HK1245673B - Oral formulations and lipophilic salts of methylnaltrexone - Google Patents

Description

Oral formulations and lipophilic salts of methylnaltrexone

This application is a divisional application of Chinese patent application No. 201180013511.1, filed on March 10, 2011, entitled "Oral Formulations and Lipophilic Salts of Methylnaltrexone."

Related applications

This application claims priority to U.S. Provisional Patent Application No.: 61/313,018 (filed March 11, 2010), the entire contents of which are hereby incorporated by reference.

Background Art

Opioids are widely used to treat patients with pain. Such patients include those with advanced cancer and other advanced diseases, as well as those with chronic non-malignant pain and acute non-malignant pain. Opioids are anesthetic drugs located in the central nervous system that activate opioid receptors to relieve pain. However, opioids also react with receptors outside the central nervous system, leading to side effects including constipation, nausea, vomiting, urinary retention, and severe itching. The effects of opioids in the gastrointestinal (GI) tract are significant, where these drugs inhibit gastric emptying and peristalsis in the intestine, thereby reducing the rate of intestinal transit and causing constipation. Due to these undesirable side effects, which can be debilitating for patients and often lead them to refuse to use opioid analgesics, the use of opioids in treating pain is often limited.

In addition to the side effects induced by exogenous opioids, studies have shown that endogenous opioids and opioid receptors can also affect the gastrointestinal (GI) tract and may be involved in the normal regulation of intestinal motility and mucosal transport of fluids. Therefore, abnormal physiological levels of endogenous opioids and/or receptor activity can also lead to intestinal dysfunction. For example, patients who have undergone surgical procedures (particularly abdominal surgery) often suffer from a specific intestinal dysfunction known as postoperative ileus, which may be caused by fluctuations in natural opioid levels. Similarly, women who have recently given birth often suffer from postpartum ileus, which may be caused by similar fluctuations in natural opioid levels (as a result of the stress of childbirth). Gastrointestinal dysfunction associated with postoperative or postpartum ileus can typically last 3 to 5 days, with some severe cases lasting more than a week. Administering opioids to patients after surgery to treat pain (now a nearly universal practice) can aggravate intestinal dysfunction, thereby delaying the recovery of normal intestinal function, prolonging hospital stays, and increasing medical care costs.

Opioid receptor antagonists, such as naloxone, naltrexone, and nalmefene, have been investigated as a means of antagonizing the adverse peripheral side effects of opioids. However, these agents act not only on peripheral opioid receptors but also on opioid receptors in the central nervous system, sometimes reversing the beneficial and desirable analgesic effects of opioids or causing symptoms of opioid withdrawal. A preferred approach for controlling opioid-induced side effects involves administering 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 late 1970s. It has been used in patients to reduce opioid-induced side effects such as constipation, pruritus, nausea, and urinary retention (see, e.g., U.S. Patents 5,972,954, 5,102,887, 4,861,781, and 4,719,215; and Yuan et al., Drug and Alcohol Dependence 1998, 52, 161). The most commonly used dosage form of methylnaltrexone in these studies is a solution of methylnaltrexone for intravenous injection.

In U.S. Patent 6,559,158, doses of methylnaltrexone for treating methadone-maintained patients were explored. In the '158 patent, it was hypothesized that, based on studies of methadone-maintained patients, patients taking opioids for a long time would respond to doses of methylnaltrexone that were previously considered too low to be clinically effective. (Methadone-maintained patients are typically addicted to opiates such as heroin, oxycontin, dilaudid, or hydrocone. They have a history of stable methadone treatment of at least 30 days at a dose greater than or equal to 30 mg/day, or more typically, higher.) Low doses of methylnaltrexone were administered intravenously. These doses ranged from 0.01 to 0.37 mg/kg, with mean peak plasma levels of 162 (30-774 ng/ml) reported. These intravenous doses in methadone-maintained patients induced "immediate" bowel movements.

Methylnaltrexone, a subcutaneous injection, was investigated, which is clinically approved in the United States for the treatment of opioid-induced constipation in patients with advanced medical illness receiving palliative care. An effective subcutaneous dose of 0.15 or 0.3 mg/kg was found. This dose did not induce "immediate" defecation, but rather induced defecation within 4 hours in a significant number of treated patients.

Attempts have been made to prepare oral dosage forms of certain opioid antagonists, including methylnaltrexone. In U.S. Patent 6,419,959, an oral dosage form was constructed to release certain compounds "throughout the gastrointestinal tract." According to the '959 patent, opioid antagonists are not always suitable for administration in a rapid-release form due to dose-limiting side effects. Furthermore, it is believed that opioid-induced constipation is caused by the direct and local effects of opioids on receptors throughout the gastrointestinal tract. To address these issues, the '959 patent proposed formulating certain opioid antagonists, including methylnaltrexone, in a controlled-release dosage form, thereby locally delivering acceptable doses of these antagonists throughout the gastrointestinal tract. However, no data specifically regarding methylnaltrexone have been reported.

U.S. Patent No. 6,274,591 shows that enteric-coated methylnaltrexone, which does not release substantially any methylnaltrexone in the stomach, is more effective than uncoated methylnaltrexone in antagonizing morphine-induced oral-cecal delay. The '591 patent suggests and claims that an effective amount of methylnaltrexone can be delivered using an oral dosage form that completely bypasses the stomach. However, no data on defecation have been reported.

In U.S. Patent No. 6,559,158, oral doses of methylnaltrexone were explored for the treatment of constipation in methadone-maintained patients (i.e., patients who have shown a high sensitivity to the effects of methylnaltrexone). The dose of methylnaltrexone administered orally in capsules was 0.3-3.0 mg/kg. Methylnaltrexone capsules administered to several test patients induced defecation in these patients, albeit over a period of 1.2-24 hours (depending on the dose). The fastest response (5.2 +/- 4.5 hours, range 1.2-10 hours) was seen in four patients who received 3.0 mg/kg.

Accordingly, a need exists for a bioavailable oral dosage formulation comprising methylnaltrexone.

Summary of the Invention

Enteric-coated sphere capsules containing a formulation of methylnaltrexone were tested in patients with opioid-induced constipation. The patients in this study were receiving opioids for non-malignant pain. (They were not long-term methadone maintenance patients.) Patients were administered 300 mg or 450 mg enteric-coated methylnaltrexone capsules (approximately 4 mg/kg and 6 mg/kg, respectively), doses within the range reported to be effective in the '591 patent. The 300 mg dose resulted in mean peak plasma levels of methylnaltrexone below 10 ng/mL, and the 450 mg dose resulted in mean peak plasma levels of methylnaltrexone below 20 ng/mL. These formulations were unexpectedly ineffective in treating opioid-induced constipation. They did not induce defecation and did not cause more bowel movements than controls. This was surprising given the teachings of the art.

Based on the results with the enteric-coated methylnaltrexone capsules, it was unclear whether the achievement of laxation depended on peak plasma levels of the drug, the timing of achieving plasma levels of the drug, or other factors such as local effects. Further experiments were conducted, and as a result, the inventors turned their attention to developing an oral formulation containing methylnaltrexone without an enteric coating.

Capsules containing methylnaltrexone formulations but without enteric coatings 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 of approximately 15-40 ng/ml. These capsules without enteric coatings did not induce laxation in this patient population and did not induce more bowel movements than controls.

Tablets containing a formulation of methylnaltrexone but without enteric-coated spheres 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 average peak plasma levels of approximately 7-40 ng/ml, which is similar to the average peak plasma levels obtained with uncoated capsules. These tablets without enteric coating showed statistically significant activity at one dose but did not consistently induce laxation across all doses. The activity of the tablets, but not the capsules, was surprising to those of ordinary skill in the art based on the information available in the prior art.

The prior art has not clarified what is required to produce an oral methylnaltrexone formulation that is effective in treating opioid-induced constipation in patients receiving opioids for non-malignant pain. First, the prior art has not clarified whether achieving laxative effects depends on overall plasma drug levels, peak plasma drug levels, or the timing of achieving drug plasma levels. Second, even if the pharmacokinetics of achieving laxative effects were established, the prior art has not clarified formulation methods for predictably controlling the pharmacokinetics of oral methylnaltrexone beyond dose modification and coating. Because of the need to further improve the performance of non-enteric-coated tablets, further formulation development studies were conducted.

Methylnaltrexone is hydrophilic and fairly soluble in aqueous solutions. The positive charge of the quaternary amine causes methylnaltrexone to be poorly absorbed in the gastrointestinal tract. Typically, when delivered orally, less than about 5% of methylnaltrexone is absorbed into the bloodstream.

There are many possible general methods for increasing the absorption of orally administered drugs. However, it is unknown which method can lead to improved efficacy of oral methylnaltrexone. The inventors tested tablet formulations, capsule formulations, liquid formulations, gap junction openers, Pgp inhibitors, active transporters, oil suspensions, effervescent solutions for rapid release, and others. Most of the methods tried did not improve absorption in the laboratory models used. In fact, when tested in certain dog models, some methods achieved the opposite effect than expected, i.e., absorption was inhibited in one or more of the parameters tested.

Ion pairing has been studied to reduce the apparent ionic charge on a molecule. The interaction between a hydrophilic charged molecule and a zwitterionic counterion can render the hydrophilic molecule sufficiently lipophilic to achieve (or increase) the molecule's solubility in non-aqueous solvents. Because ion pairing increases the rate at which a molecule enters the organic phase, much work in this area has involved extracting ionized molecules into organic solvents, separating molecules by chromatography, reacting hydrophilic molecules in organic solvents, and so on. With respect to drug absorption, most work has been limited to delivering drugs to the skin, eyes, nasal cavity, or vaginal cavity (see, e.g., 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). Limited work has been reported in the prior art on the use of ion pairs to improve the bioavailability of orally administered drugs.

The inventors hypothesize that an ion pair between the positively charged methylnaltrexone and the negatively charged moiety forms a "pair" that is more hydrophobic than methylnaltrexone bromide, thereby increasing methylnaltrexone absorption in the stomach. Various ion pairs are formed with methylnaltrexone and anions. One such ion pair is formed between methylnaltrexone and dodecyl (lauryl) sulfate.

Unexpectedly, it was discovered that methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient (which forms an ion pair or salt with methylnaltrexone when dissolved in solution) in a solid dosage form with a fast-acting disintegrant (e.g., a carbon dioxide-generating disintegrant) is effective in inducing laxatives.

Without wishing to be bound by any particular theory of invention, the inventors believe that there is a gastric local effect and a systemic effect when the formulations and preparations of the present invention are used, which combine to achieve laxative effects. This dual effect suggests that laxative effects can be achieved using the oral formulations of the present invention with peak plasma levels lower than those effective for subcutaneous injection.

The present invention relates to ion pairs of methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient, methods for forming such ion pairs, methods for selecting such ion pairs, uses of such ion pairs, compositions comprising such ion pairs, solid oral dosage forms of methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient, including formulations comprising a fast-acting disintegrant (i.e., an effervescent or carbon dioxide-generating disintegrant), and methods of using such compositions and formulations thereof.

In one aspect, the present invention provides a salt of methylnaltrexone of the formula:

wherein methylnaltrexone is the cation of the salt and ^A- is the anion of the amphiphilic pharmaceutically acceptable excipient. In certain embodiments, methylnaltrexone is (R)-N-methylnaltrexone as shown 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 may include a sulfate, sulfonate, nitrate, nitrite, phosphate, or phosphonate moiety. In one embodiment, the pharmaceutically acceptable excipient includes a ( _-OSO3- ⁾ group. Without wishing to be bound by any particular theory, this chemical functional group with a pKa value of about 3 or less allows the ion pair to remain bound together at the acidic pH found in the stomach. This is because the conjugate base of the excipient remains deprotonated and negatively charged, while methylnaltrexone is a positively charged quaternary amine. The pharmaceutically acceptable excipient also includes a hydrophobic moiety. In one embodiment, the hydrophobic portion is a branched or straight chain, saturated or unsaturated, cyclic or acyclic C _4-30 aliphatic chain, which can be optionally substituted. In some embodiments, the pharmaceutically acceptable excipient is, for example, a saturated or unsaturated, branched or straight chain, cyclic or acyclic C _4-30 aliphatic group, which can be optionally substituted. In some embodiments, it is a saturated, straight chain, acyclic, unsubstituted C _4-30 alkyl group. In some embodiments, it is a saturated, straight chain, acyclic, unsubstituted C _7-15 alkyl group. In some embodiments, it is a C ₁₂ n-alkyl group. In some embodiments, it is dodecyl (lauryl) sulfate. Without wishing to be bound by any theory, the inventors believe that the aliphatic chain naturally renders the excipient amphiphilic and surface active, which aids in the transport of the ion pair through the unstirred diffusion layer lining the inner surface of the gastrointestinal tract (GI tract), thereby increasing the availability of methylnaltrexone to the gastrointestinal membrane (GI membrane) for local action at receptor sites and/or absorption across lipophilic barriers such as the lining of the gastrointestinal tract (e.g., the stomach and upper duodenum). In certain embodiments, the methylnaltrexone ion pair is a salt, which is solid at room temperature.

According to another aspect of the present invention, a composition is provided. The composition is a salt or ion pair as described above. In the composition, the salt or ion pair can contain 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% methylnaltrexone. In some embodiments, the composition is a pharmaceutical composition.

In another aspect of the present invention, a composition for oral administration is provided. The composition comprises methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient that, when dissolved in solution, forms an ion pair or salt with methylnaltrexone, thereby increasing the octanol/water partition coefficient of methylnaltrexone. When the composition is dissolved in an aqueous solution, under acidic conditions, in some embodiments, at a pH of 1-4, methylnaltrexone has an apparent octanol/water partition coefficient of at least 0.25. A pH of 1-4 simulates the physiological conditions of the stomach. In certain embodiments, at a pH of 1-4, the apparent octanol/water partition coefficient of methylnaltrexone is at least 0.5, 1.0, 5.0, 10, 20, or 30. Typically, the pharmaceutically acceptable excipient has a pKa of about 3 or less, such that the conjugate base of the amphiphilic pharmaceutically acceptable excipient remains deprotonated and non-covalently binds to the cationic methylnaltrexone under the physiological conditions found in the stomach (i.e., solutions at an acidic pH).

The composition may also include a fast-acting disintegrant, wherein the composition dissolves in the stomach within approximately 15 minutes. In at least one embodiment, 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 any of the foregoing embodiments, the methylnaltrexone in the composition may dissolve within 10 minutes, or even within 5 minutes. Dissolution of the composition in the stomach can be simulated by in vitro studies in 900 ml of 0.1 N HCl at 37°C in a dissolution apparatus with a paddle at 100 rpm. In certain embodiments, the disintegrant is a fast-acting disintegrant. In certain embodiments, the composition has a dissolution pattern substantially similar to that shown in Figure 2. In some embodiments, the disintegrant is an effervescent disintegrant (i.e., a gas-releasing disintegrant). By generating bubbles in the composition, the composition disintegrates more easily, thereby releasing the methylnaltrexone. Effervescent disintegrants have been found to be particularly useful in aiding dissolution of tablets containing methylnaltrexone and lauryl sulfate. 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 any embodiment, the effervescent disintegrant can be a bicarbonate or a carbonate. In any embodiment, the effervescent disintegrant can be sodium bicarbonate.

According to another aspect of the present invention, a method for preparing a methylnaltrexone formulation is provided. The method comprises combining a solid pharmaceutically acceptable salt of methylnaltrexone (which is not an ion pair of methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient), such as methylnaltrexone bromide or methylnaltrexone iodide, with a solid pharmaceutically acceptable salt of an amphiphilic excipient (which is not an ion pair of methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient) to form a mixture. The mixture may 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, the wet granulation is formed by dry mixing methylnaltrexone or a pharmaceutically acceptable salt thereof, a binder, an amphiphilic pharmaceutically acceptable excipient, and an optional disintegrant; and granulating the dry mixture with a solution of a chelating agent and/or wetting agent to form wet granules. The wet granulation can be dried and milled, and the milled dry granulation mixed with additional disintegrant (such as sodium bicarbonate) and optionally a lubricant and/or glidant before preparing a solid dosage form.

In some aspects, the present invention provides a composition for oral administration comprising a cationic salt of methylnaltrexone and an anionic salt of an amphiphilic pharmaceutically acceptable excipient (e.g., lauryl sulfate). In some embodiments, the composition for oral administration is a tablet formulation. In some embodiments, the composition for oral administration is a capsule formulation.

Typically, the formulation for oral administration comprises methylnaltrexone, the amphiphilic pharmaceutically acceptable excipients described above, a disintegrant, and further optionally comprises one or more other components, such as, for example, a binder, a carrier, a chelating agent, an antioxidant, a filler, a lubricant, a wetting agent, or a combination thereof. In any of the foregoing embodiments, the oral formulation is a tablet formulation. In some embodiments, the present invention provides a unit dosage form comprising the formulation or composition described herein.

The present invention also provides methods for orally administering methylnaltrexone in any situation requiring such administration. For example, the formulation can be used to prevent, treat, or reduce the severity of side effects caused by the administration of opioids, including inhibition of intestinal activity or gastrointestinal dysfunction (e.g., constipation, gastrointestinal (GI) sphincter contraction), nausea, vomiting, and itching. The compositions and formulations can be used for administration to patients receiving long-term opioid therapy (e.g., patients suffering from postoperative ileus or gastrointestinal dysfunction caused by acute opioid administration). Such formulations are also used for administration to individuals receiving chronic opioid administration (e.g., patients with advanced diseases receiving opioid therapy (e.g., AIDS patients, cancer patients, patients with cardiovascular disease); individuals receiving long-term opioid therapy for pain control; individuals receiving opioid therapy for maintenance of opioid withdrawal). In some embodiments, individuals undergo opioid therapy for the control of chronic pain. In some embodiments, individuals undergo opioid therapy for the control of acute pain. In certain embodiments, the pain is non-malignant pain (e.g., back pain, neuralgia, pain associated with fibromyalgia, osteoarthritis, etc.). In certain embodiments, the pain is chronic non-malignant pain. In certain embodiments, the pain is malignant pain. In certain embodiments, the invention provides a method comprising the step of reducing one or more side effects of opioid therapy in an individual receiving opioid therapy, comprising administering the tablet formulation provided herein to the individual. In other embodiments, the invention provides a method comprising administering the formulation to the individual for reducing one of the multiple effects of endogenous opioid activity in the individual (e.g., postpartum ileus). In some embodiments, the individual is a methadone-maintained patient. In any preceding embodiment, the individual can fast or be fed. In an important embodiment, the individual fasts overnight.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the dissolution profile of methylnaltrexone tablets and capsules in 900 ml of 0.1 N HCl at 37°C with a paddle at 100 rpm.

Figure 2 shows the dissolution profile of methylnaltrexone (150 mg) tablets formulated with sodium lauryl sulfate and the effervescent disintegrant, sodium bicarbonate, at 37°C with a paddle at 100 rpm, analyzed using a Cary 50 spectrophotometer.

3 shows a graph of the percentage of patients with a first bowel movement response versus time in patients with chronic malignant pain who were administered (R)-N-methylnaltrexone bromide (300 mg or 450 mg) SDS tablet formulation after a 10-hour fast.

Figure 4 includes identification data for MNTX-heptyl sulfate. Figure 4A is the ¹ H NMR spectrum of MNTX-heptyl sulfate. Figure 4B is the HPLC chromatogram of MNTX-heptyl sulfate. Figure 4C is the UV spectrum of MNTX-heptyl sulfate.

Figure 5 includes identification data for MNTX-dodecyl sulfate. Figure 5A is the ¹ H NMR spectrum of MNTX-dodecyl sulfate. Figure 5B is the HPLC chromatogram of MNTX-dodecyl sulfate. Figure 5C is the UV spectrum of MNTX-dodecyl sulfate.

Figure 6 includes identification data for MNTX-sodium laurate. Figure 6A is the ^1H NMR spectrum of MNTX-sodium laurate. Figure 6B is the HPLC chromatogram of MNTX-sodium laurate. Figure 6C is the UV spectrum of MNTX-sodium laurate.

DETAILED DESCRIPTION

definition

The term "aliphatic" as used herein includes saturated and unsaturated, linear (i.e., straight chain), branched, acyclic, cyclic or polycyclic aliphatic hydrocarbons, which may be optionally substituted with one or more functional groups. It will be understood by those skilled in the art that "aliphatic" as used herein is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moieties. Thus, the term "alkyl" as used herein includes linear, branched and cyclic alkyl groups. Similar conventions apply to other general terms such as "alkenyl," "alkynyl" and the like. Moreover, the terms "alkyl," "alkenyl," "alkynyl" and the like as used herein include substituted and unsubstituted groups. In certain embodiments, the term "lower alkyl" as used herein is used to refer to those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or straight chain) having 1-6 carbon atoms.

In certain embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 1-30 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 10-30 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 5-25 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 5-20 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 10-20 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 15-25 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 1-6 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 1-4 aliphatic carbon atoms. Thus, illustrative aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, _-CH2 -cyclopropyl, ethenyl, propenyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, _-CH2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, _-CH2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, _-CH2 -cyclohexyl, heptyl, octyl (octyl), nonyl, decyl (decyl), undecyl, dodecyl (lauryl), tridecyl, tetradecyl, hexadecyl (cetyl), heptadecyl, octadecyl (octadecyl), eicosyl (eicosyl), docosyl, tetracosyl, hexacosyl, octacosyl, triacontyl moieties and the like, which again may have one or more substituents.

Some examples of substituents for the above-mentioned aliphatic moieties include, but are not limited to, aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; 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 _R independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, hydrocarbylaromatic, or heterohydrocarbylaromatic, wherein any of the aliphatic, heteroaliphatic, hydrocarbylaromatic, or heterohydrocarbylaromatic substituents described above and herein may be substituted or unsubstituted, branched or linear, cyclic or acyclic, wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.

The term "amphiphilic" or "amphipathic" as used herein to describe molecules refers to the dual hydrophobic and hydrophilic properties of a molecule. Typically, an amphiphilic molecule has a polar, water-soluble group (e.g., phosphate, carboxylic acid, sulfate) attached to a nonpolar, water-insoluble group (e.g., hydrocarbon group). The term amphiphilic is synonymous with amphipathic. Examples of amphiphilic molecules include sodium lauryl sulfate, fatty acids, phospholipids, and bile acids. Amphiphilic molecules can be uncharged, cationic, or anionic.

As used herein, the term "dissolution rate" refers to the amount of time required for an active ingredient or composition thereof (e.g., a methylnaltrexone salt) to dissolve in a solvent. The dissolution rate depends on a variety of factors, including mixing, temperature, pH, solvent, particle size, etc. The dissolution rate of a drug or composition thereof affects the bioavailability of the drug.

In certain instances, dissolution rate is used to determine the availability of drug from a solid dosage form.

An "effective amount" of the compound or pharmaceutically acceptable composition or formulation used in the present invention can achieve the desired therapeutic and/or preventive effect. In some embodiments, an "effective amount" is at least the minimum amount of the compound or formulation or composition comprising the compound, which is sufficient to treat one or more symptoms of a disorder or condition associated with modulation of peripheral μ opioid receptors, for example, side effects associated with opioid analgesic therapy (e.g., gastrointestinal dysfunction (e.g., dysmotility constipation, etc.), nausea, vomiting, etc.). In certain embodiments, an "effective amount" of a compound or a composition or formulation comprising the compound is sufficient to treat symptoms and related diseases associated with abnormal endogenous peripheral opioids or μ opioid receptor activity (e.g., idiopathic constipation, intestinal obstruction, etc.). In some embodiments, the term "effective amount" used in conjunction with the amount of methylnaltrexone or a salt of methylnaltrexone refers to an amount of methylnaltrexone or a salt of methylnaltrexone sufficient to achieve defecation in a patient.

The term "effervescent disintegrant" used in the present invention refers to a substance that causes the effervescence that causes the rapid disintegration of a dosage form after contact with an aqueous medium. Typically, an effervescent disintegrant is an alkali (such as a carbonate) that reacts with an acid (such as the HCl in the stomach) to form carbon dioxide. Therefore, this effervescent disintegrant includes a disintegrant that produces carbon dioxide. Carbonate sources include, but are not limited to, carbonates and bicarbonates, such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, sesquisodium carbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, and calcium carbonate. Effervescent disintegrants are known in the art for realizing rapidly disintegrating dosage forms.

As used herein, the term "lipophilicity" refers to the ability of a compound to associate with or dissolve in fats, lipids, oils, or non-polar solvents. Lipophilicity and hydrophobicity can be used to describe the same tendency of molecules to dissolve in fats, oils, lipids, and non-polar solvents.

The term "non-functional coating" as used herein is a coating that does not significantly affect the release characteristics of one or more compounds of therapeutic activity from the formulation when administered. Examples of non-functional coatings include seal coatings (such as hydroxypropyl cellulose, hypromellose, or polyvinyl alcohol). In certain embodiments, the non-functional coating is a polished coating or a seal coating.

The term "non-malignant pain" as used herein refers to "non-cancer pain".

The term "apparent partition coefficient" as used herein refers to the ratio of the concentrations of a compound in any form in the two phases of an equilibrium mixture of two immiscible solvents. In certain embodiments, the two immiscible solvents are octanol and water. The apparent partition coefficient can be determined under various conditions, such as temperature, pH, concentration, etc. It has been found that the apparent partition coefficient can be used to evaluate the distribution of a compound in the body. A higher apparent partition coefficient indicates a more hydrophobic (more lipophilic) compound, while a lower apparent partition coefficient indicates a hydrophilic compound. The apparent partition coefficient of a compound can be determined by methods known in the art, for example, methods in the United States Pharmacopoeia. The apparent partition coefficient can be determined by the method used to determine the apparent partition coefficients of methylnaltrexone dodecyl sulfate and methylnaltrexone heptyl sulfate in the examples.

As used herein, "individual" refers to mammals, including humans and animal individuals, such as domestic animals (e.g., horses, dogs, cats, etc.) and experimental animals (e.g., mice, rats, dogs, chimpanzees, apes, etc.).

As used herein, the term "suffer" or "suffering" means that a patient has been diagnosed with or is suspected of having one or more conditions.

The term "spheroid" as used herein has the meaning understood in the art of a substantially spherical particle. In many embodiments, the spheroids prepared or utilized according to the present invention have a size ranging from about 1 to 1500 microns. In some embodiments, the spheroids have a size ranging from about 20 to 1500 microns. In some embodiments, the spheroids have a size ranging from about 20 to 1000 microns. In some embodiments, the spheroids have a size ranging from about 20 to 500 microns. In some embodiments, the spheroids have a size ranging from about 20 to 300 microns. In certain embodiments, the spheroids have a size range in which at least 80% of the spheroids fall within the size range of about 20 to 325 microns. In some embodiments, the spheroids have a size range in which at least 50% of the spheroids fall within the size range of about 45 to 120 microns.

As used herein, the term "treat" or "treating" refers to partially or completely alleviating, inhibiting, delaying the onset of, reducing the incidence of, ameliorating and/or relieving a disorder or condition or one or more symptoms of a disorder, disease or condition.

"Therapeutically active agent" or "active agent" refers to a substance used for treatment (e.g., human treatment, veterinary treatment) (including preventive and therapeutic treatment), including biologically active substances. Therapeutically active agents include organic molecules, which are pharmaceutical compounds, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones and vitamins. Therapeutically active agents include any substance used as a drug for treating, preventing, delaying, alleviating or ameliorating a disease, condition or disorder. Opioid receptor antagonist compounds, opioid analgesic compounds and the like are among the therapeutically active agents used in the formulations of the present invention. A further detailed description of compounds used as therapeutically active agents is provided below. Therapeutically active agents include compounds that enhance the action or effectiveness of a second compound (e.g., increase the efficacy of a second compound or reduce its side effects).

As used herein, the expression "unit dosage form" refers to a physically discrete unit of a provided formulation suitable for use with the patient to be treated. However, it will be understood that the total daily usage of the provided formulation will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular individual or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific active agent being used; the specific formulation being used; the age, weight, general health, sex, and diet of the individual; the time of administration and rate of excretion of the specific active agent being used; the duration of treatment; drugs and/or additional therapies used in combination or concomitantly with the specific compound being used; and similar factors well known in the medical arts.

As used herein, the term " _pKa " refers to _-log10Ka , where Ka is _the acid dissociation constant. _pKa measures the strength 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 and is symbolically represented as:

HA A ^- + H ⁺ .

Compositions and formulations of methylnaltrexone

Methylnaltrexone, as used herein, refers to (R)-N-methylnaltrexone. (R)-N-methylnaltrexone, a peripherally acting μ-opioid receptor antagonist, has been studied and used to treat intestinal dysfunction in patients receiving opioids. Surprisingly, enteric-coated preparations of methylnaltrexone have not consistently demonstrated substantial efficacy in treating opioid-induced constipation. Contrary to prior art recommendations regarding oral administration of methylnaltrexone, localized concentrations of methylnaltrexone in the intestinal tract distal to the stomach are ineffective in inducing defecation and treating constipation.

In certain embodiments, the present invention provides compositions comprising methylnaltrexone and a pharmaceutically acceptable excipient, wherein the composition in solution under acidic conditions (in certain embodiments, a pH of 1-4) produces an apparent octanol/water partition coefficient for methylnaltrexone of at least 0.25. In some embodiments, such compositions are formulated for oral administration. In some embodiments, compositions for oral administration are formulated as tablets. The methylnaltrexone used in such compositions and formulations can be in any of a variety of forms. For example, forms of methylnaltrexone suitable for use in the compositions and formulations of the present invention include pharmaceutically acceptable salts, prodrugs, polymorphs (i.e., crystalline forms), co-crystals, hydrates, solvates, and the like. Any form of methylnaltrexone can be used in the composition or formulation, provided that the form allows for ion pairing with the amphiphilic pharmaceutically acceptable excipient.

In certain embodiments, compositions and formulations thereof include salts of Formula I:

wherein ^A- is a suitable anion. In certain embodiments, ^A- is an anion of a Brønsted acid. Exemplary Brønsted acids include hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid, and phosphoric acid. In certain embodiments, ^A- is chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate, sulfonate, methanesulfonate, 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 acidic amphiphilic 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 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 anion of the pharmaceutically acceptable excipient comprises a sulfate, sulfonate, phosphate, phosphonate, nitrate, or nitrite moiety. In certain embodiments, the anion of ^the pharmaceutically acceptable excipient comprises a sulfate ( _-OSO3- ) group. In certain embodiments, the anion is butyl sulfate, amyl 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 associated with it (e.g., bromide and dodecyl(lauryl) sulfate).

In some embodiments, the compositions and formulations thereof include ( R ) -N -methylnaltrexone bromide. ( R ) -N -methylnaltrexone bromide, also known as "MNTX," is described in International PCT Patent Publication No. WO2006/12789, which is incorporated herein by reference. The chemical name for ( R ) -N -methylnaltrexone bromide is ( R ) -N- (cyclopropylmethyl)-methylnoroxymorphone methobromide. The molecular formula for ( R ) -N - _{methylnaltrexone} bromide is _C21H26NO4Br , and the molecular weight is 436.36 g/ _mol . ( R ) -N -methylnaltrexone bromide has the following structure:

( R ) -N -methylnaltrexone bromide

wherein the compound is in the ( R ) configuration with respect to the 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 ammonia. Methods for determining the amount of brominated ( R ) -N -methylnaltrexone present in a sample compared to the amount of brominated ( S ) -N -methylnaltrexone present in the same sample are described in detail in WO 2006/127899, which is incorporated herein by reference. In other embodiments, the methylnaltrexone comprises 0.15%, 0.10%, or less of brominated ( S ) -N -methylnaltrexone.

In some embodiments, the composition or formulation thereof comprises from about 7% to about 75%, from about 25% to about 55%, from about 40%, or about 50% of the ( R ) -N -methylnaltrexone cation, based on the total weight of the formulation. In certain embodiments, provided compositions or formulations thereof comprise from about 7%, from about 8%, from about 10%, from about 20%, from about 30%, from about 40%, from about 50%, from about 60%, from about 70%, or from about 75% of the ( R ) -N -methylnaltrexone cation, based on the total weight of a given composition or formulation. It will be appreciated that the ( R ) -N -methylnaltrexone cation and the anion of the amphiphilic pharmaceutically acceptable excipient may be present in the composition as an ion pair, or may be present as a separate salt paired with other counterions, such as bromide and sodium, or mixtures thereof.

In some embodiments, the composition or formulation thereof comprises from about 7% to about 75%, from about 25% to about 55%, from about 40%, or about 50% of the ( R ) -N -methylnaltrexone cation and the lauryl sulfate anion, based on the total weight of the composition or formulation. In certain embodiments, the composition or formulation thereof comprises from about 7%, from about 8%, from about 10%, from about 20%, from about 30%, from about 40%, from about 50%, from about 60%, from about 70%, or from about 75% of the ( R ) -N -methylnaltrexone cation and the lauryl 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 through the unstirred diffusion layer in the gastrointestinal (GI) tract, resulting in increased penetration through 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 pair or salt with the positively charged methylnaltrexone. Such anionic surfactants are known in the art and are typically characterized by having a fat-soluble end and an anionic portion. Exemplary excipients for use in the present invention include aliphatic sulfates (such as sodium lauryl sulfate), aliphatic phosphates, fatty acids, and salts and derivatives thereof.

As a measure of the 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 apparent octanol/water partition coefficient used in the present invention was measured at a concentration of approximately 0.5 mg/mL at room temperature. An exemplary method for determining the apparent octanol/water partition coefficient of a methylnaltrexone salt is described in the Examples below.

Particularly useful amphiphilic pharmaceutically acceptable excipients include those that increase the oral absorption of methylnaltrexone. In certain embodiments, the excipient increases the absorption of methylnaltrexone in the stomach. In certain embodiments, the excipient increases the ability of methylnaltrexone to cross lipophilic barriers. In certain embodiments, the excipient increases the lipophilicity of methylnaltrexone by forming an ion pair with the cationic methylnaltrexone. Ion pairing increases the partitioning of methylnaltrexone into organic phases, such as lipid bilayers. In certain embodiments, the excipient forms an ion pair with methylnaltrexone such 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 partition coefficient at a pH between 1 and 4 is at least 0.5. In certain embodiments, the apparent octanol/water partition coefficient at a pH between 1 and 4 is at least 0.75. In certain embodiments, the apparent octanol/water partition coefficient at a pH between 1 and 4 is at least 1.0. In certain embodiments, the apparent octanol/water partition coefficient at a pH between 1 and 4 is at least 10. In certain embodiments, the apparent octanol/water partition coefficient at a pH between 1 and 4 is at least 15. In certain embodiments, the apparent octanol/water partition coefficient at a pH between 1 and 4 is at least 20. In certain embodiments, the apparent octanol/water partition coefficient at a pH between 1 and 4 is at least 25. In certain embodiments, the apparent octanol/water partition coefficient at a pH between 1 and 4 is at least 30.

As used herein, the term "aliphatic sulfate" refers to a compound having a sulfate moiety (which is linear or branched and saturated or unsaturated) at one end and an aliphatic tail. The aliphatic tail may be substituted and may also include a cyclic group. In some embodiments, the aliphatic tail is a _C4 - _C30 aliphatic group. In certain embodiments, the aliphatic tail is a _C7 - _C20 aliphatic group. In certain embodiments, the aliphatic tail is a _C10 - _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 that is saturated, unbranched, and unsubstituted. In certain embodiments, the aliphatic group is a _C7 - _C20 n-alkyl group. In certain embodiments, the aliphatic group is a _C10 - _C15 n-alkyl group.

In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is a compound of the formula:

R ¹ -OSO ₂ OH

Wherein R ¹ is a C _4-30 aliphatic group, which is saturated or unsaturated, linear or branched, cyclic or acyclic, the aliphatic group being optionally substituted with one or more halogen or hydroxyl groups. In certain embodiments, each R ¹ is a C _4-10 aliphatic group. In certain embodiments, each R ¹ is a C _10-15 aliphatic group. In certain embodiments, each R ¹ is a C _15-20 aliphatic group. In certain embodiments, each R ¹ is a C _20-30 aliphatic group. In certain embodiments, R ¹ is unsaturated. In certain embodiments, R ¹ is saturated. In certain embodiments, R 1 is linear. In certain embodiments, R ¹ is branched. In certain embodiments, R ¹ is substituted. In certain embodiments, R ¹ is unsubstituted. In certain embodiments, ^{R 1 is} saturated, linear, and unsubstituted. In certain embodiments, R ¹ is C _4-30 n-alkyl. In certain embodiments, R ¹ is C _5-15 n-alkyl. In certain embodiments, R ¹ is C _5-10 n-alkyl. In certain embodiments, R ¹ is C _10-15 n-alkyl. In certain embodiments, R ¹ is C ₆ n-alkyl. In certain embodiments, R ¹ is C ₇ n-alkyl. In certain embodiments, R ¹ is C ₈ n-alkyl. In certain embodiments, R ¹ is C ₉ n-alkyl. In certain embodiments, R ¹ is C ₁₀ n-alkyl. In certain embodiments, R ¹ is C ₁₁ n-alkyl. In certain embodiments, R ¹ is C ₁₂ n-alkyl. In certain embodiments, R ¹ is C ₁₃ n-alkyl. In certain embodiments, R ¹ is C ₁₄ n-alkyl. In certain embodiments, R ¹ is C ₁₅ n-alkyl. In certain embodiments, the excipient is in the form of a sodium salt.

In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is a compound of the formula:

R ¹ -SO ₂ OH

Wherein R ¹ is a C _4-30 aliphatic group, which is saturated or unsaturated, linear or branched, cyclic or acyclic, the aliphatic group being optionally substituted with one or more halogens or hydroxyl groups. In certain embodiments, each R ¹ is a C _4-10 aliphatic group. In certain embodiments, each R ¹ is a C _10-15 aliphatic group. In certain embodiments, each R ¹ is a C _15-20 aliphatic group. In certain embodiments, each R ¹ is a C _20-30 aliphatic group. In certain embodiments, R ¹ is unsaturated. In certain embodiments, R ¹ is saturated. In certain embodiments, R ¹ is linear. In certain embodiments, R ¹ is branched. In certain embodiments, R ¹ is substituted. In certain embodiments, R ¹ is unsubstituted. In certain embodiments, R ¹ is saturated, linear, and unsubstituted. In certain embodiments, R ¹ is C _4-30 n-alkyl. In certain embodiments, R ¹ is C _5-15 n-alkyl. In certain embodiments, R ¹ is C _5-10 n-alkyl. In certain embodiments, R ¹ is C _10-15 n-alkyl. In certain embodiments, R ¹ is C ₆ n-alkyl. In certain embodiments, R ¹ is C ₇ n-alkyl. In certain embodiments, R ¹ is C ₈ n-alkyl. In certain embodiments, R ¹ is C ₉ n-alkyl. In certain embodiments, R ¹ is C ₁₀ n-alkyl. In certain embodiments, R ¹ is C ₁₁ n-alkyl. In certain embodiments, R ¹ is C ₁₂ n-alkyl. In certain embodiments, R ¹ is C ₁₃ n-alkyl. In certain embodiments, R ¹ is C ₁₄ n-alkyl. In certain embodiments, R ¹ is C ₁₅ n-alkyl. In certain embodiments, the excipient is in the form of a sodium salt.

In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is a compound of the formula:

R ¹ -P(O) ₂ OH

Wherein R ¹ is a C _4-30 aliphatic group, which is saturated or unsaturated, linear or branched, cyclic or acyclic, the aliphatic group being optionally substituted with one or more halogens or hydroxyl groups. In certain embodiments, each R ¹ is a C _4-10 aliphatic group. In certain embodiments, each R ¹ is a C _10-15 aliphatic group. In certain embodiments, each R ¹ is a C _15-20 aliphatic group. In certain embodiments, each R ¹ is a C _20-30 aliphatic group. In certain embodiments, R ¹ is unsaturated. In certain embodiments, R ¹ is saturated. In certain embodiments, R ¹ is linear. In certain embodiments, R ¹ is branched. In certain embodiments, R ¹ is substituted. In certain embodiments, R ¹ is unsubstituted. In certain embodiments, R ¹ is saturated, linear, and unsubstituted. In certain embodiments, R ¹ is C _4-30 n-alkyl. In certain embodiments, R ¹ is C _5-15 n-alkyl. In certain embodiments, R ¹ is C _5-10 n-alkyl. In certain embodiments, R ¹ is C _10-15 n-alkyl. In certain embodiments, R ¹ is C ₆ n-alkyl. In certain embodiments, R ¹ is C ₇ n-alkyl. In certain embodiments, R ¹ is C ₈ n-alkyl. In certain embodiments, R ¹ is C ₉ n-alkyl. In certain embodiments, R ¹ is C ₁₀ n-alkyl. In certain embodiments, R ¹ is C ₁₁ n-alkyl. In certain embodiments, R ¹ is C ₁₂ n-alkyl. In certain embodiments, R ¹ is C ₁₃ n-alkyl. In certain embodiments, R ¹ is C ₁₄ n-alkyl. In certain embodiments, R ¹ is C ₁₅ n-alkyl. In certain embodiments, the excipient is in the form of a sodium salt.

In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is a compound of the formula:

R ¹ -OP(O) ₂ OH

Wherein R ¹ is a C _4-30 aliphatic group, which is saturated or unsaturated, linear or branched, cyclic or acyclic, the aliphatic group being optionally substituted with one or more halogens or hydroxyl groups. In certain embodiments, each R ¹ is a C _4-10 aliphatic group. In certain embodiments, each R ¹ is a C _10-15 aliphatic group. In certain embodiments, each R ¹ is a C _15-20 aliphatic group. In certain embodiments, each R ¹ is a C _20-30 aliphatic group. In certain embodiments, R ¹ is unsaturated. In certain embodiments, R ¹ is saturated. In certain embodiments, R ¹ is linear. In certain embodiments, R ¹ is branched. In certain embodiments, R ¹ is substituted. In certain embodiments, R ¹ is unsubstituted. In certain embodiments, R ¹ is saturated, linear, and unsubstituted. In certain embodiments, R ¹ is C _4-30 n-alkyl. In certain embodiments, R ¹ is C _5-15 n-alkyl. In certain embodiments, R ¹ is C _5-10 n-alkyl. In certain embodiments, R ¹ is C _10-15 n-alkyl. In certain embodiments, R ¹ is C ₆ n-alkyl. In certain embodiments, R ¹ is C ₇ n-alkyl. In certain embodiments, R ¹ is C ₈ n-alkyl. In certain embodiments, R ¹ is C ₉ n-alkyl. In certain embodiments, R ¹ is C ₁₀ n-alkyl. In certain embodiments, R ¹ is C ₁₁ n-alkyl. In certain embodiments, R ¹ is C ₁₂ n-alkyl. In certain embodiments, R ¹ is C ₁₃ n-alkyl. In certain embodiments, R ¹ is C ₁₄ n-alkyl. In certain embodiments, R ¹ is C ₁₅ n-alkyl. In certain embodiments, the excipient is in the form of a sodium salt.

One of ordinary skill in the art will recognize that methylnaltrexone can form ion pairs or salts with anionic amphiphilic pharmaceutically acceptable excipients. In some embodiments, the present invention provides a compound of formula II:

wherein ^A- is an anionic amphiphilic pharmaceutically acceptable excipient.

In some aspects, methylnaltrexone can form an ion pair with any of the formulas R ¹ -COOH, R ¹ -SO ₂ OH, R ¹ -OSO ₂ OH, R ¹ -P(O) ₂ OH, R ¹ -OP(O) ₂ OH, or salts thereof as described herein. Thus, according to another embodiment, the present invention provides a compound of any of Formula III, Formula IV, Formula V, Formula VI, or Formula VII:

wherein R ¹ is a C _4-30 aliphatic group which is saturated or unsaturated, linear or branched, cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogens or hydroxyl groups.

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, ie, pharmaceutical compositions, are provided that include methylnaltrexone and sodium dodecyl(lauryl) sulfate (also known as SDS or SLS).

In some embodiments, provided compositions or formulations thereof comprise from about 5% to about 80% of an amphiphilic pharmaceutically acceptable excipient, based on the total weight of the composition or formulation thereof. In certain embodiments, from about 5% to about 25% of an amphiphilic pharmaceutically acceptable excipient is used in the composition or formulation. In some embodiments, provided compositions or formulations thereof comprise from about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% of an excipient, based on the total weight of the composition or formulation thereof.

Certain amphiphilic pharmaceutically acceptable excipients and their corresponding methylnaltrexone ion pairs are less soluble in aqueous environments than methylnaltrexone bromide. Therefore, in certain embodiments, the present invention provides compositions or formulations comprising methylnaltrexone or a salt thereof, an amphiphilic pharmaceutically acceptable excipient, and a disintegrant. The inclusion of a suitable fast-acting disintegrant in the compositions and formulations aids in the disintegration of tablets or other solid dosage forms, particularly the rapid disintegration of tablets or other solid dosage forms in the stomach. Therefore, it is desirable to include a fast-acting disintegrant in solid dosage forms, such as tablets, containing an active ingredient. The amount of disintegrant will vary depending on the nature and amount of the amphiphilic pharmaceutically acceptable excipient (and optional other components). Based on the above parameters, one skilled in the art will understand how to prepare a solid dosage form that dissolves in the stomach. In vitro models exist for conducting such assays, such as the United States Pharmacopeia (USP) dissolution test and the USP disintegration test. 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 aforementioned amount of methylnaltrexone dissolves within about 10 minutes, or even about 5 minutes. As used herein, "a certain percentage dissolves in the stomach within a specific time period" refers to the percentage of methylnaltrexone in the composition that converts the solid to solution as a cation or as a salt, such as an ion pair, when the composition is placed in 900 ml of 1 N HCl at 37° C. with a rotor at 100 rpm.

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 (cross-linked PVP), sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose (croscarmellose), pregelatinized starch (Starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), and combinations thereof. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is an effervescent disintegrant. Effervescent disintegrants are capable of producing carbon dioxide in aqueous media, particularly acidic aqueous media such as gastric contents. In some embodiments, the disintegrant is a bicarbonate, such as sodium bicarbonate (NaHCO ₃ ) or potassium bicarbonate (KHCO ₃ ). In some embodiments, the disintegrant is a carbonate. In some embodiments, the disintegrant is sodium carbonate (Na ₂ CO ₃ ). In some embodiments, the disintegrant is calcium carbonate (CaCO ₃ ). In certain embodiments, the composition or preparation includes at least two disintegrants. For example, the composition or preparation may include an effervescent disintegrant and a non-effervescent disintegrant. In certain embodiments, the composition or preparation includes sodium bicarbonate and cross-linked polyvinylpyrrolidone as disintegrants. In some embodiments, based on the gross weight of the preparation, the preparation provided includes about 1%-about 25%, about 1%-about 15%, about 1%-about 10% or about 2%-about 5% of a disintegrant. In some embodiments, based on the gross weight of the preparation, the preparation provided includes about 1%, about 2%, about 3%, about 4%, about 5%, about 7%, about 8%, about 10%, about 12%, about 15% of a disintegrant. In certain embodiments, the composition or preparation includes materials and/or coatings that hinder or prevent the solid dosage form from dissolving in the oral cavity. Preferably, the solid dosage form disintegrates or decomposes rapidly in the stomach rather than in the oral cavity.

In some embodiments, the present invention provides a formulation of methylnaltrexone, which further comprises one or more additional components, such as, for example, a binder, a carrier, a disintegrant, a chelating agent, an antioxidant, a filler, a wetting agent, or a combination thereof. In certain embodiments, the composition is formulated into a tablet, which further comprises one or more additional components, such as, for example, a binder, a carrier, a disintegrant, a chelating agent, an antioxidant, a filler, a wetting agent, a lubricant, or a combination thereof. In some embodiments, the composition is formulated into a tablet, which further comprises an antioxidant and one or more components, such as, for example, a binder, a carrier, a chelating agent, a filler, a wetting agent, or a combination thereof. In some embodiments, the composition is formulated into a tablet, which further comprises a disintegrant and one or more components, such as, for example, a binder, a carrier, a chelating agent, an antioxidant, a filler, a wetting agent, or a combination thereof. In some embodiments, the composition is formulated into a tablet, which further comprises an antioxidant, a disintegrant and one or more components such as, for example, a binder, a carrier, a chelating agent, a filler, a wetting agent or a combination thereof. Such additional components are described in detail herein below.

In certain embodiments, a pharmaceutically acceptable formulation of the present invention is provided as a tablet comprising a composition comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient and a disintegrant, and optionally one or more of a binder, a chelating agent, and a wetting agent. In some embodiments, such a tablet comprises 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 a tablet comprises a composition comprising methylnaltrexone and one or more of an amphiphilic pharmaceutically acceptable excipient, an antioxidant, a binder, a chelating agent, a disintegrant, and a wetting agent. According to some embodiments, the provided formulation comprises a tablet having a non-functional coating. In some embodiments, the provided formulation further comprises an antioxidant.

Those skilled in the art will readily appreciate that the categories listed for a particular component are not limiting; in some cases, a particular component may appropriately fit into more than one category. Furthermore, it will be appreciated that, for example, the same component may sometimes perform different functions, or may perform more than one function, in the context of a particular formulation, depending on the amount of the component and/or the presence of other components and/or active compounds.

Wetting agent is well known in the art, and it typically helps the interaction of the water molecules in the activating agent (such as hydrophobic activating agent) and the surrounding aqueous environment.Exemplary wetting agent includes poloxamer, polyoxyethylene ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbate such as polysorbate 80, cetyl alcohol, glycerol fatty acid ester (such as triacetin, glyceryl monostearate and analogue), stearic acid polyoxymethylene, sodium lauryl sulfate, sorbitol fatty acid ester, sucrose fatty acid ester, benzalkonium chloride, polyoxyethylene castor oil and docusate sodium and analogue and combination thereof.In some embodiments, based on the gross weight of tablet, the tablet provided comprises the wetting agent of about 1%-about 25%.In some embodiments, based on the gross weight of given tablet, the tablet provided comprises the wetting agent of about 1%, about 3%, about 4%, about 5%, about 10%, about 15% or about 20%.

In certain embodiments, the wetting agent is a polysorbate. In some embodiments, the wetting agent is polysorbate 80, also known as Tween 80, obtained from sources such as Sigma-Aldrich. In some embodiments, based on the gross weight of a given tablet, the tablet provided comprises about 1% to about 25%, about 1% to about 5%, about 2% to about 5%, about 3%, or about 4% polysorbate 80. In certain embodiments, based on the gross weight of a given tablet, the tablet provided comprises about 1%, about 3%, about 4%, about 5%, about 10%, about 15% or about 20% polysorbate 80. Without wishing to be bound by any specific theory, polysorbate 80 can also work as an absorption enhancer. Moreover, without wishing to be bound by any specific theory, polysorbate 80 can help the mucous layer produced in the gastrointestinal tract to thin, thereby making the methylnaltrexone remaining in the mucous layer more easily released and quickly absorbed.

The addition of one or more chelating agents is particularly useful in formulations comprising methylnaltrexone, as such agents can provide protection of methylnaltrexone from metal-catalyzed degradation and/or precipitation. Suitable chelating agents are well known in the art and include any pharmaceutically acceptable chelating agent.

Common chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) and its derivatives, ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA) and its derivatives, diethylenetriaminepentaacetic acid (DTPA) and its derivatives, N,N-di(carboxymethyl)glycine (NTA) and its derivatives, nitrilotriacetic acid and its derivatives, citric acid and its derivatives, nicotinamide and its derivatives, and sodium deoxycholate and its derivatives.

In some embodiments, chelating agent is selected from EDTA or its derivatives. In some embodiments, chelating agent is selected from EDTA disodium calcium, EDTA diammonium, EDTA dipotassium, EDTA disodium, TEA-EDTA, EDTA tetrasodium, EDTA tripotassium, EDTA trisodium, HEDTA and HEDTA trisodium and its related salts. In some embodiments, chelating agent is EDTA disodium, EDTA trisodium or EDTA disodium calcium. In some embodiments, chelating agent is EDTA calcium (calcium EDTA) or EDTA calcium salt derivative, or EGTA calcium or EGTA calcium salt derivative. In some embodiments, chelating agent is EDTA disodium calcium, such as, for example, EDTA disodium calcium hydrate (EDTA disodium calcium dihydrate). EDTA calcium is obtained from sources such as Sigma-Aldrich. In some embodiments, provided formulations comprise about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5% of a chelating agent, based on the total weight of the formulation. In some embodiments, provided formulations comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, or about 0.6% of a chelating agent, based on the total weight of the formulation.

Suitable adhesive (also referred to as " diluent " and/or " filler ") is known in the art.For example, suitable adhesive includes but is not limited to starch, PVP (polyvinyl pyrrolidone), low molecular weight HPC (hydroxypropyl cellulose), microcrystalline cellulose (such as Avicel ⁾ , silicified microcrystalline cellulose (Prosolv 50), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose, ethyl cellulose, alginate, gelatin, polyethylene oxide, gum arabic, dextrin, sucrose, magnesium aluminum silicate and polymethacrylate.Filler includes the reagent selected from microcrystalline cellulose (such as, ^Avicel ), starch, lactitol, lactose, suitable inorganic calcium salt, sucrose, glucose, mannitol, metasilicic acid or its combination.In some embodiments, based on the gross weight of preparation, preparation comprises the adhesive of about 5%-about 90%, about 10%-about 50%, about 10%-about 40% or about 10%-about 45%. In some embodiments, the formulation comprises about 10%, about 15%, about 16%, about 20%, about 24%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of a binder based on the total weight of the tablet. In some embodiments, the formulation comprises microcrystalline cellulose as a binder. In certain embodiments, the formulation comprises microcrystalline cellulose and silicified microcrystalline cellulose as binders.

In certain embodiments, the preparations provided may include one or more antioxidants. Such antioxidants include those known to those of ordinary skill in the art. Exemplary antioxidants include ascorbic acid, and its salts and esters; citric acid, and its salts and esters; butylated hydroxyanisole ("BHA"); butylated hydroxytoluene ("BHT"); tocopherols (e.g., d -α-tocopherol, dl -α-tocopherol, d -α-tocopheryl acetate, dl -α-tocopheryl acetate, β-tocopherol, δ-tocopherol, γ-tocopherol and the like) and carotenoids (e.g., vitamin A, lutein, and zeaxanthin). In certain embodiments, the preparations include ascorbic acid. In some embodiments, the preparations include up to about 10% by mass of one or more antioxidants. In some embodiments, the preparations provided include about 0.01% to about 5% by mass of one or more antioxidants. In some embodiments, the preparations provided include about 1.0% to about 10% by mass of one or more antioxidants. In certain embodiments, provided formulations comprise about 1%, about 2%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by mass of one or more antioxidants.

In certain embodiments, the formulation may include a lubricant. Typically, a lubricant is a substance used in solid formulations to reduce friction during compression. This compound includes, by way of example but not 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 substances known to those of ordinary skill in the art. In certain embodiments, the lubricant is a stearate. In some embodiments, based on the gross weight of a given formulation, the formulation includes about 0.1% to about 7% or about 0.2% to about 1% lubricant. In certain embodiments, the lubricant is magnesium stearate, available from sources such as Sigma-Aldrich.

In certain embodiments, the formulation may include a non-functional coating. For example, in some embodiments, the tablet may include a non-functional coating. In some embodiments, the non-functional coating is a seal coating. For example, a suitable seal coating can be applied as a solution (e.g., an HPMC solution) at a concentration of about 1% w/w-25% w/w, preferably 1% w/w-about 10% w/w. After drying, under suitable conditions, the initial seal coating is in the range of about 1% w/w-about 3% w/w of the uncoated tablet or about 2% w/w. This seal coating may include a polymer (e.g., HPMC) and may be a commercially available seal coating, such as ^Opadry® Clear (Colorcon, Inc.) or HPMC E3. After drying, the seal coating can increase the weight of the total coated formulation by about 1%-about 10%. In certain embodiments, the formulation may include a coating that prevents the dosage form from disintegrating in the oral cavity.

In certain embodiments, a 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 of the formulation is ( R ) -N -methylnaltrexone bromide. In certain embodiments, the amphiphilic pharmaceutically acceptable excipient is sodium lauryl sulfate. In certain embodiments, the chelating agent is a salt of EDTA (such as 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 present invention provides a tablet formulation for oral administration, which comprises approximately 30% methylnaltrexone bromide, approximately 10% sodium lauryl sulfate, approximately 11% microcrystalline cellulose, approximately 5% crospovidone, approximately 0.25% calcium EDTA, approximately 2% polysorbate 80, approximately 30% Prosolv 50, approximately 11% sodium bicarbonate, approximately 2% talc, approximately 0.5% colloidal silicon dioxide, and approximately 0.25 magnesium stearate. It will be appreciated by those skilled in the art that, depending on how the tablet or other formulation of the invention described herein is prepared, methylnaltrexone may be present in a conjugate with a bromide, in a conjugate with an anion of an amphiphilic pharmaceutically acceptable excipient, or some combination thereof.

Production

In certain embodiments, compositions and formulations are prepared by methods including an extrusion/spheronization step. In some embodiments, formulations are prepared by wet granulation of a provided formulation followed by extrusion/spheronization to form spheres. The given spheres are then dried and ground to form a powder, which is then mixed with a suitable binder and disintegrant. The resulting mixture is then ground, mixed with a suitable lubricant, and compressed into tablets. In certain embodiments, a non-functional coating is applied.

In some embodiments, the tablets are prepared by a method that does not include an extrusion/spheronization step, according to which the tablets are prepared by wet granulation. Once dried, the granules are ground to form a granular powder, which is mixed with a suitable binder and disintegrant. The resulting mixture is then ground, mixed with a suitable lubricant, and compressed into tablets. In certain embodiments, a non-functional coating is applied.

Unit dosage form

The formulation of methylnaltrexone is prepared as a unit dosage form. In fact, a tablet is typically the unit dosage form. In some embodiments, the unit dosage form comprises 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg. In some embodiments, the unit dosage form comprises methylnaltrexone bromide in an amount of 1 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg. In some embodiments, the unit dosage form comprises 50 mg to 900 mg (inclusive) or 150 mg to 450 mg (inclusive) of methylnaltrexone bromide. In some embodiments, the unit dosage form comprises 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, such as sodium dodecyl (lauryl) sulfate (also known as SDS or SLS).

Application

Compositions and formulations can be administered to a patient as needed to provide an effective amount of methylnaltrexone. In certain embodiments, the patient orally administers methylnaltrexone or a formulation thereof at least once daily. In other embodiments, the patient orally administers methylnaltrexone or a formulation thereof up to once daily. In certain embodiments, the patient orally administers methylnaltrexone or a formulation thereof no more than once daily. In certain embodiments, the patient orally administers methylnaltrexone or a formulation thereof as needed. In certain embodiments, the patient orally administers methylnaltrexone or a formulation thereof as needed, but no more than once daily. For example, a given formulation can be orally administered to a patient on a single day in unit dosage form, e.g., a unit dosage of approximately 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 for treating opioid-induced side effects in a patient in need of treatment, comprising the step of orally administering to the patient one or more tablets of the present invention, wherein the tablet provides about 150 mg, 300 mg, or 450 mg of methylnaltrexone bromide or an equimolar amount of methylnaltrexone bromide, such as methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient such as sodium dodecyl (lauryl) sulfate (also known as SDS or SLS), sodium heptyl sulfate, sodium heptyl sulfonate, perfluorooctane sulfonate (PFOS), and the like. In certain embodiments, a single tablet of the present invention provides about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 300 mg, or about 450 mg of methylnaltrexone bromide or an equimolar amount of another salt form, or methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient such as sodium dodecyl (lauryl) sulfate (also known as SDS or SLS).

As defined above, in certain embodiments, the term "effective amount" as used in connection with the amount of methylnaltrexone refers to an amount of methylnaltrexone sufficient to achieve a laxative effect in a patient. In some embodiments, an effective amount refers to an amount of methylnaltrexone sufficient to achieve a laxative effect in a patient within about 24 hours, about 12 hours, about 8 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour of administration to the patient. In some embodiments, an effective amount refers to an amount of methylnaltrexone sufficient to achieve a laxative effect in a patient within about 4 hours of administration to the patient. In some embodiments, an effective amount refers to an amount of methylnaltrexone sufficient to achieve a laxative effect in a patient 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, an effective amount refers to an amount of methylnaltrexone sufficient to achieve a laxative effect in a patient within about 4 hours of administration to the patient for all doses administered during the first four weeks of dosing.

In some embodiments, the formulation is administered to a fasted patient. As used herein, the term "fasted" means that the patient has not consumed any food for at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, or at least 12 hours prior to administration of the provided formulation. In certain embodiments, the term "fasted" refers to an overnight fast. The inventors believe that improved effects are seen in fasting patients compared to non-fasting patients. These effects are amplified in patients administered the provided methylnaltrexone tablet formulation compared to patients administered the same dose in capsule form. Therefore, the inventors believe that administering the provided methylnaltrexone tablet formulation to patients in a fasted state is advantageous.

In other embodiments, the formulation is administered to a patient who is not fasting. Thus, the patient is not required to fast prior to administration of methylnaltrexone.

Combination products and combined administration

It should also be understood that the compositions and preparations provided can be used in combination therapy, that is, the preparations provided can be used simultaneously with one or more other needed therapies or medical methods, used before them, or used thereafter. The specific combination therapy (therapy or method) used in the combination regimen should consider the compatibility of the therapy and/or method needed with the therapeutic effect to be achieved. It should also be understood that the treatment used can achieve the desired effect for the same disorder (for example, the preparation can be administered simultaneously with another compound used to treat the same disorder), or they can achieve different effects (for example, control of any side effects). Other therapeutic compounds used in the present invention (which are normally administered to treat or prevent specific diseases or conditions) are referred to as "diseases or conditions suitable for treatment".

In some embodiments, methylnaltrexone or an ion pair or formulation of the present invention and one or more other active agents can be administered together in a single formulation (e.g., a 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.

In some embodiments, the other active agent administered in combination with the methylnaltrexone ion pairs or formulations of the present invention is an opioid. Combination therapy with methylnaltrexone and an opioid can simultaneously reduce pain and minimize opioid-related side effects, such as gastrointestinal effects (e.g., delayed gastric emptying, altered gastrointestinal motility). Accordingly, in some embodiments, the present invention provides a unit dosage form comprising a combination of methylnaltrexone and an opioid in a single-layer dosage form (e.g., a tablet). In some embodiments, such a unit dosage form can be a bilayer tablet, comprising methylnaltrexone in one layer and an opioid in another layer. In particular embodiments, the combination unit dosage form is suitable for oral administration.

Opioids for use in analgesia are known in the art. For example, opioid compounds include, but are not limited to, alfentanil, anileridine, acimadolin, bromazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, ethylmorphine, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levacetylmethadone, levophene, loperamide, meperidine, methadone, morphine, morphine-6-glucuronide, nalbuphine, nalorphine, nicomorphine, opium, oxycodone, oxymorphone, papaveretum, pentazocine, disopyramide, propoxyphene, remifentanyl, sufentanil, tolbutamide, trimeprent, and tramadol. In some embodiments, the opioid is at least one selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levofenadine, meperidine, methadone, morphine, nalbuphine, nicomorphine, oxycodone, oxymorphone, papaveretum, fentanyl, disopyramide, propoxyphene, sufentanil, and/or tramadol. In certain embodiments of the present invention, the opioid is selected from the group consisting of morphine, codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl, tramadol, and mixtures thereof. In a specific embodiment, the opioid is loperamide. In other embodiments, the opioid is a mixed agonist, such as butorphanol. In some embodiments, more than one opioid is administered to an individual, eg, morphine and heroin or methadone and heroin.

The amount of the additional active agent administered in a combination therapy typically does not exceed the amount typically administered in a monotherapy with the relevant agent. In certain embodiments, the amount of the additional active agent administered in a combination therapy does not exceed the amount typically administered in a monotherapy with the relevant agent. For example, in certain embodiments of the invention, the amount of the additional active agent is within the range of about 50%-100% of the amount typically present in a formulation comprising the compound as the sole therapeutic agent.

In certain embodiments, the formulations can also be combined and/or used in combination with conventional treatments for gastrointestinal dysfunction that help improve constipation and intestinal dysfunction. For example, conventional treatments include, but are not limited to, functional stimulation of the intestine, stool softeners, laxatives (e.g., diphenylmethane laxatives, cathartic laxatives, osmotic laxatives, saline laxatives), bolus formers and laxatives, lubricants, intravenous hydration, and nasogastric decompression.

Compositions and Uses of Formulations and Kits

The present invention provides pharmaceutically acceptable formulations as described herein, comprising orally administered methylnaltrexone for delivery of such a compound in any setting requiring such delivery. In certain embodiments, the formulations provided are used to deliver methylnaltrexone in an attempt to antagonize the adverse side effects of opioid analgesic therapy, such as gastrointestinal effects (e.g., delayed gastric emptying, altered gastrointestinal motility). Furthermore, the formulations can be used to treat individuals with disease states that can be ameliorated by binding to μ opioid receptors, or for any treatment requiring temporary inhibition of the μ opioid receptor system (e.g., intestinal obstruction). In certain embodiments of the present invention, methods of use of the formulations provided are for use in human individuals.

Accordingly, administration of provided formulations can be advantageous for treating, preventing, ameliorating, delaying, or reducing the following side effects of opioid use, for example, gastrointestinal dysfunction (e.g., inhibition of intestinal motility, constipation, GI sphincter contraction, nausea, vomiting (emesis)), cholecystitis, opioid bowel dysfunction, colic, irritability, pruritus, urinary retention, respiratory depression, nipple retraction, cardiovascular effects, chest wall stiffness and cough suppression, suppression of stress responses, and immunosuppression associated with the use of narcotic analgesia, or a combination thereof. Thus, the use of the formulations is advantageous from the perspective of improving the quality of life of individuals experiencing opioid use and reducing complications caused by chronic constipation (e.g., hemorrhoids, appetite suppression, mucosal rupture, sepsis, risk of colon cancer, and myocardial infarction).

In some embodiments, provided formulations are for administration to individuals experiencing acute opioid use. In some embodiments, provided formulations are for administration to patients suffering from post-operative gastrointestinal dysfunction.

In certain embodiments, provided formulations can also be used for administration to individuals experiencing long-term opioid administration (e.g., patients with advanced diseases receiving opioid therapy, such as AIDS patients, cancer patients, cardiovascular patients; individuals receiving long-term opioid therapy for pain control; individuals experiencing opioid therapy for maintenance of opioid withdrawal). In some embodiments, the individual is an individual using opioids for the management of chronic pain. In certain embodiments, the pain is non-malignant pain (e.g., back pain, neuralgia, pain associated with fibromyalgia, osteoarthritis). In some embodiments, the individual is a patient with advanced disease. In other embodiments, the individual is a person experiencing opioid withdrawal maintenance therapy.

In certain embodiments, the formulation provided herein is applied to an individual selected for treatment with methylnaltrexone. In a specific embodiment, the individual is selected based on the risk of an increase in the development of one or more of the above-described conditions. In another embodiment, the individual is selected based on the administration of opioid therapy for pain control, or based on the use of one or more of the conditions described herein. In certain embodiments, the individual suffers from constipation or has a history of constipation due to opioid therapy. In one embodiment, the individual with constipation did not have a bowel movement in the first three days. In one embodiment, the individual with constipation had less than three bowel movements in the first week. In certain embodiments, the individual with constipation had an average of less than three untreated (rescue-free) bowel movements per week in the last four consecutive weeks, and one or more of the following: (a) hard or lumpy stools, (b) very tight during bowel movements, and/or (c) a feeling of incomplete excretion after bowel movements.

In certain embodiments, individuals are selected for treatment with the methylnaltrexone formulations described herein based on their use of opioids (e.g., for non-malignant pain). Individuals may use opioids intermittently or regularly. In one embodiment, the selected individual uses opioids as needed. In one embodiment, the selected individual uses opioids for less than one week. In one embodiment, the selected individual uses opioids during at least one week. In another embodiment, the selected individual uses opioids during at least two weeks. In another embodiment, the selected individual uses opioids during at least three weeks. In another embodiment, the selected individual uses opioids during at least four weeks. In another embodiment, the selected individual uses opioids during at least three months. In another embodiment, the selected individual uses opioids during at least six months. In another embodiment, the selected individual uses opioids during at least twelve months. In another embodiment, the selected individual uses opioids during more than one year. In another embodiment, the selected individual uses opioids at least every other day during at least two weeks. In one embodiment, the selected individual has been receiving at least 7 doses of >25 mg oral morphine equivalents for at least 14 days. In one embodiment, the selected individual has been receiving a daily dose of >50 mg oral morphine equivalents for at least 14 days. In one embodiment, the selected individual is constipated due to opioid therapy and has been receiving a daily dose of >50 mg oral morphine equivalents for at least 14 days. In certain embodiments, the subject has been receiving a daily dose of oral morphine equivalents of >50 mg for at least 14 days; the constipated subject has an average of less than three (3) rescue-free bowel movements per week for a minimum of four consecutive weeks, the bowel movements being associated with one or more of: (a) Bristol Stool Form Scale type 1 or 2 for at least 25% of the rescue-free bowel movements, (b) straining during at least 25% of the rescue-free bowel movements; and/or (c) a sensation of incomplete evacuation after at least 25% of the rescue-free bowel movements. A rescue-free bowel movement is a bowel movement that is associated with the absence of a laxative in the 24 hours preceding the bowel movement.

In certain embodiments, the individual selected for treatment with the methylnaltrexone formulations described herein is an individual with opioid-induced constipation. In certain embodiments, the individual selected for treatment with the methylnaltrexone formulations described herein is an individual receiving palliative care and suffering from terminal illness who suffers from opioid-induced constipation. In certain embodiments, the individual selected for treatment with the methylnaltrexone formulations described herein is an individual receiving palliative care and suffering from terminal illness who suffers from opioid-induced constipation, wherein the response to laxative therapy (e.g., bisacodyl, senokot, docusate) is insufficient. In certain embodiments, the individual selected for treatment with the methylnaltrexone formulations described herein is an individual with non-malignant pain who suffers from opioid-induced constipation. In certain embodiments, the individual selected for treatment with the methylnaltrexone formulations described herein is an individual with non-malignant pain who suffers from opioid-induced constipation, wherein the response to laxative therapy (e.g., bisacodyl, senokot, docusate) is insufficient. In certain embodiments, the individual selected for treatment with the methylnaltrexone formulations described herein is unresponsive to standard laxative therapy. In certain embodiments, the individual selected for treatment with the methylnaltrexone formulations described herein is responsive to standard laxative therapy. In certain embodiments, the individual selected for treatment with the methylnaltrexone formulations described herein is concurrently administered a laxative therapy.

Alternative or Additional Uses The provided formulations described herein can be used to treat the effects of opioid use, including, for example, abnormal migration or proliferation of endothelial cells (e.g., vascular endothelial cells), increased angiogenesis, and increased production of lethal factors by opportunistic infections (e.g., Pseudomonas aeruginosa). Additional advantageous uses of the provided formulations include treatment of opioid-induced immunosuppression, inhibition of angiogenesis, inhibition of vascular proliferation, treatment of pain, treatment of inflammatory conditions (e.g., inflammatory bowel syndrome), treatment of infectious diseases and diseases of the musculoskeletal system (e.g., osteoporosis, arthritis, osteitis, periostitis, muscle diseases), and treatment of autoimmune diseases.

In certain embodiments, provided formulations can be used in methods for preventing, inhibiting, reducing, delaying, attenuating or treating gastrointestinal dysfunction, including but not limited to: irritable bowel syndrome, opioid-induced bowel dysfunction, colitis, postoperative or postpartum ileus, nausea and/or vomiting, decreased gastric motility and emptying, inhibition of gastric and small and/or large intestinal motility, increased amplitude of non-propulsive segmental contraction, sphincter of Oddi, Oddi contractions, increased anal sphincter tone, impaired reflex relaxation to rectal distension, decreased gastric, biliary, pancreatic or small intestinal secretions, increased absorption of water from intestinal contents, gastroesophageal reflux, gastroparesis, cramping, bloating, abdominal or epigastric pain and discomfort, constipation, idiopathic constipation, postoperative gastrointestinal dysfunction following abdominal surgery (e.g., colectomy (e.g., right hemicolectomy, left hemicolectomy, transverse hemicolectomy, caudal colectomy takedown, low anterior resection)), and delayed absorption of orally administered drugs or nutrients.

Provided formulations are also useful for treating conditions including cancer involving angiogenesis, immunosuppression, sickle cell anemia, vascular wounds and retinopathy, treating inflammation-related disorders (e.g., irritable bowel syndrome), immunosuppression, chronic inflammation.

In other embodiments, provided formulations and unit dosage forms can be used to prepare medicaments, including but not limited to: medicaments for treating side effects of opioid use, including gastrointestinal side effects (e.g., inhibition of intestinal motility, gastrointestinal sphincter contraction, constipation), nausea, vomiting, retching, anxiety, itching, or a combination thereof. Provided formulations can be used to prepare medicaments for treating patients receiving acute opioid therapy (e.g., patients with postoperative gastrointestinal dysfunction receiving acute opioid administration), or for treating individuals who use opioids for a long time (e.g., patients with advanced illnesses such as AIDS, cancer, and cardiovascular disease receiving opioid therapy; individuals receiving long-term opioid therapy for pain control (malignant or non-malignant pain); or individuals receiving opioid therapy for maintenance of opioid abstinence). Still further, medicaments are prepared for the treatment of pain, treatment of inflammatory conditions (e.g., inflammatory bowel syndrome), treatment of infectious diseases, treatment of diseases of the musculoskeletal system (e.g., osteoporosis, arthritis, osteitis, periostitis, muscle diseases), treatment of autoimmune diseases and immunosuppression, treatment of postoperative gastrointestinal dysfunction following abdominal surgery (e.g., colectomy (e.g., right hemicolectomy, left hemicolectomy, transverse hemicolectomy, colectomytakedown, low anterior resection), treatment of idiopathic constipation and intestinal obstruction (e.g., postoperative ileus, postpartum ileus), and treatment of conditions such as cancer involving angiogenesis, chronic inflammation and/or chronic pain, sickle cell anemia, vascular wounds, and retinopathy.

In a further embodiment, veterinary applications (e.g., treating livestock, such as horses, dogs, cats) using the provided formulations are provided. Therefore, it is also contemplated that the provided formulations may be used in veterinary applications similar to those discussed above for human subjects. For example, inhibiting equine gastrointestinal activity, such as hernia and constipation, can be fatal to horses. The resulting pain experienced by horses with hernias can lead to shock that can induce death, while cases of chronic constipation can also cause the death of horses. 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).

The present invention further includes a pharmaceutical pack and/or kit comprising a formulation as described herein and a container (eg, foil or plastic package, or other suitable container). Optionally, instructions for use are also provided in such a kit.

In order that the invention described herein may be more fully understood, the following examples are listed. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present invention in any manner.

All features of each aspect of the invention apply mutatis mutandis to all other aspects.The contents of all references, patents, pending patent applications and published patents cited in this application are expressly incorporated herein by reference.

Example

Example 1

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. A formulation containing methylnaltrexone is prepared using pharmaceutically acceptable excipients. Spheres containing methylnaltrexone are prepared. Capsules are prepared by filling capsules with the spheres. Some capsules are prepared to contain enteric-coated spheres that dissolve only after passage through the stomach. Capsules without an enteric coating or after dissolution of the enteric coating will dissolve in 10-30 minutes. Tablets are also prepared from the spheres using conventional techniques. The tablets dissolve within 10 minutes.

Spheroids are prepared by wet granulation followed by extrusion and spheronization as described in the following general method. Methylnaltrexone bromide and pharmaceutically acceptable excipients are combined in an aqueous solution. Water is added until a wet weight suitable for extrusion is achieved. The wet weight is passed through an extruder, and the extrudate is spheronized in a spheronizer. The resulting spheres are dried in a fluid bed dryer and passed through a screen. Uncoated spheres are stored in suitable containers.

Example 2

Administration of capsules containing enteric-coated methylnaltrexone spheres

Capsules containing enteric-coated spheres of methylnaltrexone as described in Example 1 were tested in patients with opioid-induced constipation. The patients in this study were not long-term methadone-maintained patients. The patients had chronic non-malignant (non-cancer) pain, where the non-malignant condition underlying the chronic pain (e.g., osteoarthritis, back pain, neuralgia) had a documented history of at least 2 months prior to screening, with stable pain persisting for at least 1 month. Prior to and during the screening visit, the patients had been taking opioids for at least 1 month, with a daily dose greater than or equal to 20 mg of morphine equivalents for at least two weeks, with no expected changes during the study. The patients also had a history of constipation due to opioid use for at least 1 month prior to the screening visit. Constipation was defined as an average of fewer than 3 bowel movements per week and one or more of the following: (i) hard or lumpy stools for at least 25% of bowel movements, (ii) a sensation of incomplete evacuation after at least 25% of bowel movements, or (iii) straining during at least 25% of bowel movements.

Patients were administered enteric-coated methylnaltrexone capsules containing 10 mg, 50 mg, 150 mg, 300 mg, or 450 mg of methylnaltrexone. Mean peak plasma levels of methylnaltrexone, depending on the dose, were as follows: (i) less than 1 ng/mL for 10 mg, (ii) less than 5 ng/mL for 50 mg, (iii) less than 5 ng/mL for 150 mg, (iv) less than 10 ng/mL for 300 mg, and (v) less than 20 ng/mL for 450 mg. These capsules containing enteric-coated preparations of methylnaltrexone were not effective for treating opioid-induced constipation. They did not induce laxation and did not cause more bowel movements than controls.

Example 3

Administration of capsules containing non-enteric-coated methylnaltrexone

Capsules containing methylnaltrexone spheres, prepared as described in Example 1, but without an enteric coating, were tested in patients receiving opioids for non-malignant pain. The patients in this study were not long-term methadone maintenance patients. Patients were selected based on the same criteria used in Example 2, except that the minimum daily dose of opioid was equal to or greater than 30 mg morphine equivalents, rather than 20 mg morphine equivalents. Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted in average peak plasma levels of approximately 15-40 ng/ml, which is approximately 3 or more times lower than the average peak plasma levels associated with effective doses of subcutaneous methylnaltrexone injections. These capsules containing spheres without an enteric coating did not induce laxation in this patient population, nor did they cause more laxation compared to controls.

Administration of tablets containing non-enteric-coated methylnaltrexone

Tablets containing spheroids of methylnaltrexone 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 not long-term methadone maintenance patients. Patients were selected based on the same criteria used in Example 3. Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted in average peak plasma levels of approximately 7-40 ng/ml. These tablets without an enteric coating showed statistically significant activity at one dose, but did not consistently induce laxatives across all doses.

Tablets and capsules containing uncoated spheres have similar compositions, except that the spheres are compressed with pharmaceutically acceptable excipients to form tablets, while the spheres are sealed into hard gelatin shells to prepare capsules. Upon contact with aqueous media, tablets disintegrate immediately, with nearly all of the drug dissolved in less than 10 minutes. In contrast, it took 10 minutes for the capsule shell to dissolve and at least 30 minutes for the drug to completely dissolve from the capsule. (Figure 1) Plasma levels associated with the two dosage forms containing uncoated spheres were different (tablets produced more consistent mean peak plasma levels relative to capsules) and overlapped between subjects.

Example 4

Determination of partition coefficient

Ion pairs of methylnaltrexone and amphiphilic pharmaceutically acceptable excipients were prepared, and the apparent octanol-water partition coefficients (APCs) were determined and compared with the apparent octanol-water partition coefficients of methylnaltrexone bromide. A predetermined amount of each MNTX-heptyl sulfate and MNTX-dodecyl sulfate salt was dissolved in 2 mL of 1-octanol saturated with water. 2 mL of water saturated with 1-octanol was added to each MNTX salt solution. The mixture was shaken overnight at room temperature, after which 1 mL of the 1-octanol phase was diluted to 10 mL with the mobile phase for chromatographic (HPLC) analysis of the samples. 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 of each MNTX salt. The pH of the aqueous phase for each salt ranged from 4.5 to 6.8. (The reported partition coefficient for MNTX is 0.025, and the logP is -1.605).

Example 5

Preparation of tablets containing methylnaltrexone bromide and sodium lauryl sulfate

This example describes the preparation of tablets containing methylnaltrexone bromide, sodium dodecyl sulfate (SDS), and an effervescent disintegrant (sodium bicarbonate). Table 5-1 provides the quantitative formula of methylnaltrexone (150 mg) tablets.

Table 5-1: Composition of 150 mg Methylnaltrexone Bromide Uncoated Tablets with SDS

^aBased on 100% purity "as is," adjustments may be made to actual potency based on the amount of microcrystalline cellulose.

^bRemoved by drying. Not present in the final dosage form.

Manufacturing and packaging methods: steps

1. Combine methylnaltrexone bromide, microcrystalline cellulose, sodium lauryl sulfate (SDS), and crospovidone in a granulator.

2. Prepare a solution containing calcium disodium EDTA and polysorbate 80 in purified water.

3. While mixing the mixture from step 1, add the calcium disodium EDTA/polysorbate 80 solution for approximately 4 minutes. Additional water may be added to obtain a suitable granulation. Note: The granulation step can be completed in batches to obtain a larger batch size.

4. Dry the granules.

5. Grind the granules from step 4 using a suitable grinder.

6. Add the materials from step 5 to the mixer.

7. The recorded yield is used for milling and adjusting the excipient levels for final blending.

8. Optionally, sift the crospovidone, silicified microcrystalline cellulose, sodium bicarbonate, talc, silicon dioxide, magnesium stearate through a suitable sieve.

9. Add crospovidone, sodium bicarbonate, talc, and silicified microcrystalline cellulose to the blender and mix.

10. Optionally, sieve the mixture from step 9 through a suitable sieve, add to a mixer and mix.

11. Optionally take a portion of the mixture, add silica and mix using a bag.

12. Optionally transfer the silica premix to the mixer and mix.

13. Take a portion of the mixture, add magnesium stearate and bag mix. Note: Step 13 is not required for batches larger than 50 kg.

14. Transfer the pre-blended magnesium stearate into the blender and mix.

15. Record the final yield of the mixture.

16. Compress the final blend from step 15 using a suitable compressor equipped with tooling to produce tablets of the required specifications.

17. Weigh the yield of acceptable tablets.

Example 6

Tablets containing methylnaltrexone bromide (150 mg), sodium dodecyl sulfate (SDS), and sodium bicarbonate were prepared using the method described in Example 5. The tablets were placed in 900 ml of 0.1 N HCl (37°C) in a dissolution apparatus with a paddle rotating at 100 rpm. Samples were then removed at specified time points and analyzed by HPLC. The dissolution rates of two tablets were measured. The dissolution profile of the SDS tablet containing sodium bicarbonate is shown in Figure 2. Over 90% of the methylnaltrexone from the tablets was dissolved within 11 minutes.

Example 7

Administration of provided formulations in dogs with altered gastrointestinal tract physiology

The oral bioavailability and pharmacokinetic profile of tablets containing methylnaltrexone bromide (150 mg), sodium dodecyl sulfate (SDS), and sodium bicarbonate, prepared as described in Example 5, were compared with tablets containing uncoated spheres of methylnaltrexone, prepared as described in Example 1, but without an amphiphilic pharmaceutically acceptable carrier or effervescent disintegrant. Male beagle dogs with altered gastrointestinal physiology were administered atropine (~20 μg/kg; IV) and pentagastrin (~10 μg/kg; IM) 15 minutes before administration of the formulations, and another dose of pentagastrin (10 μg/kg; IM) was administered 30 minutes after the dose. Atropine slowed gastrointestinal motility in dogs, and pentagastrin lowered pH, resulting in gastrointestinal conditions that were nearly similar to those in humans. The formulation (150 mg MNTX) was administered orally to six dogs (9.4–13.7 kg) after an overnight fast. Blood samples were collected at 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose; plasma was separated and assayed for methylnaltrexone.

The plasma methylnaltrexone concentration-time patterns of individual dogs were subjected to non-compartmental pharmacokinetic analyses (WinNonlin, Model 200). The results are summarized in Table 7-1 below.

Table 7-1. Individual and Mean (± SD) Pharmacokinetic Parameters of MNTX in Dogs with Gastrointestinal Physiological Changes Following a Single Oral Administration of 150 mg of the Prototype MNTX Formulation

As summarized in Table 7-1 above, oral administration of the prototype tablet formulation containing the ion pairing agent sodium dodecyl(lauryl) sulfate resulted in quantitatively higher systemic exposure of methylnaltrexone compared to the tablet without the ion pairing agent.

Example 8

This example reports the efficacy of methylnaltrexone in the SDS tablet formulation at doses of 300 and 450 mg administered orally to individuals with chronic non-malignant pain. Individuals enrolled in this study were required to have a history of constipation caused by opioid use for at least one month prior to the screening visit. This study was a Phase 1, open-label, single-dose, inpatient study. Subjects received methylnaltrexone as a single dose (2 x 150 mg or 3 x 150 mg) of the SDS tablet formulation after an overnight fast of at least 10 hours. The dose was administered orally with 240 mL of room temperature water at approximately 8:00 AM on Day 1. Opioid medication was provided at approximately the same time each week. Each subject participated in the study for approximately three weeks. This included a screening evaluation within three weeks prior to test article administration and a two-day/one-night hospitalization period.

The results are shown in Figure 3. This figure shows the percentage of patients with first bowel movement response versus time in patients with chronic malignant pain who were administered methylnaltrexone (300 mg or 450 mg) SDS tablets after a 10-hour fast. The SLS tablet formulation resulted in an increase in the percentage of bowel movements within 4 hours and 24 hours in individual patients.

In Example 8, the percentage of patients who received a single initial dose of 450 mg of the SDS formulation of the present invention with a bowel movement within 4 hours was approximately 41%. In Example 8, the percentage of patients who received a single initial dose of 450 mg of the SDS formulation of the present invention with a bowel movement within 24 hours was approximately 72%.

The research above is not designed to establish the statistical significance of defecation. There is no placebo group.It should be noted that, historically, in the larger research of chronic non-malignant pain patients with similar but stricter inclusion/exclusion criteria design, the percentage ratio of the individuality of receiving placebo and defecation within 4 hours is approximately about 9%-13%.It will be appreciated by those skilled in the art that, due to factors such as smaller research scale and different inclusion/exclusion criteria, the placebo response in this research is different from previous research.Do not wish to be bound by any theory of invention, the applicant believes that there may be a kind of dual mechanism to participate in and realize defecation when using oral dosage, and the level required when realizing the plasma level required for defecation when oral administration is lower than when subcutaneous administration.

Those skilled in the art will readily ascertain the essential characteristics of the present invention and will appreciate that the foregoing description and examples are illustrative for practicing the invention provided herein. Those skilled in the art will be able to determine, using only routine experimentation, that many changes in the details described herein may be made to the specific embodiments of the invention described herein without departing from the spirit and scope of the invention.

Claims (24)

1. A pharmaceutical composition in tablet form for oral administration, wherein the composition comprises (R)-N-methylnaltrexone bromide, sodium lauryl sulfate, a chelating agent and a disintegrant, wherein the composition comprises 5% to 80% sodium lauryl sulfate based on the total weight of the composition, and wherein methylnaltrexone has an apparent octanol/water partition coefficient of at least 0.25 at a pH of 1-4 when the composition is dissolved in solution. 2. The pharmaceutical composition of claim 1, wherein the brominated (R)-N-methylnaltrexone is present in 150 mg. 3. The pharmaceutical composition of claim 1, wherein the chelating agent is EDTA or a salt thereof. 4. The pharmaceutical composition of claim 3, wherein the chelating agent comprises calcium disodium ethylenediaminetetraacetate. 5. The pharmaceutical composition of claim 1, wherein, when dissolved in solution, the composition comprises an ion pair of (R)-N-methylnaltrexone and dodecyl sulfate. 6. The pharmaceutical composition of claim 1, wherein the disintegrant comprises an effervescent disintegrant. 7. The pharmaceutical composition of claim 1, wherein the disintegrant comprises a combination of crospovidone and crospovidone sodium carboxymethyl cellulose. 8. The pharmaceutical composition of claim 1, further comprising a binder. 9. The pharmaceutical composition of claim 8, wherein the binder is a combination of microcrystalline cellulose and silicified microcrystalline cellulose. 10. The pharmaceutical composition of claim 1, further comprising a lubricant. 11. The pharmaceutical composition of claim 10, wherein the lubricant comprises a combination of stearic acid, polyethylene glycol and talc. 12. The pharmaceutical composition of claim 1, further comprising a wetting agent. 13. The pharmaceutical composition of claim 12, wherein the wetting agent comprises poloxamer. 14. The pharmaceutical composition of claim 1, further comprising a nonfunctional coating. 15. The pharmaceutical composition of claim 14, wherein the nonfunctional coating comprises polyvinyl alcohol. 16. A pharmaceutical composition in tablet form for oral administration, wherein the composition comprises 150 mg of (R)-N-methylnaltrexone bromide and further comprises sodium lauryl sulfate; a chelating agent comprising calcium disodium EDTA; a disintegrant comprising a combination of crospovidone and crospovidone sodium carboxymethyl cellulose; a binder comprising a combination of microcrystalline cellulose and silicified microcrystalline cellulose; a lubricant comprising a combination of stearic acid, polyethylene glycol and talc; a wetting agent comprising poloxamer; and a nonfunctional coating comprising polyvinyl alcohol, wherein sodium lauryl sulfate is present in an amount of 5% to 80% based on the total weight of the composition, and wherein methylnaltrexone has an apparent octanol/water partition coefficient of at least 0.25 at pH 1-4 when the composition is dissolved in solution. 17. The pharmaceutical composition of claim 16, wherein the composition comprises: (a) 7% to 75% brominated (R)-N-methylnaltrexone based on the total weight of the composition; (b) 0.01% to 5% chelating agent based on the total weight of the composition; (c) 1% to 25% wetting agent based on the total weight of the composition; (d) 5% to 90% of the adhesive based on the total weight of the composition; (e) 1% to 25% disintegrant based on the total weight of the composition; and (f) 0.1% to 7% of lubricant based on the total weight of the composition. 18. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating opioid-induced constipation in a subject of need. 19. Use of the pharmaceutical composition of claim 16 in the preparation of a medicament for treating opioid-induced constipation in a subject of need. 20. The use according to claim 19, wherein the pharmaceutical composition is used as a plurality of tablets to achieve a dose of 450 mg once daily. 21. The pharmaceutical composition of claim 1 or 16, wherein the apparent octanol/water partition coefficient is at least 1. 22. The pharmaceutical composition of claim 1 or 16, wherein the apparent octanol/water partition coefficient is at least 10. 23. The pharmaceutical composition of claim 1 or 16, wherein the apparent octanol/water partition coefficient is at least 20. 24. The pharmaceutical composition of claim 1 or 16, wherein the apparent octanol/water partition coefficient is at least 30.