutes, the radioactivity of the 1 ml sample collected from the complete conversion product of the midgut fistula was counted and measured.
    Intestinal shift was calculated by calculating the square root of the area under the cumulative recovery curve (AUC) of the radioactive marker. The square root AUC (Sqrt AUC) value varied between 0 (ie, no recovery for 30 minutes) and 47.4 (ie, theoretical, instantaneous complete recovery at 0 hours). Results were reported as mean ± standard deviation.
    Factory braking: cumulative recovery of 99m Tc for 30 minutes Olate Content (mM)Average cumulative recovery,%sqrt AUC 0 (buffer)95.540.9 ± 2.6 1564.333.8 ± 2.9 3054.729.8 ± 3.5 6038.721.5 ± 4.6
    Intestinal migration was found to be inhibited by plant braking in a content-dependent manner by oleic acid when fat was confined to the proximal ½ small intestine (p <0.005, 1-way ANOVA). Since observed plant braking is initiated by oleic acid, the end product of fat digestion, improper fat hydrolysis (due to inadequate utilization of the end product of fat digestion) suggests that the above-mentioned researchers inhibited intestinal migration by fat in the proximal digestive tract. This is a description of what was not observed (Higham and Read, Gut , 31 (4): 453-38 (1990); Read et al., (1984)).
    Example II
    Fat in the peripheral digestive tract inhibits intestinal migration more effectively than fat in the proximal digestive tract.
    Unfortunately, bowel resection is a frequently required treatment in IBD. Depending on the degree of resection and whether pull-through treatment is performed, patients have different structures.
    In dogs, 50-70% of the proximal small intestine can be excised without a loss in body weight and fat and protein absorption. A slight liposis is the only result of this treatment, and the fat content in the stool increases from about 8 to 10% (unoperated animals) to about 15 to 24% (Kremen et al., Ann. Surg . 140 (3): 439-48 (1954).
    On the other hand, removing 50% of the peripheral small intestine was even more deadly for this animal. There was a significant decrease in body weight, and severe fatty degeneration with increased fat content of 80% to 90%.
    For rats, similar resections provided an explanation for the weight loss observed with peripheral digestive tract resection. Intestinal migration was found to be much faster after peripheral resection than in the proximal region (Reynell and Spray, Gastro ., 31 (4): 361-68 (1956)). Weight loss and malabsorption in these mice and dogs (Kremen et al., (1954)) can be explained by the rapid movement of the contact time between the lumen contents and absorbed blood. Because rapid movement is much worse after peripheral resection than proximal, intestinal movement and optimal treatment of nutrients must rely on ileal braking, the only mechanism that controls movement.
    To test the hypothesis that gut movement is more effectively suppressed by fat in the peripheral digestive tract (ileum braking) than the proximal digestive tract, six dogs with a duodenum (10 cm from the pylorus) and a middle intestine (160 cm from the pylorus) fistulas. For eosin, 0, 15, 30 or 60 mM oleate was mixed micelle solution in phosphate buffer at pH 7.0, at a rate of 2 ml / min for 90 minutes, proximal or peripheral segments of the digestive tract (between fistulas) During delivery, the intestinal migration through an isolated 150 cm test segment (between fistulas) was compared. 60 minutes after the start of perfusion, ~ 20 μCi of 99m Tc-DTPA (diethylenetriamine pentaacetic acid) was delivered to the test segment as a pill. Then, every 5 minutes, the radioactivity of the 1 ml sample collected from the complete conversion product of the midgut fistula was counted and measured.
    Intestinal shift was calculated by calculating the square root of the area under the cumulative recovery curve (AUC) of the radioactive marker. The square root of the AUC was determined using the 2-form repeated measures ANOVA, where 0 = no recovery for 30 minutes, theoretical and instantaneous complete recovery at 47.4 = 0 hours, and the condition and oleate content at the site of fat exposure. Was compared by comparison. Results were reported as mean ± standard deviation. As a control, the buffer was perfused into both the proximal and digestive tracts and the recovery was 41.4 ± 4.6.
    Effect of oleate on proximal and peripheral gut Fat exposed areaOlate Content (mM) 153060 Proximal ½ digestive tract38.8 ± 2.137.8 ± 5.929.0 ± 4.0 Peripheral ½ digestive tract22.4 ± 2.915.8 ± 2.47.2 ± 2.3
    These tests demonstrated that intestinal migration is slower when fat is exposed to the peripheral 1/2 gut (site effect: p <0.01). In addition, these tests showed that oleate was effective in inhibiting intestinal migration in a content dependent manner (content effect: p <0.05); The content-dependent inhibition of intestinal migration by oleate proved to be dependent on the site of exposure (action between site and content, p <0.01). These tests show that ileal braking is more effective than factory braking.
    When fat was perfused through the proximal 1/2 digestive tract in this test, the migration time was faster than in Example I. This difference is due to the fact that in this example, the buffer was simultaneously perfused through the distal small intestine. In this example, data were collected to support the presence of a volume, distension-driven accelerating mechanism, which is believed to be braked by perfusion of buffer in the peripheral digestive tract.
    In particular, after large loads, fat normally appeared in the gastrointestinal emptying, factory braking and ileal braking, initially proximal as well as in the peripheral digestive tract. The braked inhibitory feedback response allows time appropriate for digestion of nutrients in the proximal digestive tract. In case of ileal disease (Weser et al., Gastro ., 77 (2): 572-79 (1979)) or ileal resection, rapid movement through the proximal digestive tract (Connell, Rend. Gastro ., 2: 38-46 ( 1970) was further speeded up, leaving little time for nutrient digestion. Since factory braking is initiated by the end product of fat digestion, the remaining instruments that control movement also do not work and thus cause abnormal rapid movements. As a result, fat uptake and subsequent weight loss occur in rats, dogs, and humans with this altered structure.
    Example III
    Olate slows down the rapid digestion of the upper digestive tract and reduces diarrhea in patients with rapid digestion and diarrhea in the upper digestive tract.
    Rapid movement through the upper gut can cause diarrhea, indigestion, malabsorption and weight loss; Often medications are needed with sedatives or anticholinergics. It was tested if active lipids could be used to slow upper digestive tract migration and to reduce diarrhea in patients with rapid migration and diarrhea.
    Five patients who had persistent diarrhea for 3 to 22 months, each with vagus nerve resection, Crohn's ileal resection, and vagus nerve resection and laxative diarrheal disease, and two patients with idiopathic causes Studied. Each patient exhibited rapid intradigestive motility in conventional lactulose breath hydrogen testing (Cammack et al., Gut 23: 957-961 (1982)). This test is based on the metabolism of certain carbohydrate materials (eg lactulose) by bacteria in the peripheral digestive tract (ie, the cecum of a patient with a woundless gastrointestinal tract). By generating a gas that can be detected in the vented air, it is possible to estimate the initial arrival time of the substance administered in the colon.
    In the trial, each patient was orally randomly administered 0, 1.6 or 3.2 ml of oleate in 25 ml of Ensure ™ branded beverage, followed by 100 ml of water. Thirty minutes after each dose of oleate was administered, patients were given 10 g of lactulose followed by 25 ml of water. The hydrogen in the breath was measured every 10-15 minutes, and the upper digestive tract transit time was defined as the time from the intake of lactulose to the generation of H 2 > 10 ppm. The data were analyzed using one-step repeated measurement deviation analysis (ANOVA) and expressed as mean ± standard deviation.
    Effect of Olate on Travel Time Olate (ml)01.63.2 Travel time (minutes)46 ± 8.6116 ± 11.1140 ± 11.5
    It can be seen that the upper digestive tract migration is significantly extended content-dependently by oleate (p <0.005, significant trend). For 1-3 days, all patients reported reduced diarrhea after taking oleate 15-30 minutes before meals. Patients with Crohn's disease reported chronic abdominal pain, post-prandial awkwardness and nausea completely healed, and weight gained 22 lbs over time. In addition, patients with vagus nerve resection and thrombosis have reported that post-prandial rapid movement syndrome (fever, nausea, light-headedness, abdominal cramps, and diarrhea) has healed.
    These tests demonstrated that ingesting oleate before meals was effective in slowing upper gut transit and reducing diarrhea in patients with diarrhea due to rapid movement. These new nutrient-based therapies will be effective against other chronic diarrheal diseases associated with rapid migration.
    Example IV
    Premeal containing oleate slows the rapid movement of the upper digestive tract and reduces diarrhea in patients with inflammatory bowel disease.
    Premeal containing active lipids has been shown to be effective in many rapid mobility patients as shown in Example III. Therefore, it is necessary to test whether it is also effective for IBD patients. In the following, reliable data from two IBD patients with ileal resection and reanastomosis are presented.
    Diarrhea healing in Crohn's disease patients Patient 1CountVolume (ml)shapeIntestinal movement (minutes) Without oleic acid food preparations42400Liquid20 If you have an oleic acid food preparation31550Liquid / Semi-Solid150 Patient 2CountVolume (ml)shapeIntestinal movement (minutes) Without oleic acid food preparations8975Semisolid25.5 If you have an oleic acid food preparation2250elegance125
    IBD patient 1 was a 35-year-old man with Crohn's disease who had undergone ileal resection for reconstruction. He was diagnosed with diarrhea (12-15 times daily), abdominal cramps, rejection, liposis, poor response to oral medications, weight loss of 30+ lb, and rapid intestinal shift (time-versus-) as measured by the lactulose hydrogen breath test. 10 ppm H 2 generation). The effect of active lipids was tested by adding 1.6 or 3.2 g of oleate to 25 g of Ensure ™ branded beverages that patients drink before meals. Time-to--10 ppm H 2 respiration was delayed to 46 minutes after receiving 1.6 g of oleate and 150 minutes after receiving 3.2 g of oleate. Delayed (FIG. 1A). Diarrhea and postprandial syndrome in this patient were markedly improved when an average of 2 g of oleate was taken before each meal. Three days after receiving the active lipid dietary supplement, the patient's stool volume dropped from 2400 ml to 1500 ml and the number of bowel movements decreased from four to three times daily. After a month of active lipid treatment, the patient's bowel pattern improved markedly with an average of two bowel movements (semi-featured feces) on a daily basis, mostly between weather and mid afternoon. This time-dependent healing suggests that some time (eg, at least one month) is required to obtain maximum benefit from the method of the present invention. After two months of treatment, the patient gained 22 lbs and returned to full-time school.
    IBD patient 2 was an 18-year-old man with ulcerative colitis who underwent ileostomy 2½ years after the initial diagnosis and six months later ileum-anal pull-through. When introduced, he saw liquid / semi-solid stool up to eight times daily, was easily tired, suffered from incontinence, and was socially limited because of diarrhea. After confirming that his intestinal movement responded to active lipids (FIG. 1B), a schedule of ingesting a dietary formulation containing 3.2 g of oleic acid 30 minutes before breakfast, lunch and dinner was started. In this treatment, patient 2's bowel pattern was nearly normal (Table 3) and reported that for the first time since the onset of his disease, solid stool could be depressed. He also reported that he had recovered his happiness, the greatest possible degree of his social life, and he now looks forward to attending college.
    Example Ⅴ
    Prescription preparations containing active lipids increase the bioavailability of drugs delivered orally.
    Optimal assimilation of all intraluminal contents depends on the appropriate residence time in the small intestine (Read, Clin. Gastro., 15 (3): 657-83 (1986)). If the transit through the small intestine is too fast, the digestion and absorption time of nutrients and other intraluminal contents is insufficient (Bochenek et al., Ann. Int. Med ., 72 (2): 205-13 (1970). Thompson, Gastro. Clin. N. Am ., 23 (2): 403-20 (1994); Weser et al., Gastro. , 77 (3): 572-79 (1979); Winawer et al., NEJM , 274 (2): 72-78 (1966)). In the case of IBD patients undergoing medication, one of the most important substances in the digestive tract lumen is oral medication. In patients with fast-moving IBD, it is natural to predict that absorption of oral drugs will be poor.
    The purpose of drug treatment is to deliver a sufficient amount of the appropriate drug to the bloodstream and to the tissue site where the disease is involved (Gubbins and Bertch, Pharmacotherapy , 9 (5): 285-95 (1989)). Factors important for bioavailability of oral drugs include the physicochemical properties of the drug, the pH of the lumen, the presence of food or other drugs in the lumen, gastrointestinal motility, absorption area, and residence time in the small intestine (Dressman et al. ., J. Pharm Sci, 82 ( 9): 857-72 (1993); Gubbins and Bertch (1989); Hebbard et al, Clin Pharmacokinet, 28 (1):..... 41-66 (1995); Parsons, Clin. Pharmacokinet. , 2 (1): 46-60 (1977); Toothaker and Welling, Ann. Rev. Pharmacol.Toxicol ., 20: 173-99 (1980)). The same type of surgical and pathophysiological abnormalities that cause rapid migration in IBD patients appear to alter the bioavailability of drugs (Dressman et al., (1993); Gubbins and Bertch (1989); Parsons, ( 1977). Since these patients are often dependent on oral immune response inhibitors for treatment, such alterations in the bioavailability of the drug may lead to therapeutic consequences.
    Anti-diarrheal sedatives, such as codeine and loperamide, are often prescribed for IBD patients. These agents act by slowing migration (Barrett and Dharmsathaphorn, J. Clin. Gastro ., 10 (1): 57-63 (1988)). In addition, these drugs increase the overall bioavailability of other drugs administered simultaneously (Greiff and Rowbotham, Clin. Pharmacokinet ., 27 (6): 447-61 (1994)), which suggests that the drug's bioavailability slows intestinal migration. It can be strengthened by However, these drugs are not completely effective and cause serious side effects (Barrett and Dharmsathaphorn, (1988)).
    Responses to oral medications are largely varied among IBD patients individually and among patient groups (Gubbins and Bertch (1989)). The cause of this daily deviation is not clear, but may be related to the active state of the disease (quiescence versus sudden relapse) and the physical formulation of the drug (liquid versus solid phase; Gubbins and Bertch (1989)). In case of sudden relapse of IBD patients, more powerful drugs with narrower therapeutic windows are prescribed in an effort to change disease progression. Alternatively, or in addition, doctors often rely on high doses of medication (eg, 16 Pentasa per day) to treat relapses. This can be potentially dangerous if a large amount of drug is treated, for example if the drug is more bioavailable in the active bed. Therefore, daily changes in the bioavailability of the drug can have fatal consequences.
    In IBD patients suffering from ileal disease or undergoing ileal resection, rapid intestinal migration can result in insufficient time to dissolve (equivalent to digestion) and absorption of the drug. This problem is particularly important for drug delivery systems such as cyclosporin, which is absorbed in the proximal small intestine (Brynskov et al., Scand. J. Gastro. , 27 (4): 961-67 (1992)). Rapid movement also reduces the amount of digested drugs that can be absorbed because there is no end product of fat digestion to begin factory braking. These problems are particularly acute for solid drugs that must be dissolved before being absorbed, a step that is not necessary for liquid drugs.
    These problems are equally important for drugs that act locally on the mucosa. Typically, locally acting drugs will prolong contact time with the mucosa. The pharmaceutical industry has attempted to meet the need for the development of enteric skin (eg, sustained release formulations such as Pentasa). Unfortunately, if rapid movement through the intestine is not controlled, rapid movement will reduce the effective contact time regardless of the release rate. Significant differences in the bioavailability observed between liquid and solid dosage forms of the same drug support this idea (Gubbins and Bertch (1989)).
    In dogs with fistulas where the chyme is diverted from the middle digestive tract as a short-length model, drink 50 ml of a drink of Ensure ™ brand with 1.6 ml of oleic acid mixed (w /) or unmixed (w / o). After 30 minutes of cold, 1 g of liquid acetaminophen was delivered to the stomach. Then, blood was collected every 30 minutes for 4 hours. After plasma separation, the content of acetaminophen was analyzed using a chemical kit (Acetaminophen Assay Kit, Sigma Diagnostics).
    Effect of Active Lipids on Bioavailability of Acetaminophen in Dogs Bioavailability Variablesw / o oleic acidw / oleic acid sqrt AUC43.954.1 C max (μg / ml)2219 t max (minutes)30120
    It was found that the bioavailability of acetaminophen was increased by prior administration of active lipids. Specifically, the square root of the area under the curve AUC was larger and the time t max to reach the maximum plasma content was delayed by 400% (FIG. 2 and Table 5). These data suggest that active lipids are remarkably effective in the administration of oral medications in patients with rapid mobility IBD.
    The bioavailability of drugs in fast-moving IBD patients will be similar to that observed in dogs with fistulas without active lipid therapy, eg, relatively short duration of therapeutic activity at each dose. Delayed intestinal migration by pre-formulations containing active lipids (eg oleic acid), the same drug dosage acts similarly to formulations with ideally extended release.
    This effect has been demonstrated in a preliminary study of one patient with rapid movement IBD. The time to reach the plasma concentration of acetaminophen (after 2 g dose) was delayed from 60 minutes to 240 minutes when the drug was dosed with 3.2 g of oleic acid. The effect of rapid migration on the bioavailability of the drug was even greater when the drug was formulated in sustained release. For example, a fast-moving IBD patient may have a rapid dissemination time through the small intestine and a longer dissolution time of enteric bark in the regimen of pharmacologically prescribed release delay drugs such as Pentasa (four 250 mg capsule qid). In contrast to drugs that have not been used). As a result, many expensive drugs flow into the bathroom. When an active lipid pre-formulation is used in conjunction with a sustained release formulation, increasing the bioavailability of the drug will improve the efficacy of drug delivery. For drugs such as cyclosporine, which is typically 30% bioavailable and t max is 3.5 hours when delivered orally (Sandoz Sandimmune, Physician's Desk Reference, 49th ed., Pp. 2183-2186 (1995)) Because of the migration, there is no possibility of effectively delivering the drug via the oral route. Delaying intestinal migration by administering an active lipid dietary preparation provides a useful way to increase the bioavailability of the drug.
    Although the present invention has been described with reference to the disclosed embodiments, those skilled in the art will fully understand that the specific embodiments described above are merely illustrative of the present invention. It should be understood that various modifications may be made without departing from the spirit of the invention.
    权利要求:
    Claims (36)
    [1" claim-type="Currently amended] A method of extending the residence time of a substance in the subject's small intestine, wherein the method is effective for slowing the transfer of the substance through the small intestine to the subject for a time sufficient for absorption of the substance. A method comprising administering a composition containing an active lipid of.
    [2" claim-type="Currently amended] The method of claim 1 wherein said composition is administered prior to said substance.
    [3" claim-type="Currently amended] The method of claim 2, wherein said composition is administered up to about 24 hours prior to said substance.
    [4" claim-type="Currently amended] The method of claim 2, wherein said composition is a premeal and said premedication is administered about 0 hour to about 24 hours prior to said material.
    [5" claim-type="Currently amended] The method of claim 4, wherein said pre-medication is administered from about 0 hour to about 2 hours prior to said material.
    [6" claim-type="Currently amended] 6. The method of claim 5, wherein said pre-medication is administered about 15 minutes to about 45 minutes prior to said material.
    [7" claim-type="Currently amended] 5. The method of claim 4, wherein said food preparation includes a beverage rich in nutrients.
    [8" claim-type="Currently amended] The method of claim 1 wherein said composition is administered simultaneously with said substance.
    [9" claim-type="Currently amended] The method of claim 1 wherein the composition is a liquid or solid phase.
    [10" claim-type="Currently amended] The method of claim 1, wherein said composition is administered orally or tube-delivered.
    [11" claim-type="Currently amended] The method of claim 1, wherein said active lipid comprises digested or partially digested lipids.
    [12" claim-type="Currently amended] 12. The method of claim 11, wherein said digested or partially digested lipids are fatty acids.
    [13" claim-type="Currently amended] The method of claim 12, wherein the fatty acid is selected from fatty acids having 4 to 24 carbon atoms.
    [14" claim-type="Currently amended] The method of claim 13, wherein the fatty acid is caprolic acid (caprolic acid), caprulic acid (caprulic acid), capric acid (capric acid), lauric acid, myristic acid (myristic acid), oleic acid ( oleic acid), palmitic acid (palmitic acid), stearic acid (stearic acid), palmitoleic acid rain (palmitoleic acid), linoleic acid (linoleic acid), linolenic acid (linolenic acid), trans-hexadecanoic acid (trans -hexadecanoic acid), El Elaidic acid, columbinic acid, arachidic acid, behenic acid, eicosenoic acid, erucic acid, bressidic acid, cetoleic acid, nervonic acid, mead acid, mead acid, arachidonic acid, timnodonic acid, sarupic acid, clupanodonic acid, docosahexaene A method selected from the group consisting of acid (docosahexaenoic acid) and structured lipids.
    [15" claim-type="Currently amended] 15. The method of claim 14, wherein said fatty acid is oleic acid.
    [16" claim-type="Currently amended] A method of slowing gastrointestinal transport of a substance in a subject with a gastrointestinal disorder, the method comprising a composition containing an amount of active lipid sufficient to prolong the residence time of the substance in the small intestine of the subject. A method comprising administering a.
    [17" claim-type="Currently amended] 17. The method of claim 16, wherein the residence time in the small intestine is extended for a time sufficient to effect substantial digestion and substantial absorption of the material in the small intestine.
    [18" claim-type="Currently amended] 17. The method of claim 16, wherein the extended residence time in the small intestine increases the absorption of said material.
    [19" claim-type="Currently amended] A method of enhancing the digestion and absorption of a nutrient and / or pharmacologically active agent in a subject, said method being sufficient to prolong the residence time in said small intestine of said nutrient and / or pharmacologically active agent. A method comprising administering a composition containing an amount of active lipids.
    [20" claim-type="Currently amended] A method of treating diarrhea in a subject, the method comprising administering to the subject a composition containing an amount of active lipids sufficient to prolong the residence time of the luminal contents of the small intestine. Way.
    [21" claim-type="Currently amended] A method for reducing the content of atherosclerosis lipids in a subject in which atherogenic serum lipids are induced from the ingested substance, the method described above in the small intestine of the subject. Administering a composition containing an amount of active lipid sufficient to prolong the residence time.
    [22" claim-type="Currently amended] 22. The method of claim 21, wherein the amount of the composition is an amount sufficient to limit the distribution of the substance to the proximal segment of the small intestine and to regulate the supply of the substance to the proximal segment of the small intestine.
    [23" claim-type="Currently amended] A method of enhancing the bioavailability of an orally ingested pharmacologically active agent in a subject, the method of which is sufficient to extend the residence time of the pharmacologically active agent in the small intestine to the subject. Orally administering a composition containing a.
    [24" claim-type="Currently amended] The method of claim 23, wherein said composition is administered prior to said pharmacologically active agent.
    [25" claim-type="Currently amended] The method of claim 24, wherein said composition is administered from about 0 hour to about 24 hours prior to said pharmacologically active agent.
    [26" claim-type="Currently amended] The method of claim 25, wherein said composition is administered from about 0 hour to about 2 hours prior to said pharmacologically active agent.
    [27" claim-type="Currently amended] The method of claim 25, wherein said composition is administered about 15 minutes to about 45 minutes prior to said pharmacologically active agent.
    [28" claim-type="Currently amended] The method of claim 23, wherein said composition is administered concurrently with said pharmacologically active agent.
    [29" claim-type="Currently amended] 24. The method of claim 23, wherein the residence time in the small intestine is extended for a time sufficient to cause dissolution and absorption of said pharmacologically active agent in the small intestine.
    [30" claim-type="Currently amended] A pharmaceutical oral drug comprising a core having an active lipid coating, wherein said core is a pharmacologically active agent, said coating being substantially absorbed into the small intestine prior to release of said pharmacologically active agent. Pharmaceutical oral medications.
    [31" claim-type="Currently amended] 31. The amount of active lipid of claim 30, wherein the coating is effective to extend the residence time in the small intestine of the pharmacologically active agent to a time sufficient for dissolution and absorption of the pharmacologically active agent in the small intestine. Pharmaceutical oral drug characterized in that it contains.
    [32" claim-type="Currently amended] A pharmaceutical oral pharmaceutical product containing many particles, wherein the particles comprise active lipids with a controlled release coating, wherein the particles are substantially absorbed by the small intestine to slow and maintain gastrointestinal tract migration. Pharmaceutical oral drug characterized by.
    [33" claim-type="Currently amended] Enteral dosage forms comprising an essential lipid and an amount of active lipids effective to extend the retention time in the small intestine of the essential nutrient to a time sufficient for the digestion and absorption of the essential nutrient in the small intestine. formula).
    [34" claim-type="Currently amended] A gelatin capsule comprising a diluent and an amount of active lipids effective to prolong the residence time in the small intestine of the essential nutrients for a time sufficient to cause digestion and absorption of said essential nutrients in the small intestine.
    [35" claim-type="Currently amended] 35. The gelatin capsule of claim 34, wherein the diluent is selected from the group consisting of calcium carbonate, calcium phosphate, kaolin, liquid paraffin, or dietary oils.
    [36" claim-type="Currently amended] A method of reducing nicotine-induced inhibitory effects on intestinal motility in a subject, the method containing in said subject a sufficient amount of active lipids to prolong the residence time of the substance in the small intestine in the presence of nicotine. Administering a composition.
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    同族专利:
    公开号 | 公开日
    JPH11505258A|1999-05-18|
    AU5862996A|1996-11-29|
    US5977175A|1999-11-02|
    CA2220451A1|1996-11-21|
    MX9708858A|1998-08-30|
    EP0827402A2|1998-03-11|
    AU722133B2|2000-07-20|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1995-05-17|Priority to US44284395A
    1995-05-17|Priority to US8/442,843
    1996-05-16|Application filed by 피터 이. 브래이브맨, 세다르스-신나이메디칼센터
    1999-02-25|Publication of KR19990014865A
    优先权:
    申请号 | 申请日 | 专利标题
    US44284395A| true| 1995-05-17|1995-05-17|
    US8/442,843|1995-05-17|
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