RU2823287C1 - Liquid compositions of rifaximin - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to the pharmaceutical industry, specifically to a pharmaceutical composition for treating disorders associated with intestine or liver function. Disclosed is a pharmaceutically acceptable composition for treating disorders associated with intestine or liver function, where the composition contains rifaximin, from 25 to 50 wt.% of hydrogenated castor oil and from 45 to 65 wt.% of at least one additional solubilizing excipient, selected from castor oil, glyceryl caprylate, polysorbate 80, diethyl sebacate, diethylene glycol monoethyl ether and combinations thereof. Also disclosed is a method of treating one or more disorders associated with intestinal or liver function in a subject in need thereof, comprising a step of administering to the subject a therapeutically effective amount of the pharmaceutical composition.

EFFECT: composition described above is stable, characterized by improved availability of soluble rifaximin in stomach, small intestine and/or large intestine.

61 cl, 11 dwg, 11 tbl

Description

Related applications

This application claims priority under U.S. Provisional Patent Application No. 62/904790, filed September 24, 2019, and U.S. Provisional Patent Application No. 63/044447, filed June 26, 2020, the contents of which are incorporated herein by reference in their entirety.

State of the art

Rifaximin (eg, Xifaxan®) is a broad-spectrum oral antibiotic with antimicrobial activity against gram-positive and gram-negative aerobic and anaerobic bacteria. Rifaximin is currently indicated for the treatment of traveler's diarrhea (TD), for the maintenance of remission of hepatic encephalopathy (HE), and for the treatment of irritable bowel syndrome with diarrhea (IBS-D). Other uses of rifaximin include, for example, the treatment of C. difficile infections, infectious diarrhea, small intestinal bacterial overgrowth (SIBO), inflammatory diseases, inflammatory bowel disease (IBD) and diverticular disease. Because rifaximin is largely insoluble in water and poorly absorbed, systemic effects are unusual. For example, less than 0.5% of rifaximin is absorbed into the bloodstream when taken orally. This results in a very favorable safety profile comparable to placebo. However, rifaximin is increasingly dissolved in bile. This results in higher luminal concentrations and enhanced antimicrobial effects against intestinal bacteria. There are also more pronounced effects in the small intestine, as well as low microbial resistance and minimal effect on the microflora of the colon. Thus, rifaximin is highly preferred for use in conditions related to the small intestine, as well as for long-term use (eg, 6 months longer or in cases where bacterial resistance is a concern).

However, even with these beneficial properties, more than 90% of rifaximin is excreted almost entirely as unchanged drug in the feces. Additionally, due to low systemic availability, rifaximin has not traditionally been used to treat systemic infections caused by invasive organisms. Patient compliance is another concern, as low adsorption leads to higher and more frequent dosing. Rifaximin is currently available in 200 mg and 550 mg tablets and is approved for daily doses of 600 mg (TD) or 1650 mg (HE).

There is a need for rifaximin formulations that improve the availability of soluble rifaximin into the stomach, small intestine and/or colon

Essence

In an embodiment, the invention described herein includes a composition comprising rifaximin, hydrogenated castor oil and at least one additional solubilizing excipient. In some embodiments, the compositions described herein include a low dose of rifaximin. In some embodiments, the compositions described herein may be pharmaceutically acceptable compositions. In one embodiment, the invention described herein includes a pharmaceutically acceptable composition comprising a low dose of rifaximin, hydrogenated castor oil and at least one additional solubilizing excipient.

In some embodiments, the hydrogenated castor oil may be polyoxyl 40 hydrogenated castor oil (eg, Cremophor® RH-40).

In some embodiments, hydrogenated castor oil may be present in an amount of from about 25% to about 65% by weight. compositions.

In some embodiments, hydrogenated castor oil may be present in an amount of from about 25% to about 50% by weight. compositions.

In some embodiments, hydrogenated castor oil may be present in an amount of from about 30% to about 45% by weight. compositions.

In some embodiments, hydrogenated castor oil may be present in an amount of from about 35% to about 40% by weight. compositions. In some embodiments, hydrogenated castor oil may be present in an amount of about 35% or about 40% by weight. compositions.

In some embodiments, hydrogenated castor oil may be present in an amount of from about 45% to about 65% by weight. compositions.

In some embodiments, the at least one additional solubilizing excipient may be a plurality of additional solubilizing excipients. In some embodiments, the at least one additional solubilizing excipient may be selected from the group consisting of a water-soluble organic solvent, a nonionic surfactant, a water-insoluble lipid, long-chain triglycerides, and combinations thereof. In some embodiments, the at least one additional solubilizing excipient may comprise one or more of a water-soluble organic solvent, a nonionic surfactant, a water-insoluble lipid, and long-chain triglycerides. In some embodiments, the at least one additional solubilizing excipient may be selected from the group consisting of polyethylene glycol 600, glyceryl caprylate, polysorbate 80, castor oil, benzyl alcohol, polyethylene glycol 400, diethylene glycol monoethyl ether, glyceryl monooleate, triethylene glycol, diethyl diisopropyl adipate, sebacate, oleyl alcohol, and combinations thereof. In some embodiments, the at least one additional solubilizing excipient may contain one or more of polyethylene glycol 600, glyceryl caprylate, polysorbate 80, castor oil, benzyl alcohol, polyethylene glycol 400, diethylene glycol monoethyl ether, glyceryl monooleate, triethylene glycol, diisopropyl adipate, ata and oleyl alcohol .

In some embodiments, the at least one additional solubilizing excipient may be one or more additional solubilizing excipients that provide or otherwise provide solubility at saturation of rifaximin greater than about 10% by weight. rifaximin in the composition. In some embodiments, the at least one additional solubilizing excipient may be one or more additional solubilizing excipients that provide or otherwise provide solubility at saturation of rifaximin greater than about 14% by weight. rifaximin in the composition.

In some embodiments, the at least one additional solubilizing excipient may be selected from the group consisting of polyethylene glycol 600, glyceryl caprylate, polysorbate 80, castor oil, benzyl alcohol, polyethylene glycol 400, diethylene glycol monoethyl ether, glyceryl monooleate, triethylene glycol, diethyl diisopropyl adipate, sebacate, oleyl alcohol, polysorbate 20, oleic acid, caprylic/capric triglycerides, propylene glycol, sesame oil, soybean oil, corn oil, and combinations thereof. In some embodiments, the at least one additional solubilizing excipient may comprise at least one of polyethylene glycol 600, glyceryl caprylate, polysorbate 80, castor oil, benzyl alcohol, polyethylene glycol 400, diethylene glycol monoethyl ether, glyceryl monooleate, triethylene glycol, diethyl seb diisopropyl adipate, cynate, oleyl alcohol, polysorbate 20, oleic acid, caprylic/capric triglycerides, propylene glycol, sesame oil, soybean oil, and corn oil.

In some embodiments, the at least one additional solubilizing excipient may be selected from the group consisting of castor oil, glyceryl caprylate, polysorbate 80, diethyl sebacate, diethylene glycol monoethyl ether, and combinations thereof. In some embodiments, the at least one additional solubilizing excipient may comprise one or more of castor oil, glyceryl caprylate, polysorbate 80, and diethyl sebacate.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 25% to about 65% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 30% to about 65% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 35% to about 65% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 40% to about 65% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 45% to about 65% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 50% to about 65% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 50% to about 60% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 55% to about 60% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 55% to about 65% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 60% to about 65% by weight. compositions.

In some embodiments, at least one additional solubilizing excipient may be present in an amount of from about 62% to about 63% by weight. compositions.

In some embodiments, the at least one additional solubilizing excipient may be a combination of at least two additional solubilizing excipients. In some embodiments, the at least one additional solubilizing excipient may be a combination of at least three additional solubilizing excipients. In some embodiments, the at least one additional solubilizing excipient includes castor oil and glyceryl caprylate. In some embodiments, the at least one additional solubilizing excipient includes castor oil and polysorbate 80. In some embodiments, the at least one additional solubilizing excipient includes glyceryl caprylate and polysorbate 80. In some embodiments, the at least one additional solubilizing excipient includes castor oil, glyceryl caprylate, and polysorbate 80. In some embodiments, the at least one additional solubilizing excipient is a combination of castor oil, glyceryl caprylate, and polysorbate 80.

In some embodiments, the compositions described herein include castor oil in an amount of from about 5% to about 15% by weight. compositions; glyceryl caprylate in an amount of from about 5% to about 15% by weight. compositions; and polysorbate 80 in an amount of from about 20% to about 40% by weight. compositions.

In some embodiments, the compositions described herein include castor oil in an amount of from about 5% to about 15% by weight. compositions; glyceryl caprylate in an amount of from about 5% to about 15% by weight. compositions; and polysorbate 80 in an amount of from about 20% to about 40% by weight. compositions.

In some embodiments, the compositions described herein include castor oil in an amount of from about 8% to about 12% by weight. compositions; glyceryl caprylate in an amount of from about 10% to about 14% by weight. compositions; and polysorbate 80 in an amount of from about 30% to about 35% by weight. compositions.

In some embodiments, the compositions described herein include castor oil in an amount of from about 10% to about 20% by weight. compositions; glyceryl caprylate in an amount of from about 5% to about 15% by weight. compositions; and polysorbate 80 in an amount of from about 20% to about 40% by weight. compositions.

In some embodiments, the compositions described herein include castor oil in an amount of from about 13% to about 18% by weight. compositions; glyceryl caprylate in an amount of from about 10% to about 14% by weight. compositions; and polysorbate 80 in an amount of from about 30% to about 35% by weight. compositions.

In some embodiments, the compositions described herein include castor oil in an amount of from about 5% to about 15% by weight. compositions; glyceryl caprylate in an amount of from about 10% to about 15% by weight. compositions; and polysorbate 80 in an amount of from about 35% to about 45% by weight. compositions.

In some embodiments, the compositions described herein include castor oil in an amount of from about 8% to about 12% by weight. compositions; glyceryl caprylate in an amount of from about 10% to about 15% by weight. compositions; and polysorbate 80 in an amount of from about 38% to about 42% by weight. compositions.

In some embodiments, the at least one additional solubilizing excipient includes diethyl sebacate and diethylene glycol monoethyl ether. In some embodiments, the at least one additional solubilizing excipient includes diethyl sebacate and diethylene glycol monoethyl ether. In some embodiments, the at least one additional solubilizing excipient is a combination of diethyl sebacate and diethylene glycol monoethyl ether. In some embodiments, the at least one additional solubilizing excipient is a combination of diethyl sebacate and diethylene glycol monoethyl ether.

In some embodiments, the compositions described herein include diethyl sebacate in an amount of from about 20% to about 35% by weight. compositions; and diethylene glycol monoethyl ether in an amount of from about 20% to about 35% by weight. compositions. In some embodiments, the compositions described herein include diethyl sebacate in an amount of from about 20% to about 35% by weight. compositions; and diethylene glycol monoethyl ether in an amount of from about 20% to about 35% by weight. compositions.

In some embodiments, the compositions described herein include diethyl sebacate in an amount of from about 25% to about 30% by weight. compositions; and diethylene glycol monoethyl ether in an amount of from about 25% to about 30% by weight. compositions. In some embodiments, the compositions described herein include diethyl sebacate in an amount of from about 25% to about 30% by weight. compositions; and diethylene glycol monoethyl ether in an amount of from about 25% to about 30% by weight. compositions.

In some embodiments, the compositions described herein include diethyl sebacate in an amount of from about 10% to about 20% by weight. compositions; and diethylene glycol monoethyl ether in an amount of from about 30% to about 45% by weight. compositions. In some embodiments, the compositions described herein include diethyl sebacate in an amount of from about 10% to about 20% by weight. compositions; and diethylene glycol monoethyl ether in an amount of from about 30% to about 45% by weight. compositions.

In some embodiments, the compositions described herein include diethyl sebacate in an amount of from about 14% to about 18% by weight. compositions; and diethylene glycol monoethyl ether in an amount of from about 36% to about 40% by weight. compositions. In some embodiments, the compositions described herein include diethyl sebacate in an amount of from about 14% to about 18% by weight. compositions; and diethylene glycol monoethyl ether in an amount of from about 36% to about 40% by weight. compositions.

In some embodiments, the compositions described herein may include an antioxidant and/or a chelating agent. In some embodiments, the compositions described herein may include an antioxidant and/or chelating agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene (BHT), citric acid, potassium metabisulfite, sodium metabisulfite, cysteine, propyl gallate , sodium thiosulfate, vitamin E, 3,4-dihydroxybenzoic acid and combinations thereof. In some embodiments, the compositions described herein may include one or more of ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene (BHT), citric acid, potassium metabisulfite, sodium metabisulfite, propyl gallate, sodium thiosulfate, cysteine, vitamin E, and 3 ,4-dihydroxybenzoic acid.

In some embodiments, the compositions described herein may include an antioxidant in an amount of from about 0.01% to about 0.1% by weight. compositions.

In some embodiments, the compositions described herein may include BHT.

In some embodiments, the compositions described herein may include BHT in an amount of from about 0.01% to about 0.1% by weight. compositions.

In some embodiments, the compositions described herein may include citric acid.

In some embodiments, the compositions described herein may include citric acid in an amount of from about 0.01% to about 0.1% by weight. compositions.

In some embodiments, the compositions described herein may include ascorbyl palmitate.

In some embodiments, the compositions described herein may include ascorbyl palmitate in an amount of from about 0.05% to about 0.15% by weight. compositions.

In some embodiments, the compositions described herein may include BHT and citric acid.

In some embodiments, the compositions described herein may include BHT and citric acid, each in an amount of from about 0.01% to about 0.1% by weight. compositions.

In some embodiments, the compositions described herein may include BHT, citric acid, and ascorbyl palmitate.

In some embodiments, the compositions described herein may include BHT, citric acid, and ascorbyl palmitate, each in an amount of from about 0.05% to about 0.15% by weight. compositions.

In some embodiments, the compositions described herein may include rifaximin in an amount of from about 2.5% to about 15% by weight. compositions.

In some embodiments, the compositions described herein may include rifaximin in an amount of from about 2.5% to about 12% by weight. compositions.

In some embodiments, the compositions described herein may include rifaximin in an amount of from about 5% to about 10% by weight. compositions.

In some embodiments, the compositions described herein may include rifaximin in an amount of from about 1.0% to about 15% by weight. compositions.

In some embodiments, the compositions described herein may include rifaximin in an amount of from about 1.0% to about 5% by weight. compositions.

In some embodiments, the compositions described herein may include rifaximin in an amount that is less than about 125 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 10 mg to about 125 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 25 mg to about 125 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 25 mg to about 75 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 75 mg to about 125 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of about 50 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of about 100 mg.

In some embodiments, the compositions described herein may include rifaximin in an amount that is less than about 125 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 1 mg to about 50 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 1 mg to about 25 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 1 mg to about 10 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 1 mg to about 5 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 2 mg to about 5 mg. In some embodiments, the compositions described herein may include rifaximin in an amount of from about 3 mg to about 4 mg.

In an embodiment, the invention may include a composition comprising about 10% rifaximin, about 10% castor oil, about 12% glyceryl caprylate, about 33% polysorbate 80, and about 35% polyoxyl 40 hydrogenated castor oil, by weight of the composition. In an embodiment, the invention may include a composition comprising about 10% rifaximin, about 10% castor oil, about 12% glyceryl caprylate, about 33% polysorbate 80, and about 35% polyoxyl 40 hydrogenated castor oil, by weight of the composition.

In an embodiment, the invention may include a composition comprising about 10% rifaximin, about 35% polyoxyl 40 hydrogenated castor oil, about 27.5% diethyl sebacate, and about 27.5% diethylene glycol monoethyl ether, by weight of the composition.

In an embodiment, the invention may include a composition comprising about 5% rifaximin, about 15% castor oil, about 12% glyceryl caprylate, about 33% polysorbate 80, and about 35% polyoxyl 40 hydrogenated castor oil, by weight of the composition.

In an embodiment, the invention may include a composition comprising about 10% rifaximin, about 40% polyoxyl 40 hydrogenated castor oil, about 16.5% diethyl sebacate, and about 38.5% diethylene glycol monoethyl ether, by weight of the composition.

In an embodiment, the invention may include a composition comprising about 2.5% rifaximin, about 10% castor oil, about 12% glyceryl caprylate, about 40% polysorbate 80, and about 35% polyoxyl 40 hydrogenated castor oil, by weight of the composition.

In some embodiments, the compositions described herein are liquid compositions. In some embodiments, the compositions described herein may be provided in soft capsule dosage form. In some embodiments, the compositions described herein may be liquid compositions formulated in a soft capsule dosage form. In some embodiments, the compositions described herein can be provided in a dosage form in the form of a hard capsule. In some embodiments, the compositions described herein may be liquid compositions formulated in a hard capsule dosage form. In some embodiments, the compositions described herein may be formulated as gelatin capsules. In some embodiments, the compositions described herein may be liquid compositions formulated in gelatin capsules.

In one embodiment, the invention includes methods for treating one or more diseases in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a composition as described herein. In some embodiments, one or more diseases may include bowel or liver function disorders. In some embodiments, the invention includes methods of treating one or more bowel or liver disorders in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a composition as described herein. In some embodiments, one or more disorders related to bowel or liver function may be selected from the group consisting of irritable bowel syndrome (IBS), such as IBS-D, diarrhea, microorganism-associated diarrhea, infectious diarrhea, Clostridium infections difficile and symptoms, traveler's diarrhea, small intestinal bacterial overgrowth (SIBO), Crohn's disease, diverticular disease, pancreatitis, pancreatic insufficiency, enteritis, ulcerative colitis, antibiotic-associated colitis, hepatic encephalopathy, gastric dyspepsia, cirrhosis, polycystic liver disease, pauchitis , peritonitis, inflammatory bowel disease, rosacea, sickle cell anemia, H. pylori infection, and combinations thereof.

Brief description of the figures

In fig. 1 shows the dissolution results of the composition of the invention 5425-67A compared to placebo (i.e. without rifaximin) 5425-67B, Xifaxan 550 mg (Opadry II) and 40 mg and 80 mg solid dispersion formulations as described in WO 2018/064472 (See also US Application Publication No. 2019-0224175, which is incorporated herein by reference in its entirety.)

In fig. 2 shows the dissolution results of the composition of the invention 5425-66A compared to placebo (i.e. without rifaximin) 5425-66B, Xifaxan 550 mg (Opadry II), and 40 mg and 80 mg solid dispersion formulations as described in WO 2018/ 064472.

In fig. 3 shows the dissolution results of the inventive composition 5425-68A at pH 7.4 compared to placebo (i.e., no rifaximin) 5425-68B, Xifaxan 550 mg (Opadry II), and 40 mg and 80 mg solid dispersion formulations, as described in WO 2018/064472.

In fig. 4 shows the dissolution results of the inventive composition 5425-68A at pH 4.5 compared to placebo (i.e., no rifaximin) 5425-68B, Xifaxan 550 mg (Opadry II), and 40 mg and 80 mg solid dispersion formulations, as described in WO 2018/064472.

In fig. 5 shows the dissolution results of the inventive composition 5425-68A in 0.1 N HCl compared to placebo (i.e., no rifaximin) 5425-68B, Xifaxan 550 mg (Opadry II), and 40 mg and 80 mg solid dispersion formulations, as described in WO 2018/064472.

In fig. 6 shows the dissolution results of the composition of the invention 5425-70A, 5425-70B and 5425-70C at pH 7.4 compared to placebo (i.e. without rifaximin) 5425-66B, Xifaxan 550 mg (Opadry II), and 40 mg and 80 mg solid dispersion formulations as described in WO 2018/064472.

In fig. 7 shows the dissolution results of the composition of the invention 5425-70A, 5425-70B and 5425-70C at pH 4.5 compared to placebo (i.e. without rifaximin) 5425-66B, Xifaxan 550 mg (Opadry II), and 40 mg and 80 mg solid dispersion formulations as described in WO 2018/064472.

In fig. 8 shows the dissolution results of the composition of the invention 5425-70A, 5425-70B and 5425-70C in 0.1 N HCl compared to placebo (i.e. without rifaximin) 5425-66B, Xifaxan 550 mg (Opadry II), and 40 mg and 80 mg solid dispersion formulations as described in WO 2018/064472.

In fig. 9 shows the percentage reduction, as a function of time (minutes), in the level of E. Coli after treatment with the composition of the invention 5507-65A compared to placebo and Xifaxan 550 mg.

In fig. 10 shows the percentage reduction, as a function of time (minutes), in the level of Salmonella choleraesuis after treatment with the composition of the invention 5507-65A compared to placebo and Xifaxan 550 mg.

In fig. 11 shows the percentage reduction, as a function of time (minutes), in the level of Shigella flexneri after treatment with the composition of the invention 5507-65A compared to placebo and Xifaxan 550 mg.

Detailed description

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which the present invention relates.

When ranges are used herein to describe, for example, amounts of specific compounds or ingredients, all combinations and subcombinations of ranges and specific embodiments are intended to be included. The use of the term "about" when referring to a number or numerical range means that the number or numerical range stated is an approximation within experimental variability (or statistical experimental error), and thus the number or numerical range may vary. The term “comprising” (and related terms such as “include” or “comprises” or “having” or “comprising”) includes such embodiments as, for example, an embodiment of any composition of a substance, method or process that “ consist of” or “consist essentially of” the described features.

1. Definitions

“Rifaximin” refers to the antibiotic 4-deoxy-4'-methylpyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV, having the chemical structure depicted in Formula I:

The forms, compositions and methods of use of rifaximin are described, for example, in US Patent No. 7045620, 7906542, 7915275, 8193196, 8309569, 8518949, 8741904, 9737610, all of which are incorporated herein by reference.

The term “low dose rifaximin” means that rifaximin is present in an amount of 150 mg or less.

“Solubilizing excipient” refers to an inactive substance that is included in the disclosed compositions and that has the ability to solubilize active pharmaceutical ingredients (APIs), such as rifaximin. Solubilizing excipients can be used, for example, in oral and injectable dosage forms. In one aspect “solubilizing excipient” refers to an excipient that provides solubility at a saturation of rifaximin of greater than about 10% w/w. See, for example, the procedure for preliminary solubility determination in the illustrative examples section below. Solubilizing excipients include, but are not limited to, pH modifiers. , organic solvents (eg, water-soluble organic solvents), surfactants (eg, nonionic surfactants), lipids (eg, water-soluble lipids), long-chain triglycerides, organic liquids/semi-solids), cyclodextrins, and phospholipids.

The term “solubilize” means to make soluble or increase the solubility of a particular compound, such as rifaximin.

As used herein, “antioxidant” refers to those substances that inhibit the oxidation of rifaximin, for example, in the disclosed composition.

“Hepatic encephalopathy” or “HE” for short is defined as altered mental status, diagnosed as HE, and is defined as an increase in the Conn score to a grade of ≥ 2 (ie, 0 or 1 to ≥ 2). HE may be considered "latent" or "overt" HE (CHE or OHE, respectively) depending on the severity of the symptoms associated with it. HE can be described as a continuum outlined by the West Haven Criteria (WHC): Grade 0 - minimal hepatic encephalopathy with symptoms potentially including impairment of complex and sustained attention; Grade 1 (CHE) - symptoms include trivial lack of awareness, euphoria or restlessness, decreased concentration, impaired addition or subtraction, and changes in sleep rhythm, where clinical findings include mild asterixis or tremor; Grade 2 (OHE) - Symptoms include lethargy or apathy, disorientation over time, obvious personality changes and inappropriate behavior, where clinical findings include obvious asterixis, dyspraxia and slurred speech; Grade 3 (OHE) - Symptoms include drowsiness, sensitivity to stimuli, confusion, gross disorientation and strange behavior, where clinical manifestations include muscle rigidity, clonus and hyperreflexia; and Grade 4 (OHE) - Symptoms include coma, where clinical signs include decerebrate posturing. OHE can also be observed using the Hepatic Encephalopathy Index (HEGI) score, which uses clinical signs (present for at least 1 hour) to measure the patient's confusion and thus the severity of the HE episode (on a scale from grade 2 to grade 4) -grade 4 is the most severe, grade 2 is the least severe.

“Esophageal variceal bleeding” or “EVB” for short is defined as the occurrence of clinically significant gastrointestinal bleeding, defined as 1) bleeding from esophageal or gastric varices during endoscopy or 2) the presence of large varices with visible blood in the stomach and no other identifiable cause of bleeding detected during endoscopy, and at least one or more of the following criteria are present: i) a drop in hemoglobin of more than 2 g/dL within the first 48 hours after hospitalization, ii) the need for a transfusion of 2 units blood or more within 24 hours of hospitalization, iii) systolic blood pressure less than 100 mmHg. Art. or iv) pulse rate greater than 100 beats per minute on presentation.

“Spontaneous bacterial peritonitis” or “SBP” for short is defined as more than 250 polymorphonuclear (PMN) cells/mm ³ and/or a positive monomicrobial culture in ascitic fluid.

“Hepatorenal syndrome” (HRS) is defined as i) a progressive increase in serum creatinine (>1.5 mg/dL) without improvement at least 2 days after discontinuation of diuretics and volume expansion with albumin, ii) absence of parenchymal renal disease , iii) oliguria, iv) absence of shock, and v) absence of current or recent (within 3 months before randomization) treatment with nephrotoxic drugs.

The term "effective amount" or "therapeutically effective amount" refers to the amount of a composition described herein that will produce a biological or medical response in a subject, for example, a composition containing a dose of rifaximin from about 0.001 to about 100 mg/kg body weight/day .

As used herein, the terms “subject” and “patient” may be used interchangeably and mean mammals in need of treatment, such as domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.) and laboratory animals (for example, rats, mice, guinea pigs, etc.). Typically, the subject is a person in need of treatment.

"Pharmaceutically acceptable" means molecular compounds and compositions that do not cause an adverse, allergic or other undesirable reaction when administered to an animal or human, as the case may be.

The terms “treating,” “treating,” and “treating” refer to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progression of a disease or disorder or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e. therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be prescribed to a predisposed individual prior to the onset of symptoms (eg, based on a history of symptoms and/or genetic or other susceptibility factors), i.e. preventive treatment. Treatment can also be continued after symptoms have disappeared, for example to prevent or delay their recurrence.

2. Compositions

Disclosed herein are pharmaceutical compositions in which gut levels of soluble rifaximin are significantly increased compared to Xifaxan® powder. See, for example, Table 8, which demonstrates a more than 150-fold increase in solubility compared to Xifaxan® powder. As shown herein, the percentage of available soluble rifaximin was observed in phosphate buffer at pH 7.4. Increased solubility when using the disclosed compositions was also observed in intestinal fluid. See, for example, Tables 6A and 6B. In addition, the effect of antioxidant supplements was investigated and shown in Table 7.

The solubility results and additional data described herein suggest that the disclosed compositions provide a means for administering lower doses of rifaximin without compromising therapeutic efficacy. Such compositions include, for example, pharmaceutically acceptable compositions containing rifaximin (eg, low dose rifaximin), hydrogenated castor oil, and at least one additional solubilizing excipient. Also provided are dosage forms containing one or more of the disclosed compositions and their use for the treatment of disorders associated with intestinal or liver function.

Rifaximin, hydrogenated castor oil , and at least one additional solubilizing excipient

In a first embodiment, provided herein are pharmaceutically acceptable compositions comprising rifaximin, hydrogenated castor oil, and at least one additional solubilizing excipient. Alternatively, as part of the first embodiment, the rifaximin may be low dose rifaximin.

In the second embodiment, the hydrogenated castor oil in the disclosed compositions, for example, as in the first embodiment, is selected from Polyoxyl 8 hydrogenated castor oil, Polyoxyl 10 hydrogenated castor oil, Polyoxyl 16 hydrogenated castor oil, Polyoxyl 20 hydrogenated castor oil, Polyoxyl 25 hydrogenated castor oil , Polyoxyl 35 Hydrogenated Castor Oil, Polyoxyl 40 Hydrogenated Castor Oil (e.g. Cremophor® RH-40), Polyoxyl 45 Hydrogenated Castor Oil, Polyoxyl 50 Hydrogenated Castor Oil, Polyoxyl 54 Hydrogenated Castor Oil, Polyoxyl 55 Hydrogenated Castor Oil, Polyoxyl 60 Hydrogenated Castor Oil oils, polyoxyl 65 hydrogenated castor oil, polyoxyl 80 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil and polyoxyl 200 hydrogenated castor oil, and combinations thereof. Alternatively, as part of the second embodiment, the hydrogenated castor oil in the disclosed compositions, for example, as in the first embodiment, is polyoxyl 60 hydrogenated castor oil or polyoxyl 40 hydrogenated castor oil. In another embodiment, as part of the second embodiment, the hydrogenated castor oil in the disclosed compositions, for example, as in the first embodiment, is polyoxyl 40 hydrogenated castor oil (eg, Cremophor® RH-40).

In a third embodiment, the hydrogenated castor oil in the disclosed compositions, for example, as in the first embodiment or the second embodiment, is present in an amount of from about 25% to about 65%, from about 25% to about 60%, from about 25% to about 55%, from about 25% to about 50%, from about 30% to about 45%, from about 35% to about 40%, from about 30% to about 40%, from about 31% to about 39%, from about 32% to about 38%, about 33% to about 37%, about 34% to about 36%, about 40% to about 50%, about 41% to about 49%, about 42% to about 48 %, from about 43% to about 47%, or from about 44% to about 46%; or is present in an amount of at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38 %, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45% , at least about 46%, at least about 47%, at least about 48%, at least about 49%, or at least about 50%; or is present in an amount of no more than about 25%, no more than about 26%, no more than about 27%, no more than about 28%, no more than about 29%, no more than about 30%, no more than about 31%, no more than about 32 %, not more than about 33%, not more than about 34%, not more than about 35%, not more than about 36%, not more than about 37%, not more than about 38%, not more than about 39%, not more than about 40%, not more than about 41%, not more than about 42%, not more than about 43%, not more than about 44%, not more than about 45%, not more than about 46%, not more than about 47%, not more than about 48%, not more about 49%, or not more than about 50%; or about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49% , or approximately 50%; or present in amounts of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36 %, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, about 49%, or about 50%, by weight of the composition.

In an alternative third embodiment, the hydrogenated castor oil in the disclosed compositions, for example, as in the first embodiment or the second embodiment, is present in an amount of from about 25% to about 65%, from about 25% to about 60%, from about 25% to about 55%, from about 25% to about 50%, from about 30% to about 45%, from about 35% to about 40%, from about 30% to about 40%, from about 31% to about 39%, from about 32% to about 38%, from about 33% to about 37%, from about 34% to about 36%, from about 40% to about 50%, from about 41% to about 49%, from about 42% to about 48%, about 43% to about 47%, or about 44% to about 46%; or is present in an amount of at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38 %, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45% , at least about 46%, at least about 47%, at least about 48%, at least about 49%, or at least about 50%; or is present in an amount of no more than about 25%, no more than about 26%, no more than about 27%, no more than about 28%, no more than about 29%, no more than about 30%, no more than about 31%, no more than about 32 %, not more than about 33%, not more than about 34%, not more than about 35%, not more than about 36%, not more than about 37%, not more than about 38%, not more than about 39%, not more than about 40%, not more than about 41%, not more than about 42%, not more than about 43%, not more than about 44%, not more than about 45%, not more than about 46%, not more than about 47%, not more than about 48%, not more about 49%, or not more than about 50%; or about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49% , or approximately 50%; or present in amounts of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36 %, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, about 49%, or about 50%, by weight of the total weight of rifaximin, hydrogenated castor oil and at least one additional solubilizing excipient of the composition.

In a fourth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of embodiments one through three, is selected from a water-soluble organic solvent (e.g., polyethylene glycol (e.g., PEG 300, PEG 400, and PEG 600 ), ethanol, propylene glycol, benzyl alcohol, oleyl alcohol, triethylene glycol, n-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, diethylene glycol monoethyl ether (e.g. transcutol® HP and P grades), diisopropyl adipate and diethyl sebacate), non-ionic surfactant (e.g. PEG-8 castor oil, PEG-9 castor oil, PEG-10 castor oil, PEG-11 castor oil, PEG-15 castor oil, PEG-16 castor oil, PEG-20 castor oil, PEG-25 castor oil , PEG-26 castor oil, PEG-29 castor oil, PEG-40 castor oil, PEG-44 castor oil, PEG-50 castor oil, PEG-54 castor oil, PEG-55 castor oil, PEG-60 castor oil, PEG -75 castor oil, PEG-80 castor oil, PEG-100 castor oil, PEG-200 castor oil, polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, polyoxyethylene esters of 12-hydroxystearic acid, sorbitan monooleate, poloxamer 407, oleoyl macrogol-6/ polyoxyl-6 glycerides, caprylocaproyl macrogol-8/polyoxyl-8 glycerides, PEG-6 caprylic/capric glycerides, lauroyl polyoxyl-32 glycerides, and mono- and difatty acid esters of PEG 300, PEG 400 or PEG 1750), water-insoluble lipids ( for example, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil and medium chain triglycerides of coconut oil and palm oil), organic liquids/ semisolids (e.g., beeswax, d-α-tocopherol, oleic acid, and medium-chain mono-, di-, and triglycerides (e.g., glyceryl caprylate, glyceryl monooleate, glyceryl monolinoleate, and caprylic/capric triglycerides)), cyclodextrins, (e.g., α-cyclodextrin, β-cyclodextrin, and hydroxypropyl-β-cyclodextrin), and phospholipids (eg, hydrogenated soy phosphatidylcholine).

In a fifth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through fourth embodiments, is selected from a water-soluble organic solvent, a nonionic surfactant, a water-insoluble lipid, and long-chain triglycerides, and combinations thereof . Alternatively, as part of the fourth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through fourth embodiments, is selected from polyethylene glycol 600, glyceryl caprylate, polysorbate 80, castor oil, benzyl alcohol, polyethylene glycol 400 , diethylene glycol monoethyl ether, glyceryl monooleate, triethylene glycol, diisopropyl adipate, diethyl sebacate, oleyl alcohol, polysorbate 20, oleic acid, caprylic/capric triglycerides, propylene glycol, sesame oil, soybean oil and corn oil, and combinations thereof.

In a sixth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through fifth embodiments, is one that provides a solubility at saturation of rifaximin greater than about 10% w/w. (e.g., more than about 11% w/w, more than about 12% w/w, more than about 13% w/w, more than about 14% w/w, more than about 15% w/w wt., more than about 16% wt./wt., more than about 17% wt./wt., more than about 18% wt./wt., more than about 19% wt./wt., or more than about 20% wt. /mass.). Alternatively, as part of the sixth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through fifth embodiments, is one that provides a rifaximin solubility at saturation of about 10% w/w . to about 25% w/w, from about 12% w/w. to about 25% w/w, from about 12% w/w. to about 23% w/w, from about 13% w/w. to about 23% w/w or from about 14% w/w. to about 22% w/w

In the seventh embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through sixth embodiments, is selected from polyethylene glycol 600, glyceryl caprylate, polysorbate 80, castor oil, benzyl alcohol, polyethylene glycol 400, monoethyl diethylene glycol ether, glyceryl monooleate, triethylene glycol, diisopropyl adipate, diethyl sebacate, oleyl alcohol, and combinations thereof. Alternatively, as part of the seventh embodiment, at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through sixth embodiments, is selected from castor oil, glyceryl caprylate, polysorbate 80, diethyl sebacate, and diethylene glycol monoethyl ether, and thereof combinations.

In the eighth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through seventh embodiments, is present in an amount of from about 25% to about 70%, from about 25% to about 65% , from about 30% to about 65%, from about 35% to about 65%, from about 40% to about 65%, from about 40% to about 70%, from about 45% to about 65%, from about 46% to about 65%, from about 47% to about 65%, from about 48% to about 65%, from about 49% to about 65%, from about 50% to about 65%, from about 45% to about 60%, from about 46% to about 60%, from about 47% to about 60%, from about 48% to about 60%, from about 49% to about 60%, from about 50% to about 60%, from about 51% to about 60%, about 52% to about 60%, about 53% to about 60%, about 54% to about 60%, or about 55% to about 60%; or is present in an amount of at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38 %, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45% , at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, according to at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least at least about 67%, at least about 68%, at least about 69%, or at least about 70%; or is present in an amount of no more than about 25%, no more than about 26%, no more than about 27%, no more than about 28%, no more than about 29%, no more than about 30%, no more than about 31%, no more than about 32 %, not more than about 33%, not more than about 34%, not more than about 35%, not more than about 36%, not more than about 37%, not more than about 38%, not more than about 39%, not more than about 40%, not more than about 41%, not more than about 42%, not more than about 43%, not more than about 44%, not more than about 45%, not more than about 46%, not more than about 47%, not more than about 48%, not more about 49%, not more than about 50%, not more than about 51%, not more than about 52%, not more than about 53%, not more than about 54%, not more than about 55%, not more than about 56%, not more than about 57 %, not more than about 58%, not more than about 59%, not more than about 60%, not more than about 61%, not more than about 62%, not more than about 63%, not more than about 64%, not more than about 65%, no more than about 66%, no more than about 67%, no more than about 68%, no more than about 69%, or no more than about 70%; or present in amounts of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36 %, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, or about 70%, wt. compositions. Alternatively, as part of the eighth embodiment, at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through seventh embodiments, is present in an amount of from about 51% to about 59%, from about 52% to about 58%, from about 53% to about 57%, or from about 54% to about 56% of the mass. compositions. Alternatively, as part of the eighth embodiment, at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through seventh embodiments, is present in an amount of from about 59% to about 66%, from about 60% to about 65%, from about 61% to about 64%, or from about 62% to about 63% of the mass. compositions.

In an alternative eighth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through seventh embodiments, is present in an amount of from about 40% to about 70%, from about 45% to about 65% , from about 46% to about 65%, from about 47% to about 65%, from about 48% to about 65%, from about 49% to about 65%, from about 50% to about 65%, from about 45% to about 60%, from about 46% to about 60%, from about 47% to about 60%, from about 48% to about 60%, from about 49% to about 60%, from about 50% to about 60%, from about 51% to about 60%, from about 52% to about 60%, from about 53% to about 60%, from about 54% to about 60%, from about 55% to about 65%, from about 62% to about 63%, or about 55% to about 60%; or is present in an amount of at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53 %, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60% , at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, or at least about 70%; or is present in an amount of not more than about 40%, not more than about 41%, not more than about 42%, not more than about 43%, not more than about 44%, not more than about 45%, not more than about 46%, not more than about 47 %, not more than about 48%, not more than about 49%, not more than about 50%, not more than about 51%, not more than about 52%, not more than about 53%, not more than about 54%, not more than about 55%, not more than about 56%, not more than about 57%, not more than about 58%, not more than about 59%, not more than about 60%, not more than about 61%, not more than about 62%, not more than about 63%, not more about 64%, not more than about 65%, not more than about 66%, not more than about 67%, not more than about 68%, not more than about 69%, or not more than about 70%; or present in amounts of about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, or about 70%, by weight, of the total weight of rifaximin, hydrogenated castor oil, and at least one additional solubilizing excipient of the composition. Alternatively, as part of the eighth embodiment, at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through seventh embodiments, is present in an amount of from about 51% to about 59%, from about 52% to about 58%, about 53% to about 57%, or about 54% to about 56% by weight of the total weight of rifaximin, hydrogenated castor oil, and at least one additional solubilizing excipient of the composition.

In some embodiments of any of the first through eighth embodiments, the hydrogenated castor oil and at least one additional solubilizing excipient may be provided in a ratio of about 1:3 and about 1.5:1, respectively, by weight of the hydrogenated castor oil and by weight at least one additional solubilizing excipient. In some embodiments of any of the first through eighth embodiments, the hydrogenated castor oil and at least one additional solubilizing excipient may be provided in a ratio of about 1:3 to about 1.5:1, respectively, by weight of the hydrogenated castor oil and at least one additional solubilizing excipient.

In some embodiments of any of the first through eighth embodiments, the hydrogenated castor oil and at least one additional solubilizing excipient may be provided in a ratio of about 1:1 and about 1:2.5, respectively, by weight of the hydrogenated castor oil and by weight at least one additional solubilizing excipient. In some embodiments of any of the first through eighth embodiments, the hydrogenated castor oil and at least one additional solubilizing excipient may be provided in a ratio of from about 1:1 to about 1:2.5, respectively, by weight of the hydrogenated castor oil and at least one additional solubilizing excipient.

Rifaximin, hydrogenated castor oil , castor oil, glyceryl caprylate and polysorbate 80

In a ninth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of embodiments one through eight, is a combination of castor oil, glyceryl caprylate, and polysorbate 80.

In a tenth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of embodiments one through nine, is a combination of castor oil, glyceryl caprylate, and polysorbate 80, wherein:

castor oil is present in an amount of from about 5% to about 15%, or from about 6% to about 14%, or from about 7% to about 13%, or from about 8% to about 12%, or from about 9% to approximately 11%; or is present in an amount of at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%; or is present in an amount of not more than about 5%, not more than about 6%, not more than about 7%, not more than about 8%, not more than about 9%, not more than about 10%, not more than about 11%, not more than about 12 %, no more than about 13%, no more than about 14%, or no more than about 15%; or is present in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, by weight . compositions;

glyceryl caprylate is present in an amount of from about 5% to about 15%, or from about 10% to about 15%, or from about 38% to about 42%, or from about 6% to about 14%, or from about 7% to about 13%, or from about 8% to about 12%, or from about 9% to about 11%; or is present in an amount of at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%; or is present in an amount of not more than about 5%, not more than about 6%, not more than about 7%, not more than about 8%, not more than about 9%, not more than about 10%, not more than about 11%, not more than about 12 %, no more than about 13%, no more than about 14%, or no more than about 15%; or is present in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, by weight. compositions; And

polysorbate 80 is present in an amount of from about 20% to about 40%, 35% to about 45%, or from about 25% to about 40%, or from about 27% to about 40%, or from about 25% to about 37% , or from about 27% to about 37%, or from about 28% to about 36%, or from about 30% to about 35%, or from about 32% to about 35%; or is present in an amount of at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38 %, at least about 39%, or at least about 40%; or is present in an amount of no more than about 25%, no more than about 26%, no more than about 27%, no more than about 28%, no more than about 29%, no more than about 30%, no more than about 31%, no more than about 32 %, not more than about 33%, not more than about 34%, not more than about 35%, not more than about 36%, not more than about 37%, not more than about 38%, not more than about 39%, or not more than about 40% ; or present in amounts of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36 %, about 37%, about 38%, about 39%, or about 40%, wt. compositions.

Alternatively, as part of the tenth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through ninth embodiments, is a combination of castor oil, glyceryl caprylate and polysorbate 80, wherein the castor oil is present in an amount of from about 8% to about 12% wt. compositions; glyceryl caprylate is present in an amount of from about 10% to about 14% by weight. compositions; and polysorbate 80 is present in an amount of from about 30% to about 35% by weight. compositions. In another embodiment, as part of the tenth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through ninth embodiments, is a combination of castor oil, glyceryl caprylate and polysorbate 80, wherein:

castor oil is present in an amount of from about 10% to about 20% (e.g., from about 11% to about 19%, from about 12% to about 18%, from about 13% to about 17%, or from about 14% to about 16%), or present in an amount of at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, or at least about 20%, or present in an amount of no more than about 10%, no more than about 11% , not more than about 12%, not more than about 13%, not more than about 14%, not more than about 15%, not more than about 16%, not more than about 17%, not more than about 18%, not more than about 19%, or no more than about 20%, or present in an amount of about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or approximately 20%, wt. compositions;

glyceryl caprylate is present in an amount of from about 5% to about 15% (e.g., from about 6% to about 14%, from about 7% to about 13%, from about 8% to about 12%, or from about 9% to about 11 %), or is present in an amount of at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, according to at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%, or present in an amount of no more than about 5%, no more than about 6%, no more than about 7%, no more than about 8%, no more than about 9%, no more than about 10%, no more than about 11%, no more than about 12%, no more than about 13%, no more than about 14%, or not more than about 15%, or present in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, wt. compositions; And

polysorbate 80 is present in an amount of from about 20% to about 40% (e.g., from about 25% to about 40%, from about 27% to about 40%, from about 25% to about 37%, from about 27% to about 37 %, from about 28% to about 36%, from about 30% to about 35%, or from about 32% to about 35%), or present in an amount of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36 %, at least about 37%, at least about 38%, at least about 39%, or at least about 40%, or present in an amount of no more than about 20%, no more than about 21%, no more than about 22 %, not more than about 23%, not more than about 24%, not more than about 25%, not more than about 26%, not more than about 27%, not more than about 28%, not more than about 29%, not more than about 30%, not more than about 31%, not more than about 32%, not more than about 33%, not more than about 34%, not more than about 35%, not more than about 36%, not more than about 37%, not more than about 38%, not more about 39%, or not more than about 40%, or present in amounts of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28% , about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40%, wt. . compositions.

In another embodiment, as part of the tenth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through ninth embodiments, is a combination of castor oil, glyceryl caprylate and polysorbate 80, wherein castor oil is present in in an amount of from about 13% to about 18% by weight. compositions; glyceryl caprylate is present in an amount of from about 10% to about 14% by weight. compositions; and polysorbate 80 is present in an amount of from about 30% to about 35% by weight. compositions.

In an alternative tenth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of embodiments one through nine, is a combination of castor oil, glyceryl caprylate, and polysorbate 80, wherein:

castor oil is present in an amount of from about 5% to about 15%, or from about 6% to about 14%, or from about 7% to about 13%, or from about 8% to about 12%, or from about 9% to approximately 11%; or is present in an amount of at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%; or is present in an amount of not more than about 5%, not more than about 6%, not more than about 7%, not more than about 8%, not more than about 9%, not more than about 10%, not more than about 11%, not more than about 12 %, no more than about 13%, no more than about 14%, or no more than about 15%; or is present in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, according to weight based on the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80;

glyceryl caprylate is present in an amount of from about 5% to about 15%, or from about 6% to about 14%, or from about 7% to about 13%, or from about 8% to about 12%, or from about 9% to about eleven%; or is present in an amount of at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%; or is present in an amount of not more than about 5%, not more than about 6%, not more than about 7%, not more than about 8%, not more than about 9%, not more than about 10%, not more than about 11%, not more than about 12 %, not more than about 13%, not more than about 14%, or not more than about 15%; or is present in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, according to weight based on the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80; And

polysorbate 80 is present in an amount of from about 20% to about 40%, or from about 25% to about 40%, or from about 27% to about 40%, or from about 25% to about 37%, or from about 27% to approximately 37%, or from about 28% to about 36%, or from about 30% to about 35%, or from about 32% to about 35%; or is present in an amount of at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38 %, at least about 39%, or at least about 40%; or is present in an amount of no more than about 25%, no more than about 26%, no more than about 27%, no more than about 28%, no more than about 29%, no more than about 30%, no more than about 31%, no more than about 32 %, not more than about 33%, not more than about 34%, not more than about 35%, not more than about 36%, not more than about 37%, not more than about 38%, not more than about 39%, or not more than about 40% ; or present in amounts of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36 %, about 37%, about 38%, about 39%, or about 40%, by weight, of the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate, and polysorbate 80.

Alternatively, as part of the tenth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through ninth embodiments, is a combination of castor oil, glyceryl caprylate and polysorbate 80, wherein the castor oil is present in an amount of from about 8% to about 12% by weight of the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80; glyceryl caprylate is present in an amount of from about 10% to about 14% by weight of the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80; and polysorbate 80 is present in an amount of from about 30% to about 35% by weight of the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80. In another embodiment, as part of the tenth embodiment, at least one additional solubilizing excipient in the disclosed compositions , for example, as in any of embodiments one through nine, is a combination of castor oil, glyceryl caprylate, and polysorbate 80, wherein:

castor oil is present in an amount of from about 10% to about 20% (e.g., from about 11% to about 19%, from about 12% to about 18%, from about 13% to about 17%, or from about 14% to about 16%), or is present in an amount of at least about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%, or is present in an amount not more than about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%, or present in an amount of about 10%, 11%, 12%, 13 %, 14%, 15%, 16%, 17%, 18%, 19% or 20%, by weight, of the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80;

glyceryl caprylate is present in an amount of from about 5% to about 15% (e.g., from about 6% to about 14%, from about 7% to about 13%, from about 8% to about 12%, or from about 9% to about 11 %), or is present in an amount of at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, according to at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%, or present in an amount of no more than about 5%, no more than about 6%, no more than about 7%, no more than about 8%, no more than about 9%, no more than about 10%, no more than about 11%, no more than about 12%, no more than about 13%, no more than about 14%, or not more than about 15%, or present in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, by weight of the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80; And

polysorbate 80 is present in an amount of from about 20% to about 40% (e.g., from about 25% to about 40%, from about 27% to about 40%, from about 25% to about 37%, from about 27% to about 37 %, from about 28% to about 36%, from about 30% to about 35%, or from about 32% to about 35%), or present in an amount of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36 %, at least about 37%, at least about 38%, at least about 39%, or at least about 40%, or present in an amount of no more than about 20%, no more than about 21%, no more than about 22 %, not more than about 23%, not more than about 24%, not more than about 25%, not more than about 26%, not more than about 27%, not more than about 28%, not more than about 29%, not more than about 30%, not more than about 31%, not more than about 32%, not more than about 33%, not more than about 34%, not more than about 35%, not more than about 36%, not more than about 37%, not more than about 38%, not more about 39%, or not more than about 40%, or present in amounts of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28% , about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40%, according to weight based on the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80.

In another embodiment, as part of the tenth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through ninth embodiments, is a combination of castor oil, glyceryl caprylate and polysorbate 80, wherein castor oil is present in an amount of from about 13% to about 18% by weight of the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80; glyceryl caprylate is present in an amount of from about 10% to about 14% by weight. compositions; and polysorbate 80 is present in an amount of from about 30% to about 35% by weight of the total weight of rifaximin, hydrogenated castor oil, glyceryl caprylate and polysorbate 80.

In another embodiment, as part of the tenth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through ninth embodiments, is a combination of castor oil, glyceryl caprylate and polysorbate 80, wherein castor oil is present in in an amount of from about 5% to about 15% by weight. compositions; glyceryl caprylate is present in an amount of from about 10% to about 15% by weight. compositions; and polysorbate 80 is present in an amount of from about 35% to about 45% by weight. compositions.

In another embodiment, as part of the tenth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through ninth embodiments, is a combination of castor oil, glyceryl caprylate and polysorbate 80, wherein castor oil is present in in an amount of from about 8% to about 12% by weight. compositions; glyceryl caprylate is present in an amount of from about 10% to about 15% by weight. compositions; and polysorbate 80 is present in an amount of from about 38% to about 42% by weight. compositions.

Rifaximin, hydrogenated castor oil, diethyl sebacate and diethylene glycol monoethyl ether

In an eleventh embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through eighth embodiments, is a combination of diethyl sebacate and diethylene glycol monoethyl ether. Alternatively, as part of the eleventh embodiment, the diethylene glycol monoethyl ether is diethylene glycol monoethyl ether.

In a twelfth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through eighth and eleventh embodiments, is a combination of diethyl sebacate and diethylene glycol monoethyl ether, wherein:

diethyl sebacate is present in an amount of from about 20% to about 35%, or from about 21% to about 34%, or from about 22% to about 33%, or from about 23% to about 32%, or from about 24% to about 31%, or about 25% to about 30%, or about 26% to about 29%, or about 26% to about 38%, or about 27% to about 28%, is present in an amount of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27 %, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34% or at least about 35%, or present in an amount of no more than about 20%, no more than about 21%, no more than about 22%, no more than about 23%, no more than about 24%, no more than about 25%, no more about 26%, not more than about 27%, not more than about 28%, not more than about 29%, not more than about 30%, not more than about 31%, not more than about 32%, not more than about 33%, not more than about 34 %, or not more than about 35%, or present in amounts of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34% or about 35%, wt. compositions; And

diethylene glycol monoethyl ether is present in an amount of from about 20% to about 35%, or from about 21% to about 34%, or from about 22% to about 33%, or from about 23% to about 32%, or from about 24% to about 31%, or from about 25% to about 30%, or from about 26% to about 29%, or from about 26% to about 38%, or from about 27% to about 28%, present in an amount of at least at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34% or at least about 35%, or present in an amount of no more than about 20%, no more than about 21%, no more than about 22%, no more than about 23%, no more than about 24%, no more than about 25%, not more than about 26%, not more than about 27%, not more than about 28%, not more than about 29%, not more than about 30%, not more than about 31%, not more than about 32%, not more than about 33%, not more about 34%, or not more than about 35%, or present in amounts of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28% , about 29%, about 30%, about 31%, about 32%, about 33%, about 34% or about 35%, wt. compositions.

Alternatively, as part of the twelfth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through eighth and eleventh embodiments, is a combination of diethyl sebacate and diethylene glycol monoethyl ether, wherein diethyl sebacate is present in an amount of about 25% to about 30% wt. compositions; and diethylene glycol monoethyl ether is present in an amount of from about 25% to about 30% by weight. compositions. In another embodiment, as part of the twelfth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through eighth and eleventh embodiments, is a combination of diethyl sebacate and diethylene glycol monoethyl ether, wherein:

diethyl sebacate is present in an amount of from about 10% to about 20%, or from about 11% to about 19%, or from about 12% to about 18%, or from about 13% to about 18%, or from about 14% to about 18%, or from about 15% to about 18%, or from about 16% to about 18%, or from about 16% to about 17%, or present in an amount of at least about 10%, at least about 11% , at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19% or at least about 20%, or present in an amount of no more than about 10%, no more than about 11%, no more than about 12%, no more than about 13%, no more than about 14%, no more about 15%, not more than about 16%, not more than about 17%, not more than about 18%, not more than about 19%, or not more than about 20%, or present in an amount of about 10%, about 11%, about 12% , about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, wt. compositions; And

diethylene glycol monoethyl ether is present in an amount of from about 30% to about 45%, or from about 31% to about 44%, or from about 32% to about 43%, or from about 33% to about 42%, or from about 34% to about 41%, or from about 35% to about 40%, or from about 36% to about 49%, or from about 37% to about 49%, or present in an amount of at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38 %, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, or at least about 45% , or present in an amount of no more than about 30%, no more than about 31%, no more than about 32%, no more than about 33%, no more than about 34%, no more than about 35%, no more than about 36%, no more than about 37%, not more than about 38%, not more than about 39%, not more than about 40%, not more than about 41%, not more than about 42%, not more than about 43%, not more than about 44%, or not more than about 45 %, or present in amounts of about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44% or about 45%, wt. compositions.

In another embodiment, as part of the twelfth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through eighth and eleventh embodiments, is a combination of diethyl sebacate and diethylene glycol monoethyl ether, wherein diethyl sebacate is present in the amount from about 14% to about 18% by weight. compositions; and diethylene glycol monoethyl ether is present in an amount of from about 36% to about 40% by weight. compositions.

In an alternative twelfth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through eighth and eleventh embodiments, is a combination of diethyl sebacate and diethylene glycol monoethyl ether, wherein:

diethyl sebacate is present in an amount of from about 20% to about 35%, or from about 21% to about 34%, or from about 22% to about 33%, or from about 23% to about 32%, or from about 24% to about 31%, or about 25% to about 30%, or about 26% to about 29%, or about 26% to about 38%, or about 27% to about 28%, is present in an amount of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27 %, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34% or at least about 35%, or present in an amount of no more than about 20%, no more than about 21%, no more than about 22%, no more than about 23%, no more than about 24%, no more than about 25%, no more about 26%, not more than about 27%, not more than about 28%, not more than about 29%, not more than about 30%, not more than about 31%, not more than about 32%, not more than about 33%, not more than about 34 %, or not more than about 35%, or present in amounts of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35%, by weight, based on the total weight of rifaximin, hydrogenated castor oil, diethyl sebacate, and diethylene glycol monoethyl ether; And

diethylene glycol monoethyl ether is present in an amount of from about 20% to about 35%, or from about 21% to about 34%, or from about 22% to about 33%, or from about 23% to about 32%, or from about 24% to about 31%, or from about 25% to about 30%, or from about 26% to about 29%, or from about 26% to about 38%, or from about 27% to about 28%, present in an amount of at least at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34% or at least about 35%, or present in an amount of no more than about 20%, no more than about 21%, no more than about 22%, no more than about 23%, no more than about 24%, no more than about 25%, not more than about 26%, not more than about 27%, not more than about 28%, not more than about 29%, not more than about 30%, not more than about 31%, not more than about 32%, not more than about 33%, not more about 34%, or not more than about 35%, or present in amounts of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28% , about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35%, by weight, of the total weight of rifaximin, hydrogenated castor oil, diethyl sebacate and diethylene glycol monoethyl ether. Alternatively, as part of the twelfth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through eighth and eleventh embodiments, is a combination of diethyl sebacate and diethylene glycol monoethyl ether, wherein diethyl sebacate is present in an amount of about 25% to about 30% by weight of the total weight of rifaximin, hydrogenated castor oil, diethyl sebacate and diethylene glycol monoethyl ether; and diethylene glycol monoethyl ether is present in an amount of from about 25% to about 30% by weight of the total weight of rifaximin, hydrogenated castor oil, diethyl sebacate and diethylene glycol monoethyl ether. In another embodiment, as part of the twelfth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through eighth and eleventh embodiments, is a combination of diethyl sebacate and diethylene glycol monoethyl ether, wherein:

diethyl sebacate is present in an amount of from about 10% to about 20%, or from about 11% to about 19%, or from about 12% to about 18%, or from about 13% to about 18%, or from about 14% to about 18%, or from about 15% to about 18%, or from about 16% to about 18%, or from about 16% to about 17%, or present in an amount of at least about 10%, at least about 11% , at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19% or at least about 20%, or present in an amount of no more than about 10%, no more than about 11%, no more than about 12%, no more than about 13%, no more than about 14%, no more about 15%, not more than about 16%, not more than about 17%, not more than about 18%, not more than about 19%, or not more than about 20%, or present in an amount of about 10%, about 11%, about 12% , about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, by weight, of the total weight of rifaximin, hydrogenated castor oil, diethyl sebacate and diethylene glycol monoethyl ether; And

diethylene glycol monoethyl ether is present in an amount of from about 30% to about 45%, or from about 31% to about 44%, or from about 32% to about 43%, or from about 33% to about 42%, or from about 34% to about 41%, or from about 35% to about 40%, or from about 36% to about 49%, or from about 37% to about 49%, or present in an amount of at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38 %, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, or at least about 45% , or present in an amount of no more than about 30%, no more than about 31%, no more than about 32%, no more than about 33%, no more than about 34%, no more than about 35%, no more than about 36%, no more than about 37%, not more than about 38%, not more than about 39%, not more than about 40%, not more than about 41%, not more than about 42%, not more than about 43%, not more than about 44%, or not more than about 45 %, or present in amounts of about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45%, by weight, of the total weight of rifaximin, hydrogenated castor oil, diethyl sebacate and diethylene glycol monoethyl ether.

In another embodiment, as part of the twelfth embodiment, the at least one additional solubilizing excipient in the disclosed compositions, for example, as in any of the first through eighth and eleventh embodiments, is a combination of diethyl sebacate and diethylene glycol monoethyl ether, wherein diethyl sebacate is present in the amount from about 14% to about 18% by weight of the total weight of rifaximin, hydrogenated castor oil, diethyl sebacate and diethylene glycol monoethyl ether; and diethylene glycol monoethyl ether is present in an amount of from about 36% to about 40% by weight of the total weight of rifaximin, hydrogenated castor oil, diethyl sebacate and diethylene glycol monoethyl ether.

Antioxidants/chelating agents

In a thirteenth embodiment, the compositions described herein, for example, as in any of the first through twelfth embodiments, further comprise an antioxidant and/or a chelating agent.

In a fourteenth embodiment, the compositions described herein, for example, as in any of embodiments one through thirteen, further comprise an antioxidant and/or chelating agent selected from ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E and 3,4-dihydroxybenzoic acid. Without being limited to any one theory of the invention, BHT and citric acid, for example, can be used as antioxidants and/or chelating agents to minimize the potential degradation of rifaximin through oxidation.

Alternatively, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further contain BHT. In another embodiment, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further contain BHT in an amount of less than about 1% (for example, less than about 0.5%, less than about 0.1%, less than about 0.08%, less than about 0.06%, less than about 0.04%) wt. compositions.

In another embodiment, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further contain BHT in an amount of from about 0.01% to about 0.1%, from from about 0.02% to about 0.08%, from about 0.025% to about 0.06%, from about 0.03% to about 0.06%, from about 0.03% to about 0.05%, from about 0.05% to about 0.15%, or from about 0.03% to about 0.04% by weight. compositions.

Alternatively, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further contain citric acid. In another embodiment, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further contain citric acid in an amount of less than about 1% (for example, less than about 0.5%, less than about 0.1%, less than about 0.08%, less than about 0.06%, less than about 0.04%) wt. compositions.

In another embodiment, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further contain citric acid in an amount of from about 0.01% to about 0.1%, from about 0.02% to about 0.08%, about 0.025% to about 0.06%, about 0.03% to about 0.06%, about 0.03% to about 0.05%, or from about 0.03% to about 0.04% by weight. compositions.

Alternatively, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further comprise ascorbyl palmitate. Alternatively, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further comprise ascorbyl palmitate in an amount of from about 0.05% to about 0.15%, from about 0. 06% to about 0.14%, from about 0.07% to about 0.13%, from about 0.08% to about 0.12%, or from about 0.08% to about 0.12% by weight. compositions.

Alternatively, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further contain BHT and citric acid. In another embodiment, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further contain BHT and citric acid, each in an amount of less than about 1% (for example, less than about 0 .5%, less than about 0.1%, less than about 0.08%, less than about 0.06%, less than about 0.04%) wt. compositions.

In another embodiment, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further comprise BHT and citric acid each in an amount of from about 0.01% to about 0.1% %, from about 0.02% to about 0.08%, from about 0.025% to about 0.06%, from about 0.03% to about 0.06%, from about 0.03% to about 0.05 % or from about 0.03% to about 0.04% by weight. compositions.

In another embodiment, as part of the fourteenth embodiment, the compositions described herein, for example, as in any of the first through thirteenth embodiments, further contain BHT, citric acid, and ascorbyl palmitate, each in an amount of from about 0.05% to about 0.15%, about 0.06% to about 0.14%, about 0.7% to about 0.13%, about 0.8% to about 0.12%, or about 0. 09% to about 0.11%, wt. compositions.

Rifaximin

In a fifteenth embodiment, rifaximin in the disclosed compositions, for example, as in any of embodiments one through fourteen, is present in an amount of from about 1% to about 15%, from about 1% to about 5%, or from about 2.5 % to about 15%, or from about 2.5% to about 12%, or from about 5% to about 10%, or from about 7% to about 15%, or from about 7% to about 14%, or from from about 8% to about 14%, or from about 8% to about 13%, or from about 8% to about 12%, or from about 8% to about 11%, or from about 9% to about 12%, or from about 9% to about 12%, or about 1% to about 12%, or from 1% to about 10%, or from about 1% to about 8%, or from 2% to about 7%, from 3% to about 7%, or from 3% to about 6%, or from 4% to about 5%, or present in an amount of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%, or present in an amount of no more than about 1%, no more than about 2%, no more than about 3%, not more than about 4%, not more than about 5%, not more than about 6%, not more than about 7%, not more than about 8%, not more than about 9%, not more than about 10%, not more than about 11% , no more than about 12%, no more than about 13%, no more than about 14%, or no more than about 15%, or present in an amount of about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14% or about 15%, wt. compositions.

In an alternative fifteenth embodiment, the rifaximin in the disclosed compositions, for example, as in any of the first through fourteenth embodiments, is present in an amount of from about 1% to about 15%, or from about 2.5% to about 15%, or from about 2.5% to about 12%, or about 5% to about 10%, or about 7% to about 15%, or about 7% to about 14%, or about 8% to about 14%, or from about 8% to about 13%, or from about 8% to about 12%, or from about 8% to about 11%, or from about 9% to about 12%, or from about 9% to about 12%, or from about 1% to about 12%, or from 1% to about 10%, or from about 1% to about 8%, or from 2% to about 7%, from 3% to about 7%, or from 3% to about 6%, or from 4% to about 5%, or present in an amount of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12 %, at least about 13%, at least about 14%, or at least about 15%, or present in an amount of no more than about 1%, no more than about 2%, no more than about 3%, no more than about 4% , not more than about 5%, not more than about 6%, not more than about 7%, not more than about 8%, not more than about 9%, not more than about 10%, not more than about 11%, not more than about 12%, not more than about 13%, no more than about 14%, or no more than about 15%, or present in an amount of about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5 %, approximately 4%, approximately 4.5%, approximately 5%, approximately 5.5%, approximately 6%, approximately 6.5%, approximately 7%, approximately 7.5%, approximately 8%, approximately 8.5 %, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, by weight of rifaximin, hydrogenated castor oil, and at least one additional solubilizing excipient.

In a sixteenth embodiment, the total amount of rifaximin in the disclosed composition, for example, as in any of the first through fifteenth embodiments, is less than about 125 mg (e.g., less than about 120 mg, less than about 110 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 70 mg, less than about 60 mg, less than about 50 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, or less than about 15 mg, less than about 10 mg, or less about 9 mg, or less than about 8 mg, or less than about 7 mg, or less than about 6 mg, or less than about 5 mg, or less than about 4 mg, or less than about 3 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg). Alternatively, as part of the sixteenth embodiment, the total amount of rifaximin in the disclosed composition, for example, as in any of the first through fifteenth embodiments, is in the range of from about 1 mg to about 125 mg (for example, from about 1 mg to about 5 mg , from about 2 mg to about 5 mg, from about 3 mg to about 5 mg, from about 3 mg to about 4 mg, from about 1 mg to about 125 mg, from about 5 mg to about 125 mg, from about 10 mg to about 125 mg, from about 10 mg to about 100 mg, from about 25 mg to about 125 mg, from about 25 mg to about 100 mg, from about 25 mg to about 75 mg, from about 30 mg to about 70 mg, from about 35 mg to about 65 mg, from about 40 mg to about 60 mg, from about 45 mg to about 55 mg, from about 75 mg to about 125 mg, from about 80 mg to about 120 mg, from 85 mg to about 115 mg, about 90 mg to about 110 mg, or about 95 mg to about 105 mg). Alternatively, as part of the sixteenth embodiment, the total amount (in milligrams) of rifaximin in the disclosed composition, for example, as in any of the first through fifteenth embodiments, is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 16 , approximately 17, approximately 18, approximately 19, approximately 20, approximately 21, approximately 22, approximately 23, approximately 24, approximately 25, approximately 26, approximately 27, approximately 28, approximately 29, approximately 30, approximately 31, approximately 32, approximately 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66 , approximately 67, approximately 68, approximately 69, approximately 70, approximately 71, approximately 72, approximately 73, approximately 74, approximately 75, approximately 76, approximately 77, approximately 78, approximately 79, approximately 80, approximately 81, approximately 82, approximately 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 110, about 111, about 112, about 113, about 114, about 115, about 116 , about 117, about 118, about 119, about 120, about 121, about 122, about 123, about 124, or about 125 mg; or at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, at least about 3.5, at least about 4, according to at least about 4.5, at least about 5, at least about 5.5, at least about 6, at least about 6.5, at least about 7, at least about 7.5, according to at least about 8, at least about 8.5, at least about 9, at least about 9.5, at least about 10, at least about 10.5, at least about 11, at least about 11.5, at least about 12, at least about 12.5, at least about 13, at least about 13.5, at least about 14, at least about 14.5, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23 , at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, according to at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48 , at least about 49, at least about 50, at least about 51, at least about 52, at least about 53, at least about 54, at least about 55, at least about 56, according to at least about 57, at least about 58, at least about 59, at least about 60, at least about 61, at least about 62, at least about 63, at least about 64, at least about 65, at least about 66, at least about 67, at least about 68, at least about 69, at least about 70, at least about 71, at least about 72, at least about 73 , at least about 74, at least about 75, at least about 76, at least about 77, at least about 78, at least about 79, at least about 80, at least about 81, according at least about 82, at least about 83, at least about 84, at least about 85, at least about 86, at least about 87, at least about 88, at least about 89, at least about 90, at least about 91, at least about 92, at least about 93, at least about 94, at least about 95, at least about 96, at least about 97, at least about 98 , at least about 99, at least about 100, at least about 101, at least about 102, at least about 103, at least about 104, at least about 105, at least about 106, according to at least about 107, at least about 108, at least about 109, at least about 110, at least about 111, at least about 112, at least about 113, at least about 114, at least about 115, at least about 116, at least about 117, at least about 118, at least about 119, at least about 120, at least about 121, at least about 122, at least about 123 , at least about 124, or at least about 125 mg; or is no more than about 1, no more than about 1.5, no more than about 2, no more than about 2.5, no more than about 3, no more than about 3.5, no more than about 4, no more than about 4.5, no more than about 5, no more than about 5.5, no more than about 6, no more than about 6.5, no more than about 7, no more than about 7.5, no more than about 8, no more than about 8.5, no more about 9, not more than about 9.5, not more than about 10, not more than about 10.5, not more than about 11, not more than about 11.5, not more than about 12, not more than about 12.5, not more than about 13 , not more than about 13.5, not more than about 14, not more than about 14.5, not more than about 15, not more than about 16, not more than about 17, not more than about 18, not more than about 19, not more than about 20, not more than about 21, not more than about 22, not more than about 23, not more than about 24, not more than about 25, not more than about 26, not more than about 27, not more than about 28, not more than about 29, not more than about 30, not more than about 31, not more than about 32, not more than about 33, not more than about 34, not more than about 35, not more than about 36, not more than about 37, not more than about 38, not more than about 39, not more than about 40, not more than about 41, not more than about 42, not more than about 43, not more than about 44, not more than about 45, not more than about 46, not more than about 47, not more than about 48, not more than about 49, not more than about 50, not more than about 51, not more than about 52, not more than about 53, not more than about 54, not more than about 55, not more than about 56, not more than about 57, not more than about 58, not more than about 59, not more than about 60, not more than about 61, not more than about 62, not more than about 63, not more than about 64, not more than about 65, not more than about 66, not more than about 67, not more than about 68, not more than about 69, not more than about 70, not more than about 71, not more than about 72, not more than about 73, not more than about 74, not more than about 75, not more than about 76, not more than about 77, not more than about 78, not more than about 79, not more than about 80, no more than about 81, no more than about 82, no more than about 83, no more than about 84, no more than about 85, no more than about 86, no more than about 87, no more than about 88, no more than about 89, no more than about 90, not more than about 91, not more than about 92, not more than about 93, not more than about 94, not more than about 95, not more than about 96, not more than about 97, not more than about 98, not more than about 99, not more than about 100, no more than about 101, no more than about 102, no more than about 103, no more than about 104, no more than about 105, no more than about 106, no more than about 107, no more than about 108, no more than about 109, no more than about 110, not more than about 111, not more than about 112, not more than about 113, not more than about 114, not more than about 115, not more than about 116, not more than about 117, not more than about 118, not more than about 119, not more than about 120, no more than about 121, no more than about 122, no more than about 123, no more than about 124, or no more than about 125 mg.

Alternatively, as part of a further embodiment, the total amount (in milligrams) of rifaximin in the disclosed composition, for example, as in any of embodiments one through sixteen, is at least about 0.5, at least about 1.0, at at least about 1.5, at least about 2.0, at least about 2.5, at least about 3.0, at least about 3.5, at least about 4.0, at least about 4.5, at least about 5.0, at least about 5.5, at least about 6.0, at least about 6.5, at least about 7.0, at least about 7 .5, at least about 8.0, at least about 8.5, at least about 9.0, at least about 9.5, at least about 10.0, at least about 10.5 or at least about 11 mg, or not more than about 0.5, not more than about 1.0, not more than about 1.5, not more than about 2.0, not more than about 2.5, not more than about 3.0 , not more than about 3.5, not more than about 4.0, not more than about 4.5, not more than about 5.0, not more than about 5.5, not more than about 6.0, not more than about 6.5, not more than about 7.0, not more than about 7.5, not more than about 8.0, not more than about 8.5, not more than about 9.0, not more than about 9.5, not more than about 10.0, not more than about 10.5, or no more than about 11 mg, or about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, or about 11 mg.

Liquid composition

In the seventeenth embodiment, the compositions described herein, for example, as in any of the first through sixteenth embodiments, are a liquid composition.

3. Dosage form

For administration purposes, in some embodiments, the compositions described herein can be administered as is or formulated in alternative dosage forms, for example, for oral delivery. Oral dosage forms may be in the form of lozenges, aqueous or oily suspensions, emulsions, capsules, syrups or elixirs. Compositions for oral administration may contain one or more optional agents, for example, sweeteners such as fructose, aspartame or saccharin; flavorings such as peppermint, oil of wintergreen or cherry; coloring matter; and preservatives to obtain a pharmaceutically palatable drug. The compositions may be coated to delay dissolution and absorption in the gastrointestinal tract, thereby providing sustained action over an extended period of time.

In some embodiments, the disclosed compositions are provided in capsule dosage forms. In some embodiments, the disclosed compositions are provided in soft or hard capsule dosage forms. In some embodiments, the disclosed compositions are formulated in soft or hard gelatin capsule dosage forms.

It should be noted that the specific dose and treatment regimen for any given patient will depend on a variety of factors, including age, body weight, general health, gender, nutrition, timing of administration, excretion rate, combination of drugs, the judgment of the treating physician, and the severity of the specific disease. subject to treatment.

4. Methods of application

The compositions described herein can be used in methods of treating or preventing diseases. For example, the invention described herein includes a method of treating or preventing a disease or disorder in a subject in need thereof. Such methods may include the step of administering to said subject a therapeutically effective amount of one or more of any of the above compositions, which may be in unit dosage form.

The compositions described herein are useful for the treatment of one or more disorders associated with intestinal or liver function. Such disorders include, for example, irritable bowel syndrome (IBS) (eg, IBS-D), diarrhea, organism-associated diarrhea, infectious diarrhea , Clostridium difficile infections and symptoms (eg, Clostridium difficile -associated diarrhea), traveler's diarrhea, excess small intestinal bacterial overgrowth (SIBO), Crohn's disease, diverticular disease, pancreatitis (including chronic), pancreatic insufficiency, enteritis, colitis (eg, ulcerative colitis, antibiotic-associated colitis, and microscopic colitis), hepatic encephalopathy (or other diseases which lead to increased ammonia levels) and its symptoms, gastric dyspepsia, cirrhosis (eg, alcoholic cirrhosis), polycystic liver disease, pauchitis, peritonitis, short bowel syndrome, inflammatory bowel disease, rosacea, sickle cell disease, and H. pylori infection.

In some embodiments, the compositions described herein are useful for the treatment and/or prevention of hepatic encephalopathy. For example, the compositions described herein may be useful for treating relapsed hepatic encephalopathy; and/or for the treatment of severe hepatic encephalopathy; and/or for the prevention of severe hepatic encephalopathy.

The compositions described herein are useful in preparation for liver transplantation.

The compositions described herein are useful in the treatment of cardiovascular diseases (eg, atherosclerotic cardiovascular disease).

The compositions described herein are useful for the treatment of disorders affecting the central nervous system and disorders associated with cognitive impairment, such as Parkinson's disease, Alzheimer's disease and autism.

The compositions described herein are useful for the treatment of certain types of cancer, such as acute myeloid leukemia.

The compositions described herein are useful for the treatment of sickle cell anemia and/or related symptoms.

Thus, methods are provided for treating one or more disorders related to bowel or liver function described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a disclosed composition. Also contemplated is the use of the disclosed composition for the preparation of a medicament for the treatment of one or more of the disorders associated with intestinal or liver function described herein. The disclosed composition is also contemplated for use in the treatment of one or more of the disorders associated with intestinal or liver function described herein.

In some embodiments, the methods described herein may include administering the above composition once daily, twice daily, three times daily, or four times daily to a subject to provide a daily dose (in milligrams) of rifaximin to the subject in an amount of at least about 1.0, at least about 1.5, at least about 2.0, at least about 2.5, at least about 3.0, at least about 3.5, at least about 4.0, at least about 4.5, at least about 5.0, at least about 5.5, at least about 6.0, at least about 6.5, at least about 7 .0, at least about 7.5, at least about 8.0, at least about 8.5, at least about 9.0, at least about 9.5, at least about 10.0 , at least about 10.5, at least about 11.0, at least about 11.5, at least about 12.0, at least about 12.5, at least about 13.0, according to at least about 13.5, at least about 14.0, at least about 14.5, at least about 15.0, at least about 15.5, at least about 16.0, at least about 16.5, at least about 17.0, at least about 17.5, at least about 18.0, at least about 18.5, at least about 19.0, at least about 19 .5, at least about 20.0, at least about 20.5, at least about 21.0, at least about 21.5, at least about 22.0, at least about 22.5 , at least about 23.0, at least about 23.5, at least about 24.0, at least about 24.5, at least about 25.0, at least about 25.5, according to at least about 26.0, 26.5, at least about 27.0, at least about 27.5, at least about 28.0, at least about 28.5, at least about 29.0 , at least about 29.5, at least about 30.0, at least about 30.5, at least about 31.0, at least about 31.5, at least about 32.0, according to at least about 32.5, at least about 33.0, at least about 33.5, at least about 34.0, at least about 34.5, at least about 35.0, at least about 35.5, at least about 36.0, at least about 36.5, at least about 37.0, at least about 37.5, at least about 38.0, at least about 38 .5, at least about 39.0, at least about 39.5, or at least about 40.0 mg. In some embodiments, the methods described herein may include administering the above composition once daily, twice daily, three times daily, or four times daily to a subject to provide the subject with a daily dose of rifaximin in an amount (in milligrams) of no more than about 1.0, not more than about 1.5, not more than about 2.0, not more than about 2.5, not more than about 3.0, not more than about 3.5, not more than about 4.0, not more than about 4.5, not more than about 5.0, not more than about 5.5, not more than about 6.0, not more than about 6.5, not more than about 7.0, not more than about 7.5, not more than about 8 ,0, not more than about 8.5, not more than about 9.0, not more than about 9.5, not more than about 10.0, not more than about 10.5, not more than about 11.0, not more than about 11, 5, not more than about 12.0, not more than about 12.5, not more than about 13.0, not more than about 13.5, not more than about 14.0, not more than about 14.5, not more than about 15.0 , not more than about 15.5, not more than about 16.0, not more than about 16.5, not more than about 17.0, not more than about 17.5, not more than about 18.0, not more than about 18.5, not more than about 19.0, not more than about 19.5, not more than about 20.0, not more than about 20.5, not more than about 21.0, not more than about 21.5, not more than about 22.0, not more than about 22.5, no more than about 23.0, no more than about 23.5, no more than about 24.0, no more than about 24.5, no more than about 25.0, no more than about 25.5, no more about 26.0, 26.5, not more than about 27.0, not more than about 27.5, not more than about 28.0, not more than about 28.5, not more than about 29.0, not more than about 29.5 , not more than about 30.0, not more than about 30.5, not more than about 31.0, not more than about 31.5, not more than about 32.0, not more than about 32.5, not more than about 33.0, not more than about 33.5, not more than about 34.0, not more than about 34.5, not more than about 35.0, not more than about 35.5, not more than about 36.0, not more than about 36.5, not more than about 37.0, no more than about 37.5, no more than about 38.0, no more than about 38.5, no more than about 39.0, no more than about 39.5, or no more than about 40.0 mg. In some embodiments, the methods described herein may include administering the above composition once daily, twice daily, three times daily, or four times daily to a subject to provide the subject with a daily dose of rifaximin in an amount (in milligrams) of about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5, about 12.0, about 12.5, about 13.0, about 13.5, about 14.0, about 14.5, about 15.0, about 15.5, about 16.0, approximately 16.5, approximately 17.0, approximately 17.5, approximately 18.0, approximately 18.5, approximately 19.0, approximately 19.5, approximately 20.0, approximately 20.5, approximately 21.0, approximately 21.5, approximately 22.0, approximately 22.5, approximately 23.0, approximately 23.5, approximately 24.0, approximately 24.5, approximately 25.0, approximately 25.5, approximately 26.0, 26.5, approximately 27.0, approximately 27.5, approximately 28.0, approximately 28.5, approximately 29.0, approximately 29.5, approximately 30.0, approximately 30.5, approximately 31 ,0, approximately 31.5, approximately 32.0, approximately 32.5, approximately 33.0, approximately 33.5, approximately 34.0, approximately 34.5, approximately 35.0, approximately 35.5, approximately 36 .0, about 36.5, about 37.0, about 37.5, about 38.0, about 38.5, about 39.0, about 39.5, or about 40.0 mg.

In some embodiments, the methods described herein may include administering the above composition at a dose of 3.5 mg, or 7.0 mg, or 10.5 mg twice daily to provide the subject with a daily dose of about 7.0 mg of rifaximin mg, or 14.0 mg, or 21.0 mg, respectively.

In some embodiments, the above dosages or daily dosages may be provided by administering to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms of the composition (e.g., capsules) per dose or per day , depending on the circumstances. In some embodiments, the above doses or daily doses may be provided by administering to a subject no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms of the composition (e.g., capsules) per dose or per day, depending on the circumstances. In some embodiments, the above dosages or daily dosages may be provided by administering to a subject about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms of the composition (e.g., capsules) per dose or per day, per depending on the circumstances.

Although certain embodiments of the invention have been described and/or illustrated above, various other embodiments will be apparent to those skilled in the art from this disclosure. The invention, therefore, is not limited to the specific embodiments described and/or exemplified, but is capable of significant changes and modifications without departing from the scope and spirit of the appended claims.

Examples

The following representative examples are intended to illustrate the present invention and are not intended and should not be construed as limiting the scope of the invention.

1. Preliminary studies of the components of the dosage form

A. Solubility

The solubility of rifaximin in various solubilizing excipients was examined by adding an excess amount of rifaximin to each solubilizing excipient to determine saturation solubility. The amount of dissolved rifaximin was analyzed by HPLC. The solubility screening results are shown below in Table 1.

Table 1

Solubilizing excipient Solubility (% w/w) Solubilizing excipient Solubility (% w/w) Diethylene glycol monoethyl ether brand HP 21.25 Glyceryl caprylate 20.20 polyoxyl 40 hydrogenated castor oil 20.30 Castor oil 17.10 Polysorbate 80 19.90 glyceryl monooleate
(type 40) 15.30 Benzyl alcohol 16.22 Glyceryl monolinoleate 15.00 Polyethylene glycol 400 15.12 triethylene glycol 14.62 diethyl sebacate 11.22 oleyl alcohol 10.27 Polysorbate 20 9.27 oleic acid 3.79 caprylic/capric triglycerides 2.00 propylene glycol 0.73 Sesame oil 0.60 soybean oil 0.55 corn oil 0.30 diisopropyl adipate 12.71 Polyethylene glycol 600 21.20

B. Compatibility with excipients

To determine excipient compatibility, predetermined amounts of rifaximin were added to each solvent and the resulting solutions were exposed to various temperature conditions for up to 4 weeks. The chemical purity was then analyzed by HPLC, the results of which are presented in Table 2.

table 2

Solvent T0 Rifaximin % nominal amount (LC) T 2 weeks T 4 weeks 25°C 40°C 50°C 25°C 40°C 50°C Castor oil 94.0 99.3 104.3 106.4 100.7 104.3 101.4 diethyl sebacate 102.7 102.1 101.7 101.7 101.1 98.8 99.8 propylene glycol 97.9 96.9 97.0 95.7 96.2 95.6 98.6 polyoxyl 40 hydrogenated castor oil 102.7 100.0 100.0 97.4 101.3 99.4 96.1 PEG 600 102.0 98.0 98.7 98.0 100.0 99.3 96.1 Polysorbate 80 104.7 98.7 98.1 96.8 96.8 96.8 94.3 Benzyl alcohol 99.3 99.8 96.3 96.9 98.2 94.0 93.0 Glyceryl monolinoleate 102.7 98.7 100.0 97.4 100.6 100.0 92.9 triethylene glycol 97.5 98.3 96.7 95.6 97.0 95.0 92.5 oleyl alcohol 98.7 96.3 97.1 95.2 96.9 95.0 91.8 Caprylic/capric triglyceride 86.8 92.2 93.0 94.5 NT 92.0 89.3 PEG 400 98.1 96.0 95.4 91.8 95.8 92.2 86.7 diethylene glycol monoethyl ether grade P 97.3 96.1 89.3 81.5 95.4 82.7 74.2 glyceryl monooleate 92.7 96.4 58.3 48.9 95.0 59.0 41.7 diisopropyl adipate 97.6 95.3 71.3 50.3 95.1 64.8 30.4

C. Compatibility with gelatin shells

The physical compatibility of individual excipients with the gelatin shell matrix was investigated. For hard gelatin capsules, the solvent was poured into the hard capsules and placed in scintillation vials. For soft gelatin capsules, each capsule was immersed in the excipient and then placed in scintillation vials. The vials were then exposed to various temperature conditions for up to 4 weeks. The capsules were then assessed for physical changes (softening or hardening of the capsule shell).

Hard gelatin capsules were purchased from VWR (catalog number 70102) with a volume of 0.68 ml, a diameter of 6.63 mm, a length of 19.0 mm and a size of 1. The soft gelatin capsules were Advil liquid-gels, strength 200 mg, 80 units. The results are presented in Tables 3 and 4.

Table 3 - Hard gelatin capsules

Solvent Physical changes (yes or no) T 2 weeks T 4 weeks 25°C 40°C 50°C 25°C 40°C 50°C PEG 600 No No No No No No PEG 400 No Yes --- No Yes --- Polysorbate 80 No No No No No No Castor oil No No No No No No polyoxyl 40 hydrogenated castor oil No No No No No No glyceryl monooleate No No No No No No Glyceryl monolinoleate No No No No No No corn oil No No No No No No Diethylene glycol monoethyl ether HP grade No No No No No No Diethyl sebacate No No --- No No --- Benzyl alcohol Yes Yes --- Yes Yes --- Triethylene glycol Yes Yes --- Yes Yes --- oleyl alcohol No No --- No No --- Caprylic/capric triglyceride No No --- No No ---

Table 4 - Soft gelatin capsules

Solvent Physical changes (yes or no) T 2 weeks T 4 weeks 25 °C 40°C 50°C 25°C 40°C 50°C PEG 600 No No No No No No Polysorbate 80 No No No No No No Castor oil No No No No No No polyoxyl 40 hydrogenated castor oil No No Yes No No Yes PEG 400 No No No No No No glyceryl monooleate No Yes Yes No Yes Yes Glyceryl monolinoleate No No No No No No

2. Composition studies

A. Estimating the percentage of soluble drug available

The percentage of drug (rifaximin) soluble in phosphate buffer (pH ~ 6.8) or artificial intestinal fluid (SIF, pH ~ 6.8) was examined using the following criteria. The control sample was Xifaxan® tablet (200 mg) or Xifaxan® powder (200 mg API+glycerol distearate - to represent an enteric-coated tablet). Supplements, where indicated, included bile acid (cholic acid), butylated hydroxytoluene (BHT), and isooctyl acrylate/acrylamide/vinyl acetate copolymer (Kollidon® VA64).

The compositions were prepared by weighing hydrogenated castor oil and at least one additional solubilizing excipient and then mixing. BHT was then added to the mixture and dissolved where applicable. Rifaximin was added last.

Dissolution studies were performed to evaluate the percentage of drug solubilized over a period of time from SEDDS formulations of rifaximin compared to Xifaxan at a buffer pH of 7.4, 37 degrees Celsius. Samples were analyzed using HPLC. The results are shown below in Table 5 as well as in FIG. 1 and fig. 2. As shown in the figures, the dissolution of the compositions of the invention (5425-66A; 70 mg rifaximin and 5425-67A; 35 mg rifaximin) was significantly faster than the previously disclosed solid dispersion compositions of 40 mg rifaximin IR and 80 mg rifaximin SER (see WO 2018/064472) and Xifaxan 550 mg.

Table 5

% w/w Series No. 5425-66A 5425-67A API concentration 10% API 5% API Rifaximin 10.00 5.00 Castor oil 10.00 15.00 polyoxyl 40 hydrogenated castor oil 34.96 34.96 Glyceryl caprylate type I 12.00 12.00 Polysorbate (Tween) 80 33.00 33.00 butylated hydroxytoluene (BHT) 0.04 0.04 Total 100.00 100.00 Ratio of % soluble drug compared to Xifaxan after 1 hour, buffer pH 7.4 71.59 35.42

For SIF, prototype formulations (1 gram total, each containing 100 mg API) or Xifaxan® powder were mixed at 37°C for 1 hour in SIF (100 ml). The mixture was then centrifuged for 20 min and analyzed by HPLC. The results are presented below in Tables 6A and 6B.

Table 6A - Percent Soluble Drug in Phosphate Buffer

Ingredient 5256-27C 5394-58A 5256-34E 5394-57A 5256-35A 5394-60A Xifaxan® powder wt/wt% Rifaximin 10.0 5.00 10.0 5.00 10.0 5.00 200 mg Castor oil 10.0 15.00 ---- ---- ---- ---- ---- Glyceryl caprylate 12.0 12.00 ---- ---- ---- ---- ---- Polysorbate (Tween) 80 33.0 33.0 ---- ---- ---- ---- ---- Polyoxyl 40 Hydrogenated castor oil 34.96 34.96 35.0 19.96 34.96 39.96 ---- diethyl sebacate ---- ---- 27.5 37.50 27.5 27.50 ---- Diethylene glycol monoethyl ether ---- ---- 27.5 37.50 27.5 27.50 butylated hydroxytoluene 0.038 0.038 ---- 0.038 0.038 0.038 ---- glycerol distearate ---- ---- ---- ---- ---- ---- 18 mg Total 100.00 100.00 100.00 100.00 100.00 100.00 218.00 Percentage of soluble drug (%w/w) 0.0131 0.0503 0.0021 0.0064 0.0024 0.0065 0.0003 Ratio of the composition according to the invention compared to Xifaxan® 44.00 168.00 7.00 21.00 8.00 22.00 1.00

Table 6B - Percentage of soluble drug in SIF

Ingredients Phosphate buffer SIF 5256-34E Xifaxan® powder 5256-34E Xifaxan® % w/w Rifaximin 10.0 200 mg 10.0 Colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose polyoxyl 40 hydrogenated castor oil 35.0 ---- 35.0 diethyl sebacate 27.5 ---- 27.5 Diethylene glycol monoethyl ether 27.5 ---- 27.5 butylated hydroxytoluene ---- ---- ---- Total 100.0 218.00 100.0 Percentage of soluble drug (%w/w) 0.0021 0.0003 0.0057 0.001 Ratio of the composition according to the invention compared to Xifaxan® 7.00 1.00 6.00 1.00

The effects of the inclusion of certain additives such as butylated hydroxytoluene (BHT), crystallization inhibitor (CI) and bile acid are shown in Table 7. Similar to the above, the inventive compositions in Table 7 contained only 1 gram, each containing 100 mg of rifaximin.

Table 7 - Effect of additives

Ingredients No BHT BHT No CI C.I. No bile acid bile acid 5256-34E 5256-34E 5256-35A 5256-35A 5246-34E 5256-34E Xifaxan powder % w/w Rifaximin 10.0 10.0 10.0 10.0 10.0 10.0 200 mg polyoxyl 40 hydrogenated castor oil 35.0 34.96 34.96 29,962 35.0 34.8 ---- diethyl sebacate 27.5 27.5 27.5 27.5 27.5 27.5 ---- Diethylene glycol monoethyl ether 27.5 27.5 27.5 27.5 27.5 27.5 ---- butylated hydroxytoluene ---- 0.038 0.038 0.038 ---- ---- ---- Isooctyl acrylate/acrylamide/vinyl acetate copolymer
(Kollidone® VA 64) ---- ---- ---- 5.0 ---- ---- ---- glycerol distearate ---- ---- ---- ---- ---- ---- 18 mg cholic acid ---- ---- ---- ---- ---- 0.2 ---- Total 100.0 100.0 100.0 100.0 100.0 100.0 218.00 Percentage of soluble drug (%w/w) 0.0021 0.0024 0.0024 0.0016 0.0021 0.0014 0.0003 Ratio of the composition according to the invention compared to Xifaxan 7.00 8.00 8.00 5.00 7.00 5.00 1.00

B. Compatibility of the prototype with gelatin shells

The compatibility of certain compositions of the invention with the gelatin shell matrix was examined. The capsules were size 1, VWR catalog number 70102. The vials were then exposed to various temperature conditions for up to 5 weeks. The capsules were then assessed for physical changes (softening or hardening of the capsule shell). The results of this study are shown in Table 8 below. The compositions of the invention in Table 7 contained only 1 gram, each containing 50 mg or 100 mg of rifaximin.

Table 8

5256-27C 5394-58A 5256-34E 5394-57A 5256-35A 5394-60A Ingredients % w/w Rifaximin 10.0 5.00 10.0 5.00 10.0 5.00 Castor oil 10.0 15.00 ---- ---- ---- ---- Glyceryl caprylate 12.0 12.00 ---- ---- ---- ---- Polysorbate 80 33.0 33.00 ---- ---- ---- ---- Polyoxyl 40 hydrogenated castor oil 34.96 34.96 35.0 19.96 34.96 39.96 diethyl sebacate ---- ---- 27.5 37.50 27.5 27.50 Diethylene glycol monoethyl ether ---- ---- 27.5 37.50 27.5 27.50 butylated hydroxytoluene 0.038 0.038 ---- 0.038 0.038 0.038 Total 100.00 100.00 100.00 100.00 100.00 100.00 Percentage of soluble drug (%w/w) 0.0131 0.0503 0.0021 0.0064 0.0024 0.0065 Ratio of the composition according to the invention compared to Xifaxan® 44.00 168.00 7.00 21.00 8.00 22.00 Hard Shell Compatible Yes Yes Yes Yes Yes Yes Soft Shell Compatible TBD Yes No No No No

As shown above, the compositions of the invention significantly improve the solubility of rifaximin under conditions similar to those found in vivo. In some cases, this effect represents more than a 150-fold increase in the percentage of soluble rifaximin compared to commercially available Xifaxan®.

3. ADDITIONAL COMPOSITIONS

Additional compositions are shown below in Table 9.

Talitsa 9

5507-65A 5425-68A 5425-70A 5425-70B 5425-70C A Ingredients % w/w Rifaximin 10.0 2.5 10.0 5.0 2.5 2.5 Castor oil 10.0 17.5 ---- ---- ---- 10.0 polyoxyl 40 hydrogenated castor oil (RH-40) 34.90 34,962 34.96 39.96 42.46 35.0 Glyceryl caprylate type I 12.0 12.0 ---- ---- ---- 12.0 Polysorbate (Tween) 80 33.0 33.0 ---- ---- ---- 40.29 butylated hydroxytoluene (BHT) 0.05 0.038 0.038 0.038 0.038 0.1 Lemon acid 0.05 ---- ---- ---- ---- 0.01 Ascorbyl palmitate ---- ---- ---- ---- ---- 0.1 diethyl sebacate ---- ---- 16.5 16.5 16.5 ---- Diethylene glycol monoethyl ether ---- ---- 38.5 38.5 38.5 ---- Total 100.0 100.0 100.0 100.0 100.0 100.0

The compositions can be placed in non-enteric coated capsules such as Quali-G, size 4, 140 mg filling. The dissolution results of 5425-68A, 5425-70A, 5425-70B and 5425-70C under different pH conditions are shown in FIG. 3-8, compared to the previously described 40 mg rifaximin IR and 80 mg rifaximin SER solid dispersion compositions (see WO 2018/064472) and Xifaxan 550 mg.

4. ANTIBACTERIAL ACTIVITY

The antibacterial properties of representative compositions were tested as described herein.

Organisms were obtained by inoculating the surface of casein soybean agar (TSA) plates incubated at 30 to 35°C for 18 to 24 hours. After the incubation period, the plates were washed with sterile serological saline to collect the microorganisms used and dilutions were made with saline, plated on TSA and incubated at 30-35°C for 18-24 hours to determine the concentration. The inoculum level was then adjusted to 10^ cfW ml for use as an initial suspension. The initial suspensions were well mixed and homogenized at each inoculation interval.

The organisms used in this time-kill activity study were Escherichia coli ATCC 8739, Shigella flexneri ATCC 12022, and Salmonella choleraesuis ATCC 10708. Positive controls were performed at initiation and at the end by plating to calculate inoculum levels and verify culture purity during testing, and negative controls carried out to establish the sterility of media, reagents and substances used during initiation. Neutralizer suitability using modified lethine broth (MLB) was performed concurrently with time-of-kill activity testing to confirm recovery of <100 CFU of the test organism in the subculture medium in the presence of the product.

1.0 g of the composition (5507-65A) was weighed. In a separate container, a mixture of 70 ml of 0.1 N hydrochloric acid (pH 1.1) and 30 ml of 0.20 M tribasic sodium phosphate was prepared and the pH was adjusted to approximately 6.8. The mixture was added to the composition and stirred for 1 hour at room temperature. The mixture was then filtered through a 0.45 μm filter to remove any sediment and collect the filtrate. Containers of 10 mL were prepared in duplicate for each sample or substance concentration treated, equilibrated to 25 ± 2°C, and 0.1 mL of inoculum was added to each container to achieve a final concentration of 10 CFU/mL in the product.

Serial dilutions from each replicate were made at intervals of 10 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours and 4 hours using 1 ml of inoculated test product in 9 ml of MLB from 1:10 to 1:1,000,000. Then 1 ml from each dilution was inoculated with TSA in duplicate and incubated at 30-35°C for 48 hours. After the incubation period, all plates were counted to determine the number of microorganisms, the results were averaged and presented as log reduction. Placebo control (5507-66A) composition 5507-65A was prepared in the same manner. The placebo did not contain rifaximin and contained 44.90% w/w. polyoxyl 40 hydrogenated castor oil instead of 34.90% w/w. Xifaxan 550 mg tablet was also tested and compared. The results are shown in Fig. 9-11.

5. STABILITY STUDIES

A stability study was conducted to determine whether rifaximin would degrade in a representative liquid composition described herein during storage. The composition of Table 10 was stored at 5°C and 25°C (relative humidity (RH) 60%) and checked after 0.5 and 1.0 months for changes in the appearance and concentration of rifaximin using LC-MS. The results of such a study are shown in Table 11, which indicate that little or no degradation of rifaximin was observed in a representative liquid composition.

Table 10

Ingredients % w/w Rifaximin 2.50 Castor oil 10.00 polyoxyl 40 hydrogenated castor oil 35.00 Glyceryl caprylate type I 12.00 Polysorbate (Tween) 80 40.29 butylated hydroxytoluene 0.10 anhydrous citric acid 0.01 Ascorbyl palmitate 0.10 Total 100.00

Table 11

Storage conditions Reference point in time Description (visual) Rifaximin %LC N/A Elementary Compliant 100.20 5°C 0.5 months Compliant 101.00 1M Compliant 100.10 25°C/ 60% RH 0.5 months Compliant 99.10 1M Compliant 100.00

The contents of all references (including literature references, issued patents, published patent applications and concurrently pending patent applications) cited in this application are expressly incorporated herein by reference in their entirety.

Claims (86)

1. A pharmaceutically acceptable composition for the treatment of disorders associated with intestinal or liver function, where the composition contains rifaximin, from 25 to 50% by weight. hydrogenated castor oil and from 45 to 65% wt. at least one additional solubilizing excipient selected from castor oil, glyceryl caprylate, polysorbate 80, diethyl sebacate, diethylene glycol monoethyl ether, and combinations thereof. 2. The composition according to claim 1, wherein the hydrogenated castor oil is polyoxyl 60 hydrogenated castor oil or polyoxyl 40 hydrogenated castor oil. 3. The composition according to claim 1 or 2, wherein the hydrogenated castor oil is polyoxyl 40 hydrogenated castor oil. 4. Composition according to any one of paragraphs. 1-3, where hydrogenated castor oil is present in an amount from 30 to 45 wt%. compositions. 5. Composition according to any one of paragraphs. 1-4, where hydrogenated castor oil is present in an amount of from 35 to 40 wt%. compositions. 6. Composition according to any one of paragraphs. 1-5, where the solubility at saturation of rifaximin is more than 10% wt./mass. 7. Composition according to any one of paragraphs. 1-6, where the saturation with rifaximin is more than 14% wt./mass. 8. Composition according to any one of paragraphs. 1-7, where at least one additional solubilizing excipient is present in an amount of from 50 to 65 wt%. compositions. 9. Composition according to any one of paragraphs. 1-8, where at least one additional solubilizing excipient is present in an amount of from 55 to 65 wt%. compositions. 10. Composition according to any one of paragraphs. 1-9, where at least one additional solubilizing excipient is present in an amount of from 60 to 65 wt%. compositions. 11. Composition according to any one of paragraphs. 1-9, where at least one additional solubilizing excipient is present in an amount of from 55 to 60 wt%. compositions. 12. Composition according to any one of paragraphs. 1-9 and 11, where at least one additional solubilizing excipient is present in an amount of 55 wt%. compositions. 13. Composition according to any one of paragraphs. 1-10, where at least one additional solubilizing excipient is present in an amount of 62 or 63 wt%. compositions. 14. Composition according to any one of paragraphs. 1-13, wherein the at least one additional solubilizing excipient is a combination of castor oil, glyceryl caprylate and polysorbate 80. 15. Composition according to claim 14, where castor oil is present in amounts from 5 to 15% by weight. compositions; glyceryl caprylate is present in an amount from 5 to 15% by weight. compositions; And polysorbate 80 is present in amounts from 20 to 40% by weight. compositions. 16. Composition according to claim 14 or 15, where castor oil is present in amounts from 8 to 12% by weight. compositions; glyceryl caprylate is present in an amount of 10 to 14% by weight. compositions; And polysorbate 80 is present in an amount of 30 to 35% by weight. compositions. 17. Composition according to claim 14, where castor oil is present in amounts from 10 to 20% by weight. compositions; glyceryl caprylate is present in an amount from 5 to 15% by weight. compositions; And polysorbate 80 is present in amounts from 20 to 40% by weight. compositions. 18. Composition according to claim 14 or 17, where castor oil is present in amounts from 13 to 18% by weight. compositions; glyceryl caprylate is present in an amount of 10 to 14% by weight. compositions; And polysorbate 80 is present in an amount of 30 to 35% by weight. compositions. 19. Composition according to claim 14, where castor oil is present in amounts from 5 to 15% by weight. compositions; glyceryl caprylate is present in an amount of 10 to 15% by weight. compositions; And polysorbate 80 is present in an amount from 35 to 45% by weight. compositions. 20. Composition according to claim 14 or 19, where castor oil is present in amounts from 8 to 12% by weight. compositions; And polysorbate 80 is present in amounts from 38 to 42% by weight. compositions. 21. Composition according to any one of paragraphs. 1-13, wherein the at least one additional solubilizing excipient is a combination of diethyl sebacate and diethylene glycol monoethyl ether. 22. Composition according to claim 21, where diethyl sebacate is present in amounts from 20 to 35% by weight. compositions; And Diethylene glycol monoethyl ether is present in an amount from 20 to 35% by weight. compositions. 23. Composition according to claim 21 or 22, where diethyl sebacate is present in an amount of 25 to 30% by weight. compositions; And Diethylene glycol monoethyl ether is present in an amount of 25 to 30% by weight. compositions. 24. Composition according to claim 21, where diethyl sebacate is present in an amount of 10 to 20% by weight. compositions; And Diethylene glycol monoethyl ether is present in an amount of 30 to 45% by weight. compositions. 25. Composition according to claim 21 or 24, where diethyl sebacate is present in amounts from 14 to 18% by weight. compositions; And Diethylene glycol monoethyl ether is present in an amount of 36 to 40% by weight. compositions. 26. Composition according to any one of paragraphs. 1-25, where the composition further contains an antioxidant and/or a chelating agent. 27. Composition according to any one of paragraphs. 1-25, where the composition further contains an antioxidant and/or chelating agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene (BHT), potassium metabisulfite, sodium metabisulfite, cysteine, propyl gallate, sodium thiosulfate, vitamin E, 3, 4-dihydroxybenzoic acid and combinations thereof. 28. Composition according to any one of paragraphs. 1-25, where the composition further contains one or more of butylated hydroxytoluene (BHT) and citric acid. 29. Composition according to any one of paragraphs. 1-25, where the composition further contains one or more of butylated hydroxytoluene (BHT) and citric acid, each in an amount of from 0.01 to 0.1 wt%. compositions. 30. Composition according to any one of paragraphs. 1-25, where the composition further contains one or more of butylated hydroxytoluene (BHT), citric acid and ascorbyl palmitate. 31. Composition according to any one of paragraphs. 1-25, where the composition further contains one or more of butylated hydroxytoluene (BHT), citric acid and ascorbyl palmitate, each in an amount of from 0.05 to 0.15 wt%. compositions. 32. Composition according to any one of paragraphs. 1-31, where rifaximin is present in an amount from 1.0 to 15% of the mass. compositions. 33. Composition according to any one of paragraphs. 1-32, where rifaximin is present in an amount from 2.5 to 15 wt%. compositions. 34. Composition according to any one of paragraphs. 1-33, where rifaximin is present in an amount from 2.5 to 12 wt%. compositions. 35. Composition according to any one of paragraphs. 1-34, where rifaximin is present in an amount of 5 to 10 wt%. compositions. 36. Composition according to any one of paragraphs. 1-35, where rifaximin is present in an amount of 5 or 10 wt%. compositions. 37. Composition according to any one of paragraphs. 1-32, where rifaximin is present in an amount from 1 to 5 wt%. compositions. 38. Composition according to any one of paragraphs. 1-34 and 37, where rifaximin is present in an amount of 2.5 wt%. compositions. 39. Composition according to any one of paragraphs. 1-38, wherein the total amount of rifaximin in the composition is less than 125 mg. 40. Composition according to any one of paragraphs. 1-39, where the total amount of rifaximin in the composition is from 1 mg to 125 mg. 41. Composition according to any one of paragraphs. 1-40, where the total amount of rifaximin in the composition is from 1 mg to 50 mg. 42. Composition according to any one of paragraphs. 1-41, where the total amount of rifaximin in the composition is from 1 mg to 25 mg or from 1 mg to 10 mg. 43. Composition according to any one of paragraphs. 1-42, where the total amount of rifaximin in the composition is 1 mg or 5 mg. 44. The composition of claim 1, wherein the composition contains 10% rifaximin, 10% castor oil, 12% glyceryl caprylate, 33% polysorbate 80 and 35% polyoxyl 40 hydrogenated castor oil by weight of the composition. 45. The composition according to claim 1, where the composition contains 10% rifaximin, 35% polyoxyl 40 hydrogenated castor oil, 27.5% diethyl sebacate and 27.5% diethylene glycol monoethyl ether by weight of the composition. 46. The composition of claim 1, wherein the composition contains 5% rifaximin, 15% castor oil, 12% glyceryl caprylate, 33% polysorbate 80 and 35% polyoxyl 40 hydrogenated castor oil by weight of the composition. 47. The composition according to claim 1, where the composition contains 10% rifaximin, 40% polyoxyl 40 hydrogenated castor oil, 16.5% diethyl sebacate and 38.5% diethylene glycol monoethyl ether by weight of the composition. 48. The composition of claim 1, wherein the composition contains 2.5% rifaximin, 10% castor oil, 12% glyceryl caprylate, 40% polysorbate 80 and 35% polyoxyl 40 hydrogenated castor oil by weight of the composition. 49. Composition according to any one of paragraphs. 44-48, wherein the composition further contains less than 0.03% butylated hydroxytoluene (BHT) to 0.06% BHT by weight of the composition. 50. Composition according to any one of paragraphs. 44-48, wherein the composition further contains less than 0.03% butylated hydroxytoluene (BHT) to 0.04% BHT by weight of the composition. 51. Composition according to any one of paragraphs. 44-48, wherein the composition further contains from 0.05% butylated hydroxytoluene (BHT) to 0.15% BHT by weight of the composition. 52. Composition according to any one of paragraphs. 44-48, wherein the composition further contains 0.1% butylated hydroxytoluene (BHT) by weight of the composition. 53. Composition according to any one of paragraphs. 44-52, where the composition additionally contains from 0.05 to 0.15% ascorbyl palmitate by weight of the composition. 54. Composition according to any one of paragraphs. 44-52, where the composition additionally contains 0.1% ascorbyl palmitate by weight of the composition. 55. Composition according to any one of paragraphs. 1-54, where the composition is a liquid composition. 56. Composition according to any one of paragraphs. 1-55, where the composition is present in a soft or hard capsule. 57. Composition according to any one of paragraphs. 1-56, where the composition is present in a gelatin capsule. 58. A method of treating one or more disorders associated with intestinal or liver function in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims. 1-57. 59. The method of claim 58, wherein the one or more disorders related to bowel or liver function is selected from the group consisting of irritable bowel syndrome (IBS), diarrhea, microorganism-associated diarrhea, infectious diarrhea, Clostridium difficile infections and symptoms , traveler's diarrhea, small intestinal bacterial overgrowth (SIBO), Crohn's disease, diverticular disease, pancreatitis, pancreatic insufficiency, enteritis, ulcerative colitis, antibiotic-associated colitis, hepatic encephalopathy, gastric dyspepsia, cirrhosis, polycystic liver disease, pauchitis, peritonitis, inflammatory bowel disease, rosacea, sickle cell disease and H. pylori infection. 60. The method of claim 58 or 59, wherein the pharmaceutical composition is administered to the subject once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID). 61. Method according to any one of paragraphs. 58-60, wherein the pharmaceutical composition is administered to the subject twice daily (BID).