PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION INCLUDING METHYLTREXONE BROMIDE AND SODIUM DODECY

专利摘要:
lipophilic salt of methylnaltrexone and pharmaceutical compositions thereof for oral administration, in addition to its use, method of preparation and multi-day pack. the present invention relates to compositions comprising methylnaltrexone or a salt thereof, and compositions and formulations thereof, for oral administration.
公开号:BR112012022873B1
申请号:R112012022873-0
申请日:2011-03-10
公开日:2021-09-14
发明作者:Syed M. Shah；Christopher Richard Diorio；Eric C. Ehrnsperger；Xu Meng；Kadum A. Al Shareffi；Jonathan Marc Cohen
申请人:Wyeth Llc；
IPC主号:

专利说明:

Related Orders
[001] This application claims the benefit of United States Provisional Application No. 61/313,018, filed March 11, 2010, the contents of which are hereby incorporated by reference herein. Background of the Invention
[002] Opioids are widely used to treat patients with pain. Such patients include those with advanced cancers and other terminal illnesses as well as those with chronic non-malignant pain and acute non-malignant pain. Opioids are narcotic drugs that activate opioid receptors located in the central nervous system to relieve pain. Opioids, however, also react with receptors outside the central nervous system, resulting in side effects including constipation, nausea, vomiting, urinary retention, and severe itching. The effects of opioids are notable in the gastrointestinal (GI) tract where these drugs inhibit gastric emptying and peristalsis in the intestines, thereby decreasing the rate of intestinal transit and producing constipation. The use of opioids for pain management is often limited due to these unwanted side effects, which can be debilitating and often cause patients to reject the use of opioid analgesics.
[003] In addition to exogenous opioid-induced side effects, studies have suggested that endogenous opioids and opioid receptors may also affect the gastrointestinal (GI) tract and may be involved in the normal regulation of intestinal motility and mucosal fluid transport. Thus, an abnormal physiological level of endogenous opioids and/or receptor activity can also induce bowel dysfunction. For example, patients who have undergone surgical procedures, especially abdominal surgery, often suffer from a dysfunction of the particular bowel, called post-operative ileus, which can be caused by fluctuations in natural opioid levels. Similarly, women who have recently given birth commonly suffer from postpartum ileus, which can be caused by similar fluctuations in natural opioid levels as a result of the stress of childbirth. Gastrointestinal dysfunction associated with post-operative or postpartum ileus can typically last 3 to 5 days, with some severe cases lasting longer than a week. Administering opioids to a patient after surgery to treat pain, which is now an almost universal practice, can aggravate bowel dysfunction, thereby delaying recovery of normal bowel function, prolonging hospital stays, and increasing costs of medical care.
[004] Opioid receptor antagonists, such as naloxone, naltrexone, and nalmefene, have been studied as a method of antagonizing the unwanted peripheral side effects of opioids. However, these agents not only act on peripheral opioid receptors, but also on opioid receptors in the central nervous system, sometimes reversing the beneficial and desired analgesic effects of opioids or causing opioid withdrawal symptoms. Preferred methods for use in controlling opioid-induced side effects include administration of peripherally acting opioid receptor antagonists that do not readily cross the blood-brain barrier.
The peripheral µ opioid receptor antagonist methylnaltrexone has been studied since the 1970s. It has been used in patients to reduce opioid-induced side effects such as constipation, itching, nausea, and urinary retention (see, for example, , United States Patents 5,972,954, 5,102,887, 4,861,781, and 4,719,215; and Yuan et al., Drug and alchool Dependence 1998, 52, 161). The most frequently used methylnaltrexone dosage form in these studies was a methylnaltrexone solution for intravenous injection.
[006] In United States Patent 6,559,158, the dose of methylnaltrexone for the treatment of methadone maintenance patients was explored. It was hypothesized in the '158 patent, based on studies of methadone maintenance patients, that patients taking opioids would be chronically responsive to doses of methylnaltrexone that were previously considered to be too low to be clinically effective. (Methadone maintenance patients typically have an addiction to opiates such as heroin, oxycontin, dilaudid or hydrocone. They would have a history of a stable dose of methadone treatment for at least 30 days greater than or equal to 30 mg/day, and more typically larger). Low doses of methylnaltrexone were administered intravenously. These doses were between 0.01 and 0.37 mg/kg, at which mean peak plasma levels of 162 (30-774 ng/ml) were reported. These intravenous doses in methadone maintenance patients induced "immediate" laxation.
[007] Subcutaneous injection of methylnaltrexone has been explored and has been clinically approved in the United States to treat opioid-induced constipation in patients with advanced medical illness who are receiving palliative care. The subcutaneous injection dose found to be effective was 0.15 or 0.3 mg/kg. This dose would not induce "mediate" laxation, but instead would induce laxation within 4 hours in a significant number of treated patients.
Attempts have been made to prepare an oral dosage form of certain opioid antagonists, including methylnaltrexone. In United States Patent 6,419,959, an oral dosage form is constructed in order to release certain compounds "over the entire gastrointestinal tract". According to the '959 patent, opioid antagonists are not always suitable for administration in an immediate release form due to dose-limiting side effects. In addition, opioid-induced constipation is believed to result from the direct and local effects of opioids on receptors throughout the entire gastrointestinal tract. To address these issues, the '959 patent suggests dosing certain opioid antagonists, including methylnaltrexone, in a controlled dosage form, thereby releasing these antagonists in locally acceptable doses throughout the entire gastrointestinal tract. Data regarding methylnaltrexone specifically, however, have not been reported.
[009] In United States Patent 6,274,591, it was shown that an enterically coated methylnaltrexone that released substantially no methylnaltrexone into the stomach was more effective in antagonizing oral-cecal delay caused by morphine than was an uncoated methylnaltrexone. The '591 patent suggests and claims the release of effective amounts of methylnaltrexone using an oral dosage that bypasses the stomach completely. Data regarding laxation, however, were not reported.
[0010] In United States Patent 6,559,158, an oral dose of methylnaltrexone was explored for the treatment of constipation in methadone maintenance patients (ie, patients were shown to be highly sensitive to the effects of methylnaltrexone). The dose of methylnaltrexone administered orally in one capsule was 0.3 to 3.0 mg/kg. Methylnaltrexone capsules administered to these patients induced laxation in the various patients tested, albeit for periods of time between 1.2 and 24 hours depending on the dose. The fastest response was seen in the four patients receiving 3.0 mg/kg (5.2+/- 4.5 hours, with a range of 1.2 to 10 hours).
Consequently, there is a need for bioavailable oral dosage formulations comprising methylnaltrexone. Invention Summary
[0012] Capsules containing enterically coated spheroids of a methylnaltrexone formulation were tested in patients suffering from opioid-induced constipation. Patients in this study were receiving opioids for non-malignant pain. (They were non-chronic methadone maintenance patients). Patients were administered 300 mg or 450 mg of enteric coated methylnaltrexone capsules (approximately 4 mg/kg and 6 mg/kg, respectively), which were doses within the ranges reported to be effective in the '591 patent. The mean peak plasma level of methylnaltrexone resulting from the 300 mg dose was less than 10 ng/mL and the mean peak plasma level of methylnaltrexone resulting from the 450 mg dose was less than 20 ng/mL. These preparations were unexpectedly not effective for the treatment of opioid-induced constipation. They would not induce laxation and would not cause more bowel movements in patients compared to controls. This was surprising in view of the teachings in the technique.
[0013] As in the results of the enteric-coated methylnaltrexone capsules, it was unclear whether achieving laxation depends on peak plasma drug levels, timing of achievement of drug plasma levels, or other factors such as a local effect . Other experiments were conducted, and as a result, the inventors turned their attention to developing an oral formulation containing methylnaltrexone that was not enteric-coated.
[0014] Capsules containing spheroids of a methylnaltrexone formulation, but without the enteric coating, were tested in patients receiving opioids for non-malignant pain. Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted in mean peak plasma levels between about 15 and 40 ng/ml. These capsules without the enteric coating would not induce laxation and would not cause more bowel movements in this patient population than in controls.
[0015] Tablets containing spheroids of a methylnaltrexone formulation, without an enteric coating, were tested in patients receiving opioids for non-malignant pain. Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted in mean peak plasma levels between about 7 and 40 ng/ml, similar to the peak plasma levels obtained with the uncoated capsules. These tablets without an enteric coating showed activity with statistical significance at one dose, but would not consistently induce laxation across all doses. That there was activity with a tablet but not a capsule would have been surprising to one of skill in the art based on the information available in the prior art.
[0016] The prior art has not made clear what would be required to create an effective oral methylnaltrexone for the treatment of opioid-induced constipation in patients receiving opioids for non-malignant pain. First, the prior art has not made it clear whether achievement depends on total plasma drug levels, peak plasma drug levels, or timing of achievement of drug plasma levels. Second, even if the pharmacokinetics for achieving laxation are established, the prior art has not made clear formulation methodology to predictively control the pharmacokinetics of oral methylnaltrexone, rather than through dose shifts and caps. Because of the desire to also improve the performance of the non-enteric coated tablet, further formulation development studies were undertaken.
[0017] Methylnaltrexone is hydrophilic and very soluble in aqueous solutions. The positive charge of the quaternary amine causes methylnaltrexone to be poorly absorbed from the gastrointestinal tract. In general, less than about 5% of methylnaltrexone is absorbed into the bloodstream when released orally.
[0018] There are many possible general methods of increasing the absorption of an orally administered drug. It is not known, however, which method can result in an improvement in the efficacy of oral methylnaltrexone. The inventors have tested tablet formulations, capsule formulations, liquid formulations, gap junction openers, Pgp inhibitors, active carriers, oil suspensions, quick-release effervescent solutions, and others. Most of the methods tried did not improve absorption in the laboratory models used. In fact, when tested on certain dog models. Some of the methods had the opposite of the anticipated effect, that is, absorption was inhibited in one or more of the tested parameters.
[0019] Ion pairing has been investigated to reduce the apparent ionic charge on a molecule. The interaction between a hydrophilic charged molecule and an amphiphilic counterion can make the hydrophilic molecule sufficiently lipophilic to allow (or increase) the molecule's solubility in a non-aqueous solvent. Since ion pairing increases the splitting of the molecule into an organic phase, much of the work in this area has been directed towards extracting ionic molecules in organic solvents, molecule separation by chromatography, reaction of hydrophilic molecules in organic solvents, and so on. . With respect to absorption, much of the work has been limited to delivering a drug to the skin, eyes, nasal cavity, or vaginal cavity (see, for example, J. Hadgraft, "Skin Deep", European Journal of Pharmaceutics and Biopharmaceutics 58, 291 -299, 2004; Quintanar-Guerrero et al., Application of the Ion-Pair Concept to Hydrophilic Substances with Special Emphasis on Peptides", Pharmaceutical Research 14, 119-127, 1997). There has only been limited work reported in the prior art for improvement of the bioavailability of drugs orally administered using ion pairs.
An ion pair between a positively charged and a negatively charged methylnaltrexone moiety has been postulated by the inventors to prepare a "pair" that is more hydrophobic than methylnaltrexone bromide and thereby enhance the absorption of methylnaltrexone in the stomach. Several ion pairs were formed using methylnaltrexone and anions. Such an ion pair was formed between methylnaltrexone and dodecyl sulfate (lauryl).
[0021] It has been unexpectedly found that methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient which form an ion or salt pair with methylnaltrexone when dissolved in solution in a solid dosage form together with a fast acting disintegrant (for example , a carbon dioxide-generating disintegrant) was effective in inducing laxation.
[0022] Without wishing to be bound by any particular theory of the invention, it is believed that there is a local gastric effect and a systemic effect, which combine to obtain laxation when using the formulations and preparations of the invention. Such a dual effect may suggest that laxation can be achieved using the oral formulations of the invention at lower peak plasma levels than those shown to be effective for subcutaneous injection.
[0023] The present invention relates to methylnal-trexone ion pairs and an amphiphilic pharmaceutically acceptable excipient, methods for forming such ion pairs, methods for selecting such ion pairs, use of such ion pairs, compositions including such ion pairs, solid oral formulations of methylnaltrexone and a pharmaceutically acceptable amphiphilic excipient, including formulations containing a fast acting disintegrant (eg carbon dioxide producing disintegrant or effervescent) as well as methods of using such compositions and formulations thereof.
[0024] In one aspect, the present invention provides a methylnaltrexone salt of the formula:

[0025] wherein methylnaltrexone is the cation of the salt, and A- is an anion of an amphiphilic pharmaceutically acceptable excipient. In certain embodiments, the methylnaltrexone is (R)-N-methylnaltrexone as shown in the formula above. The amphiphilic pharmaceutically acceptable excipient is acidic. In certain embodiments, the amphiphilic pharmaceutically acceptable excipient has a pKa of about 3 or less. For example, the amphiphilic pharmaceutically acceptable excipient can include a sulfate, sulfonate, nitrate, nitrite, phosphate, or phosphonate moiety. In one embodiment, the pharmaceutically acceptable excipient comprises a group (-OSO3-). Without wanting to be bound by any particular theory, such chemical functional groups with pKa values at or below about 3 allow the ion pair to remain linked together at the acidic pH found in the stomach. This is because the conjugate base of the excipient remains deprotonated and negatively charged, and methylnaltrexone is a quaternary amine that is positively charged. The pharmaceutically acceptable excipient also includes a hydrophobic moiety. In some embodiments, the hydrophobic moiety is a branched or unbranched C4-30 aliphatic chain, saturated or unsaturated, cyclic or acyclic, which may be optionally substituted. In some embodiments the pharmaceutically acceptable excipient is, for example, a saturated, or unsaturated, branched or unbranched, cyclic or acyclic C4-30 aliphatic group which is optionally substituted. In some embodiments it is a saturated, unbranched, acyclic, unsubstituted C4-30 alkyl group. In some embodiments, it is a saturated, unbranched, acyclic, unsubstituted C7-15 alkyl group. In some embodiments it is a C12 n-alkyl group. In some modalities, it is dodecyl sulfate (lauryl). Without wanting to be bound by any theory, it is believed that the aliphatic chain makes the excipients amphiphilic or surfactant in nature, which helps transport the ion pair through the unstirred diffusion layer lining the inner surface of the GI tract, thereby , increasing the availability of methylnaltrexone to the GI membrane for local effects on receptor sites and/or absorption through lipophilic barriers such as the lining of the GI tract, eg the stomach and upper duodenum. In certain embodiments, a methylnaltrexone ion pair is a salt that is solid at room temperature.
[0026] According to another aspect of the invention, a composition is provided. The composition is the salt or ion pair described above. The salt or ion pair may comprise at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 75%, at least 90%, at least 95% or at least 99% of the methylnaltrexone in the composition. In some embodiments, the composition is a pharmaceutical composition.
[0027] In another aspect of the invention, a composition for oral administration is provided. The composition includes methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient which form an ion or salt pair with methylnaltrexone when dissolved in solution, thereby increasing the octanol/water partition coefficient of methylnaltrexone. When the composition is dissolved in an aqueous solution, methylnaltrexone has an apparent octanol/water partition coefficient of at least 0.25 under acidic conditions, and in some embodiments at a pH between 1 and 4. A pH between 1 and 4 is used to simulate the physiological conditions of the stomach. In certain embodiments, the apparent octanol/water partition coefficient of methylnaltrexone is at least 0.5, 1.0, 5.0, 10, 20, or 30 at a pH between 1 and 4. Typically, the excipient The pharmaceutically acceptable excipient has a pKa of about 3 or less so that the conjugated base of the amphiphilic pharmaceutically acceptable excipient remains deprotonated and is noncovalently linked to the cationic methylnaltrexone under physiological conditions found in the stomach (i.e., a solution at acidic pH) .
The composition may also include a fast acting disintegrant, wherein the composition dissolves within about 15 minutes in the stomach. In at least one embodiment, at least 50% of the methylnaltrexone in the composition is dissolved within 15 minutes. In other embodiments, at least 75%, 80%, 85%, 90%, 95%, or even 99% of the methylnaltrexone in the composition is dissolved within 15 minutes. In either of the above embodiments, the methylnaltrexone in the composition can dissolve within 10 minutes or even within 5 minutes. The dissolution of the composition in the stomach can be simulated by in vitro studies in a dissolution apparatus with paddles at 100 rpm in 900 ml of 0.1 HCl at 37°C. In certain embodiments, the disintegrant is a fast-acting disintegrant. In certain embodiments, the composition has a dissolution profile substantially similar to that depicted in Figure 2. In some embodiments, the disintegrant is an effervescent (ie, one involving gas) disintegrant. By creating gas bubbles in the composition, the composition is more easily broken, thereby releasing methylnaltrexone. Effervescent disintegrants have been found to be particularly useful in aiding the dissolution of tablets containing methylnaltrexone and dodecyl sulphate. In certain embodiments, the disintegrant is an effervescent disintegrant that is capable of generating carbon dioxide when the composition is contacted with an aqueous medium. In either embodiment, the effervescent disintegrant can be a bicarbonate or carbonate. In either embodiment, the effervescent disintegrant can be sodium bicarbonate.
[0029] According to another aspect of the invention, a method of preparing a formulation of methylnaltrexone is provided. The method includes combining a solid pharmaceutically acceptable salt of methylnaltrexone (which is not a pair of methylnaltrexone ion and an amphiphilic pharmaceutically acceptable excipient), such as methylnaltrexone bromide or iodide, with a solid pharmaceutically acceptable salt of the amphiphilic excipient (which is not the ion pair of methylnaltrexone and the pharmaceutically acceptable excipient amphiphilic) to form a mixture. The mixture can be wet granulated. In certain embodiments, a wet granulation of methylnaltrexone or a pharmaceutically acceptable salt thereof, an amphiphilic pharmaceutically acceptable excipient, at least one disintegrant, at least one binder, at least one chelating agent, at least one wetting agent, and optionally at least one filler is prepared and formed into a solid dosage form. In certain embodiments, a wet granulation is formed by dry mixing methylnaltrexone or a pharmaceutically acceptable salt thereof, a binder, an amphiphilic pharmaceutically acceptable excipient, and optionally a disintegrant; and granulating the dry mixture with a solution of a chelating agent and/or a wetting agent to form a wet granulation. The wet granulation can be dried and milled, and the milled granulation mixture dried with an additional disintegrant (eg, sodium bicarbonate) and optionally a lubricant and/or a glidant before a solid dosage form is prepared.
In some aspects, the present invention provides compositions for oral administration comprising a cation methylnaltrexone salt and the anion of the amphiphilic pharmaceutically acceptable excipient (e.g., dodecyl sulfate). In some embodiments, compositions for oral administration are tablet formulations. In some embodiments, compositions for oral administration are capsule formulations.
In general, formulations for oral administration comprise methylnaltrexone, an amphiphilic pharmaceutically acceptable excipient as described above, and a disintegrant, and also optionally comprise one or more other components, such as, for example, binders, vehicles, agents of chelation, antioxidants, fillers, lubricants, wetting agents, or combinations thereof. In any of the above embodiments, oral formulations are tablet formulations. In some embodiments, the present invention provides a unit dosage form comprising a formulation or composition described herein.
The present invention also provides methods of oral administration of methylnaltrexone in any context where such administration is desirable. For example, the formulations are useful for preventing, treating, or reducing the severity of side effects resulting from opioid administration, including inhibition of intestinal motility or gastrointestinal dysfunction (eg, constipation, GI sphincter constriction), nausea, emesis, and itching. The compositions and formulations are useful for administration to patients receiving acute opioid treatment (for example, patients suffering from post-operative ileus or gastrointestinal dysfunction resulting from acute opioid administration). Such formulations are also useful for administration to individuals receiving chronic opioid administration (for example, terminally ill patients receiving opioid therapy (for example, an AIDS patient, a cancer patient, a cardiovascular disease patient); individuals receiving chronic therapy opioid for pain control; individuals receiving opioid therapy to maintain opioid abstinence). In some modalities, the individual is undergoing opioid therapy to control chronic pain. In other modalities, the individual is undergoing opioid therapy for acute pain management. In certain modalities, the pain is non-malignant pain (eg, back pain, neuropathic pain, pain associated with fibromyalgia, osteoarthritis, etc.). In certain modalities the pain is chronic non-malignant pain. In certain modalities the pain is malignant pain. In certain embodiments, the present invention provides a method comprising the step of reducing one or more side effects of opioid therapy in a subject receiving opioid treatment comprising administering to the subject a provided tablet formulation as described above. In other embodiments, the present invention provides a method of reducing one or more effects of endogenous opioid activity in an individual (e.g., postpartum ileum) comprising administering to the individual a formulation. In some modalities the individual is not a methadone maintenance patient. In any of the above modalities, the individual can be fasted or fed. In one important modality, the individual is fasted overnight. Brief Description of Drawings
[0033] Figure 1 shows the dissolution profile of methylnaltrexone tablets and capsules in 900 ml of 0.1 N HCl, at 37 degrees C, pa at 100 rpm.
[0034] Figure 2 shows the dissolution profile of methylnaltrexone tablets (150 mg) formulated with sodium dodecyl sulfate and an effervescent disintegrant, sodium bicarbonate (as described in Example 5), at 37 degrees C, pa at 100 rpm, analyzed using a Cary 50 spectrophotometer.
Figure 3 shows a plot of the time and percentage of patients having a laxation response in patients with chronic malignant pain given an (R)-N-methylnaltrexone bromide SDS tablet formulation (300 mg or 450 mg ) after a 10-hour fast.
[0036] Figure 4 includes the characterization data for MNTX-heptyl sulfate. Figure 4A is the 1 H NMR spectrum of MNTX-heptyl sulfate. Figure 4B is an HPLC chromatogram for MNTX-heptyl sulfate. Figure 4C is the UV spectrum of MNTX-heptyl sulfate.
[0037] Figure 5 includes the characterization data for MNTX dodecyl sulfate. Figure 5A is the 1 H NMR spectrum of MNTX dodecyl sulfate. Figure 5B is an HPLC chromatogram for MNTX dodecyl sulfate. Figure 5C is the UV spectrum of MNTX dodecyl sulfate.
[0038] Figure 6 includes the characterization data for MNTX sodium sulfate. Figure 6A is the 1 H NMR spectrum of MNTX sodium laurate. Figure 6B is an HPLC chromatogram for MNTX sodium laurate. Figure 6C is the UV spectrum of MNTX sodium laurate. Detailed Description of Certain Modalities of the Invention Definitions
The term "aliphatic", as used herein, includes both saturated and unsaturated hydrocarbons, straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic, which are optionally substituted with one or more functional groups. As will be appreciated by one of skill in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, as used herein, the term "alkyl" includes linear, branched, and cyclic alkyl groups. An analogous convention applies to other generic terms such as "alkenyl", "alkynyl" and the like. Also, as used herein, the terms "alkyl", "alkenyl", "alkynyl" and the like encompass both substituted and unsubstituted groups. In certain embodiments, as used herein, "lower alkyl" is used to denote those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having from 1 to 6 carbon atoms.
In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain from 1 to 30 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain from 10 to 30 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain from 5 to 25 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain from 5 to 20 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain from 10 to 20 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain from 15 to 25 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain from 1 to 10 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain from 1 to 6 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain from 1 to 4 carbon atoms. Illustrative aliphatic groups, therefore, include, but are not limited to, for example, the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl moieties, tert-butyl, cyclobutyl, -CH2-cyclobutyl, n-pentyl, secpentyl, isopentyl, tert-pentyl, cyclopentyl, -CH2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH2-cyclohexyl, heptyl, octyl (capryl ), nonyl, decyl (capric), undecyl, dodecyl (lauryl), tridecyl, tetradecyl, hexadecyl (cetyl), heptadecyl, octadecyl (stearyl), eicosyl (arachidyl), docosyl, tetracosyl, hexacosyl, octacosyl, triacontyl and the like, which again, they may carry one or more substituents.
[0041] Some examples of substituents from the aliphatic moieties described above include, but are not limited to, aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -CH2OH; - CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; - OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(Rx)2; -S(O)2Rx; and -NRx(CO)Rx; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.
[0042] The term "amphiphilic" as used herein to describe a molecule refers to the dual hydrophobic and hydrophilic properties of the molecule. Typically, amphiphilic molecules have a polar, water-soluble group (eg, a phosphate, carboxylic acid, sulfate) attached to a non-polar, water-insoluble group (eg, a hydrocarbon). The term amphiphilic is synonymous with amphipathic. Examples of amphiphilic molecules include sodium dodecyl (lauryl) sulfate, fatty acids, phospholipids, and bile acids. Amphiphilic molecules can be uncharged, cationic or anionic.
[0043] As used herein, the term "dissolution rate" refers to the amount of time it takes for an active ingredient or composition thereof (eg, a salt methylnaltrexone) to dissolve in a solvent. The rate of dissolution can depend on a variety of factors including mixture, temperature, pH, solvent, particle size, etc. The dissolution rate of a drug or drug composition affects the drug's bioavailability. In certain circumstances, dissolution rate is used to determine the availability of solid dosage forms.
As used herein, an "effective amount" of a pharmaceutically acceptable compound or composition or formulation can obtain a therapeutic and/or prophylactic effect. In some embodiments, an "effective amount" is at least a minimal amount of a compound, or formulation or composition containing it, that is sufficient to treat one or more symptoms of a disorder or condition associated with modulation of peripheral µ opioid receptors. , such as side effects associated with opioid analgesic therapy (eg, gastrointestinal dysfunction (eg, constipation due to dysmotility, etc.), nausea, emesis, etc.). In certain embodiments, an "effective amount" of a compound, composition, or formulation containing a compound is sufficient to treat symptoms associated with, a disease associated with abnormal endogenous peripheral opioid or µ opioid receptor activity (e.g., idiopathic constipation, ileum, etc.). In some embodiments, the term "effective amount", as used in connection with an amount of methylnaltrexone or methylnaltrexone salt, means an amount of methylnaltrexone or methylnaltrexone salt sufficient to achieve laxation in a patient.
The term "effervescent disintegrant", as used herein, refers to material which causes effervescence resulting in rapid disintegration of the dosage form upon contact with aqueous media. Typically the effervescent disintegrant is a base (eg carbonate) which reacts with an acid (eg HCl in the stomach) to form carbon dioxide. Therefore, such effervescent disintegrants include carbon dioxide producing disintegrants. Carbonate sources include, but are not limited to, carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, sodium sesquicarbonate, sodium glycine carbonate, L-carbonate -lysine, arginine carbonate, and calcium carbonate. Effervescent disintegrants are known in the art to obtain fast-disintegrating dosage forms.
[0046] As used herein, the term "lipophilicity" refers to the ability of the compound to associate with or dissolve in a fat, lipid, oil, or non-polar solvent. Lipophilicity and hydrophobicity can be used to describe the same tendency for a molecule to dissolve in fats, oils, lipids. And non-polar solvents.
[0047] As used herein the term "non-functional coating" is a coating that does not significantly affect the release characteristics of a therapeutically active compound or compounds from a formulation when administered. Examples of a non-functional coating include a seal coating (for example, hydroxypropyl cellulose, hypromellose or polyvinyl alcohol). In certain embodiments, a non-functional coating is a polish coating or seal coating.
[0048] As used herein the term "non-malignant pain" refers to "non-cancer pain."
[0049] The term "apparent partition coefficient", as used herein, refers to the ratio of concentrations of a compound in any form in the two phases of a mixture of two immiscible solvents in equilibrium. In certain embodiments, the two immiscible solvents are octanol and water. The apparent division coefficient can be determined under various conditions, eg temperature, pH, concentration, etc. Apparent division coefficients have been found to be useful in estimating the distribution of compounds in the body. Apparent division coefficients mean a more hydrophobic (more lipophilic) compound, while apparent division coefficients mean a hydrophilic compound. The apparent division coefficient of a compound can be determined by procedures known in the art, for example, in the United States Pharmacopoeia. The apparent partition coefficient can be determined by the procedure used to determine the apparent partition coefficients of methylnaltrexone dodecyl sulfate and methylnaltrexone heptyl sulfate in the Examples.
The term "individual", as used herein, means a mammal and includes both human and animal individuals, such as domesticated animals (eg, horses, dogs, cats, etc.) and experimental animals (eg, mice, rats, dogs, chimpanzees, monkeys, etc.).
[0051] The terms "suffering" or "suffering" as used herein refers to one or more conditions that a patient has been diagnosed with or is suspected of having.
[0052] The term "spheroid", as used herein, has its meaning understood from a substantially spherical particulate. In many embodiments, spheroids prepared or used in accordance with the present invention have a size within the range of about 1 to 1500 microns. In some embodiments, such spheroids have a size within the range of about 20 to 1500 microns. In some embodiments, such spheroids are in the range of about 20 to 1000 microns. In some embodiments, such spheroids are in the range of about 20 to 500 microns. In some embodiments, such spheroids are in the range of about 20 to 300 microns. In certain embodiments, such spheroids are of a size where at least 80% of the spheroids fall within the range of about 20 to 325 microns. In some embodiments, such spheroids are of a size where at least 50% of the spheroids fall within the range of about 45 to 120 microns.
[0053] The terms "treat" or "treatment", as used herein, refers to alleviating, inhibiting, delaying the onset of, reducing the incidence of, ameliorating and/or partially or completely alleviating a disorder or condition, or one or more symptoms of the disorder, disease or condition.
"Therapeutically active agent" or "active agent" refers to a substance, including a biologically active substance, that is useful for therapy (eg, human therapy, veterinary therapy), including prophylactic and therapeutic treatment. Therapeutically active agents include organic molecules that are composed of drug, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoprotein, mucoprotein, lipoprotein, synthetic polypeptide or protein, small molecules linked to a protein, glycoprotein, steroid, nucleic acid, DNA, RNA, nucleotide, nucleoside, oligonucleotide, antisense oligonucleotides, lipid, hormone, and vitamin. Therapeutically active agents include any substance used as a medicine to treat, prevent, delay, reduce or ameliorate a disease, condition, or disorder. Among the therapeutically active agents useful in the formulations of the present invention are opioid receptor antagonist compounds, opioid analgesic compounds, and the like. Another detailed description of compounds useful as therapeutically active agents is provided below. A therapeutically active agent includes a compound that enhances the effect or efficacy of a second compound, for example, enhancing the potency or reducing adverse effects of a second compound.
The term "unit dosage form" as used herein refers to the physically discrete unit of a formulation provided appropriate for the individual to be treated. It will be understood, however, that the total daily use of the formulation provided will be decided by the treating physician within the scope of sound medical judgment. The specific effective dose level for any particular individual or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific active agent employed; specific formulation employed; age, body weight, general health, sex and diet of the individual; administration time, and excretion rate of the specific active agent employed; duration of treatment; additional drugs and/or therapies used in combination or coincidental with the specific compound(s) employed, and similar factors well known in the medical arts.
[0056] The term "pKa," as used herein, refers to -logioKa, where Ka is the dissociation constant of acid. pKa measures the intensity of an acid in solution on a logarithmic scale. The acid dissociation constant Ka is the equilibrium constant for the dissociation of a compound into a proton and its conjugate base, symbolically written as:
Methylnaltrexone Compositions and Formulations
As used herein, methylnaltrexone refers to (R)-N-methylnaltrexone. (R)-N-methylnaltrexone, a peripherally acting µ opioid receptor antagonist, has been studied and used to treat bowel dysfunction in patients being administered opioids. Surprisingly, enteric-coated preparations of methylnaltrexone do not consistently demonstrate a substantial effect in the treatment of opioid-induced constipation. Contrary to prior art suggestions involving oral methylnaltrexone, local concentrations of methylnaltrexone in the intestinal tract to remove from the stomach are not effective in inducing laxation and treating constipation.
In certain embodiments, the present invention provides a composition comprising methylnaltrexone and a pharmaceutically acceptable excipient, wherein the composition in solution produces an apparent octanol/water partition coefficient for methylnaltrexone of at least 0.25 under acidic conditions , in certain embodiments at a pH between 1 and 4. In some embodiments, such compositions are formulated for oral administration. In some embodiments, a composition for oral administration is formulated into a tablet. Methylnaltrexone for use in such compositions and formulations can be in any of a variety of forms. For example, forms of methylnaltrexone suitable for use in the inventive compositions and formulations include pharmaceutically acceptable salts, prodrugs, polymorphs (i.e., crystalline forms), cocrystals, hydrates, solvates, and the like. Any form of methylnaltrexone can be used in the compositions or formulations, but the form must allow for ion pairing with the amphiphilic pharmaceutically acceptable excipient.
[0059] In certain embodiments, the compositions, and formulations thereof, comprise a salt of formula I:

[0060] where A- is a suitable anion. In certain embodiments, A- is the anion of a Br0nsted acid. Br0nsted acids include hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid, and phosphoric acid. In certain embodiments, A- is the chloride salt, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate sulfonate, methylsulfonate, formate, carboxylate, sulfate, methylsulfate or succinate. In certain embodiments, A- is trifluoroacetate. In certain embodiments, A- is bromide. In certain embodiments, A- is an anion of an amphiphilic pharmaceutically acceptable excipient. In certain embodiments, A- is an amphiphilic acidic pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutically acceptable excipient has a pKa of about 3 or less. In certain embodiments, the pharmaceutically acceptable excipient has a pKa of about 2 or less. In certain embodiments, the pharmaceutically acceptable excipient has a pKa of between about 1 and about 2. In certain embodiments, the pharmaceutically acceptable excipient has a pKa of about 1 or less. In certain embodiments, the pharmaceutically acceptable excipient anion includes a sulfate, sulfonate, phosphate, phosphonate, nitrate, or nitrite moiety. In certain embodiments, the pharmaceutically acceptable excipient anion includes a sulfate group (-OSO3-). In certain embodiments, the anion is butyl sulfate, pentyl sulfate, hexyl sulfate, heptyl sulfate, octyl sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate, dodecyl sulfate, tridecyl sulfate, tetradecyl sulfate , pentadecyl sulfate, hexadecyl sulfate, heptadecyl sulfate, octadecyl sulfate, eicosyl sulfate, docosyl sulfate, tetracosyl sulfate, hexacosyl sulfate, octacosyl sulfate, and triacontyl sulfate. In certain embodiments, the methylnaltrexone in the composition or formulation can have multiple anions (eg, dodecyl bromide and sulfate (lauryl)) associated with it.
[0061] In some embodiments, the compositions, and formulations thereof, comprise (R)-N-methylnaltrexone bromide. (R)-N-Methylnaltrexone bromide, which is also known as "MNTX" and is described in International PCT Patent Application Publication Number WO2006/12789, which is incorporated herein by reference. The chemical name for (R)-N-methylnaltrexone bromide is (R)-N-(cyclopropylmethyl) noroxymorphone methbromide. (R)-N-Methylnaltrexone bromide has the molecular formula C21H26NO4Br and a molecular weight of 436.36 g/mol. (R)-N-Methylnaltrexone bromide has the following structure:
(R)-N-Methylnaltrexone bromide
[0062] where the compost is in the (R) configuration with respect to quaternary nitrogen. In certain embodiments of the present invention, at least about 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or 99.95% of the compound is in the (R) configuration with respect to nitrogen. Methods for determining the amount of (R)-N-methylnaltrexone bromide present in a sample compared to the amount of (S)-N-methylnaltrexone bromide present in the same sample are described in detail in WO2006/127899, which is incorporated herein by reference. In other embodiments, methylnaltrexone contains 0.15%, 0.10%, or less of (S)-N-methylnaltrexone bromide.
[0063] In some embodiments, a composition, or formulation thereof, comprises from about 7% to about 75%, from about 25% to about 55%, from about 40%, or to about 50% of (R)-N-methylnaltrexone cation, based on the total weight of the formulation. In certain embodiments, a provided composition, or formulation thereof, comprises about 7%, about 8%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 75% (R)-N-methylnaltrexone cation, based on the total weight of the formulation or composition provided. It will be understood that the (R)-N-methylnaltrexone cation and the amphiphilic pharmaceutically acceptable excipient anion may exist in the composition as an ion pair or may exist as separate salts paired with other counterions such as bromide and sodium, or mixtures thereof .
[0064] In some embodiments, a composition, or formulation thereof, comprises from about 7% to about 75%, from about 25% to about 55%, from about 40%, or to about 50% of (R)-N-methylnaltrexone cation and dodecyl sulfate anion, based on the total weight of the composition or formulation. In certain embodiments, a composition, or formulation thereof, comprises about 7%, about 8%, about 10%, about 20%, about 30%, about 40%, about 50 %, about 60%, about 70%, or about 75% (R)-N-methylnaltrexone cation and dodecyl sulfate anion, based on the total weight of the composition or formulation.
In certain embodiments, the present invention provides a composition comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient. The amphiphilic pharmaceutically acceptable excipient increases the lipophilicity of the composition, thereby allowing increased transport across the unstirred diffusion layer in the GI tract, resulting in increased permeation across biological membranes. In certain embodiments, the excipient increases the lipophilicity of the drug. In certain embodiments, the excipient is a surfactant. In some embodiments, the excipient is an anionic surfactant. In certain embodiments, the excipient is an anionic surfactant that forms an ion or salt pair with positively charged methylnaltrexone. Such anionic surfactants are known in the art and are typically characterized by having a lipophilic end and an anionic portion. Exemplary excipients useful in the present invention include aliphatic sulfates (e.g., sodium dodecyl (lauryl) sulfate), aliphatic phosphates, fatty acids, and salts and derivatives thereof.
[0066] As an assessment of lipophilicity of the resulting ion pair, a solution of the composition produces an apparent octanol/water partition coefficient for methylnaltrexone of at least 0.25 at a pH between 1 and 4. The partition coefficient of Apparent octanol/water as used herein is determined at room temperature at a concentration of approximately 0.5 mg/mL. Exemplary methods for determining an apparent octanol/water partition coefficient of methylnaltrexone salts are described in the Examples below.
Particularly useful amphiphilic pharmaceutically acceptable excipients include those which enhance oral absorption of methylnaltrexone. In certain embodiments, the excipient enhances the absorption of methylnaltrexone from the stomach. In certain embodiments, the excipient increases the ability of methylnaltrexone to cross the lipophilic barrier. In certain embodiments, the excipient increases the lipophilicity of methylnaltrexone by forming an ion pair with cationic methylnaltrexone. Ion pairing enhances the breakdown of methylnaltrexone into an organic phase such as a lipid bilayer. In certain embodiments, the excipient forms an ion pair with methylnaltrexone so that when the composition is in solution, the methylnaltrexone has an apparent octanol/water partition coefficient of at least 0.25 at a pH between 1 and 4 In certain embodiments, the apparent octanol/water split coefficient is at least 0.5 at a pH between 1 and 4. In certain embodiments, the apparent octanol/water split coefficient is at least 0. 75 at a pH between 1 and 4. In certain embodiments, the apparent octanol/water splitting coefficient is at least 1.0 at a pH between 1 and 4. In certain embodiments, the apparent octanol/water splitting coefficient is at least 10 at a pH between 1 and 4. In certain embodiments, the apparent octanol/water split coefficient is at least 15 at a pH between 1 and 4. In certain embodiments, the apparent octanol/water split coefficient is at least 20 at a pH between 1 and 4. In certain embodiments, the octanol/water split coefficient apparent is at least 25 at a pH between 1 and 4. In certain embodiments, the apparent octanol/water split coefficient is at least 30 at a pH between 1 and 4.
[0068] As used herein, the term "aliphatic sulfate" refers to the compound having a sulfate moiety at at least one end and an aliphatic tail, which is linear or branched, and saturated or unsaturated. The aliphatic tail can be substituted and can also include cyclic groups. In some embodiments, the aliphatic tail is a C4 to C30 aliphatic group. In certain embodiments, the aliphatic tail is a C7 to C20 aliphatic group. In certain embodiments, the aliphatic tail is a C10 to C20 aliphatic group. In certain embodiments, the aliphatic tail is a C10, C11, C12, C13, C14, or C15 aliphatic group. In certain embodiments, the aliphatic group is an n-alkyl group, which is saturated, unbranched, and unsubstituted. In certain embodiments, the aliphatic group is C7-C20 n-alkyl. In certain embodiments, the aliphatic group is C10-C15 n-alkyl.
[0069] In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is a compound of formula: R1-OSO2OH
[0070] or a salt thereof, wherein R1 is a C4-30 aliphatic group that is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups . In certain embodiments, each R1 is an aliphatic C4-10 group. In certain embodiments, each R1 is an aliphatic C10-15 group. In certain embodiments, each R1 is an aliphatic C15-20 group. In certain embodiments, each R1 is an aliphatic C20-30 group. In certain modalities, R1 is unsaturated. In certain embodiments, R1 is saturated. In certain embodiments, R1 is unbranched. In certain embodiments, R1 is branched. In certain embodiments, R1 is substituted. In certain embodiments, R1 is unsubstituted. In certain embodiments, R1 is saturated, unbranched, and unsubstituted. In certain embodiments, R1 is C4-30 n-alkyl. In certain embodiments, R1 is C5-15 n-alkyl. In certain embodiments, R1 is C5-10 n-alkyl. In certain embodiments, R1 is C10-15 n-alkyl. In certain embodiments, R1 is C6 n-alkyl. In certain embodiments, R1 is C7 n-alkyl. In certain embodiments, R1 is C8 n-alkyl. In certain embodiments, R1 is C9 n-alkyl. In certain embodiments, R1 is C10 n-alkyl. In certain embodiments, R1 is C11 n-alkyl. In certain embodiments, R1 is C12 n-alkyl. In certain embodiments, R1 is C13 n-alkyl. In certain embodiments, R1 is C14 n-alkyl. In certain embodiments, R1 is C15 n-alkyl. In certain embodiments, the excipient is a sodium salt form.
[0071] In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is a compound of formula: R1-SO2OH
[0072] or a salt thereof, wherein R1 is a C4-30 aliphatic group that is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups . In certain embodiments, each R1 is an aliphatic C4-10 group. In certain embodiments, each R1 is an aliphatic C10-15 group. In certain embodiments, each R1 is an aliphatic C15-20 group. In certain embodiments, each R1 is an aliphatic C20-30 group. In certain modalities, R1 is unsaturated. In certain embodiments, R1 is saturated. In certain embodiments, R1 is unbranched. In certain embodiments, R1 is branched. In certain embodiments, R1 is substituted. In certain embodiments, R1 is unsubstituted. In certain embodiments, R1 is saturated, unbranched, and unsubstituted. In certain embodiments, R1 is C4-30 n-alkyl. In certain embodiments, R1 is C5-15 n-alkyl. In certain embodiments, R1 is C5-10 n-alkyl. In certain embodiments, R1 is C10-15 n-alkyl. In certain embodiments, R1 is C6 n-alkyl. In certain embodiments, R1 is C7 n-alkyl. In certain embodiments, R1 is C8 n-alkyl. In certain embodiments, R1 is C9 n-alkyl. In certain embodiments, R1 is C10 n-alkyl. In certain embodiments, R1 is C11 n-alkyl. In certain embodiments, R1 is C12 n-alkyl. In certain embodiments, R1 is C13 n-alkyl. In certain embodiments, R1 is C14 n-alkyl. In certain embodiments, R1 is C15 n-alkyl. In certain embodiments, the excipient is a sodium salt form.
[0073] In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is a compound of formula: R1-P(O)2OH
[0074] or a salt thereof, wherein R1 is a C4-30 aliphatic group that is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups . In certain embodiments, each R1 is an aliphatic C4-10 group. In certain embodiments, each R1 is an aliphatic C10-15 group. In certain embodiments, each R1 is an aliphatic C15-20 group. In certain embodiments, each R1 is an aliphatic C20-30 group. In certain modalities, R1 is unsaturated. In certain embodiments, R1 is saturated. In certain embodiments, R1 is unbranched. In certain embodiments, R1 is branched. In certain embodiments, R1 is substituted. In certain embodiments, R1 is unsubstituted. In certain embodiments, R1 is saturated, unbranched, and unsubstituted. In certain embodiments, R1 is C4-30 n-alkyl. In certain embodiments, R1 is C5-15 n-alkyl. In certain embodiments, R1 is C5-10 n-alkyl. In certain embodiments, R1 is C10-15 n-alkyl. In certain embodiments, R1 is C6 n-alkyl. In certain embodiments, R1 is C7 n-alkyl. In certain embodiments, R1 is C8 n-alkyl. In certain embodiments, R1 is C9 n-alkyl. In certain embodiments, R1 is C10 n-alkyl. In certain embodiments, R1 is C11 n-alkyl. In certain embodiments, R1 is C12 n-alkyl. In certain embodiments, R1 is C13 n-alkyl. In certain embodiments, R1 is C14 n-alkyl. In certain embodiments, R1 is C15 n-alkyl. In certain embodiments, the excipient is a sodium salt form.
[0075] In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is a compound of formula: R1-OP(O)2OH
[0076] or a salt thereof, wherein R1 is a C4-30 aliphatic group that is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups . In certain embodiments, each R1 is an aliphatic C4-10 group. In certain embodiments, each R1 is an aliphatic C10-15 group. In certain embodiments, each R1 is an aliphatic C15-20 group. In certain embodiments, each R1 is an aliphatic C20-30 group. In certain modalities, R1 is unsaturated. In certain embodiments, R1 is saturated. In certain embodiments, R1 is unbranched. In certain embodiments, R1 is branched. In certain embodiments, R1 is substituted. In certain embodiments, R1 is unsubstituted. In certain embodiments, R1 is saturated, unbranched, and unsubstituted. In certain embodiments, R1 is C4-30 n-alkyl. In certain embodiments, R1 is C5-15 n-alkyl. In certain embodiments, R1 is C5-10 n-alkyl. In certain embodiments, R1 is C10-15 n-alkyl. In certain embodiments, R1 is C6 n-alkyl. In certain embodiments, R1 is C7 n-alkyl. In certain embodiments, R1 is C8 n-alkyl. In certain embodiments, R1 is C9 n-alkyl. In certain embodiments, R1 is C10 n-alkyl. In certain embodiments, R1 is C11 n-alkyl. In certain embodiments, R1 is C12 n-alkyl. In certain embodiments, R1 is C13 n-alkyl. In certain embodiments, R1 is C14 n-alkyl. In certain embodiments, R1 is C15 n-alkyl. In certain embodiments, the excipient is a sodium salt form.
[0077] One of skill in the art will recognize that methylnaltrexone can form an ion or salt pair with an anionic amphiphilic pharmaceutically acceptable excipient. In some embodiments, the present invention provides a compound of formula II:

[0078] wherein A- is an anionic amphiphilic pharmaceutically acceptable excipient.
[0079] In some aspects, methylnaltrexone can form an ion pair with any of the formulas R1-COOH, R1-SO2OH, R1-OSO2OH, R1-P(O)2OH, R1-OP(O)2OH, or a salt of the same, as described above. Thus, according to another embodiment, the present invention provides a compound of any one of formulas III, formula IV, formula V, formula VI, or formula VII:


[0080] wherein R1 is a C4-30 aliphatic group which is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups.
[0081] In some embodiments, the amphiphilic pharmaceutically acceptable excipient is sodium dodecyl (lauryl) sulfate (also known as SDS or SLS), sodium heptyl sulfate, sodium heptyl sulfonate, perfluorooctane sulfonate (PFOS), and the like.
In some embodiments, compositions, i.e., pharmaceutical compositions comprising methylnaltrexone and sodium dodecyl (lauryl) sulfate (also known as SDS or SLS), are provided.
[0083] In some embodiments, a provided composition, or formulation thereof, comprises about 5% to about 80% of the amphiphilic pharmaceutically acceptable excipient, based on the total weight of the composition, or formulation thereof. In certain embodiments, about 5% to about 25% of amphiphilic pharmaceutically acceptable excipient is used in the composition or formulation. In some embodiments, a given composition, or formulation thereof, comprises about 5%, about 10%, about 15%, according to 20%, according to 25%, according to 30%, about 35 %, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% of the excipient, based on the total weight of the composition, or formulation thereof.
[0084] Certain amphiphilic pharmaceutically acceptable excipients and their corresponding methylnaltrexone ion pairs are less soluble compared to methylnaltrexone bromide in an aqueous environment. In certain embodiments, therefore, the present invention provides a composition or formulation comprising methylnaltrexone, or a salt thereof, an amphiphilic pharmaceutically acceptable excipient, and a disintegrant. Incorporation of a suitable fast acting disintegrant into compositions and formulations facilitates the breaking of tablets or other solid dosage forms, in particular, the rapid breaking of tablets or other solid dosage forms in the stomach. Thus, the inclusion of fast-acting disintegrants is desired in solid dosage forms, such as tablets, which contain the active ingredient. The amount of the disintegrant will vary depending on the nature and amount of the amphiphilic pharmaceutically acceptable excipient (and, optionally, other ingredients). Those skilled in the art will understand how to manufacture a solid dosage form that will dissolve in the stomach according to the parameters described above. There are in vitro models for making such determinations, such as the United States Pharmacopoeia (USP) dissolution test, the USP disintegration test, etc. In some embodiments, at least 50% of the methylnaltrexone in the composition dissolves within 15 minutes. In other embodiments, at least 75%, 80%, 85%, 90%, 95%, or even 99% of the methylnaltrexone in the composition dissolves within 15 minutes. In some embodiments, the amounts of methylnaltrexone indicated above dissolve in about 10 minutes, or even in about 5 minutes. As used herein by dissolving a certain percentage in the stomach within a particular period of time is meant a percentage of the methylnaltrexone, as a cation or as a salt such as an ion pair, in the composition that will convert to a solid. in solution when the composition is placed in 900 mL of 1N HCl at 37°C, paddle at 100 rpm.
[0085] Suitable disintegrants are known in the art and include, but are not limited to agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, sodium bicarbonate, crospovidone (crosslinked PVP), sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose (croscarmellose), pregelatinized starch (1500 starch), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate ( Veegum), and combinations thereof. In some embodiments, the disintegrant is crospovidone. In certain modalities, the disintegrant is an effervescent disintegrant. Effervescent disintegrants are capable of generating carbon dioxide in an aqueous medium, particularly acidic aqueous medium such as stomach contents. In certain embodiments, the disintegrant is a bicarbonate, such as sodium bicarbonate (NaHCO3) or potassium bicarbonate (KHCO3). In certain modalities, the disintegrant is a carbonate. In certain embodiments, the disintegrant is sodium carbonate (Na2CO3). In certain embodiments, the disintegrant is calcium carbonate (CaCO3). In certain embodiments, the composition or formulation comprises at least two disintegrants. For example, the composition or formulation can include an effervescent disintegrant and a disintegrant that is not effervescent. In certain embodiments, the compositions or formulation comprise sodium bicarbonate and crospovidone as disintegrants. In some embodiments, formulations provided comprise from about 1% to about 25%, about 1% to about 15%, about 1% to about 10%, or about 2% to about 5% disintegrant. , based on the total weight of the formulation. In some embodiments, formulations provided comprise from about 1%, about 2%, about 3%, about 4%, about 5%, about 7%, about 8%, about 10%, about 12%, or about 15% disintegrant, based on the total weight of the formulation. In certain embodiments, the composition or formulation includes a material and/or coating that delays or prevents dissolution of the solid dosage form in the oral cavity. Preferably, the solid dosage form rapidly breaks up or disintegrates in the stomach, not the oral cavity.
[0086] In some embodiments, the present invention provides a formulation of methylnaltrexone that also comprises one or more additional components, such as, for example, binders, vehicles, disintegrants, chelating agents, antioxidants, fillers, wetting agents, or combinations of the same. In certain embodiments, a composition is formulated into a tablet which also comprises one or more additional components, such as, for example, binders, carriers, disintegrants, chelating agents, antioxidants, fillers, wetting agents, lubricants, or combinations thereof. In some embodiments, a composition is formulated into a tablet that also comprises an antioxidant and one or more components, such as, for example, binders, vehicles, chelating agents, fillers, wetting agents, or combinations thereof. In some embodiments, a composition is formulated into a tablet which also comprises a disintegrant and one or more components, such as, for example, binders, vehicles, chelating agents, antioxidants, fillers, wetting agents, or combinations of the same. In some embodiments, a composition is formulated into a tablet that also comprises an antioxidant, a disintegrant, and one or more components, such as, for example, binders, vehicles, chelating agents, fillers, wetting agents, or combinations thereof. Such additional components are described here in detail, infra.
In certain embodiments, pharmaceutically acceptable formulations of the present invention are provided as tablets which comprise a composition comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient, and a disintegrant, and optionally one or more of a binder, an agent of chelation, and a wetting agent. In some embodiments such tablets comprise a composition comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient, a binder, a chelating agent, a disintegrant, and a wetting agent. In certain embodiments such tablets comprise a composition comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient, an antioxidant, and one or more of a binder, a chelating agent, a disintegrant, and a wetting agent. In accordance with some embodiments, formulations provided comprise tablets that have a non-functional coating. In some embodiments, formulations provided also comprise an antioxidant.
[0088] One skilled in the art will easily appreciate that the category under which a particular component is listed is not intended to be limiting; in some cases a particular component may suitably fall into more than one category. Also, as will be appreciated, the same component may sometimes perform different functions, or may perform more than one function, in the context of a particular formulation, for example depending on the amount of the ingredient and/or the presence of other ingredients and/ or active compound(s).
[0089] Wetting agents are well known in the art and typically facilitate the interaction of an active agent, such as one that is hydrophobic, with water molecules in a surrounding aqueous environment. Exemplary wetting agents include poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates, such as polysorbate 80, cetyl alcohol, glycerol fatty acid esters (eg, triacetin, glycerol monostearate, and the like), polyoxymethylene stearate, sodium dodecyl sulfate, sorbitan fatty acid esters, acid esters sucrose fatty acid, benzalkonium chloride, polyethoxylated castor oil, and docusate sodium, and the like, and combinations thereof. In some embodiments, tablets provided comprise from about 1% to about 25% wetting agent, based on the total weight of the tablets. In some embodiments, tablets provided comprise from about 1%, about 3%, about 4%, about 5%, about 10%, about 15%, or about 20% wetting agent, with based on the total weight of certain tablets.
[0090] In certain embodiments, a wetting agent is a polysorbate. In some embodiments, a wetting agent is polysorbate 80, also known as Tween 80, and is available from Sigma-Aldrich, among other sources. In some embodiments, tablets provided comprise from about 1% to about 25% polysorbate 80, about 1% to about 5%, about 2% to about 5%, about 3%, or about 5%. about 4% based on the total weight of a given tablet. In certain embodiments, tablets provided comprise from about 1%, about 3%, about 4%, about 5%, about 10%, about 15%, or about 20% polysorbate 80, based on the total weight of certain pills. Without wanting to be bound by any particular theory, polysorbate 80 can also act as an absorption enhancer. Furthermore, without wanting to be bound by any particular theory, polysorbate 80 can facilitate the reduction of the mucus layer created in the gastrointestinal tract so that the remaining methylnaltrexone in the mucus layer is more easily released for rapid absorption.
The addition of one or more chelating agents may be particularly useful in formulations that include methylnaltrexone, and such agents may provide protection from metal catalyzed degradation and/or precipitation of methylnaltrexone. Suitable chelating agents are known to those of skill in the art, and include any pharmaceutically acceptable chelating agent. Common chelating agents include, but are not limited to, ethylene-diaminetetraacetic acid (EDTA) and derivatives thereof, ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA) ) and derivatives thereof, diethylenetriaminepentacetic acid (DTPA) and derivatives thereof, N,N-bis(carboxymethyl)glycine (NTA) and derivatives thereof, nitrilotriacetic acid and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof thereof, and sodium deoxycholate and derivatives thereof.
[0092] In some embodiments, the chelating agent is selected from the group consisting of EDTA or derivatives thereof. In some embodiments, the chelating agent is selected from the group consisting of calcium EDTA disodium, diammonium EDTA, potassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA , HEDTA, and trisodium HEDTA, and related salts thereof. In some embodiments, the chelating agent is EDTA disodium, EDTA trisodium, or calcium EDTA disodium. In some embodiments, the chelating agent is calcium EDTA (edetate calcium) or a calcium salt EDTA derivative EDTA or a calcium EGTA or a calcium salt EGTA derivative. In some embodiments, the chelating agent is calcium EDTA disodium, such as, for example, calcium EDTA disodium hydrate (edetate calcium disodium dihydrate). Calcium EDTA is available from Sigma-Aldrich, among other sources. In some embodiments, formulations provided comprise from about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, 0.01% to about 2%, 0.01% to about 1%, about 0.1% to about 5%, about 0.1% to about 4%, 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, or about 0.1% to about 0.5% of the agent of chelation, based on the total weight of the formulation. In some embodiments, formulations provided comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0. 5%, or about 0.6% of the chelating agent, based on the total weight of the formulation.
Suitable binders (also referred to as "diluents" and/or "fillers") are known in the art. For example, suitable binders include, but are not limited to starch, PVP (polyvinyl pyrrolidone), low molecular weight HPC (hydroxypropyl cellulose), microcrystalline cellulose (eg Avicel®), silicified microcrystalline cellulose (Prosolv 50 ), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose, ethylcellulose, alginates, gelatin, polyethylene oxide, acacia, dextrin, sucrose, magnesium aluminum silicate, and polymethacrylates. Fillers include agents selected from the group consisting of microcrystalline cellulose (eg, Avicel®), starch, lactitol, lactose, a suitable inorganic calcium salt, sucrose, glucose, mannitol, silicic acid, or a combination thereof. In some embodiments, formulations that comprise about 5%, to about 90%, or about 10% to about 50%, or about 10% to about 40%, or about 10% to about 45% binder, based on the total weight of the formulation. In some embodiments, formulations comprising about 10%, about 15%, about 16%, about 20%, about 24%, about 25%, about 30%, about 35 %, about 40%, about 45%, or about 50% binder, based on the total weight of the tablets. In some embodiments, the formulations comprise microcrystalline cellulose as a binder. In certain embodiments, the formulations comprise binders, microcrystalline cellulose and silicified microcrystalline cellulose.
[0094] In certain embodiments, formulations provided may comprise one or more antioxidants. Such antioxidants include those known to one of skill in the art. Exemplary antioxidants include ascorbic acid, and salts and esters thereof; citric acid, and salts and esters thereof; butylated hydroxyanisole ("BHA"); butylated hydroxytoluene ("BHT"); tocopherols (eg, d-alpha tocopherol, dl-alpha tocopherol, d-alpha tocopherol acetate, dl-alpha tocopherol acetate, beta tocopherol, delta tocopherol, gamma tocopherol, and the like), and carotenoids (eg, vitamin A, lutein, and zeaxanthin). In certain embodiments, a formulation comprises ascorbic acid. In some embodiments, the formulation comprises up to about 10% of one or more antioxidants by weight. In some embodiments, a formulation provided comprises from about 0.01% to about 5% of one or more antioxidants by weight. In some embodiments, a formulation provided comprises about 1.0% to about 10% of one or more antioxidants by weight. In certain embodiments, a formulation provided comprises about 1%, about 2%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% of one or more antioxidants by weight.
[0095] In certain embodiments, the formulations may comprise a lubricant. Lubricants are generally substances used in solid dosage formulations to reduce friction during compression. Such compounds include, by way of example and without limitation, sodium oleate, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, polyethylene glycol, talc, mineral oil, stearic acid, sodium benzoate , sodium acetate, sodium chloride, and other materials known to one of skill in the art. In certain embodiments, the lubricant is a stearate salt. In some embodiments, formulations that comprise about 0.1% to about 7%, or about 0.2% to about 1% lubricant, based on the total weight of formulations provided. In certain embodiments, the lubricant is magnesium stearate and is available from Sigma-Aldrich, among other sources.
[0096] In certain embodiments, formulations may comprise a non-functional coating. For example, in some embodiments, the tablet may comprise a non-functional coating. In some embodiments, the non-functional coating is a sealant coating. For example, a suitable seal coat can be applied as a solution (eg HPMC solution) in a concentration of about 1% wt/wt to 25% wt/wt, and preferably 1% wt/wt to about 10% weight/weight. On drying, under suitable conditions, the initial seal coat is in the range of about 1% w/w to about 3% w/w, or about 2% w/w, of the uncoated tablet. Such seal coat may comprise a polymer (for example, HPMC) and may be a commercially available seal coat such as Opadry® Clear (Colorcon, Inc.), or HPMC E3. On drying, seal coat can be from about 1% to about 10% weight gain of the coated formulation. In certain embodiments, the formulation can comprise a coating to prevent disintegration of the dosage form in the oral cavity.
In certain embodiments, the formulation for oral administration comprises (a) about 7% to about 75% methylnaltrexone bromide, based on the total weight of the formulation; (b) about 5% to about 80% of an amphiphilic pharmaceutically acceptable excipient, based on the total weight of the formulation; (c) about 0.01% to about 5% of a chelating agent, based on the total weight of the formulation; (d) about 1% to about 25% of a wetting agent, based on the total weight of the formulation; (e) about 5% to about 90% of a binder, based on the total weight of the formulation; (f) about 1% to about 25% of a disintegrant, based on the total weight of the formulation; (g) about 0.1% to about 7% of a lubricant, based on the total weight of the formulation; and optionally, (h) about 0.01% to about 5% of an antioxidant, based on the total weight of the formulation. In certain embodiments, the methylnaltrexone bromide in the formulation is (R)-N-methylnaltrexone bromide. In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is sodium dodecyl (lauryl) sulfate. In certain embodiments, the chelating agent is an EDTA salt (eg, calcium EDTA). In certain embodiments, the wetting agent is polysorbate 80. In certain embodiments, the disintegrant is sodium bicarbonate. In other embodiments, the disintegrant is crospovidone. In certain embodiments, the disintegrant is a combination of sodium bicarbonate and crospovidone. In certain embodiments, the lubricant is magnesium stearate. In certain embodiments, the antioxidant is ascorbic acid. In certain embodiments, the invention provides a tablet formulation for oral administration comprising about 30% methylnaltrexone bromide, about 10% sodium dodecyl sulfate, about 11% microcrystalline cellulose, about 5% crospovidone, about about 0.25% calcium EDTA, about 2% polysorbate 80, about 30% Prosolv 50, about 11% sodium bicarbonate, about 2% talc, about 0.5% dioxide of colloidal silicon, and about 0.25 magnesium stearate. It will be understood by those skilled in the art that, depending on the manner of preparing the tablet or other formulation of the invention described herein, methylnaltrexone may exist paired with bromide, paired with the anion of the amphiphilic pharmaceutically acceptable excipient, or some combination thereof. Production
[0098] In certain embodiments, compositions and formulations are prepared by methods that include an extrusion/spheronization step. In some embodiments, formulations are manufactured by wet granulation of a supplied formulation followed by extrusion/spheronization to form spheroids. Certain spheroids are then dried and ground to form a powder which is mixed with suitable binder(s) and disintegrant(s). The resulting mixture is then milled and blended with a suitable lubricant and compressed into tablets. In certain embodiments, a non-functional coating is applied.
[0099] In some embodiments, tablets are prepared by methods that do not include extrusion/spheronization steps and, according to such methods, are manufactured by means of wet granulation. Once dried, the granulation is milled to form a granular powder which is mixed with suitable binder(s) and disintegrant(s). The resulting mixture is then milled and blended with a suitable lubricant and compressed into tablets. In certain embodiments, a non-functional coating is applied. Unit Dosage Form
[00100] Methylnaltrexone formulations can be prepared as a unit dosage form. In fact, a tablet is typically a unit dosage form. In some embodiments, a unit dosage form contains 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350 mg, 375mg, 400mg, 425mg, 450mg, 475mg, or 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg , 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1025mg, 1050mg, 1075mg, 1100mg, 1125mg, 1150mg, 1175 mg, 1200mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, or 1500mg of methylnaltrexone bromide. In some embodiments, a unit dosage form contains between 50 mg and 900 mg, inclusive, or between 150 mg and 450 mg, inclusive, of methylnaltrexone bromide. In some embodiments, a unit dosage form contains 50 mg, 75 mg, 150 mg, 225 mg, 300 mg, 450 mg, 600 mg, or 900 mg of methylnaltrexone bromide. In some embodiments, the unit dosage form comprises methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient, for example, sodium dodecyl (lauryl) sulfate (also known as SDS or SLS). Management
The compositions and formulations can be administered to a patient when required to deliver an effective amount of methylnaltrexone. In certain modalities, the patient is orally administered methylnaltrexone or a formulation thereof at least once a day. In other modalities, the patient is orally administered methylnaltrexone or a formulation thereof up to once a day. In certain modalities, the patient is orally administered methylnaltrexone or a formulation thereof no more than once a day. In certain modalities, the patient is orally administered methylnaltrexone or a formulation thereof as needed. In certain modalities, the patient is orally given methylnaltrexone or a formulation thereof as needed, but not more than once a day. For example, a unit dosage form of a formulation provided may be orally administered to a patient in a single day, for example, a unit dosage of about 150 mg, 300 mg, or 450 mg of methylnaltrexone bromide or an equivalent molar amount of methylnaltrexone. In some embodiments, the present invention provides a method of treating an opioid-induced side effect in a patient in need thereof, comprising the step of orally administering to said patient one or more tablets of the present invention wherein said tablet provides about 150 mg, 300 mg, or 450 mg of methylnaltrexone or an equivalent molar amount of methylnaltrexone bromide, for example, methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient such as sodium dodecyl sulfate (lauryl) (also known as SDS or SLS), sodium heptyl sulfate, sodium heptyl sulfonate, perfluorooctane sulfonate (PFOS), and the like. In certain embodiments, a single tablet formulation of the present invention provides about 25mg, about 50mg, about 75mg, about 100mg, about 125mg, about 150mg, about 300mg, or about of 450 mg of methylnaltrexone bromide, or equivalent moles of another salt form, or methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient such as sodium dodecyl sulfate (lauryl) (also known as SDS or SLS).
[00102] As defined above, in certain embodiments the term "effective amount", when used in conjunction with an amount of methylnaltrexone, means an amount of methylnaltrexone sufficient to achieve laxation in a patient. In some embodiments, an effective amount means an amount of methylnaltrexone sufficient to achieve laxation in a patient within about 24 hours, within about 12 hours, within about 8 hours, within about 5 hours, within about 4 hours, within about 3 hours, within about two hours, or within about one hour of administration to said patient. In some embodiments, the effective amount means an amount of methylnaltrexone sufficient to achieve laxation within about 4 hours of administration to the patient. In some embodiments, the effective amount means an amount of methylnaltrexone sufficient to achieve laxation within about 4 hours of administration to the patient for at least 99%, at least 95%, at least 90%, at least 85%, at least 80 %, at least 75%, or at least 50% of all doses administered. In some embodiments, the effective amount is an amount of methylnaltrexone sufficient to achieve laxation within about 4 hours of administration to the patient for all doses administered during the first four weeks of dosing.
[00103] In some embodiments, the formulations are administered to a patient in a fasted state. As used herein, the term "fasted" means that the patient has not eaten any food for at least two hours, at least 4 hours, for at least 6 hours, for at least 8 hours, for at least 10 hours, or for at least at least 12 hours before administration of a given formulation. In certain embodiments, the term "fasting" means an overnight fast. It is believed that improved effects will be seen in fasting patients than in fed patients. These effects may be magnified in patients given methylnatrexone in a given tablet compared to patients given the same dose in capsule form. Thus, it is believed to be advantageous to administer a formulation of methylnaltrexone given to a patient in a fasted state.
[00104] In other embodiments, formulations are administered to a patient who has not fasted. Therefore, there is no requirement that the patient not have to have eaten before methylnaltrexone is administered. Combination Products and Combined Administration
[00105] It will also be appreciated that the compositions and formulations provided can be employed in combination therapies, i.e., as long as the formulations can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination therapies (therapeutics or procedures) to employ in a combination regimen will take into account the compatibility of the desired procedures and/or therapeutics and the desired therapeutic effect to be obtained. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (eg, a formulation may be administered concurrently with another compound used to treat the same disorder), or may achieve different effects (eg, control of any effect adverse). As used herein, additional therapeutic compounds that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated".
[00106] In some embodiments, methylnaltrexone or an ion pair or formulation of the invention and one or more other active agents may be administered together in a single formulation (eg, unit dosage form); in other embodiments, methylnaltrexone and one or more other active agents can be administered as separate formulations. In certain embodiments, methylnaltrexone and/or one or more other active agents can be administered in multiple doses.
[00107] In some embodiments, the other active agent administered in combination with a methylnaltrexone ion pair or formulation of the invention is an opioid. Combination therapy of methylnaltrexone and an opioid may allow simultaneous pain relief and minimization of side effects associated with the opioid (eg, gastrointestinal effects (eg, delayed gastric emptying, altered GI tract motility)). Accordingly, and in certain embodiments, the present invention provides a unit dosage form comprising a combination of methylnaltrexone with an opioid together in a single layer dosage form (e.g., tablet). In some embodiments, such unit dosage form can be a bi-layer tablet comprising methylnaltrexone in one layer and an opioid in another layer. In a specific embodiment, the combination unit dosage form is suitable for oral administration.
[00108] Opioids useful for analgesia are known in the art. For example, opioid compounds include, but are not limited to, alfentanil, anileridine, asimadoline, bremazocin, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, ethylmorphine, fedotozine, fentanyl, funaltrexamine , hydrocodone, hydromorphone, levalorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, nicomorphine, opium, oxycodone, oxymorphone, papaveretum, pentazocine propiram, propoxyphene, remifentanil, sufentanil, tilidine, trimebutine, and tramadol. In some embodiments the opioid is at least one opioid selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, nicomorphine, oxycodone , oxymorphone, papaveretum, pentazocine, propyram, propoxyphene, sufentanil and/or tramadol. In certain embodiments of the present invention, the opioid is selected from morphine, codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl, tramadol, and mixtures thereof. In a particular modality, the opioid is loperamide. In other embodiments, the opioid is a mixed agonist such as butorphanol. In some modalities, individuals are given more than one opioid, for example, morphine and heroin or methadone and heroin.
[00109] Typically, an amount of other active agent(s) administered in combination therapy may be no greater than the amount that would normally be administered in monotherapy with the relevant agent(s). In certain embodiments, an amount of another active agent administered in combination therapy may be less than that normally administered in monotherapy with the relevant agent(s). For example, in certain embodiments of the present invention, an amount of additional active agent may range from about 50% to 100% of the amount normally present in a formulation comprising that compound as the therapeutic agent alone.
[00110] In certain embodiments, the formulations may also be used in conjunction with and/or in combination with conventional therapies for gastrointestinal dysfunction to help ameliorate constipation and bowel dysfunction. For example, conventional therapies include, but cannot be limited to functional stimulation of the intestinal tract, stool softening agents, laxatives (eg, diphlymethane laxatives, cathartic laxatives, osmotic laxatives, saline laxatives), agents bulking and laxatives, lubricants, intravenous hydration, and nasogastric decompression. Uses and Kits of Compositions and Formulations
[00111] The present invention provides pharmaceutically acceptable formulations as described above comprising methylnaltrexone for oral administration useful for the release of such compounds in any context in which such release is desirable. In certain embodiments, the formulations provided are useful for the release of methylnaltrexone in antagonizing undesirable side effects of opioid analgesic therapy (eg, gastrointestinal effects (eg, delayed gastric emptying, altered GI tract motility)). Furthermore, the formulations can be used as to treat individuals having disease states that are ameliorated by binding to µ opioid receptors, or in any treatment where temporary suppression of the µ opioid receptor system is desired (e.g., ileum). In certain embodiments of the present invention, the methods of using the formulations provided are in human subjects.
[00112] Consequently, the administration of formulations provided may be advantageous for the treatment, prevention, amelioration, delay or reduction of side effects of opioid use, such as, for example, gastrointestinal dysfunction (e.g., inhibition of intestinal motility, constipation , GI sphincter constriction, nausea, emesis (vomiting)), biliary spasm, opioid bowel dysfunction, colic, dysphoria, pruritus, urinary retention, respiratory depression, papillary constriction, cardiovascular effects, chest wall stiffness, and suppression of cough, depression of the tension response, and immune suppression associated with the use of narcotic analgesia, or combinations thereof. Use of a formulation can thus be beneficial from a quality of life standpoint for individuals suffering from opioid use, as well as to reduce complications arising from chronic constipation such as hemorrhoids, appetite suppression, mucosal collapse, sepsis , risk of colon cancer, and myocardial infarction.
[00113] In some embodiments, the formulations provided are useful for administration to a subject suffering from acute opioid use. In some embodiments, the formulations provided are useful for administration to patients suffering from postoperative gastrointestinal dysfunction.
In certain embodiments, the formulations provided are also useful for administration to individuals suffering from chronic opioid use (for example, terminally ill patients receiving opioid therapy such as an AIDS patient, a cancer patient, a cardiovascular patient; individuals receiving chronic opioid therapy for pain control; individuals undergoing opioid therapy for opioid withdrawal control). In some modalities, the individual is an individual using opioid therapy for chronic pain management. In certain modalities the pain is non-malignant pain (eg, back pain, neuropathic pain, pain associated with fibromyalgia, osteoarthritis). In some embodiments, the individual is a terminally ill patient. In other modalities the individual is a person undergoing opioid withdrawal control therapy.
[00115] In certain embodiments, the formulations provided herein are administered to individuals who have been selected for treatment with methylnaltrexone. In specific embodiments, the individual is selected based on the individual having an increased risk for developing one or more of the conditions outlined above. In another embodiment, the subject is selected based on the use of opioid therapy for pain control, or based on having one or more of the conditions presented here. In certain modalities, the individual is constipated or has a history of constipation due to opioid therapy. In one modality, a constipated individual has not had a bowel movement in the previous three days. In one modality, a constipated individual has had no fewer than three bowel movements in the previous week. In certain modalities, a constipated individual has had less than three unaided bowel movements per week on average for the past four consecutive weeks, and one or more of the following: (a) hard or lumpy stools, (b) straining during movements bowel movement, and/or (c) feeling of incomplete evacuation after bowel movements.
[00116] In certain embodiments, the individual is selected for treatment with a formulation of methylnaltrexone described herein based on the use of opioids, eg, for non-malignant pain. The individual may be using opioids intermittently or regularly. In one modality, the individual who is selected was taking opioids when needed. In one modality, the individual who is selected has taken opioids for less than a week. In one modality, the individual who is selected has taken opioids during the course of at least one week. In another modality, the individual who is selected has taken opioids during the course of at least two weeks. In another modality, the individual who is selected has taken opioids during the course of at least three weeks. In another modality, the individual who is selected has taken opioids during the course of at least four weeks. In another modality, the individual who is selected has taken opioids during the course of at least three months. In another modality, the individual who is selected has taken opioids during the course of at least six months. In another modality, the individual who is selected has taken opioids during the course of at least twelve months. In another modality, the individual who is selected has taken opioids during the course of more than one year. In another modality, the individual who is selected has taken opioids at least every other day during the course of at least two weeks. In one embodiment, the subject who is selected has received at least 7 doses >25 mg of oral morphine equivalents for at least 14 days. In one embodiment, the subject who is selected received a daily dose of >50 mg of oral morphine equivalents for at least 14 days. In one embodiment, the individual who is selected is constipated due to opioid therapy and received a daily dose of >50 mg of oral morphine equivalents for at least 14 days. In certain modalities, the subject received a daily dose of >50 mg of oral morphine equivalents for at least 14 days; and had fewer than three (3) unassisted bowel movements per week on average during the last four consecutive weeks that were associated with one or more of the following: (a) a Type 1 or 2 Bristol Stool Shape Scale during fur. at least 25% of unaided bowel movements, (b) exerting during at least 25% of unaided bowel movements; and/or (c) a feeling of incomplete evacuation after at least 25% of bowel movements without assistance. An unassisted bowel movement refers to a bowel movement associated with no laxative use within 24 hours prior to bowel movement.
[00117] In certain embodiments, the individual selected for treatment with a formulation of methylnaltrexone described herein is an individual suffering from opioid-induced constipation. In certain embodiments, the individual selected for treatment with a formulation of methylnaltrexone described herein is an individual with advanced disease who is receiving palliative care and is suffering from opioid-induced constipation. In certain modalities, the individual selected for treatment with a formulation of methylnaltrexone described herein is an individual with advanced disease who is receiving palliative care and is suffering from opioid-induced constipation where the response to laxative therapy (eg, bisacodi- la, senokot, docussato) was not enough. In certain embodiments, the individual selected for treatment with a methylnaltrexone formulation described herein is an individual with non-malignant pain who is suffering from opioid-induced constipation. In certain embodiments, the individual selected for treatment with a methylnaltrexone formulation described herein is an individual with non-malignant pain who is suffering from opioid-induced constipation where the response to laxative therapy (eg, bisacodyl, senokot, docussate) does not was enough. In certain modalities, the individual selected for treatment with a methylnaltrexone formulation described herein has not responded to standard laxative therapy. In certain modalities, the individual selected for treatment with a methylnaltrexone formulation described herein has responded to standard laxative therapy. In certain embodiments, the individual selected for treatment with a formulation of methylnaltrexone described herein is concurrently administered laxative therapy.
[00118] Alternative or additional uses for the provided formulations described herein are useful to treat the effects of opioid use including, for example, abnormal proliferation or migration of endothelial cells (eg, vascular endothelial cells), increased angiogenesis, and increase in lethal factor production from opportunistic infectious agents (eg, Pseudomonas aeruginosa). Additional beneficial uses of the formulations provided include treatment of opioid-induced immune suppression, inhibition of angiogenesis, inhibition of vascular proliferation, treatment of pain, treatment of inflammatory conditions such as inflammatory bowel syndrome, treatment of infectious diseases and diseases of the musculoskeletal system such as osteoporosis, arthritis, osteitis, periostitis, myopathies, and treatment of autoimmune diseases.
[00119] In certain embodiments, the formulations provided can be used in methods to prevent, inhibit, reduce, delay, lessen or treat gastrointestinal dysfunction, including, but not limited to, irritable bowel syndrome, opioid-induced bowel dysfunction. oid, colitis, postoperative or postpartum ileus, nausea and/or vomiting, decreased gastric emptying and motility, inhibition of stomach, and small and/or large intestine propulsion, increased amplitude of non-propulsive segmental contractions, sphincter constriction of Oddi, increased anal sphincter tone, impaired reflex relaxation with rectal distension, decreased gastric, biliary, pancreatic or intestinal secretions, increased water absorption from bowel contents, gastroesophageal reflux, gastroparesis, cramps, swelling, pain abdominal or epigastric and discomfort, constipation, idiopathic constipation, postoperative gastrointestinal dysfunction following abdominal surgery (eg plo, colectomy (eg, right hemicolectomy, left hemicolectomy, transverse hemicolectomy, colectomy drop, anterior low resection), hysterectomy), and delayed absorption of orally administered medications or nutritional substances.
[00120] The formulations provided are also useful in the treatment of conditions including cancers involving angiogenesis, immune suppression, sickle cell anemia, vascular wounds, and retinopathy, treatment of disorders associated with inflammation (eg, irritable bowel syndrome) , immune suppression, chronic inflammation.
[00121] In other embodiments, the formulations provided and unit dose forms are useful in drug preparation, including but not limited to drugs useful in treating side effects of opioid use, including gastrointestinal side effects (eg, inhibition intestinal motility, GI sphincter constriction, constipation), nausea, emesis, vomiting, dysphoria, pruritus, or a combination of these. The formulations provided are useful for drug preparations useful in treating patients receiving acute opioid therapy (eg, patients suffering from postoperative gastrointestinal dysfunction receiving acute opioid administration) or individuals chronically using opioids (eg, terminally ill patients patients receiving opioid therapy such as an AIDS patient, a cancer patient, a patient with cardiovascular disease; individuals receiving chronic opioid therapy for pain control (malignant or non-malignant pain); or individuals receiving chronic opioid therapy; opioid for the control of opioid withdrawal). Still further, the preparation of drugs useful in the treatment of pain, treatment of inflammatory conditions such as inflammatory bowel syndrome, treatment of infectious diseases, treatment of diseases of the musculoskeletal system such as osteoporosis, arthritis, osteitis, periostitis, myopathies, treatment of autoimmune diseases and immune suppression, therapy of postoperative gastrointestinal dysfunction following abdominal surgery (eg, colectomy (eg, right hemicolectomy, left hemicolectomy, transverse hemicolectomy, colectomy drop, anterior low resection), idiopathic constipation, and ileus (eg, postoperative ileus, postpartum ileus), and treatment of disorders such as cancers involving angiogenesis, chronic inflammation and/or chronic pain, sickle cell anemia, vascular wounds, and retinopathy.
[00122] In still other embodiments, veterinary applications (eg treatment of domestic animals, eg horse, dog, cats) of using provided formulations are provided. Thus, the use of formulations provided in veterinary applications analogous to those described above for human subjects is contemplated. For example, inhibition of equine gastrointestinal motility, such as colic and constipation, can be fatal to a horse. The resulting pain suffered by the colicky horse can result in shock leading to death, while a long-term case of constipation can also lead to the horse's death. Treatment of horses with peripheral opioid receptor antagonists has been described, for example, in U.S. Patent Publication No. 2005/0124657, published January 20, 2005, which is incorporated herein by reference.
[00123] Further also encompassed by the invention are pharmaceutical kits and/or bags comprising formulations described herein, and a container (e.g., a plastic or metallic packaging, or other suitable container). Optional instructions for use are additionally provided in such kits.
[00124] In order that the invention described herein may be more fully understood, the following examples are presented. It is to be understood that these examples are for illustrative purposes only and are not to be considered as limiting this invention in any way.
[00125] All features of each aspect of the invention apply to all other aspects mutatis mutandis. The contents of all references, patents, pending patent applications, and published patents cited throughout this application are hereby expressly incorporated by reference. Examples Example 1
[00126] Methylnaltrexone bromide can be prepared according to the methods described in detail in International PCT Patent Application Publication No. WO 2006/127899, or obtained from commercial sources such as Covidien, Saint Louis, Mo. Formulations containing methylnaltrexone were prepared using pharmaceutically acceptable excipients. Spheroids containing methylnaltrexone were prepared. Capsules were prepared by filling the capsules with spheroids. Some capsules have been prepared to contain enteric coated spheroids, in which the spheroids dissolve only after passing through the stomach. Capsules, without an enteric coating, or after dissolving the enteric coating, will dissolve for 10 to 30 minutes. Tablets were also prepared from spheroids using conventional techniques. The tablets dissolve in less than 10 minutes.
[00127] The spheroids were prepared by a granulation process followed by extrusion and spheronization as described in the following general method. Methylnaltrexone bromide and pharmaceutically acceptable excipients were combined in an aqueous solution. Water was added until a wet mass suitable for extrusion was obtained. The wet mass was passed through an extruder, and the extrudate was spheronized in a spheronizer. The resulting spheroids were dried in a fluid bed dryer and passed through a sieve. Uncoated spheroids were stored in an appropriate container. Example 2 Administration of Capsules Containing Enterically Coated Methylnaltrexone Spheroids
[00128] Capsules containing methylnaltrexone enterically coated spheroids as described in Example 1 were tested in patients suffering from opioid-induced constipation. The patients in this study were non-chronic methadone maintenance patients. Patients had chronic non-malignant (non-cancer) pain where the non-malignant condition supporting the chronic pain (eg, osteoarthritis, back pain, neuropathic pain) had a documented history of at least 2 months prior to analysis, stable pain for at least 1 month. Patients were on opioids for at least one month and on a daily dose greater than or equal to 20 mg morphine equivalents per day for at least two weeks prior to the review visit and during the review visit period with no change anticipated during the study. Patients also had a history of constipation due to opioid use for at least one month prior to the review visit. Constipation defined as less than 3 bowel movements per week on average and 1 or more of the following: (i) hard lumpy stools for at least 25% of bowel movements, (ii) a feeling of incomplete bowel movement following at least 25% of bowel movements, (iii) distending for at least 25% of bowel movements.
[00129] Patients were administered with enteric coated methylnaltrexone capsules containing 10 mg, 50 mg, 150 mg, 300 mg or 450 mg of methylnaltrexone. The mean peak plasma level of methylnaltrexone resulting from the doses was as follows: (i) for 10 mg, less than 1 ng/ml, (ii) for 50 mg, less than 5 ng/ml, (iii) for 150 mg, less than 5 ng/ml, (iv) for 300 mg, less than 10 ng/ml, and (v) for 450 mg, less than 20 ng/ml. These capsules containing enteric coated preparations of methylnaltrexone were not effective for treating opioid-induced constipation. They would not induce laxation and would not cause more bowel movements in patients compared to controls. Example 3 Administration of Non-Enteric Coated Methylnaltrexone Capsules
[00130] Capsules containing methylnaltrexone spheroids but without the enteric coating, prepared as described in Example 1, were tested in patients receiving opioids for non-malignant pain. The patients in this study were not non-chronic methadone maintenance patients. Patients were selected based on the same criteria as the criteria used in Example 2, except that the minimum daily dose of opioids was equal to or greater than 30 mg instead of 20 mg of morphine equivalents. Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted in mean peak plasma levels of between about 15 and 40 ng/ml, on the order of 3 or more times lower than the mean peak plasma levels associated with effective doses of subcutaneous methylnaltrexone injection. These capsules containing spheroids without the enteric coating would not induce laxation and would not cause more bowel movements in this patient population than in controls. Administration of Non-Enterically Coated Methylnaltrexone Pills
Tablets containing methylnaltrexone spheroids, without an enteric coating, prepared as described in Example 1, were tested in patients receiving opioids for non-malignant pain. The patients in this study were non-chronic methadone maintenance patients. Patients were selected based on the same criteria as the criteria used in Example 3. Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted in mean peak plasma levels between about 7 and 40 ng/ml. These tablets without an enteric coating showed statistically significant activity at one dose, but did not significantly induce laxation across doses.
[00132] Both tablets and capsules containing uncoated spheroids had similar compositions, except that the spheroids were compressed with pharmaceutically acceptable excipients to form tablets, while the spheroids were encapsulated in hard gelatine shells to prepare the capsules. Once contacted with an aqueous medium, the tablets disintegrated immediately and almost all of the drug dissolved in less than 10 minutes. In contrast, it took 10 minutes for the capsule shells to dissolve and at least 30 minutes for the drug to completely dissolve from the capsules. (Figure 1) Plasma levels associated with both dosage forms containing uncoated spheroids were available (tablets produced more consistent mean peak plasma levels relative to capsules) and overlapped between subjects. Example 4 Determination of Division Coefficient
[00133] Methylnaltrexone ion pairs with amphiphilic pharmaceutically acceptable excipient were prepared and the apparent octanol-water purification coefficient (APC) was measured and compared with that of methylnaltrexone bromide. A predetermined amount of each of MNTX-heptyl sulfate and MNTX-dodecyl sulfate was dissolved in 2 mL of 1-octanol which was saturated with water. Two mL of water that had been saturated with 1-octanol was added to each MNTX salt solution. The mixtures were stirred overnight at room temperature, and 1 ml of the 1-octanol phase was then diluted to 10 ml with the mobile phase used for chromatographic analysis (HPLC) of the samples and 1 ml of the aqueous phase was diluted to 5 mL with the mobile phase. The samples were then analyzed by HPLC to determine the apparent partition coefficient and logP for each MTNX salt. The pH of the aqueous phase for each of the salts was between 4.5 and 6.8. (The division coefficient described for MNTX is 0.025 and the LogP is -1.605.)
Example 5 Preparation of Tablets Containing Methylnaltrexone Bromide and Sodium Dodecyl Sulfate
The present example describes the preparation of tablets containing methylnaltrexone, sodium dodecyl sulfate (SDS), and an effervescent disintegrant (sodium bicarbonate). The quantitative formulation of methylnaltrexone tablets (150 mg) is given in Table 5-1. Table 5-1: Composition of Methylnaltrexone Bromide 150 mg Uncoated Tablets with SDS
aBased on 100% purity "as is", amount can be adjusted based on actual potency, with corresponding adjustments made for microcrystalline cellulose. b Removed by drying. Doses do not appear in the final dosage form. Manufacturing and Packaging Method: Procedure 1. Mix methylnaltrexone bromide, microcrystalline cellulose, sodium dodecyl sulfate (SDS), and crospovidone in a granulator. 2. Prepare a solution containing disodium calcium edetate and polysorbate 80 in purified water. 3. While mixing the mixture from Step 1, add the disodium calcium edetate/polysorbate 80 solution for approximately 4 minutes. More water can be added to obtain proper granulation. Note: granulation steps can be contemplated in sub-batches to obtain larger batch sizes. 4. Dry the granulation. 5. Use suitable mill, grind #4 granulation. 6. Add #5 material to a suitable blender. 7. Record milling yield and adjust excipient levels for final blend. 8. Optional sieving of crospovidone, silicified microcrystalline cellulose, sodium bicarbonate, talc, silicon dioxide, and magnesium stearate through a suitable sieve. 9. Add crospovidone, sodium bicarbonate, talc, and silicified microcrystalline cellulose to blender, and mix. 10. Optionally sieve the blend from Step 9 through a suitable sieve and add to blender and blend. 11. Optionally remove a portion of the mixture, add to the silicone dioxide and bag mixture. 12. Optionally, transfer silicone dioxide premix and add to blender and mix. 13. Take out a portion of the mixture, add to the magnesium stearate and bag mixture. Note: Step 13 may not be required for batches larger than 50 kg. 14. Transfer magnesium stearate premix and add to blender and mix. 15. Record the final blend yield. 16. Compress the final blend from step 15 using a suitable compression machine equipped with instrumentation that can produce tablets of the required specification. 17. Weigh the yield of acceptable tablets. Example 6
[00135] Tablets including methylnaltrexone bromide (150 mg), sodium dodecyl sulfate (SDS), and sodium bicarbonate were manufactured using the method described in Example 5. The tablet was placed in a paddle dissolution apparatus at 100°C rpm in 900 mL 0.1 HCl at 37°C. Samples were then removed at specific time points and analyzed by HPLC. Dissolution rates for two tablets were determined. The dissolution profile of the SDS tablet with sodium bicarbonate is shown in Figure 2. More than 90% of the methylnaltrexone from the tablets was dissolved within 11 minutes. Example 7 Administration of Formulations in Dogs Altered in GI Physiology
[00136] The pharmacokinetic and oral bioavailability profiles of tablets containing methylnaltraxone bromide (150 mg), sodium dodecyl sulfonate (SDS) and sodium bicarbonate, prepared as described in Example 5, were compared to tablets containing uncoated spheroids of methylnaltrexone, but not containing a pharmaceutically acceptable amphiphilic vehicle or an effervescent disintegrant, prepared as described in Example 1. Using male beagle dogs altered in GI physiology, atropine (~20 μg/kg; IV) and pentagastrin (~10 μg/ kg; IM) were administered 15 minutes before administration of the formulation and another dose of pentagastrin (10 μg/kg; IM) was administered 30 minutes after the dose. Atropine slows canine GI motility and pentagastrin lowers the pH resulting in GI conditions always similar to those in humans. The formulations (150 mg MNTX) were dosed into six dogs (9.4 - 13.7 kg) via oral administration after an overnight fast and blood samples were taken at 0 (pre-dose) , 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after dosing; plasma was separated and assayed for methylnaltrexone content.
[00137] The time profiles of methylnaltrexone concentration in dog plasma were subjected to non-compartmental pharmacokinetic analyzes (WinNonlin, Model 200). The results are summarized in Table 7-1 below. Table 7-1. Mean (± SD) and Individual MNTX Pharmacokinetic Parameters in Dogs Regulated by GI Physiology Following One Oral Administration of 150 mg MNTX Prototype Formulations

[00138] As summarized in Table 7-1, oral administration of a prototype tablet formulation containing dodecyl sulfate containing sodium dodecyl sulfonate (lauryl) ion pairing agent resulted in qualitatively greater systemic exposures of methylnaltrexone than non-tablet tablets. containing no ion pairing agent. Example 8
[00139] This example describes the efficacy of methylnaltrexone in the SDS tablet formulation at a dose of 300 and 450 mg given orally to subjects with chronic non-malignant pain. Subjects involved in this study had to have a history of constipation due to opioid use for at least one month prior to the review visit. The study was a phase 1, open-label, unit dose, inpatient study. Subjects received methylnaltrexone as a unit dose (2x150 mg or 3x150 mg) of the SLS tablet formulation after an overnight fast of at least 10 hours. The dose was taken orally with 240 mL of room temperature water at approximately 0800 hours on day 1. The opioid medication was given at approximately the same time each day. Each subject participated in the study for approximately 3 weeks. This included a review assessment within 3 weeks of test article administration and a 2 day/1 night hospital stay.
[00140] The results are presented in Figure 3. These figures show a plot comparing the time and percentage of patients having a first laxation response in patients with chronic malignant pain given a methylnaltrexone SDS tablet (300 mg and 450 mg) after a 10-hour fast. The SLS tablet formulation resulted in an increase in percent laxation within 4 hours and within 24 hours in individual patients.
In example 8, the percentage of patients who laxed within 4 hours receiving an initial unit dose of 450 mg of the SDS formulation of the invention was approximately 41%. In example 8, the percentage of patients who laxed within 24 hours receiving an initial unit dose of 450 mg of the SDS formulation of the invention was approximately 72%.
[00142] The previous study was not designed to establish statistical significance of laxation. There was no placebo group. It is observed that, historically, in larger studies of patients with chronic non-malignant pain designed with similar but more vigorous inclusion/exclusion criteria, the percentage of subjects receiving placebo who laxed within 4 hours was in the same order as 9% to 13%. One of skill in the art will appreciate that the placebo response in the present study may differ from previous studies due to such factors as smaller study size and different inclusion/exclusion criteria. Without wishing to be bound by any theory of the invention, it is believed that there may be a dual mechanism involved in achieving laxation when an oral dose is administered and that the plasma levels required to achieve laxation when dosing orally may be less than those required when dosing subcutaneously.
[00143] One skilled in the art will easily verify the essential features of the invention and will understand that the foregoing description and examples are illustrative of the practice of the invention provided. Those skilled in the art will be able to ascertain usage with no more than routine experimentation, many variations of the detail presented herein may be made to the specific embodiments of the invention described herein without departing from the spirit and scope of the present invention.

权利要求:
Claims (25)
[0001]
1. Pharmaceutical composition for oral administration, characterized by the fact that it comprises a solid dosage of (i) methylnaltrexone bromide, and (ii) sodium dodecyl sulfate (SDS), in which the composition is a tablet, in which the Methylnaltrexone bromide is the only active agent, and in that the tablet is free from enteric coating.
[0002]
2. Pharmaceutical composition according to claim 1, characterized in that it further comprises a fast-acting disintegrant.
[0003]
3. Pharmaceutical composition according to claim 2, characterized in that the fast-acting disintegrant is an effervescent disintegrant.
[0004]
4. Pharmaceutical composition according to claim 2, characterized in that the fast-acting disintegrant is sodium bicarbonate.
[0005]
5. Pharmaceutical composition according to claim 1, characterized in that a pair of ions is formed when methylnaltrexone bromide and sodium dodecyl sulfate (SDS) are dissolved in solution.
[0006]
6. Pharmaceutical composition according to claim 5, characterized in that the solution is at a pH of 1 to 4.
[0007]
7. Pharmaceutical composition according to claim 2, characterized in that a pair of ions is formed when methylnaltrexone bromide and sodium dodecyl sulfate (SDS) are dissolved in solution.
[0008]
8. Pharmaceutical composition according to claim 7, characterized in that the solution is at a pH of 1 to 4.
[0009]
9. Pharmaceutical composition according to claim 1, characterized in that the composition in solution has an apparent octanol/water partition coefficient for methylnaltrexone of 0.25 to 30 at a pH between 1 and 4.
[0010]
10. Pharmaceutical composition according to claim 9, characterized in that the apparent octanol/water partition coefficient for methylnaltrexone is from 0.5 to 20.
[0011]
11. Pharmaceutical composition according to claim 9, characterized in that the apparent octanol/water partition coefficient for methylnaltrexone is from 1 to 10.
[0012]
12. Pharmaceutical composition according to claim 1, characterized in that the ratio between methylnaltrexone bromide and sodium dodecyl sulfate in the tablet is 3:1 by weight.
[0013]
13. Pharmaceutical composition according to claim 12, characterized in that a pair of ions is formed when methylnaltrexone bromide and sodium dodecyl sulfate (SDS) are dissolved in solution.
[0014]
14. Pharmaceutical composition according to claim 13, characterized in that the solution is at a pH of 1 to 4.
[0015]
15. Pharmaceutical composition according to claim 1, characterized in that it is made with methylnaltrexone bromide and sodium dodecyl sulfate in a ratio of 3:1 by weight.
[0016]
16. Pharmaceutical composition according to claim 1, characterized in that it further comprises a chelating agent.
[0017]
17. Pharmaceutical composition according to claim 16, characterized in that the chelating agent is disodium calcium EDTA.
[0018]
18. Pharmaceutical composition according to claim 12, characterized in that it further comprises a chelating agent.
[0019]
19. Pharmaceutical composition according to claim 18, characterized in that the chelating agent is disodium calcium EDTA.
[0020]
20. Pharmaceutical composition according to claim 12, characterized in that the amount of methylnaltrexone bromide is present as 150 mg.
[0021]
21. Pharmaceutical composition according to claim 20, characterized in that the amount of methylnaltrexone bromide is present as 150 mg and the amount of sodium dodecyl sulfate (SDS) is present as 50 mg.
[0022]
22. Pharmaceutical composition according to claim 13, characterized in that the amount of methylnaltrexone bromide is 150 mg.
[0023]
23. Pharmaceutical composition according to claim 22, characterized in that the amount of methylnaltrexone bromide is present as 150 mg and the amount of sodium dodecyl sulfate (SDS) is present as 50 mg.
[0024]
24. Pharmaceutical composition according to claim 15, characterized in that the amount of methylnaltrexone bromide is present as 150 mg.
[0025]
25. Pharmaceutical composition according to claim 24, characterized in that the amount of methylnaltrexone bromide is present as 150 mg and the amount of sodium dodecyl sulfate (SDS) is present as 50 mg.

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US10722510B2|2014-07-08|2020-07-28|Hikma Pharmaceuticals Usa Inc.|Liquid naloxone spray|

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EP3206491B1|2014-10-17|2019-11-27|Salix Pharmaceuticals, Inc.|Use of methylnaltrexone to attenuate tumor progression|

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EP3965731A1|2019-05-07|2022-03-16|Bausch Health Ireland Limited|Liquid oral dosage formulations of methylnaltrexone|

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WO2020245214A1|2019-06-03|2020-12-10|Bausch Health Ireland Limited|Use of methylnaltrexone and rifaximin for treatment of increased gut permeability or associated disorders|

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WO2021224138A1|2020-05-02|2021-11-11|Bausch Health Ireland Limited|Methods of reducing mortality risk in subjects suffering from an underlying disease or condition by administration of methylnaltrexone|

法律状态:
2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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

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2020-07-21| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-01-19| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-02-09| B15K| Others concerning applications: alteration of classification|Free format text: A CLASSIFICACAO ANTERIOR ERA: C07D 471/00 Ipc: C07D 471/00 (2006.01), A61K 31/385 (2006.01), A61P |

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2021-03-30| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2021-07-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-09-14| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 10/03/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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申请号 | 申请日 | 专利标题

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US31301810P| true| 2010-03-11|2010-03-11|

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US61/313,018|2010-03-11|

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PCT/US2011/027913|WO2011112816A1|2010-03-11|2011-03-10|Oral formulations and lipophilic salts of methylnaltrexone|

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