Liquid oral dosage form of methylnaltrexone

Abstract

Provided herein is a pharmaceutical composition comprising methylnaltrexone, lauryl sulfate or docusate, and at least one of an oil, a surfactant, or a co-solvent, wherein the methylnaltrexone and the lauryl sulfate or docusate are present as an ion pair. The pharmaceutical composition may further comprise a surfactant to provide a self-emulsifying methylnaltrexone delivery system.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of and relates to U.S. Provisional Application No. 62 / 844,613, filed May 7, 2019, and U.S. Provisional Application No. 63 / 010,528, filed April 15, 2020, the entire contents of each of which are hereby incorporated by reference in their entirety.

Background Art

[0002] Opioids are widely used to treat patients with pain. Opioids are narcotic drugs that activate opioid receptors located within the central nervous system to relieve pain. However, opioids also react with receptors outside the central nervous system, resulting in side effects including constipation, nausea, vomiting, urinary retention, and intense itching. Notably, the action of opioids in the gastrointestinal (GI) tract is significant. In the GI tract, these drugs inhibit gastric emptying and intestinal peristalsis, thereby reducing intestinal transit speed and causing constipation. The use of opioids in pain treatment is often limited by these unwanted side effects, which can be debilitating and often cause patients to refuse the use of opioid analgesics. Therefore, new therapies and formulations are desired in this field to address such unwanted side effects.

Prior Art Documents

Non - Patent Documents

[0003]

Non - Patent Document 1

Patent Documents

[0004]

Patent Document 1

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Patent Document 7

Patent Document 8

Summary of the Invention

Problems to be Solved by the Invention

[0005] Opioid receptor antagonists, such as naloxone, naltrexone, and nalmefene, have been studied as a means to antagonize the unwanted peripheral side effects of opioids. However, these agents act not only on peripheral opioid receptors but also on opioid receptors within the central nervous system, sometimes reversing the beneficial and desired analgesic effects of opioids or causing symptoms of opioid withdrawal. A preferred approach for use in controlling opioid-induced side effects involves administration of a peripherally acting opioid receptor antagonist that does not readily cross the blood-brain barrier.

[0006] The peripheral μ-opioid receptor antagonist, methylnaltrexone, has been studied since the late 1970s and is used in patients to reduce opioid-induced side effects such as constipation, pruritus, nausea, and urinary retention (see, e.g., U.S. Patent Nos. 5,972,954, 5,102,887, 4,861,781, and 4,719,215; and Yuan et al., Drug and Alcohol Dependence, vol. 52, p. 161, 1998). The dosage form of methylnaltrexone most frequently used in these studies was a methylnaltrexone solution for intravenous injection. See also U.S. Patent No. 6,559,158. A subcutaneous methylnaltrexone formulation marketed under the trade name RELISTOR® is approved for the treatment of opioid-induced constipation in adults with chronic non-cancer pain and in adults with advanced disease receiving palliative care. For example, in clinical studies, 59% of patients with chronic non-cancer pain who received a 12 mg subcutaneous injection of methylnaltrexone for the treatment of opioid-induced constipation had a natural bowel movement three or more times per week for four weeks. However, it is difficult to prepare an oral dosage form of methylnaltrexone. See, e.g., U.S. Patent Nos. 6,419,959, 6,274,591, 6,559,158.

[0007] Oral RELISTOR® tablets have been shown to be a safe and effective treatment for opioid-induced constipation, but there is a desire to reduce the dose of methylnaltrexone to 450 mg administered as three 150 mg tablets. Additionally, or alternatively, bowel movements after subcutaneous injection are correlated with a higher C max higher C max such that the development of an oral dosage form that provides greater systemic exposure is desired. At the same time, it is also desired to reduce T max to achieve a faster bowel movement response.

Means for Solving the Problems

[0008] Regarding certain aspects of the present invention described herein, (a) an ion pair having the formula: [Chemical formula] (wherein R - may be an anion), and (b) a pharmaceutical composition in a liquid oral dosage form comprising an oil, a surfactant, a co-solvent, or a combination thereof, are disclosed. In some embodiments, R - may be any anion that enables the formation of the ion pair. In some embodiments, R - may be an anion selected from the group consisting of lauryl sulfate and docetate.

[0009] In certain embodiments, the anion may be lauryl sulfate. Alternatively, the anion may be docetate.

[0010] In some embodiments, the pharmaceutical composition comprises an oil and a surfactant. In some embodiments, the pharmaceutical composition comprises an oil and at least two surfactants. In some embodiments, the pharmaceutical composition comprises a surfactant and a co-solvent. In some embodiments, the pharmaceutical composition comprises at least two surfactants. In some embodiments, the pharmaceutical composition does not contain an oil and comprises a surfactant. In some embodiments, the pharmaceutical composition does not contain an oil and contains at least two surfactants.

[0011] In certain embodiments, the pharmaceutical composition comprises from about 1% to about 75%, from about 10% to about 60%, from about 15% to about 50%, or from about 20% to about 40% by weight of the ion pair.

[0012] In another embodiment, the oil may be at least one of glyceryl monooleate, glyceryl monolaurate, dicaprolate / dicaprylate propylene glycol, soybean oil, polyglyceryl-3 dioleate, oleic acid, glyceryl caprylate, medium-chain triglycerides, and combinations thereof. In some embodiments, the oil may be glyceryl monolaurate. In some embodiments, the oil may be oleic acid. In other embodiments, the oil may be glyceryl caprylate. In still further embodiments, the oil comprises medium-chain triglycerides.

[0013] In further embodiments, the pharmaceutical composition comprises at least two, three, four, five, or more oils. In some embodiments, the pharmaceutical composition comprises at least two oils. For example, in some embodiments, the oils comprise glyceryl caprylate and medium-chain triglycerides. In alternative embodiments, the pharmaceutical composition comprises at least three oils, such as caprylic / capric / succinic triglyceride, glyceryl caprylate (monoglyceride and diglyceride), and oleic acid. In various embodiments, the total oil content of the pharmaceutical composition is from about 10 wt% to about 80 wt%, from about 10 wt% to about 20 wt%, from about 20 wt% to about 50 wt%, or from about 50 wt% to about 70 wt%. In some embodiments, the pharmaceutical composition has no oil.

[0014] In certain embodiments, the pharmaceutical compositions described herein further comprise a surfactant. Suitable surfactants for use in the pharmaceutical compositions described herein include, but are not limited to, oleoylpoxyl-6 glyceride, linoleoylpoxyl-6 glyceride, caprylocapryloylpoxyl-8 glyceride, polysorbate 80, polyoxyl 40 hydrogenated castor oil, polyoxyl 15 hydroxystearate, lauroylpoxyl-32 glyceride, and / or combinations thereof. In one embodiment, the surfactant comprises caprylocapryloylpoxyl-8 glyceride. In another embodiment, the surfactant comprises polysorbate 80. In yet another embodiment, the surfactant comprises linoleoylpoxyl-6 glyceride. In yet another embodiment, the surfactant comprises polyoxyl 40 hydrogenated castor oil. In yet another embodiment, the surfactant comprises polyoxyl 15 hydroxystearate. In yet another embodiment, the surfactant comprises lauroylpoxyl-32 glyceride.

[0015] In various embodiments, the pharmaceutical composition comprises from about 10 wt% to about 70 wt%, from about 15 wt% to about 40 wt%, or from about 20 wt% to about 35 wt% of the surfactant.

[0016] In some embodiments, the pharmaceutical composition comprises one or more co-surfactants. In an exemplary embodiment, the pharmaceutical composition comprises up to about 20% (w / w) of the co-surfactant. For example, the co-surfactant may include Capryol™ (propylene glycol caprylate) and / or Lauroglycol™ (propylene glycol monolaurate).

[0017] In certain embodiments, the pharmaceutical composition comprises from about 1 mg to about 100 mg, from about 50 mg to about 900 mg, from about 75 mg to about 850 mg, from about 100 mg to about 850 mg, from about 150 mg to about 850 mg, from about 200 mg to about 800 mg, or from about 200 mg to about 700 mg of an ion pair. In other embodiments, the pharmaceutical compositions of the present disclosure comprise from about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg or about 900 mg of an ion pair.

[0018] In further embodiments, the pharmaceutical composition comprises from about 1 mg to about 100 mg, from about 50 mg to about 800 mg, from about 100 mg to about 750 mg, from about 150 mg to about 750 mg, or from about 200 mg to about 700 mg of methylnaltrexone and lauryl sulfate. In alternative embodiments, the pharmaceutical composition comprises from about 1 mg to about 100 mg, from about 50 mg to about 900 mg, from about 100 mg to about 900 mg, from about 150 mg to about 850 mg, or from about 200 mg to about 800 mg of methylnaltrexone and docetate.

[0019] In further embodiments, the pharmaceutical composition comprises water, whereby the liquid composition is an emulsion. In another alternative embodiment, the pharmaceutical composition forms an emulsion upon contact with an aqueous liquid, such as gastric and / or intestinal fluids.

[0020] In some embodiments, the co-solvent may be one or more of triacetin, ethanol, glycerol, propylene glycol, and polyethylene glycol (e.g., PEG-400). In some embodiments, the co-solvent comprises ethanol.

[0021] In another aspect, (a) the formula:

Chemical formula

[0022] In a further aspect, the pharmaceutical composition in liquid oral dosage form includes (i) methylnaltrexone, (ii) lauryl sulfate or docusate, and (iii) one or more of an oil, a surfactant, and a co-solvent, and methylnaltrexone and lauryl sulfate or docusate are present in substantially equimolar amounts. As used herein, the term "substantially equimolar" means that the moles of lauryl sulfate or docusate are within 5%, 4%, 3%, 2%, 1%, 0.1%, or 0.01% of the moles of methylnaltrexone. In one embodiment, the pharmaceutical composition includes lauryl sulfate. In another embodiment, the pharmaceutical composition includes docusate.

[0023] In one embodiment, the pharmaceutical composition includes methylnaltrexone and lauryl sulfate in an amount of about 1 wt% to about 75 wt%, about 10 wt% to about 60 wt%, about 15 wt% to about 50 wt%, or about 20 wt% to about 40 wt% of the pharmaceutical composition. In another embodiment, the pharmaceutical composition includes methylnaltrexone and docusate in an amount of about 1 wt% to about 75 wt%, about 10 wt% to about 60 wt%, about 15 wt% to about 50 wt%, or about 20 wt% to about 40 wt% of the pharmaceutical composition.

[0024] In some embodiments, the oil comprises at least one of glyceryl monooleate, glyceryl monolaurate, propylene glycol dicaprylate / dicaprate, soybean oil, polyglyceryl-3 dioleate, oleic acid, glyceryl caprylate, medium-chain triglycerides, and combinations thereof. For example, in one embodiment, the oil comprises glyceryl monolaurate. In another exemplary embodiment, the oil comprises oleic acid. In a further embodiment, the oil comprises glyceryl caprylate. In a particular embodiment, the oil comprises medium-chain triglycerides. In certain embodiments, the oil comprises at least two oils, such as glyceryl caprylate and medium-chain triglycerides. In some embodiments, the total oil content of the pharmaceutical composition is about 10 wt% to about 80 wt%, about 10 wt% to about 20 wt%, about 20 wt% to about 50 wt%, or about 50 wt% to about 70 wt% of the composition.

[0025] In a further embodiment, the pharmaceutical composition comprises a surfactant. Suitable surfactants for use in the pharmaceutical compositions of the present disclosure include oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, caprylocapryloyl polyoxyl-8 glyceride, polysorbate 80, polyoxyl 40 hydrogenated castor oil, polyoxyl 15 hydroxystearate, lauroyl polyoxyl-32 glyceride, or combinations thereof. In an exemplary embodiment, the surfactant comprises caprylocapryloyl polyoxyl-8 glyceride. In another exemplary embodiment, the surfactant is polysorbate 80. In yet another exemplary embodiment, the surfactant is linoleoyl polyoxyl-6 glyceride. In some embodiments, the surfactant comprises polyoxyl 40 hydrogenated castor oil. In some embodiments, the surfactant comprises polyoxyl 15 hydroxystearate. In some embodiments, the surfactant comprises lauroyl polyoxyl-32 glyceride. In some embodiments, the pharmaceutical composition comprises about 10 wt% to about 70 wt%, about 15 wt% to about 40 wt%, or about 20 wt% to about 35 wt% of the surfactant of the composition.

[0026] The pharmaceutical composition may contain methylnaltrexone and lauryl sulfate in an amount of about 1 mg to about 100 mg, about 50 mg to about 800 mg, about 100 mg to about 750 mg, about 150 mg to about 750 mg, or about 200 mg to about 700 mg. For example, the pharmaceutical composition may contain methylnaltrexone and lauryl sulfate in an amount of about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg or about 700 mg.

[0027] Alternatively, the pharmaceutical composition may contain methylnaltrexone and docusate in an amount of about 1 mg to about 100 mg, about 50 mg to about 900 mg, about 100 mg to about 900 mg, about 150 mg to about 850 mg, or about 200 mg to about 800 mg. In an exemplary pharmaceutical composition, methylnaltrexone and docusate are present in the pharmaceutical composition in an amount of about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg or about 900 mg.

[0028] In certain embodiments, the pharmaceutical composition also contains water and the liquid composition is an emulsion. In other embodiments, the composition forms an emulsion upon contact with an aqueous liquid.

[0029] In another aspect, the present invention provides a formula:

Chemical formula

[0030] In some embodiments, the pharmaceutical composition of any of the foregoing aspects of the invention is formulated as a capsule, such as a soft gel capsule, a hard gel capsule, or an enteric capsule.

[0031] In another aspect, provided is a method of treating opioid-induced constipation in a subject in need thereof, the method comprising orally administering the pharmaceutical composition described herein. In certain embodiments, oral administration of the pharmaceutical composition to the subject results in a C in the range of about 50 ng / mL to about 200 ng / mL max and in certain embodiments, oral administration of the pharmaceutical composition to the subject is a T of less than about 4 hours, less than about 2 hours, less than about 1 hour, less than about 30 minutes, less than about 15 minutes, or less than about 10 minutes max and results in.

Brief Description of the Drawings

[0032]

Figure 1

Figure 2

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Figure 6

Mode for Carrying Out the Invention

[0033] The invention described herein is at least partially based on the discovery of an oral formulation of methylnaltrexone having improved pharmacokinetic properties and response time compared to previous oral formulations. Specifically, the formulations disclosed herein provide enhanced absorption rate, enhanced C max and / or reduced T max , thereby providing an improved profile for treating peripheral side effects of opioids, such as constipation.

[0034] Specifically, provided herein is a pharmaceutical composition in a liquid oral dosage form comprising (a) an ion pair having the formula:

Chemical formula

[0035] In certain embodiments, the pharmaceutical composition of the present invention is formulated and administered as a capsule, such as a soft gel capsule, a hard gel capsule, and an enteric gel capsule. In certain embodiments, the pharmaceutical composition is formulated as a soft gel capsule.

[0036] However, the composition may alternatively be formulated as a tablet. In some embodiments, the solid granules can be produced by melt granulation. In other embodiments, the wax-like powder can be produced by solvent evaporation. In further embodiments, the solid granules and / or powder can be produced by spray drying. Such granules and powders can be compressed into tablets according to the subject matter of the present invention. In some embodiments, the lipid is adsorbed onto a solid carrier such as silicon dioxide, calcium silicate, and / or magnesium aluminometasilicate and compressed to form a tablet.

[0037] 1. Composition 1.1. Methylnaltrexone ion pair As used herein, methylnaltrexone refers to (R)-N-methylnaltrexone. (R)-N-methylnaltrexone, a peripherally acting μ-opioid receptor antagonist, has been studied and used for treating bowel dysfunction in patients receiving opioids.

[0038] Methylnaltrexone is a quaternary amine and thus has a positive charge. This charge results in a slower absorption rate across membranes (compared to neutral molecules). Existing RELISTOR® tablets, such as those described in U.S. Patent No. 9,314,461, enhance absorption by combining methylnaltrexone bromide with sodium lauryl sulfate and relying on the in situ formation of an ion pair of neutral methylnaltrexone and lauryl sulfate. However, the invention described herein is premised, at least in part, on the discovery that the formulation and administration of a pre-existing ion pair of methylnaltrexone with either docetate or lauryl sulfate can function to enhance the absorption rate. Since methylnaltrexone has been reported to have high first-pass metabolism, the increased absorption rate functions to saturate the metabolic pathway and thus further enhance the amount of methylnaltrexone absorbed by the body.

[0039] Accordingly, the pharmaceutical compositions of the invention described herein include an ion pair of methylnaltrexone with either lauryl sulfate or docetate, resulting in improved pharmacokinetic properties. In certain embodiments, the pharmaceutical composition includes an ion pair of methylnaltrexone and lauryl sulfate. In alternative embodiments, the pharmaceutical composition includes an ion pair of methylnaltrexone and docetate.

[0040] An ion pair is generally a salt that includes a hydrophilic active agent (cation or anion) and a more lipophilic pharmaceutically acceptable counterion. See, e.g., Krisztina Tkacs-Novak & Gyorgy Szaz, Ion-Pair Partition of Quaternary Ammonium Drugs: The Influence of Counter Ions of Different Lipophilicity, Size, and Flexibility, 16(10) Pharmaceutical Research 1633-38 (1999). Ion pairs have a partition coefficient, e.g.,

Number

[0041] In some embodiments, the pharmaceutical composition comprises from about 1 wt% to about 75 wt%, from about 10 wt% to about 60 wt%, from about 15 wt% to about 50 wt%, or from about 20 wt% to about 40 wt% of the ion pair. In some embodiments, the pharmaceutical composition comprises at least 1 wt%, or at least 2 wt%, or at least 3 wt%, or at least 4 wt%, or at least 5 wt%, or at least 6 wt%, or at least 7 wt%, or at least 8 wt%, or at least 9 wt%, or at least 10 wt%, or at least 11 wt%, or at least 12 wt%, or at least 13 wt%, or at least 14 wt%, or at least 15 wt%, or at least 16 wt%, or at least 17 wt%, or at least 18 wt%, or at least 19 wt%, or at least 20 wt%, or at least 21 wt%, or at least 22 wt%, or at least 23 wt%, or at least 24 wt%, or at least 25 wt%, or at least 26 wt%, or at least 27 wt%, or at least 28 wt%, or at least 29 wt%, or at least 30 wt%, or at least 31 wt%, or at least 32 wt%, or at least 33 wt%, or at least 34 wt%, or at least 35 wt%, or at least 36 wt%, or at least 37 wt%, or at least 38 wt%, or at least 39 wt%, or at least 40 wt%, or at least 41 wt%, or at least 42 wt%, or at least 43 wt%, or at least 44 wt%, or at least 45 wt%, or at least 46 wt%, or at least 47 wt%, or at least 48 wt%, or at least 49 wt%, or at least 50 wt%, or at least 51 wt%, or at least 52 wt%, or at least 53 wt%, or at least 54 wt%, or at least 55 wt%, or at least 56 wt%, or at least 57 wt%, or at least 58 wt%, or at least 59 wt%, or at least 60 wt% of the ion pair.In some embodiments, the pharmaceutical composition comprises up to 1 wt%, or up to 2 wt%, or up to 3 wt%, or up to 4 wt%, or up to 5 wt%, or up to 6 wt%, or up to 7 wt%, or up to 8 wt%, or up to 9 wt%, or up to 10 wt%, or up to 11 wt%, or up to 12 wt%, or up to 13 wt%, or up to 14 wt%, or up to 15 wt%, or up to 16 wt%, or up to 17 wt%, or up to 18 wt%, or up to 19 wt%, or up to 20 wt%, or up to 21 wt%, or up to 22 wt%, or up to 23 wt%, or up to 24 wt%, or up to 25 wt%, or up to 26 wt%, or up to 27 wt%, or up to 28 wt%, or up to 29 wt%, or up to 30 wt%, or up to 31 wt%, or up to 32 wt%, or up to 33 wt%, or up to 34 wt%, or up to 35 wt%, or up to 36 wt%, or up to 37 wt%, or up to 38 wt%, or up to 39 wt%, or up to 40 wt%, or up to 41 wt%, or up to 42 wt%, or up to 43 wt%, or up to 44 wt%, or up to 45 wt%, or up to 46 wt%, or up to 47 wt%, or up to 48 wt%, or up to 49 wt%, or up to 50 wt%, or up to 51 wt%, or up to 52 wt%, or up to 53 wt%, or up to 54 wt%, or up to 55 wt%, or up to 56 wt%, or up to 57 wt%, or up to 58 wt%, or up to 59 wt%, or up to 60 wt% of an ion pair.In some embodiments, the pharmaceutical composition comprises about 1 wt%, or about 2 wt%, or about 3 wt%, or about 4 wt%, or about 5 wt%, or about 6 wt%, or about 7 wt%, or about 8 wt%, or about 9 wt%, or about 10 wt%, or about 11 wt%, or about 12 wt%, or about 13 wt%, or about 14 wt%, or about 15 wt%, or about 16 wt%, or about 17 wt%, or about 18 wt%, or about 19 wt%, or about 20 wt%, or about 21 wt%, or about 22 wt%, or about 23 wt%, or about 24 wt%, or about 25 wt%, or about 26 wt%, or about 27 wt%, or about 28 wt%, or about 29 wt%, or about 30 wt%, or about 31 wt%, or about 32 wt%, or about 33 wt%, or about 34 wt%, or about 35 wt%, or about 36 wt%, or about 37 wt%, or about 38 wt%, or about 39 wt%, or about 40 wt%, or about 41 wt%, or about 42 wt%, or about 43 wt%, or about 44 wt%, or about 45 wt%, or about 46 wt%, or about 47 wt%, or about 48 wt%, or about 49 wt%, or about 50 wt%, or about 51 wt%, or about 52 wt%, or about 53 wt%, or about 54 wt%, or about 55 wt%, or about 56 wt%, or about 57 wt%, or about 58 wt%, or about 59 wt%, or about 60 wt% of an ion pair.

[0042] In certain embodiments, when the pharmaceutical composition comprises an ion pair of methylnaltrexone and lauryl sulfate, the ion pair is present in the composition at about 1 wt% to about 50 wt%, about 5 wt% to about 45 wt%, about 10 wt% to about 40 wt%, about 10 wt% to about 35 wt%, about 10 wt% to about 30 wt%, or about 15 wt% to about 25 wt%. For example, the ion pair of methylnaltrexone and lauryl sulfate may be present in an amount of at least about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt% or 30 wt% of the composition. In some embodiments, the ion pair of methylnaltrexone and lauryl sulfate may be present in the composition at a maximum of about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt% or 30 wt%. In some embodiments, the ion pair of methylnaltrexone and lauryl sulfate may be present in the composition at about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt% or 30 wt%.

[0043] In certain embodiments, when the pharmaceutical composition comprises an ion pair of methylnaltrexone and docetate, the ion pair is present in the composition in an amount of about 1 wt% to about 50 wt%, about 10 wt% to about 50 wt%, about 15 wt% to about 45 wt%, about 20 wt% to about 40 wt%, about 15 wt% to about 30 wt%, or about 30 wt% to about 45 wt%. For example, the ion pair of methylnaltrexone and docetate may be present in an amount of at least about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt% or 45 wt% of the composition. In some embodiments, the ion pair of methylnaltrexone and docetate is present in the composition in an amount of at most about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt% or 45 wt% of the composition. In some embodiments, the ion pair of methylnaltrexone and docetate is present in the composition in an amount of about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt% or 45 wt% of the composition.

[0044] In some embodiments, the pharmaceutical composition comprises from about 1 mg to about 100 mg, from about 50 mg to about 900 mg, from about 75 mg to about 850 mg, from about 100 mg to about 850 mg, from about 150 mg to about 850 mg, from about 200 mg to about 800 mg, or from about 200 mg to about 700 mg of an ion pair. In some embodiments, the pharmaceutical composition comprises about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg or about 900 mg of an ion pair. In some embodiments, the pharmaceutical composition comprises at least about 1 mg, 10 mg, 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, 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, or 900 mg of an ion pair. In some embodiments, the pharmaceutical composition comprises at most about 1 mg, 10 mg, 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, 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, or 900 mg of an ion pair.

[0045] 1.2. Lipid-based drug delivery systems The pharmaceutical compositions disclosed herein are lipid-based drug delivery systems. Lipid-based drug delivery systems stimulate bile flow and pancreatic secretion; prolong gastric emptying; increase membrane fluidity; open tight junctions and facilitate drug penetration across the intestinal epithelium; stimulate chylomicron secretion; inhibit efflux transporters; and enhance oral drug absorption by enhancing drug uptake via the lymphatic pathway, thus bypassing initial metabolism by the liver, by utilizing oils and / or surfactants. Medium-chain lipids (C <12 ) diffuse directly into blood vessels through intestinal cells. Unsaturated long-chain lipids (C 18:1 , C 18:2 ) are absorbed via the lymphatic pathway. See, for example, Sandeep Kalepu et al., Oral lipid-based drug delivery systems - an overview, Volume 3 (Issue 6) Acta Pharmaceutica Sinica B, pages 361-72 (2013).

[0046] As used herein, the term "oil" refers to a pharmaceutically acceptable lipid having an unsaturated fatty acid chain that is liquid at room temperature. Oils include monoglycerides, diglycerides, and triglycerides as well as fatty acids. Long-chain, medium-chain, and short-chain glycerides are suitable for use in the pharmaceutical compositions disclosed herein.

[0047] As used herein, the term "surfactant" refers to any amphiphilic compound (molecule or ion) that contains a hydrophilic moiety and a lipophilic moiety. Surfactants often operate by accumulating at the oil-water interface such that the hydrophilic moiety is oriented towards the aqueous phase and the lipophilic moiety is oriented towards the hydrophobic phase, thus reducing surface tension. Suitable surfactants include water-insoluble surfactants, water-dispersible surfactants, and water-soluble surfactants. It should be appreciated that the surfactants utilized in the disclosed pharmaceutical compositions are present at pharmaceutically acceptable concentrations. However, as used herein, the term "surfactant" or "co-surfactant" does not include sodium alkyl sulfates, such as sodium lauryl sulfate.

[0048] Surfactants and oils can be further characterized by their hydrophilic-lipophilic balance ("HLB") values, which are a balance of the size and strength of the hydrophilic and lipophilic portions of the molecule. See, for example, A. Rabaron et al., Physical methods for measurement of the HLB of ether and ester non-ionic surface active agents: H-NMR and dielectric constant, 99, Int. J. Pharm. 29-36 (1993). The HLB scale ranges from 0 to 20, with higher HLB values corresponding to more water-soluble molecules and lower HLB values corresponding to more lipid-soluble molecules.

[0049] Oils have an HLB value of about 1. Thus, in certain embodiments, it should be appreciated that the oil contained in the disclosed pharmaceutical composition has an HLB value of about 1.

[0050] In certain embodiments, the surfactant is an oil-soluble surfactant having an HLB value of about 2 to about 4. In certain embodiments, the surfactant is a water-dispersible surfactant having an HLB value between about 9 and about 12. In certain embodiments, the surfactant is a water-soluble surfactant having an HLB value of about 12 to about 20. The HLB value of the lipid-based excipient determines what type of lipid-based formulation is formed, i.e., an oil solubilizer, emulsion, microemulsion, or micelle, as summarized in Table 1 below. Thus, in various embodiments, the pharmaceutical compositions of the present invention can be characterized as oil solubilizers, emulsions, microemulsions or micelles, based on the composition. Surfactants suitable for use in the disclosed pharmaceutical compositions can be selected based on the HLB value to prepare the desired lipid-based drug delivery system.

[0051] [Table 1]

[0052] Lipid formulations can be further classified into four main types based on their composition and the type of dispersion formed. In one embodiment, the pharmaceutical composition is a type I formulation, which does not form a dispersion, forms an emulsion, and contains an oil excipient that requires digestion to be absorbed.

[0053] Alternatively, the pharmaceutical composition is a type II, IIIA, or IIIB formulation, each of which is a mixture of an oil and a surfactant that forms an emulsion with an aqueous liquid. For example, the pharmaceutical composition may be a type II formulation, which contains an oil and a water-insoluble surfactant that forms an emulsion containing a self-emulsifying drug delivery system (SEDDS). A self-emulsifying drug delivery system forms an emulsion upon contact with an aqueous liquid without mechanical agitation or heating. Exemplary SEDDS for use in the invention described herein include self-emulsifying microemulsion (SMEDDS) or self-emulsifying nanoemulsion (SNEDDS) drug delivery systems, which can be distinguished based on droplet diameter. Alternatively, the pharmaceutical composition may be a type IIIA or IIIB formulation, which contains an oil, a water-insoluble and / or water-soluble surfactant, and optionally a co-solvent. Exemplary co-solvents include triacetin, ethanol, glycerol, propylene glycol, and polyethylene glycol, such as (PEG)-400.

[0054] Finally, the pharmaceutical composition may be a type IV formulation, which contains a water-soluble surfactant and optionally a non-oily co-solvent that forms a micellar dispersion. The types of lipid-based formulations and their compositions are summarized in Table 2, and exemplary excipients, their HLB values, and uses are summarized in Table 3 below.

[0055]

Table 2

[0056]

Table 3

[0057] 1.2.1. Oil Oils suitable for use in the pharmaceutical compositions of the invention described herein include lipids and fatty acids derived from plant sources via esterification of fatty acids with alcohols such as glycerol, polyglycerol, propylene glycol, and polyethylene glycol, and via alcoholysis of vegetable oils and fats with glycerol, polyethylene glycol, and propylene glycol.

[0058] In some embodiments, oils suitable for inclusion in the pharmaceutical compositions of the invention include, but are not limited to, glyceryl monooleate, glyceryl monolaurate, propylene glycol dicaprylate / dicaprate, soybean oil, polyglyceryl-3 dioleate, oleic acid, glyceryl caprylate, medium-chain triglycerides, and combinations thereof.

[0059] In certain embodiments, the pharmaceutical composition includes glyceryl monooleate, such as Peceol™ available from Gattefosse, which contains monoglycerides, diglycerides, and triglycerides of oleic acid (C 18:1 ) and has a major monoester fraction. Glyceryl monooleate is used as a solubilizer for lipophilic active pharmaceutical ingredients (APIs). Glyceryl monooleate is also used in SEDDS and SMEDDS as described herein.

[0060] Alternatively or in combination, the pharmaceutical compositions of the invention can include glyceryl monolaurate. Glyceryl monolaurate, such as Maisine® CC available from Gattefosse, is a deodorized oil composed of long-chain monoglycerides, diglycerides, and triglycerides, mainly of lauric acid (C 18:2 ) and oleic acid (C 18:1) It is. Glyceryl monolaurate is used in lipid-based formulations to solubilize APIs with insufficient water solubility and lipophilicity, and is also used in self-emulsifying lipid formulations (SEDDS and SMEDDS). In some embodiments, the pharmaceutical composition comprises glyceryl monolaurate in an amount of about 3% to about 30% by weight, about 5% to about 25% by weight, or about 10% to about 20% by weight of the composition. In some embodiments, the pharmaceutical composition comprises glyceryl monolaurate in an amount of at least about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight of the composition. In some embodiments, the pharmaceutical composition comprises glyceryl monolaurate in an amount of at most about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight of the composition. In some embodiments, the pharmaceutical composition comprises glyceryl monolaurate in an amount of about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight of the composition.

[0061] Alternatively, or in combination, the pharmaceutical composition of the present invention comprises propylene glycol. Propylene glycol dicaprylate / dicaprate, such as Labrafac™ PG available from Gattefosse, is caprylic acid (C 8 ) and capric acid (C 10) includes propylene glycol esters of. Dicaprylyl / dicaprin propylene glycol is also used in lipid-based formulations, SEDDS, and SMEDDS.

[0062] The pharmaceutical compositions of the invention described herein may further comprise medium-chain triglycerides. Medium-chain triglycerides, such as MIGLYOL® 812 available from IOI Oleo GmbH and Labrafac™ Lipophile WL 1349 available from Gattefosse, are caprylic acid (C 8 ) and capric acid (C 10It consists of medium-chain triglycerides. Medium-chain triglycerides are also used in lipid-based formulations, SEDDS, and SMEDDS. In some embodiments, the pharmaceutical composition comprises medium-chain triglycerides in an amount of about 3 wt% to about 30 wt%, about 5 wt% to about 20 wt%, or about 10 wt% to about 15 wt% of the composition. In some embodiments, the pharmaceutical composition comprises medium-chain triglycerides in an amount of at least about 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, or 30 wt% of the composition. In some embodiments, the pharmaceutical composition comprises medium-chain triglycerides in an amount of at most about 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, or 30 wt% of the composition. In some embodiments, the pharmaceutical composition comprises medium-chain triglycerides in an amount of about 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, or 30 wt% of the composition.

[0063] In a further embodiment, the oil comprises caprylic / capric triglyceride. Caprylic / capric triglyceride, such as MIGLYOL® 810 and MIGLYOL® 812 available from CREMER OLEO GmbH&Co.KG, are esters of caprylic and capric fatty acids with glycerin derived from saturated coconut oil and palm kernel oil.

[0064] In some embodiments, the oil comprises a soybean oil-based excipient. A soybean oil-based excipient, such as Geloil™ SC available from Gattefosse, comprises a mixture of soybean oil, glyceryl distearate (C 18 ) and polyglyceryl-3 dioleate (C 18:1 ). Geloil™ SC functions as a vehicle for suspending pharmaceutical ingredients in soft gelatin capsules and has good dispersibility in aqueous fluids.

[0065] In some embodiments, the oil comprises polyglyceryl-3 dioleate. Polyglyceryl-3 dioleate, such as Plurol® Oleique CC 497, comprises polyglyceryl-3-esters of oleic acid (C 18:1 ) and has a major diester fraction. Polyglyceryl-3 dioleate also functions as a co-surfactant in SEDDS and SMEDDS formulations.

[0066] In some embodiments, the oil comprises oleic acid. Oleic acid is a monounsaturated omega-9 fatty acid (C 18:1) It is. In some embodiments, the pharmaceutical composition comprises oleic acid in an amount of about 10 wt% to about 40 wt%, about 15 wt% to about 35 wt%, or about 20 wt% to about 30 wt% of the composition. In some embodiments, the pharmaceutical composition comprises oleic acid in an amount of at least about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, or 40 wt% of the composition. In some embodiments, the pharmaceutical composition comprises oleic acid in an amount of at most about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, or 40 wt% of the composition. In some embodiments, the pharmaceutical composition comprises oleic acid in an amount of about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, or 40 wt% of the composition.

[0067] In some embodiments, the oil comprises glyceryl monocaprylate and diglycerides. Glyceryl monocaprylate and diglycerides, such as IMWITOR® 988 and / or IMWITOR® 742 available from CREMER, are capric acid (C 8 H 16 O 2It includes a blend of glycerol esters of . In some embodiments, the pharmaceutical composition comprises glyceryl monocaprylate and diglyceride in an amount of about 10 wt% to about 40 wt%, about 20 wt% to about 35 wt%, or about 20 wt% to about 30 wt%, or about 30 wt% to about 35 wt% of the composition. In alternative embodiments, the pharmaceutical composition comprises glyceryl monocaprylate and diglyceride in an amount of about 15 wt% to about 45 wt%, about 25 wt% to about 40 wt%, or about 30 wt% to about 35 wt% of the composition. In some embodiments, the pharmaceutical composition comprises glyceryl monocaprylate and diglyceride in an amount of at least about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, or 45 wt% of the composition. In some embodiments, the pharmaceutical composition comprises glyceryl monocaprylate and diglyceride in an amount of at most about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, or 45 wt% of the composition.In some embodiments, the pharmaceutical composition comprises glyceryl monocaprylate and diglyceride in an amount of about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, or 45 wt% of the composition.

[0068] In some embodiments, the total oil content of the pharmaceutical composition is about 10 wt% to about 80 wt%, about 15 wt% to about 70 wt%, about 20 wt% to about 60 wt%, or about 30 wt% to about 50 wt% of the composition. In some embodiments, the total oil content of the pharmaceutical composition is at least about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition.In some embodiments, the total oil content of the pharmaceutical composition is at most about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition. In some embodiments, the total oil content of the pharmaceutical composition is about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition.

[0069] In some embodiments, the pharmaceutical composition comprises one oil. In some embodiments, the pharmaceutical composition comprises two, three, four, five, or more oils. In an exemplary embodiment, the pharmaceutical composition comprises two oils, such as medium-chain triglycerides and glyceryl monocaprylate and diglycerides. In another exemplary embodiment, the pharmaceutical composition comprises three oils, such as medium-chain triglycerides, glyceryl monocaprylate and diglycerides, and oleic acid. In some embodiments, the pharmaceutical composition does not contain the oils described herein.

[0070] 1.2.2. Surfactant Surfactants can be added to the pharmaceutical compositions disclosed herein, for example, to prepare self-emulsifying, self-microemulsifying drug delivery systems, and self-nanoemulsifying drug delivery systems.

[0071] Suitable surfactants for use in the pharmaceutical compositions of the invention described herein include oleoylpoxyl-6 glyceride, linoleoylpoxyl-6 glyceride, caprylocaprylylpoxyl-8 glyceride, polysorbate 80, polyoxyl 40 hydrogenated castor oil, polyoxyl 15 hydroxystearate, lauroylpoxyl-32 glyceride, and combinations thereof.

[0072] In certain embodiments, the pharmaceutical composition of the invention comprises oleoylpoxyl-6 glyceride. Oleoylpoxyl-6 glyceride, such as Labrafil® M 1944 CS available from Gattefosse, is a mixture of monoglycerides, diglycerides, and triglycerides and oleic acid (C 18:1) contains PEG-6 (MW300) monoesters and diesters of oleoyl polyoxyl-6 glycerides. Oleoyl polyoxyl-6 glycerides are used to solubilize APIs with insufficient solubility. Oleoyl polyoxyl-6 glycerides are also used in single excipient formulation systems to prepare SEDDS and can form SMEDDS when combined with high HLB surfactants such as Labrasol® ALF or Gelucire® 44 / 14.

[0073] In some embodiments, the surfactant comprises linoleoyl polyoxyl-6 glyceride. Linoleoyl polyoxyl-6 glyceride, such as Labrafil® M 2125CS available from Gattefosse, contains monoglycerides, diglycerides, and triglycerides and PEG-6 (MW300) monoesters and diesters of linoleic acid (C 18:2 ) contains PEG-6 (MW300) monoesters and diesters of linoleoyl polyoxyl-6 glycerides. Linoleoyl polyoxyl-6 glyceride solubilizes APIs with insufficient water solubility in lipid-based formulations. Linoleoyl polyoxyl-6 glyceride also self-emulsifies in an aqueous medium to form a coarse dispersion, i.e., SEDDS, and forms SMEDDS in pharmaceutical compositions that also contain surfactants such as Labrasol® ALF or Gelucire® 44 / 14.

[0074] In some embodiments, the surfactant comprises caprylocapryloyl polyoxyl-8 glyceride. Caprylocapryloyl polyoxyl-8 glyceride, such as Labrasol® ALF available from Gattefosse, contains a small fraction of monoglycerides, diglycerides and triglycerides, and mainly caprylic acid (C 8 ) and capric acid (C 10) includes PEG-8 (MW400) monoesters and diesters. Caprylocaprylyl polyoxyl-8 glyceride is a solubilizer for APIs with insufficient solubility. Caprylocaprylyl polyoxyl-8 glyceride is also used in single excipient formulation systems that self-emulsify into microemulsions (SMEDDS) in aqueous fluids. In some embodiments, the pharmaceutical composition comprises caprylocaprylyl polyoxyl-8 glyceride in an amount of about 50% to about 80% by weight, about 55% to about 70% by weight, or about 60% to about 65% by weight of the composition. In some embodiments, the pharmaceutical composition comprises caprylocaprylyl polyoxyl-8 glyceride in an amount of at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% by weight of the composition. In some embodiments, the pharmaceutical composition comprises caprylocaprylyl polyoxyl-8 glyceride in an amount of at most about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% by weight of the composition. In some embodiments, the pharmaceutical composition comprises caprylocaprylyl polyoxyl-8 glyceride in an amount of about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% by weight of the composition.

[0075] In some embodiments, the surfactant comprises propylene glycol monolaurate. Propylene glycol monolaurate, such as Lauroglycol (trademark) 90, contains propylene monoesters and diesters of lauric acid (C 12 ) and is a monoester having mainly a small fraction of diesters. Propylene glycol monolaurate is used as a co-surfactant in SEDDS and SMEDDS.

[0076] In some embodiments, the surfactant comprises propylene glycol monocaprylate. Propylene glycol monocaprylate, such as Capryol (trademark) 90 available from Gattefosse, contains propylene glycol esters of caprylic acid (C 8 ) and is mainly monoesters and a small fraction of diesters. Propylene glycol monocaprylate is a nonionic water-insoluble surfactant used as a co-surfactant in SEDDS and SMEDDS.

[0077] It should be recognized that the pharmaceutical compositions of some embodiments include one or more co-surfactants. For example, the pharmaceutical compositions of some embodiments include up to 20% (w / w) co-surfactants (such as Capryol (trademark) (propylene glycol monocaprylate) and / or Lauroglycol (trademark) (propylene glycol monolaurate)).

[0078] Suitable surfactants also include polysorbate 80 (e.g., TWEEN (registered trademark) 80, manufactured by Croda International Plc), polyoxyethylene sorbitan trioleate (e.g., TWEEN (registered trademark) 85, manufactured by Croda International Plc), PEG-35 castor oil, polyoxyl 40 hydrogenated castor oil (e.g., KOLLIPHOR (registered trademark) RH 40), polyoxyl 15 hydroxystearate (e.g., KOLLIPHOR (registered trademark) HS 15), lauroyl polyoxyl-32 glyceride (e.g., GELUCIRE (registered trademark) 44 / 14), and / or vitamin E TPGS.

[0079] In some embodiments, the surfactant comprises TWEEN® 80 in an amount of about 15 wt% to about 50 wt%, about 20 wt% to about 40 wt%, or about 30 wt% to about 35 wt% of the composition. In some embodiments, the composition comprises TWEEN® 80 in an amount of at least about 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, or 50 wt% of the composition. In some embodiments, the composition comprises TWEEN® 80 in an amount of at most about 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, or 50 wt% of the composition. In some embodiments, the composition comprises TWEEN® 80 in an amount of about 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, or 50 wt% of the composition.

[0080] In some embodiments, the surfactant includes polyoxyl 40 hydrogenated castor oil, such as KOLLIPHOR® RH40. In some embodiments, the polyoxyl 40 hydrogenated castor oil is KOLLIPHOR® RH 40. KOLLIPHOR® RH 40 is an easily digestible surfactant. In some embodiments, the pharmaceutical composition includes polyoxyl 40 hydrogenated castor oil in an amount of about 10 wt% to about 80 wt%, about 20 wt% to about 70 wt%, or about 25 wt% to about 65 wt% of the composition. In alternative embodiments, the pharmaceutical composition includes polyoxyl 40 hydrogenated castor oil in an amount of about 15 wt% to about 45 wt%, about 25 wt% to about 40 wt%, or about 30 wt% to about 40 wt% of the composition. In some embodiments, the pharmaceutical composition includes polyoxyl 40 hydrogenated castor oil in an amount of at least about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition.In some embodiments, the pharmaceutical composition comprises polyoxyl 40 hydrogenated castor oil in an amount of up to about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition. In some embodiments, the pharmaceutical composition comprises polyoxyl 40 hydrogenated castor oil in an amount of about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition.

[0081] In some embodiments, the surfactant comprises from about 15 wt% to about 50 wt%, from about 20 wt% to about 40 wt%, from about 30 wt% to about 35 wt% of polyoxyl 15 hydroxystearate in the composition. In some embodiments, polyoxyl 15 hydroxystearate is KOLLIPHOR® HS 15. KOLLIPHOR® HS 15 is a non-digestible surfactant. In some embodiments, the composition comprises polyoxyl 15 hydroxystearate (e.g., KOLLIPHOR® HS15) in an amount of at least about 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, or 50 wt% of the composition. In some embodiments, the composition comprises polyoxyl 15 hydroxystearate (e.g., KOLLIPHOR® HS15) in an amount of at most about 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, or 50 wt% of the composition.In some embodiments, the composition comprises polyoxyl 15 hydroxystearate (e.g., KOLLIPHOR® HS15) in an amount of about 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, or 50 wt% of the composition.

[0082] In some embodiments, the surfactant comprises lauroyl polyoxyl-32 glyceride, such as GELUCIRE® 44 / 14. In some embodiments, the lauroyl polyoxyl-32 glyceride is GELUCIRE® 44 / 14. In some embodiments, the pharmaceutical composition comprises lauroyl polyoxyl-32 glyceride in an amount of about 10 wt% to about 80 wt%, about 20 wt% to about 70 wt%, or about 25 wt% to about 65 wt% of the composition. In alternative embodiments, the pharmaceutical composition comprises lauroyl polyoxyl-32 glyceride in an amount of about 15 wt% to about 45 wt%, about 25 wt% to about 40 wt%, or about 30 wt% to about 40 wt% of the composition. In some embodiments, the pharmaceutical composition comprises lauroyl polyoxyl-32 glyceride in an amount of at least about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition.In some embodiments, the pharmaceutical composition comprises lauroyl polyoxyl-32 glyceride in an amount of up to about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition. In some embodiments, the pharmaceutical composition comprises lauroyl polyoxyl-32 glyceride in an amount of about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition.

[0083] In some embodiments, the pharmaceutical composition comprises vitamin E TPGS, which can act as both a surfactant and a stabilizer. When used as a surfactant, vitamin E TPGS may be provided in an amount of about 10 wt% to about 80 wt% or about 20 wt% to about 70 wt% of the composition. In some embodiments, the pharmaceutical composition comprises vitamin E TPGS in an amount of at least about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition.In some embodiments, the pharmaceutical composition comprises vitamin E TPGS in an amount of up to about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition. In some embodiments, the pharmaceutical composition comprises vitamin E TPGS in an amount of about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt% of the composition.

[0084] 1.3. Additives In some embodiments, the compositions described herein may include an additive. In some embodiments, the additive may be a stabilizer such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, ascorbyl-6-palmitate, alpha tocopherol, vitamin E TPGS (when provided as a stabilizer rather than a surfactant), or combinations thereof. In some embodiments, the stabilizer (e.g., BHT) may be provided in an amount of about 0.01 wt% to about 10 wt% of the composition. In some embodiments, the stabilizer (e.g., BHT) may be provided in an amount of at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wt% of the composition. In some embodiments, the stabilizer (e.g., BHT) may be provided in an amount of up to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wt% of the composition. In some embodiments, the stabilizer (e.g., BHT) may be provided in an amount of about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wt% of the composition.

[0085] For example, butylated hydroxyanisole (BHA) may be provided in an amount up to about 0.05 wt% of the composition. Propyl gallate may be provided in an amount up to about 0.1 wt% of the composition. Ascorbyl-6-palmitate may be provided in an amount up to about 3 wt% of the composition. Alpha tocopherol may be provided in an amount up to about 4 wt% of the composition.

[0086] 1.4. Co-solvent As described herein, in some embodiments, the pharmaceutical composition may include a co-solvent. In some embodiments, the co-solvent may be triacetin, ethanol, glycerol, propylene glycol, polyethylene glycol (e.g., PEG-400), or a combination thereof. In some embodiments, the co-solvent includes ethanol. In some embodiments, the co-solvent (e.g., ethanol) may be provided in an amount of about 1 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, or about 5 wt% to about 15 wt% of the composition. In some embodiments, the co-solvent (e.g., ethanol) may be provided in an amount of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 wt% of the composition. In some embodiments, the co-solvent (e.g., ethanol) may be provided in an amount of at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 wt% of the composition. In some embodiments, the co-solvent (e.g., ethanol) may be provided in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 wt% of the composition.

[0087] 1.5. Enteral Delivery In some embodiments, the pharmaceutical compositions disclosed herein are formulated for enteral delivery. Enteral drug delivery vehicles, such as coatings, capsules, and other encapsulation techniques, are used to protect acid-sensitive APIs from the low pH environment of the stomach, protect the stomach from irritating APIs, and facilitate colon drug delivery.

[0088] The delayed release of drugs from enteral formulations results from the insolubility of enteral polymers at low pH values. Enteral polymers dissolve at pH values of about 5.0 - 5.5 and higher. Enteral formulations may also be affected by factors such as the nature of the API (e.g., whether the API is ionic), the thickness of the coating / capsule shell, the presence of imperfections (e.g., cracks, holes, etc.), the properties of the polymer(s) used (e.g., dissolution rate at the relevant pH), and the agitation rate.

[0089] As enteric polymers for use in the invention described herein, polyacids such as cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylate-ethyl acrylate copolymer, and methacrylate-methyl methacrylate copolymer can be mentioned.

[0090] To target the colon, a combination of pH-responsive (e.g., at pH 6.8 to 7.2) polymers and enzyme-responsive polymers can be used. Further, to target colon delivery, capsule-in-capsule formulations containing liquid-filled hard capsules and coated or uncoated capsules can be used.

[0091] Suitable enteric capsules for use in the pharmaceutical compositions of the present disclosure include gelatin and EUDRAGIT® (L100-based capsules as described in US8,685,445) and hydroxypropyl methylcellulose acetate succinate-based capsules (as described in US2013 / 0295188A1). Enteric-coated capsules are also contemplated. See, for example, US4,518,433, US4,816,259, and US5,330,759. In some embodiments, the enteric capsules are Vcaps® Enteric Capsules, manufactured by Capsugel.

[0092] The enteric-coated methylnaltrexone formulation produced unpredictable results. For example, the enteric-coated methylnaltrexone formulation more effectively reduced the delay from mouth to cecum caused by morphine than the uncoated formulation (bowel movement data was not reported) (see, e.g., US6,274,591), but capsules containing an enteric-coated spherical formulation of methylnaltrexone surprisingly did not induce bowel movement in patients suffering from opioid-induced constipation (see, e.g., US8,524,276).

[0093] 2. Administration The pharmaceutical composition can be administered to a patient, if needed, to provide an effective amount of an ion pair of methylnaltrexone with docetate or lauryl sulfate as described herein.

[0094] In certain embodiments, the pharmaceutical composition described herein is orally administered to the patient at least once a day. In certain embodiments, the pharmaceutical composition described herein is orally administered to the patient at least twice a day. In certain embodiments, the pharmaceutical composition described herein is orally administered to the patient at least three times a day. In other embodiments, the pharmaceutical composition is orally administered to the patient up to once a day. In other embodiments, the pharmaceutical composition is orally administered to the patient up to twice a day. In other embodiments, the pharmaceutical composition is orally administered to the patient up to three times a day. In certain embodiments, the pharmaceutical composition is orally administered to the patient up to once a day or less. In certain embodiments, the pharmaceutical composition is orally administered to the patient up to twice a day or less. In certain embodiments, the pharmaceutical composition is orally administered to the patient up to three times a day or less. In certain embodiments, the pharmaceutical composition is orally administered to the patient as needed. In certain embodiments, the pharmaceutical composition is orally administered to the patient as needed, provided that it is orally administered up to once a day or less. In certain embodiments, the pharmaceutical composition is orally administered to the patient as needed, provided that it is orally administered up to twice a day or less. In certain embodiments, the pharmaceutical composition is orally administered to the patient as needed, provided that it is orally administered up to three times a day or less.

[0095] For example, the liquid dosage form of the provided pharmaceutical composition may be orally administered to a patient in a unit dose of, for example, about 1 mg to about 100 mg, about 50 mg to about 900 mg, about 75 mg to about 850 mg, about 100 mg to about 850 mg, about 150 mg to about 850 mg, about 200 mg to about 800 mg, or about 200 mg to about 700 mg of ion pair per day. In other embodiments, the pharmaceutical composition may be orally administered to a patient in a unit dose of, for example, at least about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg of ion pair per day. In other embodiments, the pharmaceutical composition may be orally administered to a patient in a unit dose of, for example, at most about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg of ion pair per day.In other embodiments, the pharmaceutical composition may be orally administered to a patient in a unit dose of, for example, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg of the ion pair per day.

[0096] In some embodiments, the invention described herein is a method for treating opioid-induced side effects in a patient in need thereof, the method comprising the step of orally administering to the patient one or more capsules, wherein the liquid oral dosage form provides from about 1 mg to about 100 mg, from about 50 mg to about 900 mg, from about 75 mg to about 850 mg, from about 100 mg to about 850 mg, from about 150 mg to about 850 mg, from about 200 mg to about 800 mg, or from about 200 mg to about 700 mg of an ion pair. In some embodiments, the invention described herein is a method for treating opioid-induced side effects in a patient in need thereof, the method comprising the step of orally administering to the patient one or more capsules, wherein the liquid oral dosage form provides at least about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg of an ion pair.In some embodiments, the invention described herein is a method for treating opioid-induced side effects in a patient in need thereof, the method comprising orally administering to the patient one or more capsules, wherein the liquid oral dosage form provides an ion pair of at most about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg. In some embodiments, the invention described herein is a method for treating opioid-induced side effects in a patient in need thereof, the method comprising orally administering to the patient one or more capsules, wherein the liquid oral dosage form provides an ion pair of about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg.

[0097] In certain embodiments, a single capsule formulation of the invention described herein provides from about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg of a methylnaltrexone-lauryl sulfate or methylnaltrexone-docusate ion pair. In certain embodiments, a single capsule formulation of the invention described herein provides at least about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg of a methylnaltrexone-lauryl sulfate or methylnaltrexone-docusate ion pair.In certain embodiments, a single capsule formulation of the invention described herein provides a methylnaltrexone-lauryl sulfate or methylnaltrexone-docusate ion pair of up to about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg.

[0098] As defined above, in certain embodiments, the term "effective amount," when used in connection with the amount of a methylnaltrexone ion pair, means, for example, an amount of the methylnaltrexone ion pair sufficient to achieve a desired treatment, such as achieving bowel movement in a patient. In some embodiments, an effective amount means an amount of the methylnaltrexone ion pair sufficient to achieve bowel movement in the 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 means an amount of the methylnaltrexone ion pair sufficient to achieve bowel movement in the patient within about 4 hours of administration to the patient. In some embodiments, an effective amount means an amount of the methylnaltrexone ion pair such that 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 is sufficient to achieve bowel movement in the patient within about 4 hours of administration to the patient. In some embodiments, an effective amount means an amount of the methylnaltrexone ion pair such that all doses administered during the first 4 weeks of dosing are sufficient to achieve bowel movement in the patient within about 4 hours of administration to the patient.

[0099] In some embodiments, the pharmaceutical composition is administered to a fasting patient. As used herein, the term "fasting" means that the patient has not eaten 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" means fasting overnight. Improved effects are thought to be seen in fasting patients rather than fed patients. These effects can be amplified in patients administered a liquid methylnaltrexone ion pair pharmaceutical composition provided in an encapsulated form, such as a soft gel capsule, a hard gel capsule, and an enteric gel capsule.

[0100] In other embodiments, the pharmaceutical composition is administered to a non-fasting patient. Thus, there is no requirement that the patient not have eaten a meal prior to administration of the pharmaceutical composition.

[0101] 3. Combination Products and Co-Administration It should also be recognized that the pharmaceutical compositions provided herein can be utilized in combination therapies, i.e., the provided pharmaceutical compositions can be administered concurrently with, before, or after one or more other desired therapeutic agents or medical procedures. The specific combination therapies (therapeutic agents or procedures) utilized in a combination regimen take into account the compatibility of the desired therapeutic agents and / or procedures as well as the desired therapeutic effect to be achieved. The therapies utilized may achieve the desired effect on the same disorder (e.g., the formulation can be administered concurrently with another compound used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic compounds that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease or condition being treated".

[0102] In certain embodiments, the pharmaceutical composition of the present disclosure and one or more other active agents can be administered together in a single formulation (e.g., unit dosage form). In other embodiments, the pharmaceutical composition and one or more other active agents can be administered as separate pharmaceutical compositions. In certain embodiments, the methylnaltrexone ion pair and / or one or more other active agents can be administered in multiple doses.

[0103] In other embodiments, the methylnaltrexone ion pair or other active agents administered in combination with the formulation of the invention are opioids. The combination therapy of the methylnaltrexone ion pair and an opioid enables the simultaneous alleviation of pain and minimization of side effects associated with the opioid (e.g., gastrointestinal effects such as delay in gastric emptying and modification of gastrointestinal motility). Thus, in certain embodiments, the invention described herein provides a unit dosage form that includes a combination of the methylnaltrexone ion pair and an opioid together in a liquid oral dosage form (e.g., capsule) suitable for oral administration.

[0104] Opioids useful for analgesia are known in the art. For example, opioid compounds include, but are not limited to, alfentanil, anileridine, asimadoline, bremazocine, buprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, ethylmorphine, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, nicomorphine, opium, oxycodone, oxymorphone, papaveretum, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol. In some embodiments, the opioid is at least one opioid selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, nicomorphine, oxycodone, oxymorphone, papaveretum, pentazocine, propiram, propoxyphene, sufentanil and / or tramadol. In certain embodiments of the invention described herein, the opioid is selected from morphine, codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl, tramadol, and mixtures thereof. In a particular embodiment, the opioid is loperamide. In other embodiments, the opioid is a mixed agonist such as butorphanol. In some embodiments, more than one opioid, such as morphine and heroin or methadone and heroin, is administered to the subject.

[0105] Generally, the amount of other active agent(s) administered in combination therapy may be less than or equal to the amount normally administered in monotherapy with the relevant agent(s). In certain embodiments, the amount of other active agent administered in combination therapy may be lower than the amount normally administered in monotherapy with the relevant agent(s). For example, in certain embodiments of the invention described herein, the amount of additional active agent can range from about 50% to about 100% of the amount normally present in a formulation containing the compound as the sole therapeutic agent.

[0106] In certain embodiments, the pharmaceutical composition can also be used in conjunction with and / or in combination with conventional therapies for gastrointestinal disorders that are useful for the restoration of constipation and intestinal dysfunction. For example, conventional therapies include, but are not limited to, functional stimulation of the intestinal tract, stool softeners, laxatives (e.g., diphenylmethane laxatives, cathartic laxatives, osmotic laxatives, saline laxatives), bulking agents and laxatives, lubricants, intravenous fluid replacement, and nasogastric decompression.

[0107] 4. Use of the pharmaceutical composition and kits The invention described herein provides a pharmaceutically acceptable composition containing methylnaltrexone together with docetate or lauryl sulfate for oral administration useful for the delivery of such pharmaceutical compositions in any context where such delivery is desired. In certain embodiments, the pharmaceutical composition provided is useful for the delivery of methylnaltrexone as an ion pair with docetate or lauryl sulfate, for example, in antagonizing the unwanted side effects of opioid analgesic therapy (e.g., gastrointestinal effects such as delayed gastric emptying, altered gastrointestinal motility). Further, the pharmaceutical composition can be used to treat a subject having a condition that recovers in any treatment where binding to the μ-opioid receptor or transient inhibition of the μ-opioid receptor system is desired (e.g., intestinal obstruction). In certain embodiments of the invention described herein, the method is for use in human subjects.

[0108] Thus, administration of the provided pharmaceutical composition can be advantageous for the treatment, prevention, recovery, delay, or alleviation of side effects of opioid use, such as gastrointestinal disorders (e.g., inhibition of bowel motility, constipation, contraction of the GI sphincter, nausea, emesis (vomiting)), biliary spasm, opioid bowel dysfunction, colic, dysphoria, pruritus, urinary retention, respiratory depression, miosis, cardiovascular effects, chest wall rigidity, and cough suppression, suppression of the stress response, and immunosuppression associated with the use of narcotic analgesics, or combinations thereof. Thus, the use of the pharmaceutical composition can be beneficial from the perspective of quality of life for subjects undergoing opioid use and to reduce complications arising from chronic constipation, such as hemorrhoids, anorexia, mucosal breakdown, sepsis, risk of colon cancer, and myocardial infarction.

[0109] In some embodiments, the provided pharmaceutical composition is useful for administration to subjects undergoing acute opioid administration. In some embodiments, the provided pharmaceutical composition is useful for administration to patients suffering from postoperative gastrointestinal disorders.

[0110] In certain embodiments, the provided pharmaceutical composition is also useful for administration to subjects undergoing chronic opioid administration (e.g., terminally ill patients undergoing opioid therapy, such as AIDS patients, cancer patients, cardiovascular patients; subjects undergoing long-term opioid therapy for pain management; subjects undergoing opioid therapy for opioid withdrawal maintenance). In some embodiments, the subject is a subject using opioid therapy for the management of chronic pain. In certain embodiments, the pain is non-malignant pain (e.g., back pain, neuropathic pain, pain associated with fibromyalgia, osteoarthritis). In some embodiments, the subject is a terminally ill patient. In other embodiments, the subject is a human undergoing opioid withdrawal maintenance therapy.

[0111] In certain embodiments, the pharmaceutical compositions provided herein are administered to a subject selected for treatment. In certain embodiments, the subject is selected based on a subject having a higher risk of developing one or more of the conditions described above. In another embodiment, the subject is selected based on the use of opioid therapy for pain management or based on having one or more of the conditions described herein. In certain embodiments, the subject is constipated by opioid therapy or has a history of constipation. In one embodiment, the constipated subject has not had a bowel movement in the past three days. In one embodiment, the constipated subject had fewer than three bowel movements in the previous week. In certain embodiments, the constipated subject has had, for four consecutive weeks recently, on average fewer than three bowel movements per week without rescue and one or more of the following: (a) hard or lumpy stools, (b) straining during bowel movement, and / or (c) a feeling of incomplete evacuation after bowel movement.

[0112] In certain embodiments, the subject is selected for treatment with the pharmaceutical compositions described herein based on, for example, the use of opioids for non - malignant pain. The subject may be using opioids intermittently or regularly. In one embodiment, the selected subject is taking opioids as needed. In one embodiment, the selected subject has been taking opioids for less than one week. In one embodiment, the selected subject has been taking opioids for at least one week. In another embodiment, the selected subject has been taking opioids for at least two weeks. In another embodiment, the selected subject has been taking opioids for at least three weeks. In another embodiment, the selected subject has been taking opioids for at least four weeks. In another embodiment, the selected subject has been taking opioids for at least three months. In another embodiment, the selected subject has been taking opioids for at least six months. In another embodiment, the selected subject has been taking opioids for at least twelve months. In another embodiment, the selected subject has been taking opioids for longer than one year. In another embodiment, the selected subject has been taking opioids at least every other day for at least two weeks. In one embodiment, the selected subject has received at least 7 doses of at least 25 mg of oral morphine equivalents over at least 14 days. In one embodiment, the selected subject has received a daily dose of at least 50 mg of oral morphine equivalents for at least 14 days. In one embodiment, the selected subject is constipated due to opioid therapy and has received a daily dose of at least 50 mg of oral morphine equivalents for at least 14 days. In certain embodiments, the subject has received a daily dose of at least 50 mg of oral morphine equivalents for at least 14 days and has had less than 3 bowel movements without rescue per week on average for at least 4 consecutive weeks in one or more of the following: (a) at least 25% of the bowel movements without rescue were type 1 or 2 on the Bristol Stool Form Scale; (b) there was straining during at least 25% of the bowel movements without rescue; and / or (c) there was a feeling of incomplete evacuation after at least 25% of the bowel movements without rescue.Defecation without rescue refers to defecation without the use of a laxative within 24 hours prior to defecation.

[0113] In certain embodiments, the subject selected for treatment with the pharmaceutical compositions described herein is a subject suffering from opioid-induced constipation. In certain embodiments, the subject selected for treatment with the pharmaceutical compositions described herein is a subject with an advanced disease who is receiving palliative care and suffering from opioid-induced constipation. In certain embodiments, the subject selected for treatment with the pharmaceutical compositions described herein is a subject with an advanced disease who is receiving palliative care and suffering from opioid-induced constipation and who has an inadequate response to laxative therapy (e.g., bisacodyl, senokot, docusate). In certain embodiments, the subject selected for treatment with the pharmaceutical compositions described herein is a subject with non-malignant pain who is suffering from opioid-induced constipation. In certain embodiments, the subject selected for treatment with the pharmaceutical compositions described herein is a subject with non-malignant pain who is suffering from opioid-induced constipation and who has an inadequate response to laxative therapy (e.g., bisacodyl, senokot, docusate). In certain embodiments, the subject selected for treatment with the pharmaceutical compositions described herein has not responded to standard laxative therapy. In certain embodiments, the subject selected for treatment with the pharmaceutical compositions described herein has responded to standard laxative therapy. In certain embodiments, the subject selected for treatment with the pharmaceutical compositions described herein is receiving laxative therapy concomitantly.

[0114] Alternative or additional uses for the provided pharmaceutical compositions described herein are useful for treating 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 infectious agents (e.g., Pseudomonas aeruginosa). Additional advantageous uses of the pharmaceutical compositions described herein include treatment of opioid-induced immunosuppression, inhibition of angiogenesis, inhibition of vascular system proliferation, treatment of pain, treatment of inflammatory conditions such as inflammatory bowel syndrome, treatment of infectious diseases and musculoskeletal diseases such as osteoporosis, arthritis, osteitis, periostitis, myopathy, and treatment of autoimmune diseases.

[0115] In certain embodiments, the provided pharmaceutical compositions are useful for preventing, inhibiting, alleviating, delaying, reducing, or treating gastrointestinal disorders including, but not limited to, irritable bowel syndrome, opioid-induced bowel dysfunction, colitis, postoperative or postpartum intestinal obstruction, nausea and / or vomiting, decreased gastric motility and emptying, inhibition of gastric, intestinal, and / or colonic transit, increased amplitude of non-propulsive segmental contractions, contraction of the sphincter of Oddi, increased anal sphincter tone, loss of reflex relaxation associated with rectal distension, decreased secretion of the stomach, bile duct, pancreas, or intestine, increased water absorption from intestinal contents, gastroesophageal reflux, gastric ileus, muscle spasms, abdominal distension, abdominal or epigastric pain and discomfort, constipation, idiopathic constipation, postoperative gastrointestinal disorders after abdominal surgery (e.g., hysterectomy and colectomy, such as right hemicolectomy, left hemicolectomy, transverse hemicolectomy, colectomy takedown, or low anterior resection), and delayed absorption of orally administered drugs or nutrients.

[0116] The provided pharmaceutical compositions are also useful for treating conditions including cancer with angiogenesis, immunosuppression, sickle cell anemia, vascular trauma, retinopathy, inflammation associated with disorders (e.g., irritable bowel syndrome), immunosuppression, and chronic inflammation.

[0117] In other embodiments, the pharmaceutical composition provided is useful for the preparation of a medicament comprising a medicament useful for the treatment of side effects of opioid use including, but not limited to, gastrointestinal side effects (such as inhibition of bowel motility, GI sphincter contraction, constipation), nausea, emesis, vomiting, dysphoria, pruritus, or combinations thereof. The pharmaceutical composition provided is useful for the preparation of a medicament useful for the treatment of patients undergoing acute opioid therapy (such as patients receiving acute opioid administration, patients suffering from postoperative gastrointestinal disorders) or subjects using opioids chronically (such as terminally ill patients receiving opioid therapy, such as AIDS patients, cancer patients, patients with cardiovascular diseases; subjects receiving chronic opioid therapy for pain management (malignant or non-malignant pain); or subjects receiving opioid maintenance therapy for opioid withdrawal). Even further, the treatment of pain, inflammatory conditions such as the treatment of inflammatory bowel syndrome, the treatment of infectious diseases, musculoskeletal diseases such as osteoporosis, arthritis, osteitis, periostitis, myopathy, the treatment of autoimmune diseases and immunosuppression, abdominal surgery (such as postoperative gastrointestinal disorders after colectomy (such as right hemicolectomy, left hemicolectomy, transverse hemicolectomy, colectomy takedown, low anterior resection), idiopathic constipation, and intestinal obstruction (such as postoperative intestinal obstruction, postpartum intestinal obstruction), and the preparation of a medicament useful for the treatment of disorders such as cancer including angiogenesis, chronic inflammation and / or chronic pain, sickle cell anemia, vascular trauma, and retinopathy.

[0118] In yet further embodiments, veterinary uses of the disclosed pharmaceutical compositions (such as the treatment of livestock, such as horses, dogs, cats) are provided. Thus, the use of the provided pharmaceutical compositions in veterinary uses similar to those discussed above for human subjects is contemplated. For example, inhibition of gastrointestinal motility in horses, such as colic and constipation, can be lethal to horses. The pain that occurs in a horse suffering from colic can lead to shock that induces death, while long-term cases of constipation can also cause the death of a horse. Treatment of horses with a peripheral opioid receptor antagonist is described, for example, in US2005 / 0124657.

[0119] Also further encompassed by the present invention are pharmaceutical packs and / or kits comprising the pharmaceutical compositions described herein, and containers (such as foil or plastic packages, or other suitable containers). Optionally, instructions for use may also be further provided within such kits.

[0120] For example, if physical or chemical properties, such as molecular weight or chemical formula, are described herein using ranges, all combinations and sub-combinations of the ranges, and specific embodiments therein, are intended to be included. The use of the term "about" when referring to a number or numerical range means that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically from 0% to 15%, preferably from 0% to 10%, more preferably from 0% to 5% of the recited number or numerical range. The term "comprising" (and related terms such as "comprise", "comprises", "has", or "including") includes embodiments of any composition, method, or process that "consists of" or "consists essentially of" the features described.

[0121] Furthermore, the transitional phrases "comprising," "consisting essentially of," and "consisting of," when used in the appended claims, define the scope of the claims in terms of what is excluded from the scope of the claim if additional claim elements or steps not recited in the original form and in the amended form are present. The term "comprising" is intended to be inclusive or open-ended and does not exclude any additional, unrecited elements, method, steps, or materials. The term "consisting of" excludes any element, step, or material not specified in the claim, and in the case of materials, excludes impurities normally associated with the specified material(s). The term "consisting essentially of" limits the scope of the claim to the specified element, step, or material(s) and those that do not materially affect the basic and novel characteristics of the claimed invention. All embodiments described herein that include the present invention can be more specifically defined in alternative embodiments by any of the transitional phrases "comprising," "consisting essentially of," and "consisting of."

[0122] For a more complete understanding of the invention described herein, the following examples are set forth. It is to be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

[0123] All features of each aspect of the invention apply, with necessary modifications, to all other aspects. The contents of all references, patents, pending patent applications, and published patents cited throughout this application are hereby expressly incorporated by reference herein.

Examples

[0124] 1. Synthesis and Characterization of Ion Pairs 1.1. Methylnaltrexone Methylnaltrexone can be prepared by the method described in detail in US7,674,904 or obtained from commercial sources, such as Covidien, Saint Louis, Mo.

[0125] 1.2. Methylnaltrexone Lauryl Sulfate Ion Pair Methylnaltrexone bromide and sodium lauryl sulfate (molar ratio 1:1) were mixed in water to prepare the methylnaltrexone lauryl sulfate ion pair. A colloidal suspension was obtained by mixing. Insoluble materials were separated from the liquid by centrifugation. The liquid phase was decanted, and after centrifugation, the wet solid obtained from the aqueous suspension was dissolved in ethanol, and water was removed by azeotropic drying. The dried residue was further dried in a vacuum oven to obtain a solid powder. The product was analyzed by HPLC and found to contain up to 61% (w / w) of methylnaltrexone bromide equivalents.

[0126] 1.3. Methylnaltrexone Docetate Ion Pair An aqueous solution of methylnaltrexone bromide was slowly added with stirring to an aqueous solution of sodium docetate. An opalescent white suspension was formed, which indicated the formation of the ion pair. The white, insoluble material formed was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed once with water and concentrated by rotary evaporation to obtain a foamy solid. After rotary evaporation, the residue was dried in a vacuum oven at 60 °C to obtain a dry powder. The dry powder was equivalent to 46% (w / w) methylnaltrexone bromide as determined by HPLC.

[0127] 1.4. Lipophilicity The partition coefficients (LogP) between octanol and water for each ion pair prepared as described herein are summarized in the following table:

[0128] [Table 4]

[0129] To determine the partition coefficient of each ion pair, approximately 15 mg of each ion pair was dissolved in separate 100 ml portions of n - octanol (pre - saturated with water). Three n - octanol solutions were prepared for each ion pair. By adding water and stirring the mixture with a bench - top stirrer for 2 hours, mixtures with three different volume ratios of n - octanol to water (9:1, 7:3, and 1:1) were prepared. After stirring, samples from each mixture were centrifuged at 10,000 rpm for 10 minutes to separate the aqueous phase and the n - octanol phase. The concentrations of methylnaltrexone in the aqueous and n - octanol phases were determined by HPLC. LogP was calculated from the ratio of the drug concentration in n - octanol to the drug concentration in water.

[0130] 2. Pharmaceutical composition 2.1. Capsule - methylnaltrexone lauryl sulfate ion pair

[0131]

Table 5

[0132] Labrasol (registered trademark) and Maisine (registered trademark) CC were mixed according to the ratios listed above. Methylnaltrexone - lauryl sulfate was added and the mixture was incubated in a water bath at approximately 60 °C for 6 hours with mixing, continuing until a single - phase pharmaceutical composition was obtained. An emulsion was prepared by emulsifying 0.5 ml of the pharmaceutical composition in 25 ml of 100 mM phosphate buffer pH 6.8. The mean droplet diameter and the polydispersity index (PDI) were measured via dynamic light scattering. The mean droplet diameter was approximately 158 nm and the PDI was 0.16. Also, after 12 hours, the emulsion was visually tested for any precipitation or phase separation and was found to be stable without any precipitation or phase separation. The pharmaceutical composition was filled into size 00 hard gelatin capsules. Using a USP dissolution apparatus 2, the dissolution rate was measured in pH 2 and pH 6.8 media by visual observation of shell dissolution. The capsule shell completely dissolved and released the pharmaceutical composition within 10 minutes in both media.

[0133] 2.2. Capsule - Methylnaltrexone Docusate Ion Pair

[0134]

Table 6

[0135] Medium - chain triglycerides, IMWITOR® 988, and oleic acid were mixed according to the ratios listed above. Methylnaltrexone - docusate was added and incubated in a water bath at about 60 °C for 6 hours with mixing until a single - phase pharmaceutical composition was obtained. An emulsion was prepared by emulsifying 0.5 ml of the pharmaceutical composition in 25 ml of 100 mM phosphate buffer pH 6.8. The average droplet diameter and PDI were measured via dynamic light scattering. The average droplet diameter was about 300 nm and the PDI was 0.45. The emulsion was visually tested for any precipitation or phase separation. The emulsion was stable for up to 2 hours and then precipitation was observed.

[0136] 2.3. Enteric Capsule - Methylnaltrexone Docusate Ion Pair

[0137]

Table 7

[0138] Medium-chain triglycerides, IMWITOR® 988, and TWEEN® 80 were mixed according to the ratios listed above. Methylnaltrexone-docusate was added and incubated in a water bath at approximately 60 °C with mixing for 12 hours, continuing until the pharmaceutical composition was obtained as a single phase. An emulsion was prepared by emulsifying 0.5 ml of the pharmaceutical composition in 25 ml of 100 mM phosphate buffer pH 6.8. The average droplet diameter and PDI were measured via dynamic light scattering. The average droplet diameter was approximately 135 nm and the PDI was 0.27. The emulsion was visually tested for any precipitation or phase separation and was found to be stable with no precipitation or phase separation up to 12 hours. The pharmaceutical composition was filled into size 0 hard gelatin capsules and then each was encapsulated within a size 00Vcaps® enteric capsule. The enteric capsule was not intended for liquid injection and was found to be incompatible with IMWITOR® 988, so a capsule-in-capsule delivery vehicle was utilized. Using a USP dissolution apparatus 2, the dissolution rate was measured in pH 2 and pH 6.8 media by visual observation of shell dissolution. After 2 hours, the capsule shell did not degrade in the pH 2 media and completely degraded within 7 minutes in the pH 6.8 media, releasing the pharmaceutical composition.

[0139] 2.4. Capsule - Methylnaltrexone Docusate Ion Pair

[0140]

Table 8

[0141] Medium-chain triglycerides, IMWITOR® 988, and TWEEN® 80 were mixed according to the ratios listed above. Methylnaltrexone-docusate was added and incubated in a water bath at around 60 °C under continuous mixing for 12 h, continuing until the pharmaceutical composition was obtained as a single phase. An emulsion was prepared by emulsifying 0.5 ml of the pharmaceutical composition in 25 ml of 100 mM phosphate buffer pH 6.8. The average droplet diameter and PDI were measured via dynamic light scattering. The average droplet diameter was about 131 nm and the PDI was 0.16. The emulsion was visually tested for any precipitation or phase separation at 12 h and found to be stable without any precipitation or phase separation. The pharmaceutical composition was filled into hard gelatin capsules of size 00. The dissolution rate was measured in pH 2 and pH 6.8 media by visual observation of shell dissolution in a USP dissolution apparatus 2. In both media, the capsule shell completely disintegrated and released the pharmaceutical composition within 10 min.

[0142] 2.5. Methylnaltrexone Docusate Ion Pairs with Various Drug Contents The formulations described in Example 2.5 are capsule-based MNTX-DS formulations having various drug contents and prepared according to the procedures described herein. Formulations 1 and 2 are self-emulsifying (i.e., SEDDS) formulations containing oil as described herein. Formulations 3 - 6 are micelle-based (i.e., SMDDS) formulations having the same drug content as Formulation 2 and containing surfactants and co-solvents. As described herein, KOLLIPHOR® RH 40 is a digestive surfactant whereas KOLLIPHOR® HS 15 is a non-digestive surfactant. The goal in preparing these formulations was to observe the results of the digestibility of the surfactants on the bioavailability and / or efficacy of the MNTX-DS formulations in further animal experiments.

[0143] Formulation 1: As described below in this specification, exemplary formulations include methylnaltrexone-doxetate, IMWITOR® 988, medium-chain triglycerides (MCT), TWEEN® 80, and a stabilizer (e.g., butylated hydroxytoluene).

[0144]

Table 9

[0145] Formulation 2: As described below in this specification, exemplary formulations include methylnaltrexone-doxetate, IMWITOR® 988, intermediate-chain triglycerides (MCT), TWEEN® 80, and a stabilizer (e.g., butylated hydroxytoluene).

[0146]

Table 10

[0147] Formulation 3: As described below in this specification, exemplary formulations include methylnaltrexone-doxetate, ethanol, KOLLIPHOR® RH 40, and a stabilizer (e.g., butylated hydroxytoluene).

[0148]

Table 11

[0149] Formulation 4: As described below in this specification, exemplary formulations include methylnaltrexone-doxetate, ethanol, KOLLIPHOR® RH 40, KOLLIPHOR® HS 15, and a stabilizer (e.g., butylated hydroxytoluene).

[0150]

Table 12

[0151] Formulation 5: As described below in this specification, an exemplary formulation comprises methylnaltrexone-doxetate, ethanol, vitamin E TPGS, and a stabilizer (e.g., butylated hydroxytoluene).

[0152]

Table 13

[0153] Formulation 6: As described below in this specification, an exemplary formulation comprises methylnaltrexone-doxetate, ethanol, GELUCIRE® 44 / 14, and a stabilizer (e.g., butylated hydroxytoluene).

[0154]

Table 14

[0155] 3. Pharmacokinetics of the Liquid Pharmaceutical Composition in Beagle Dogs In each experiment, a 150 mg dose of methylnaltrexone was administered to each of six dogs (3 males and 3 females). In the first experiment, a 150 mg dose of methylnaltrexone was administered to each dog with the composition according to Example 2.1. In the second experiment, a 150 mg dose of methylnaltrexone was administered to each dog with the composition according to Example 2.2. In the third experiment, a 150 mg dose of methylnaltrexone was administered to each dog with the composition according to Example 2.3. In the fourth experiment, a 150 mg dose of methylnaltrexone was administered to each dog with the composition according to Example 2.4. In the positive control experiment, RELISTOR® tablets were administered to each dog. The plasma concentration of methylnaltrexone was measured at 0, 5, 15, 30, 60, 90, 120, 150, 180, 240, 360, 720 minutes after dosing.

[0156] Figure 1 shows the mean plasma concentration of methylnaltrexone after administration of five oral pharmaceutical compositions. The lipid-based formulation containing methylnaltrexone-doxetate (the pharmaceutical composition prepared according to Section 2.2) had the highest mean C maxand the shortest average T max was caused.

[0157] Figure 2 shows a comparison of the plasma concentration of methylnaltrexone and the time after administration of RELISTOR (registered trademark) tablets (control). The maximum plasma concentration was between about 1,000 ng / mL and 5,000 ng / mL. T for each of the 6 dogs max was observed within about 2 hours.

[0158] Figure 3 shows a comparison of the average plasma concentration of methylnaltrexone and the time after administration of a self-emulsifying drug delivery system containing methylnaltrexone-lauryl sulfate prepared according to Section 2.1 above. The maximum methylnaltrexone concentration was observed at the 60-minute time point and was less than 4,000 ng / mL.

[0159] Figure 4 shows a comparison of the average plasma concentration of methylnaltrexone and the time after administration of a lipid-based liquid formulation containing methylnaltrexone-docusate prepared according to Section 2.2 above. The peak plasma concentration of methylnaltrexone was observed within 60 minutes for 3 dogs, and a peak plasma concentration between 6,000 ng / mL and 8,000 ng / mL was observed in dog 2.

[0160] Figure 5 shows a comparison of the average plasma concentration of methylnaltrexone and the time after administration of a self-emulsifying drug delivery system containing methylnaltrexone-docusate in an enteric capsule prepared according to Section 2.3 above. The maximum plasma concentration between 8,000 ng / mL and 10,000 ng / mL was observed within 1 hour in dog 4.

[0161] Figure 6 shows a comparison of the average plasma concentration of methylnaltrexone and the time after administration of a self-emulsifying drug delivery system containing methylnaltrexone-docusate prepared according to Section 2.4 above. The highest plasma concentration of methylnaltrexone, about 8,000 ng / mL, was observed within 1 hour of administration in dog 5. The present invention encompasses the following embodiments. (Embodiment 1) (a) A formula:

Chem.

Chem.

Chem.

Claims

1. (a) formula: 【Chemical 1】 (wherein R - is an anion selected from the group consisting of lauryl sulfate and docetate) having at least 5% by weight of an ion pair; (b) An oil selected from glyceryl monooleate, glyceryl monolaurate, propylene glycol dicaprylate / dicaprate, soybean oil, polyglyceryl-3 dioleate, oleic acid, glyceryl caprylate, medium-chain triglycerides, and combinations thereof; (c) Optionally, a surfactant selected from oleoylpoxyl-6 glyceride, linoleoylpoxyl-6 glyceride, caprylocaprylylpoxyl-8 glyceride, polysorbate 80, polyoxyl 40 hydrogenated castor oil, polyoxyl 15 hydroxystearate, lauroylpoxyl-32 glyceride, and combinations thereof; (d) Optionally, a co-solvent; A single-phase pharmaceutical composition in a liquid oral dosage form comprising the above.

2. (i) Containing 10% to 60% by weight, 15% to 50% by weight, or 20% to 40% by weight of the said ion pair, (ii) Containing 1 mg to 100 mg, 50 mg to 900 mg, 75 mg to 850 mg, 100 mg to 850 mg, 150 mg to 850 mg, 200 mg to 800 mg, or 200 mg to 700 mg of the said ion pair, and / or (iii) Containing at least 1 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg or 900 mg of the said ion pair, The pharmaceutical composition according to Claim 1.

3. The pharmaceutical composition in a liquid oral dosage form according to Claim 1 or 2, wherein the ions in the ion pair are present in substantially equimolar amounts.

4. (i) The oil contains at least one of glyceryl monolaurate, oleic acid, glyceryl caprylate, medium-chain triglycerides, and combinations thereof, (ii) Containing at least two surfactants, (iii) The surfactant is selected from the group consisting of linoleoylpoxyl-6 glyceride, caprylocaprylylpoxyl-8 glyceride, and polysorbate 80, and combinations thereof, (iv) Containing 10% to 70% by weight, 15% to 40% by weight, or 20% to 35% by weight of the said surfactant, and / or (v) Containing a surfactant and a co-solvent, The pharmaceutical composition according to any one of Claims 1 to 3.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition contains at least two kinds of oils.

6. The pharmaceutical composition according to claim 5, wherein the two kinds of oils contain glyceryl caprylate and medium-chain triglycerides.

7. The pharmaceutical composition according to claim 4, wherein the co-solvent (v) is selected from the group consisting of triacetin, ethanol, glycerol, propylene glycol, and polyethylene glycol.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition forms an emulsion upon contact with an aqueous liquid.

9. (i) containing a surfactant and a co-solvent, (ii) further containing a stabilizer, The pharmaceutical composition according to any one of claims 1 to 8.

10. The pharmaceutical composition according to claim 9, wherein the co-solvent (i) is selected from the group consisting of triacetin, ethanol, glycerol, propylene glycol, and polyethylene glycol.

11. The pharmaceutical composition according to claim 9, wherein the stabilizer is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, ascorbyl-6-palmitate, alpha-tocopherol, vitamin E TPGS, and combinations thereof.

12. The pharmaceutical composition according to claim 9 or 11, wherein the stabilizer is present in an amount of at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight of the composition.

13. (a) Formula 【Chemical 2】 (wherein R - is docetaxel) of at least 5% by weight of the ion pair; (b) an oil selected from glyceryl monooleate, glyceryl monolaurate, propylene glycol dicaprylate / dicaprate, soybean oil, polyglyceryl-3 dioleate, oleic acid, glyceryl caprylate, medium-chain triglycerides, and combinations thereof; (c) optionally, a surfactant selected from oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, caprylocapryloyl polyoxyl-8 glyceride, polysorbate 80, polyoxyl 40 hydrogenated castor oil, polyoxyl 15 hydroxystearate, lauroyl polyoxyl-32 glyceride, and combinations thereof; (d) optionally, a co-solvent; A single-phase pharmaceutical composition comprising, which is a liquid composition for oral administration, said pharmaceutical composition.

14. The pharmaceutical composition according to any one of claims 1 to 13, encapsulated in a capsule.

15. A pharmaceutical composition according to any one of claims 1 to 14 for use in the treatment of opioid-induced constipation in a subject in need thereof, comprising orally administering said pharmaceutical composition to said subject, optionally, the oral administration of said pharmaceutical composition to said subject is C of methylnaltrexone in the range of -50 ng / mL to 200 ng / mL max resulting in, and / or - less than 4 hours, less than 2 hours, less than 1 hour, less than 30 minutes, less than 15 minutes, or less than 10 minutes, of the T of methylnaltrexone max resulting in Said pharmaceutical composition.

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