Formulation of rifaximin and N-acetylcysteine

Abstract

Formulations of rifaximin and N-acetylcysteine (NAC) are described herein. Methods of using the formulations for treating various gastrointestinal diseases, including IBS-D and SIBO, are also provided. TIFF2025516807000002.tif131128

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority under 35 U.S.C.§119(e) to U.S. Provisional Patent Application No. 63 / 343,860, filed May 19, 2022, and No. 63 / 343,862, filed May 19, 2022, both of which are hereby incorporated by reference in their entirety.

[0002] Technical Field The present invention relates to formulations of rifaximin and N - acetylcysteine and their use for gastrointestinal purposes.

Background Art

[0003] Background All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention described herein. None of the information provided herein admits that any of the information is prior art or relevant to the presently claimed invention, or that any of the publications specifically or implicitly referenced is prior art.

[0004] Small intestinal bacterial overgrowth (SIBO) occurs when there is an abnormal increase in the overall bacterial population of the small intestine, particularly types of bacteria not normally found in that part of the gastrointestinal tract.

[0005] Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder with an estimated prevalence of 10% - 15% in the United States. IBS is characterized by symptoms including abdominal pain, abdominal bloating, and chronic changes in bowel function that can present as diarrhea - predominant (D - IBS), constipation - predominant (C - IBS), or alternating between the two (M - IBS).

[0006] Changes in gut bacteria have been associated with the onset of IBS symptoms. Antimicrobial agents often do not penetrate the mucus layer sufficiently to control infection, while at the same time, the mucus layer provides an important protective role.

[0007] The inventors have discovered various compositions for treating IBS and methods for treating IBS, which are described in International Publication No. WO2020 / 191076 (Patent Document 1), which is incorporated herein by reference in its entirety as if fully set forth herein. However, there remains a need in the art to provide additional formulations and methods for treating these conditions.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Summary of the Invention

[0009] The following aspects and their aspects are described and illustrated in conjunction with compositions and methods that are intended to be exemplary and illustrative without limiting the scope.

[0010] Various aspects of the present invention provide a formulation of rifaximin and N-acetylcysteine (NAC) comprising a shell; a first solid composition containing an amount of rifaximin within the shell; and a plurality of coated second solid compositions containing an amount of NAC within the shell.

[0011] Various aspects of the present invention provide a formulation of rifaximin and N-acetylcysteine (NAC) comprising a solid core composition containing an amount of rifaximin and an amount of NAC; and a coating surrounding the solid core composition.

[0012] In various embodiments, the amount of rifaximin can be about 66 mg. In various embodiments, the amount of rifaximin can be about 62 - 70 mg. In various embodiments, the amount of rifaximin can be about 59 - 73 mg. In various embodiments, the amount of rifaximin can be about 132 mg. In various embodiments, the amount of rifaximin can be about 125 - 139 mg. In various embodiments, the amount of rifaximin can be about 118 - 146 mg.

[0013] In various embodiments, the amount of NAC can be about 560 mg. In various embodiments, the amount of NAC can be about 532 - 588 mg. In various embodiments, the amount of NAC can be about 504 - 616 mg. In various embodiments, the amount of NAC can be about 450 - 560 mg. In various embodiments, the amount of NAC can be about 427 - 588 mg. In various embodiments, the amount of NAC can be about 405 - 616 mg.

[0014] In various embodiments of the formulation having the first solid composition and the second solid composition, the first solid composition can further comprise one or more excipients. In various embodiments of the formulation having the first solid composition and the second solid composition, the second solid composition can further comprise one or more excipients. In various embodiments, the first solid composition can be in tablet form.

[0015] In various embodiments of the formulation having the first solid composition and the second solid composition, the second solid composition can be in the form of mini - tablets, crystals, pellets, or beads.

[0016] In various embodiments of a formulation having a first solid composition and a second solid composition, the coating of the second solid composition can include at least one polymer. In various embodiments of a formulation having a first solid composition and a second solid composition, the coating of the second solid composition can include at least one polymer that is insoluble at a pH lower than 5. In various embodiments of a formulation having a first solid composition and a second solid composition, the coating of the second solid composition can include at least one polymer that is insoluble at a pH lower than 3.5. In various embodiments of a formulation having a first solid composition and a second solid composition, the coating of the second solid composition can include at least one polymer that is insoluble at a pH between 1.5 and 3.5.

[0017] In various embodiments of a formulation having a first solid composition and a second solid composition, the shell does not contain gelatin. In various embodiments of a formulation having a first solid composition and a second solid composition, the shell can include hypromellose.

[0018] In various embodiments of a formulation having a first solid composition and a second solid composition, the first solid composition containing rifaximin may not be substantially dissolved after 1 hour in a Type 2 dissolution bath containing about 0.1 N hydrochloric acid.

[0019] In various embodiments of a formulation having a first solid composition and a second solid composition, the first solid composition containing rifaximin can be substantially dispersed in simulated intestinal fluid in a fed state.

[0020] In various embodiments of a formulation having a solid core composition, the solid core composition constitutes a single layer that is uniform or essentially uniform in composition state.

[0021] In various embodiments of a formulation having a first solid composition and a second solid composition, the first solid composition containing rifaximin may not be substantially dissolved after 1 hour in a Type 2 dissolution bath containing about 0.1 N hydrochloric acid.

[0022] In various embodiments of a formulation having a first solid composition and a second solid composition, the first solid composition containing rifaximin is a tablet containing rifaximin and one or more excipients; the multiple coated second solid compositions containing NAC are multiple mini-tablets containing NAC and one or more excipients; and the coating contains at least one polymer that is substantially insoluble at a pH lower than 3.5.

[0023] In various embodiments of a formulation having a solid core composition, NAC in the solid core composition enhances the dissolution of rifaximin as compared to a solid core composition without NAC.

[0024] In various embodiments of a formulation having a solid core composition, the coating does not contain gelatin. In various embodiments of a formulation having a solid core composition, the coating can contain hypromellose.

[0025] Various embodiments provide a method of treating irritable bowel syndrome (IBS) comprising administering to a subject in need thereof one or more doses of the formulation of the invention described herein.

[0026] In various embodiments, the IBS can be diarrhea-predominant IBS (IBS-D). In various embodiments, the IBS can be hydrogen sulfide (H 2 S)-positive IBS.

[0027] Various embodiments provide a method of treating small intestinal bacterial overgrowth (SIBO) comprising administering to a subject in need thereof one or more doses of the formulation of the invention described herein.

[0028] Various embodiments provide a method of reducing the Escherichia coli (E. Coli) load, Klebsiella load, and total bacterial load in the small intestine comprising administering to a subject in need thereof one or more doses of the formulation of the invention described herein.

[0029] In various aspects, a decrease in the Escherichia coli load, Klebsiella load, and total bacterial load can occur in the ileum. For example, the formulation is configured to substantially release rifaximin and NAC in the ileum. In various aspects, a decrease in the Escherichia coli load, Klebsiella load, and total bacterial load can occur in the duodenum. For example, the formulation is configured to substantially release rifaximin and NAC in the duodenum.

[0030] Various aspects provide a method of improving stool hardness, reducing systemic inflammation, or both, including the step of administering to a subject in need thereof one or more doses of the formulation described herein.

[0031] In various aspects, the step of administering one or more doses of the formulation can include the step of administering to a subject in need thereof a dosing regimen three times a day. In various aspects, the step of administering one or more doses of the formulation can include the step of administering to a subject in need thereof a dosing regimen three times a day for about 7 to 10 days. In various aspects, administration can be via oral administration.

[0032] Other features and advantages of the present invention will be apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, various features of embodiments of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Exemplary embodiments are illustrated in the reference figures. It is intended that the embodiments and figures disclosed herein be considered as illustrative rather than limiting.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5A

Figure 5B

Figure 6

Figure 7

Figure 8

Figure 9

Mode for Carrying Out the Invention

[0034] Description of the Invention All references cited herein are incorporated by reference in their entirety as if fully set forth. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 3 rded., Revised, J. Wiley & Sons (New York, NY 2006); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 7 th ed., J. Wiley & Sons (New York, NY 2013); and Sambrook and Russel, Molecular Cloning: A Laboratory Manual 4 th ed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012) provides those of ordinary skill in the art with general guidance for many of the terms used in this application.

[0035] Those of ordinary skill in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the invention described herein. In fact, the invention described herein is in no way limited to the methods and materials described. For the purposes of the invention described herein, the following terms are defined below.

[0036] As used herein, the term "about" when used in connection with a recited numerical indication means, unless otherwise specified herein, the recited numerical indication plus or minus up to 5% of the recited numerical indication. For example, the language "about 50%" covers the range from 45% to 55%. In various embodiments, the term "about" when used in connection with a recited numerical indication can mean, when specified in the claims, the recited numerical indication plus or minus up to 4%, 3%, 2%, 1%, 0.5%, 0.25%, or 0.1% of the recited numerical indication.

[0037] As used herein, "substantially" refers to at least 60%. In various embodiments, when specifically specified, "substantially" refers to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

[0038] As used herein, "tablet" refers to a solid pharmaceutical form produced by compressing one or more active pharmaceutical ingredients and optionally one or more excipients.

[0039] As used herein, "minitablet" or "minitab" refers to a tablet sized so that a plurality of such tablets can be encapsulated within a capsule, e.g., a size 00 capsule or a size 0 capsule. Exemplary minitablets can have a longest dimension of up to 3 mm.

[0040] As used herein, "essentially homogeneous in the composition state" refers to the homogeneity in the composition state that is at least 95% homogeneous in the composition state. In various embodiments, when specifically specified, "essentially homogeneous in the composition state" refers to the homogeneity in the composition state that is at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9% homogeneous in the composition state.

[0041] As used herein, "subject" means a human or an animal. Usually, the animal is a vertebrate such as a primate or a rodent. Primates include humans, chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., rhesus monkeys. Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters.

[0042] The terms "patient", "individual", and "subject" are used interchangeably herein. In one aspect, the subject is a mammal. The mammal can be, but is not limited to, a human, non-human primate, mouse, rat, dog, cat, horse, or female cow. In some aspects, the subject is a human.

[0043] As used herein, "mammal" includes, without limitation, humans and non-human primates such as chimpanzees as well as other apes and monkey species; domestic animals such as cows, sheep, pigs, goats, and horses; companion mammals such as dogs and cats; and laboratory animals including rodents such as mice, rats, and guinea pigs, etc., and refers to any member of the class Mammalia. The term does not imply a particular age or sex. Thus, adult and neonatal subjects, whether male or female, are intended to be included within the scope of this term.

[0044] The subject has been previously identified as having been diagnosed with, suffering from, or having a disease, disorder, or condition that requires treatment, or one or more complications associated with the disease, disorder, or condition, and optionally, has already received treatment for the disease, disorder, or condition, or one or more complications associated with the disease, disorder, or condition. Alternatively, the subject may also have not been previously diagnosed as having a disease, disorder, and condition, and one or more complications associated with the disease, disorder, and condition. For example, the subject may or may not exhibit one or more risk factors for a disease, disorder, or condition, or one or more complications associated with the disease, disorder, or condition. A "subject in need of treatment" for a particular disease, disorder, or condition is a subject who is suspected of having, diagnosed with having, already treated or being treated for, untreated for, or at risk of developing that disease, disorder, or condition.

[0045] As used herein, "treatment" and "treating" refer to both therapeutic treatment and prophylactic or preventive measures, the purpose being to prevent, blunt, and / or reduce a disease even if the treatment is ultimately unsuccessful.

[0046] Various aspects provide a formulation of rifaximin and N-acetylcysteine (NAC) comprising a shell that includes a first solid composition comprising an amount of rifaximin and a plurality of second solid compositions comprising an amount of NAC.

[0047] Various aspects provide a formulation of rifaximin and N-acetylcysteine (NAC) comprising a shell that includes a first solid composition comprising an amount of rifaximin and a plurality of coated second solid compositions comprising an amount of NAC.

[0048] In various aspects, the amount of rifaximin is about 66 mg. In various aspects, the amount of rifaximin is about 66.5 mg. In various aspects, the amount of rifaximin is about 62 - 70 mg. In various aspects, the amount of rifaximin is about 59 - 73 mg.

[0049] In various aspects, the amount of rifaximin is about 132 mg. In various aspects, the amount of rifaximin is about 133 mg. In various aspects, the amount of rifaximin is about 125 - 139 mg. In various aspects, the amount of rifaximin is about 118 - 146 mg.

[0050] In various aspects, the amount of NAC is about 560 mg. In various aspects, the amount of NAC is about 561.3 mg. In various aspects, the amount of NAC is about 532 - 588 mg. In various aspects, the amount of NAC is about 504 - 616 mg. In various aspects, the amount of NAC is about 450 - 560 mg. In various aspects, the amount of NAC is about 427 - 588 mg. In various aspects, the amount of NAC is about 405 - 616 mg.

[0051] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 66 mg of rifaximin and a plurality of second solid compositions comprising about 560 mg of NAC.

[0052] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 66.5 mg of rifaximin and a plurality of second solid compositions comprising about 561.3 mg of NAC.

[0053] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 132 mg of rifaximin and a plurality of second solid compositions comprising about 560 mg of NAC.

[0054] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 133 mg of rifaximin and a plurality of second solid compositions comprising about 561.3 mg of NAC.

[0055] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 59 - 73 mg or 62 - 70 mg of rifaximin and a plurality of second solid compositions comprising about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC.

[0056] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 118 - 146 mg or 125 - 139 mg of rifaximin and a plurality of second solid compositions comprising about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC.

[0057] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 66 mg of rifaximin and a plurality of coated second solid compositions comprising about 560 mg of NAC.

[0058] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 66.5 mg of rifaximin and a plurality of coated second solid compositions comprising about 561.3 mg of NAC.

[0059] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 132 mg of rifaximin and a plurality of coated second solid compositions comprising about 560 mg of NAC.

[0060] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 133 mg of rifaximin and a plurality of coated second solid compositions comprising about 561.3 mg of NAC.

[0061] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 59 - 73 mg or 62 - 70 mg of rifaximin and a plurality of coated second solid compositions comprising about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC.

[0062] One aspect provides a formulation of rifaximin and NAC comprising a shell that includes a first solid composition comprising about 118 - 146 mg or 125 - 139 mg of rifaximin and a plurality of coated second solid compositions comprising about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC.

[0063] In various aspects, the first solid composition further comprises one or more excipients. In various aspects, the second solid composition further comprises one or more excipients.

[0064] In various aspects, the first solid composition is in tablet form.

[0065] In various embodiments, as used herein, the second solid composition is in the form of crystals, pellets, beads, or mini - tablets. In various embodiments, the crystals, pellets, beads, or mini - tablets have a size with a longest dimension of 3 mm or less. In various embodiments, the crystals, pellets, beads, or mini - tablets have a size with a longest dimension of 2 mm or less. In various embodiments, the crystals, pellets, beads, or mini - tablets have a size with a longest dimension of 1 mm or less.

[0066] In various embodiments, the coating of the second solid composition comprises a polymer.

[0067] In various embodiments, the coating of the second solid composition comprises at least one polymer that is insoluble at a pH lower than 5. In various embodiments, the coating of the second solid composition comprises at least one polymer that is insoluble at a pH lower than 3.5. In various embodiments, the coating of the second solid composition comprises at least one polymer that is insoluble at a pH between 1.5 and 3.5.

[0068] In various embodiments, the shell does not contain gelatin. In various embodiments, the shell contains hypromellose.

[0069] In various embodiments, the first solid composition containing rifaximin is not substantially dissolved after 1 hour in a Type 2 dissolution bath containing about 0.1 N hydrochloric acid.

[0070] In various embodiments, the first solid composition containing rifaximin disperses or substantially disperses in simulated intestinal fluid in a fed state.

[0071] Various aspects provide a formulation of rifaximin and N-acetylcysteine (NAC) comprising a shell; a first solid composition comprising an amount of rifaximin; and a plurality of coated second solid compositions comprising an amount of NAC, wherein the first solid composition comprising rifaximin is a tablet comprising rifaximin and one or more excipients; the plurality of coated second solid compositions comprising NAC are a plurality of mini-tablets comprising NAC and one or more excipients; and the coating comprises at least one polymer that is substantially insoluble at a pH lower than 3.5.

[0072] Unless otherwise specified, the rifaximin provided in these formulations can be rifaximin base, rifaximin polymorphs (e.g., rifaximin-α), amorphous rifaximin, pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, or enantiomers thereof. In certain aspects, the rifaximin provided in these formulations is rifaximin base. In other certain aspects, the rifaximin provided in these formulations is polymorph-α. In other certain aspects, it is amorphous form of rifaximin.

[0073] By way of non-limiting example, rifaximin is provided in a form where at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% is present. For example, if rifaximin is provided in the rifaximin-α form, at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the rifaximin is considered to be in the rifaximin-α form. If rifaximin is provided as rifaximin base, at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the rifaximin is considered to be in the rifaximin base form. In various aspects, the rifaximin base form is not purified with respect to the polymorph.

[0074] In various embodiments, the formulation does not contain 200 mg of rifaximin. In various embodiments, the formulation does not contain 600 mg of NAC. In various embodiments, the formulation does not contain 200 mg of rifaximin and 600 mg of NAC.

[0075] Various embodiments of the present invention provide a formulation of rifaximin and N-acetylcysteine (NAC) comprising a solid core composition containing an amount of rifaximin and an amount of NAC and a coating surrounding the solid core composition.

[0076] In various embodiments, the solid core composition constitutes a single layer that is uniform in composition state. In various embodiments, the solid core composition constitutes a single layer that is essentially uniform in composition state.

[0077] In various embodiments, NAC in the solid core composition enhances the dissolution of rifaximin compared to the solid core composition without NAC.

[0078] In various embodiments, the amount of rifaximin is about 66 mg. In various embodiments, the amount of rifaximin is about 66.5 mg. In various embodiments, the amount of rifaximin is about 62 - 70 mg. In various embodiments, the amount of rifaximin is about 59 - 73 mg.

[0079] In various embodiments, the amount of rifaximin is about 132 mg. In various embodiments, the amount of rifaximin is about 133 mg. In various embodiments, the amount of rifaximin is about 125 - 139 mg. In various embodiments, the amount of rifaximin is about 118 - 146 mg.

[0080] In various embodiments, the amount of NAC is about 560 mg. In various embodiments, the amount of NAC is about 561.3. In various embodiments, the amount of NAC is about 532 - 588 mg. In various embodiments, the amount of NAC is about 504 - 616 mg. In various embodiments, the amount of NAC is about 450 - 560 mg. In various embodiments, the amount of NAC is about 427 - 588 mg. In various embodiments, the amount of NAC is about 405 - 616 mg.

[0081] One aspect provides a formulation of rifaximin and NAC comprising a solid core composition comprising about 66 mg of rifaximin and about 560 mg of NAC and a coating surrounding the solid core composition.

[0082] One aspect provides a formulation of rifaximin and NAC comprising a solid core composition comprising about 66.5 mg of rifaximin and about 561.3 mg of NAC and a coating surrounding the solid core composition.

[0083] One aspect provides a formulation of rifaximin and NAC comprising a solid core composition comprising about 132 mg of rifaximin and about 560 mg of NAC and a coating surrounding the solid core composition.

[0084] One aspect provides a formulation of rifaximin and NAC comprising a solid core composition comprising about 133 mg of rifaximin and about 561.3 mg of NAC and a coating surrounding the solid core composition.

[0085] One aspect provides a formulation of rifaximin and NAC comprising a solid core composition comprising about 59 - 73 mg or 62 - 70 mg of rifaximin and about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC and a coating surrounding the solid core composition.

[0086] One aspect provides a formulation of rifaximin and NAC comprising a solid core composition comprising about 118 - 146 mg or 125 - 139 mg of rifaximin and about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC and a coating surrounding the solid core composition.

[0087] In various aspects, the solid core composition further comprises one or more excipients.

[0088] In various embodiments, the solid core composition is in tablet form.

[0089] In various embodiments, the coating comprises at least one polymer.

[0090] In various embodiments, the coating composition comprises at least one polymer that is insoluble at a pH lower than 5. In various embodiments, the coating comprises at least one polymer that is insoluble at a pH lower than 3.5. In various embodiments, the coating comprises at least one polymer that is insoluble at a pH between 1.5 and 3.5.

[0091] In various embodiments, the coating does not contain gelatin. In various embodiments, the coating contains hypromellose.

[0092] In various embodiments, the solid core composition containing rifaximin is not substantially dissolved after 1 hour in a Type 2 dissolution bath containing about 0.1 N hydrochloric acid.

[0093] In various embodiments, the solid core composition containing rifaximin disperses or substantially disperses in simulated intestinal fluid in a fed state.

[0094] In various embodiments, rifaximin, NAC, or both are in granular form.

[0095] Rifaximin provided in these formulations can be, unless otherwise specified, rifaximin base, rifaximin polymorphs (e.g., rifaximin-α), amorphous rifaximin, pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, or enantiomers thereof. In certain embodiments, rifaximin provided in these formulations is rifaximin base. In other certain embodiments, rifaximin provided in these formulations is rifaximin polymorph-α. In other certain embodiments, rifaximin provided in these formulations is amorphous form of rifaximin.

[0096] As a non-limiting example, rifaximin is provided in a form where at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% is provided. For example, when rifaximin is provided in the rifaximin-α form, it is contemplated that at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the rifaximin is in the rifaximin-α form. When rifaximin is provided as the rifaximin base, it is contemplated that at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the rifaximin is in the rifaximin base form. In various embodiments, the rifaximin base form is not purified with respect to the polymorphs.

[0097] In various embodiments, the formulation does not contain 200 mg of rifaximin. In various embodiments, the formulation does not contain 600 mg of NAC. In various embodiments, the formulation does not contain 200 mg of rifaximin and 600 mg of NAC.

[0098] In various embodiments, the formulations described herein may have a sustained release profile, i.e., they may slowly release the active ingredient in the body (e.g., the small intestine) over an extended period of time. In various embodiments, the formulations described herein may have a delayed release profile, i.e., they do not immediately release the active ingredient upon ingestion, but rather delay the release of the active ingredient until the composition reaches the gastrointestinal tract, e.g., the small intestine (e.g., one or more of the duodenum, jejunum, ileum) or the large intestine (e.g., one or more of the cecum, ascending, transverse, descending, or sigmoid portions of the colon, and the rectum). For example, the formulation is enteric-coated to delay the release of the active ingredient until it reaches the small intestine or the large intestine.

[0099] In various embodiments, the formulation releases NAC and rifaximin in the small intestine. In various embodiments, the formulations of the invention described herein release at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of NAC and rifaximin in the small intestine. For example, the formulation releases at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of NAC and rifaximin in the small intestine.

[0100] In one aspect, the formulation releases NAC and rifaximin in the duodenum. In various aspects, the formulations of the invention described herein release at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of NAC and rifaximin in the duodenum. For example, the formulation releases at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of NAC and rifaximin in the duodenum.

[0101] In another aspect, the formulation releases NAC and rifaximin in the jejunum. In various aspects, the formulations of the invention described herein release at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of NAC and rifaximin in the jejunum. For example, the formulation releases at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of NAC and rifaximin in the jejunum.

[0102] In a further aspect, the formulation releases NAC and rifaximin in the ileum and / or the ileocecal junction. In various aspects, the formulations of the invention described herein release at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of NAC and rifaximin in the ileum and / or the ileocecal junction. For example, the formulation releases at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of NAC and rifaximin in the ileum and / or the ileocecal junction.

[0103] In certain aspects, the formulation does not substantially release NAC and rifaximin in the stomach.

[0104] In certain embodiments, the formulation releases NAC and rifaximin at a specific pH. For example, in some embodiments, the formulation is substantially non-dispersible in an acidic environment and substantially dispersible (e.g., rapidly dissolves) in a neutral to alkaline environment. In some embodiments, stability indicates substantially non-release, while instability indicates substantially release. For example, in some embodiments, the formulation is substantially non-dispersible at a pH of about 7.0 or less or about 6.5 or less or about 6.0 or less or about 5.5 or less or about 5.0 or less or about 4.5 or less or about 4.0 or less or about 3.5 or less or about 3.0 or less or about 2.5 or less or about 2.0 or less or about 1.5 or less or about 1.0 or less. In some embodiments, the formulation is non-dispersible in a relatively low pH range and thus, for example, in the stomach, is substantially non-released. In some embodiments, the formulation is substantially non-dispersible at a pH of about 1 to about 4 or less and is substantially dispersible at higher pH values. In these embodiments, the formulation is substantially not released in the stomach. In these embodiments, the formulation is substantially released in the small intestine (e.g., one or more of the duodenum, jejunum, and ileum). In various embodiments, the pH values recited herein can be adjusted as known in the art taking into account the state of the subject, e.g., whether in a fasting state or a postprandial state.

[0105] In some embodiments, the formulation is substantially non-dispersible in gastric juice and substantially dispersible in intestinal juice and thus is substantially released in the small intestine (e.g., one or more of the duodenum, jejunum, and ileum).

[0106] In some embodiments, the formulation is non-dispersible in gastric juice or non-dispersible in an acidic environment. These formulations release no more than about 30% by weight of NAC and rifaximin in the formulation within about 15 or about 30 or about 45 or about 60 or about 90 minutes in gastric juice having a pH of about 4 to about 5 or less than 4 or less than 5, or in simulated gastric juice having a pH of about 4 to about 5 or less than 4 or less than 5. The formulations of the present invention can release from about 0% to about 30%, from about 0% to about 25%, from about 0% to about 20%, from about 0% to about 15%, from about 0% to about 10%, from about 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, from about 5% to about 15%, from about 5% to about 10% by weight of NAC and rifaximin in the formulation within about 15 or about 30 or about 45 or about 60 or about 90 minutes in gastric juice having a pH of 4 to 5 or less than 4 or less than 5, or in simulated gastric juice having a pH of 4 to 5 or less than 4 or less than 5. The formulations of the present invention can release about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight of total NAC and rifaximin in the formulation within about 15 or about 30 or about 45 or about 60 or about 90 minutes in gastric juice having a pH of 5 or less or in simulated gastric juice having a pH of 5 or less.

[0107] In some embodiments, the formulation is dispersible in intestinal fluid. These formulations release at least about 70% by weight of NAC and rifaximin in the formulation in intestinal fluid or simulated intestinal fluid within about 15 or about 30 or about 45 or about 60 or about 90 minutes. In some embodiments, the formulation is dispersible in an environment ranging from near neutral to alkaline. These formulations release at least about 70% by weight of NAC and rifaximin in the formulation in intestinal fluid with a pH of about 4 - 5 or greater than 4 or greater than 5, or in simulated intestinal fluid with a pH of about 4 - 5 or greater than 4 or greater than 5 within about 15 or about 30 or about 45 or about 60 or about 90 minutes. Formulations that are dispersible in an environment ranging from near neutral to alkaline can release at least 70% by weight of NAC and rifaximin in the formulation in a fluid with a pH greater than about 5 (e.g., a fluid with a pH of about 5 - about 14, about 6 - about 14, about 7 - about 14, about 8 - about 14, about 9 - about 14, about 10 - about 14, or about 11 - about 14) within about 5 minutes to about 90 minutes or about 10 minutes to about 90 minutes or about 15 minutes to about 90 minutes or about 20 minutes to about 90 minutes or about 25 minutes to about 90 minutes or about 30 minutes to about 90 minutes or about 5 minutes to about 60 minutes or about 10 minutes to about 60 minutes or about 15 minutes to about 60 minutes or about 20 minutes to about 60 minutes or about 25 minutes to about 90 minutes or about 30 minutes to about 60 minutes.

[0108] In one embodiment, the formulation can remain essentially unchanged or be essentially insoluble in gastric fluid. The stability of the delayed release coating can be pH - dependent. A pH - dependent delayed release coating is thought to be substantially non - dispersible in an acidic environment (pH of about 5 or less) and substantially dispersible in an environment ranging from near neutral to alkaline (pH greater than about 5). For example, the delayed release coating can essentially disintegrate or dissolve in an environment ranging from near neutral to alkaline as found in the small intestine (e.g., one or more of the duodenum, jejunum, and ileum).

[0109] Examples of simulated gastric fluid and simulated intestinal fluid include those disclosed in 2005 Pharmacopeia 23NF / 28USP in Test Solutions at page 2858, and / or other simulated gastric fluids and simulated intestinal fluids known to those skilled in the art, such as simulated gastric fluid and / or intestinal fluid prepared without using enzymes, but are not limited thereto.

[0110] Alternatively, the stability of the formulation may be enzyme-dependent. Enzyme-dependent sustained-release coatings are considered to be substantially non-dispersible in fluids without specific enzymes and substantially dispersible in fluids containing enzymes. The sustained-release coating is considered to essentially disintegrate or dissolve in a fluid containing an appropriate enzyme. Enzyme-dependent control can be achieved, for example, by using materials that release the active ingredient only upon exposure to enzymes in the intestine, such as galactomannan. Also, the stability of the formulation may depend on the stability of the enzyme in the presence of enzymes of microorganisms present in the intestinal flora.

[0111] Carriers, excipients, coatings, and salts The compositions and formulations of the present invention described herein may further comprise a pharmaceutically acceptable carrier or excipient. As will be recognized by those skilled in the art, the formulation can be in any suitable form appropriate for the desired use and route of administration. Examples of suitable dosage forms include, for example, oral dosage forms and parenteral dosage forms.

[0112] Suitable dosage forms for oral use include, for example, solid dosage forms. In another aspect, the formulation is in the form of a capsule. In yet another aspect, the formulation is in the form of a soft gel capsule. In some aspects, the shell does not contain gelatin. In a further aspect, the formulation is in the form of a hydroxypropyl methylcellulose (HPMC) (also known as hypromellose) capsule.

[0113] In another aspect, the formulation is in the form of a coated tablet. In yet another aspect, the formulation is in the form of a soft gel tablet. In some aspects, the coating is gelatin-free. In a further aspect, the formulation is coated with hydroxypropyl methylcellulose (HPMC), also known as hypromellose.

[0114] In these various dosage forms, the active compound is combined with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate, dicalcium phosphate, etc., and / or a) fillers, diluents, or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, silicic acid, microcrystalline cellulose (e.g., Avicel PH102), and Bakers Special Sugar, etc., b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, and copovidone, such as Kollidon® VA64 and Kollidon® VA64 Fine, etc., c) water retention agents, such as glycerol, etc., d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, cross-linked polymers, such as crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, etc., e) dissolution retardants, such as paraffin, etc., f) absorption promoters, such as quaternary ammonium compounds, etc., g) wetting agents, such as cetyl alcohol and glycerol monostearate, etc., h) absorbents, such as kaolin and bentonite clay, etc., i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, glyceryl behenate, etc., j) antioxidants, such as propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediaminetetraacetic acid (also known as edetic acid or EDTA), etc., k) viscosity and dispersing agents, such as silicon dioxide or silica, and can be mixed with mixtures of such excipients. Those skilled in the art will recognize that certain excipients may have more than one function in oral dosage forms. In the case of oral dosage forms, such as capsules or tablets, the dosage form may also contain buffering agents.

[0115] The composition and the modified release formulation can further contain a surfactant. Surfactants suitable for use in the present invention described herein include, but are not limited to, any pharmaceutically acceptable non-toxic surfactant. Classes of surfactants suitable for use in the compositions of the present invention include polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono- and diester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification reaction products, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters-glycerol esters, mono- and diglycerides, sterols and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, lower alcohol fatty acid esters, ionic surfactants, and mixtures thereof, but are not limited thereto. In some embodiments, the composition of the present invention can contain one or more surfactants including, but not limited to, sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and triethyl citrate.

[0116] The composition and the formulation can also contain a pharmaceutically acceptable plasticizer to obtain the desired mechanical properties, such as flexibility and hardness. Such plasticizers include, but are not limited to, triacetin, citrate esters, phthalate esters, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbate, or other plasticizers.

[0117] The compositions and formulations can also include one or more coating solvents. For example, some of the more common solvents that can be used to apply a delayed release coating composition include isopropyl alcohol, acetone, methylene chloride, and the like.

[0118] The compositions and formulations can also include one or more disintegrants. Exemplary disintegrants that can be utilized include, but are not limited to, crospovidone, such as Kollidon® CL, Kollidon® CL-F, Kollidon® CL-SF, or Kollidon® CL-M.

[0119] The compositions and formulations can also include one or more alkaline substances. Alkaline substances suitable for use in the compositions of the present invention include, but are not limited to, sodium, potassium, calcium, magnesium, and aluminum salts of acids such as phosphoric acid, carbonic acid, citric acid, and other aluminum / magnesium compounds. Further, the alkaline substance can be selected from antacid substances such as aluminum hydroxide, calcium hydroxide, magnesium hydroxide, and magnesium oxide.

[0120] Solid oral dosage forms can be prepared by any conventional method known in the art, for example, by granulation (e.g., wet or dry granulation) of the active compound (e.g., NAC and rifaximin) with one or more suitable excipients. Alternatively, the active compound can be layered onto an inert core (e.g., nonpareil / sugar spheres or silica spheres) using conventional methods such as fluid bed or pan coating, or can be extruded and spheronized using methods known in the art to form active compound-containing beads. Such beads can then be incorporated into tablets or capsules using conventional methods.

[0121] In addition to the inert diluent, the oral composition can also contain adjuvants such as sweeteners, flavoring agents, and fragrances.

[0122] In addition to the active compound, the suspending agent can include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and mixtures thereof.

[0123] The compositions and formulations containing NAC and rifaximin of the present invention described herein can be provided in unit dosage forms and can be prepared by any of the methods known in the pharmaceutical art. Such methods generally include the step of combining the therapeutic agent with a carrier that constitutes one or more auxiliary components. Typically, the formulation uniformly and intimately combines the therapeutic agent with a liquid carrier, a micronized solid carrier, or both, and then, if necessary, shapes the product into the dosage form of the desired formulation (for example, after wet or dry granulation, powder blending, etc., tableting using conventional methods known in the art).

[0124] In various embodiments, the compositions and formulations of the present invention described herein can utilize one or more coatings, such as a delayed release coating, to provide effective and substantially delayed delivery of NAC and rifaximin to a specific region of the gastrointestinal tract.

[0125] In one aspect, the delayed release coating comprises an enteric solvent that is substantially non-dispersible in an acidic environment and substantially dispersible in a neutral to alkaline environment. In one aspect, the delayed release coating comprises an enteric solvent that is substantially non-dispersible in gastric juice. The enteric solvent can be selected, for example, from copolymers of methacrylic acid, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethylcellulose, and solutions or dispersions of EUDRAGIT® type polymers (poly(methacrylic acid, methyl methacrylate), hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac, or other suitable enteric coating polymers). EUDRAGIT® type polymers include, for example, EUDRAGIT® FS 30D, L 30 D-55, L 100-55, L 100, L 12.5, L 12.5 P, RL 30 D, RL PO, RL 100, RL 12.5, RS 30 D, RS PO, RS 100, RS 12.5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12.5, and S 12.5 P. Similar polymers include Kollicoat® MAE 30 DP and Kollicoat® MAE 100 P. In some aspects, one or more of EUDRAGIT® FS 30D, L 30 D-55, L 100-55, L 100, L 12.5, L 12.5 P RL 30 D, RL PO, RL 100, RL 12.5, RS 30 D, RS PO, RS 100, RS 12.5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12.5 S 12.5 P, Kollicoat® MAE 30 DP, and Kollicoat® MAE 100 P are used. In various aspects, the enteric solvent may be a combination of the aforementioned solutions or dispersions. In certain aspects, one or more coating system additives are used with the enteric solvent. For example, one or more PlasACRYL™ additives can be used as anti-tack coating additives.Exemplary PlasACRYL™ additives include, but are not limited to, PlasACRYL™ HTP20 and PlasACRYL™ T20. In one aspect, PlasACRYL™ HTP20 is formulated with EUDRAGIT® L 30 D-55 coating. In another aspect, PlasACRYL™ T20 is formulated with EUDRAGIT® FS 30 D coating.

[0126] In another aspect, the delayed-release coating can degrade according to the time it is in the aqueous solution, regardless of the pH in the solution and / or the presence of an enzyme. Such a coating may contain a water-insoluble polymer. Thus, its solubility in the aqueous solution is pH-independent. As used herein, the term "pH-independent" means that the water permeability of the polymer and its ability to release the pharmaceutical component are not due to the action of pH and / or are only very slightly dependent on pH. Such a coating can be used, for example, to prepare a sustained-release formulation. Suitable water-insoluble polymers include pharmaceutically acceptable non-toxic polymers that are pH-independent in the solution and substantially insoluble in an aqueous medium, such as water. Suitable polymers include cellulose ethers, cellulose esters, or cellulose ether-esters, i.e., cellulose derivatives in which some of the hydroxy groups on the cellulose backbone are substituted with alkyl groups and some are modified with alkanoyl groups, but are not limited thereto. Examples include ethyl cellulose, acetyl cellulose, nitrocellulose, etc. Other examples of insoluble polymers include lacquers and acrylic acid and / or methacrylic acid ester polymers, polymers or copolymers of acrylates or methacrylates with a low quaternary ammonium content, or mixtures thereof, but are not limited thereto. Other examples of insoluble polymers include EUDRAGIT RS®, EUDRAGIT RL®, and EUDRAGIT NE®. Insoluble polymers useful in the present invention described herein include polyvinyl esters, polyvinyl acetals, polyacrylic acid esters, copolymers of butadiene and styrene, etc. In one aspect, colonic delivery is achieved by the use of a wax plug that erodes slowly (e.g., various PEGs including, for example, PEG6000).

[0127] In a further aspect, the delayed-release coating can be degraded by enzymes of microorganisms present in the intestinal flora. In one aspect, the delayed-release coating can be degraded by bacteria present in the small intestine.

[0128] Furthermore, in various aspects, the agents described herein may be in the form of pharmaceutically acceptable salts, i.e., salts that are suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, etc., and that have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Such salts can be prepared in situ during the final isolation and purification of the therapeutic agent, or separately by reacting the free base functional groups with a suitable acid, or the free acid functional groups with a suitable alkaline moiety. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0129] Kit Various aspects of the invention described herein provide a kit comprising a formulation of the invention described herein. In various aspects, the kit further comprises instructions for using a formulation comprising NAC and rifaximin.

[0130] A kit is an assembly of materials or components that includes at least one of the compositions of the invention. Thus, in some aspects, the kit includes a composition comprising NAC and rifaximin as described herein.

[0131] Various aspects provide a kit comprising a formulation comprising rifaximin and N-acetylcysteine (NAC), wherein the formulation is provided in one or more doses totaling about 198 mg of rifaximin per day and about 1680 mg of N-acetylcysteine (NAC) per day. In various aspects, the kit includes a dosage for 5 to 10 days. In various aspects, the kit includes a dosage for 7 to 14 days. In various aspects, the kit includes a dosage for 7 to 10 days. In various aspects, the kit can include a dosage for long-term treatment, e.g., a dosage for 30 days, 60 days, or 90 days at a time.

[0132] Various aspects provide a kit comprising a formulation comprising rifaximin and N-acetylcysteine (NAC), wherein the formulation is provided in one or more doses totaling about 198 mg of rifaximin per day and about 1350 mg to about 1680 mg of N-acetylcysteine (NAC) per day. In various aspects, the kit includes a dosage for 5 to 10 days. In various aspects, the kit includes a dosage for 7 to 14 days. In various aspects, the kit includes a dosage for 7 to 10 days. In various aspects, the kit can include a dosage for long-term treatment, e.g., a dosage for 30 days, 60 days, or 90 days at a time.

[0133] Various aspects provide a kit comprising a formulation comprising rifaximin and N-acetylcysteine (NAC), wherein the formulation is provided in one or more doses totaling from about 186 to 210 mg of rifaximin per day and from about 1350 mg to about 1680 mg of N-acetylcysteine (NAC) per day. In various aspects, the kit comprises a dosage for 7 to 14 days. In various aspects, the kit comprises a dosage for 5 to 10 days. In various aspects, the kit comprises a dosage for 7 to 10 days. In various aspects, the kit can comprise a dosage for long-term treatment, e.g., a dosage for 30, 60, or 90 days at a time.

[0134] Various aspects provide a kit comprising a formulation comprising rifaximin and N-acetylcysteine (NAC), wherein the formulation is provided in one or more doses totaling from about 177 to 219 mg of rifaximin per day and from 1350 mg to about 1680 mg of N-acetylcysteine (NAC) per day. In various aspects, the kit comprises a dosage for 5 to 10 days. In various aspects, the kit comprises a dosage for 7 to 14 days. In various aspects, the kit comprises a dosage for 7 to 10 days. In various aspects, the kit can comprise a dosage for long-term treatment, e.g., a dosage for 30, 60, or 90 days at a time.

[0135] Various aspects provide a kit comprising a formulation comprising rifaximin and N-acetylcysteine (NAC), wherein the formulation is provided in one or more doses totaling from about 396 mg of rifaximin per day and from about 1680 mg of N-acetylcysteine (NAC) per day. In various aspects, the kit comprises a dosage for 5 to 10 days. In various aspects, the kit comprises a dosage for 7 to 14 days. In various aspects, the kit comprises a dosage for 7 to 10 days. In various aspects, the kit can comprise a dosage for long-term treatment, e.g., a dosage for 30, 60, or 90 days at a time.

[0136] Various aspects provide a kit comprising a formulation comprising rifaximin and N-acetylcysteine (NAC), wherein the formulation is provided in one or more doses totaling about 396 mg of rifaximin per day and 1350 mg to about 1680 mg of N-acetylcysteine (NAC) per day. In various aspects, the kit comprises a dosage for 5 to 10 days. In various aspects, the kit comprises a dosage for 7 to 14 days. In various aspects, the kit comprises a dosage for 7 to 10 days. In various aspects, the kit can comprise a dosage for long-term treatment, e.g., a dosage for 30 days, 60 days, or 90 days at a time.

[0137] Various aspects provide a kit comprising a formulation comprising rifaximin and N-acetylcysteine (NAC), wherein the formulation is provided in one or more doses totaling about 375 - 417 mg of rifaximin per day and 1350 mg to about 1680 mg of N-acetylcysteine (NAC) per day. In various aspects, the kit comprises a dosage for 5 to 10 days. In various aspects, the kit comprises a dosage for 7 to 14 days. In various aspects, the kit comprises a dosage for 7 to 10 days. In various aspects, the kit can comprise a dosage for long-term treatment, e.g., a dosage for 30 days, 60 days, or 90 days at a time.

[0138] Various aspects provide a kit comprising a formulation comprising rifaximin and N-acetylcysteine (NAC), wherein the formulation is provided in one or more doses totaling about 354 - 438 mg of rifaximin per day and 1350 mg to about 1680 mg of N-acetylcysteine (NAC) per day. In various aspects, the kit comprises a dosage for 5 to 10 days. In various aspects, the kit comprises a dosage for 7 to 14 days. In various aspects, the kit comprises a dosage for 7 to 10 days. In various aspects, the kit can comprise a dosage for long-term treatment, e.g., a dosage for 30 days, 60 days, or 90 days at a time.

[0139] Refaximin provided in these formulations can be, unless otherwise specified, refaximin base, refaximin polymorphs (e.g., refaximin-α), amorphous refaximin, pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, or enantiomers thereof. In certain embodiments, refaximin provided in these formulations is refaximin base. In other certain embodiments, refaximin provided in these formulations is polymorph-α. In other certain embodiments, refaximin provided in these formulations is in amorphous form of refaximin.

[0140] By way of non-limiting example, refaximin is in a form provided at at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. For example, if refaximin is provided in the refaximin-α form, at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the refaximin is considered to be in the refaximin-α form. If refaximin is provided as refaximin base, at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the refaximin is considered to be in the refaximin base form. In various embodiments, the refaximin base form is not purified with respect to the polymorph.

[0141] The exact nature of the components configured in the kits of the present invention depends on their intended purpose. For example, some embodiments are configured for the purpose of treating irritable bowel syndrome (IBS), IBS-D, or H 2 S positive IBS; other embodiments are configured for treating SIBO; and still other embodiments are configured for reducing the E. coli load, Klebsiella load, and total bacterial load in the small intestine, or for improving stool hardness, reducing systemic inflammation, or both.

[0142] In one aspect, the kit is configured, in particular, for the purpose of treating a mammalian subject. In another aspect, the kit is configured, in particular, for the purpose of treating a human subject. In a further aspect, the kit is configured for veterinary applications, i.e., for the treatment of subjects such as, but not limited to, livestock, companion animals, and laboratory animals.

[0143] Instructions for use can be included in the kit. The "instructions for use" typically include clear statements explaining the techniques to be used when employing the components of the kit in order to achieve a desired outcome, e.g., treating IBS, treating H 2 S-positive IBS, treating D-IBS, treating SIBO, reducing the E. coli load, Klebsiella load, and total bacterial load in the small intestine, or improving stool hardness, reducing systemic inflammation, or both. Optionally, the kit also includes other useful components, such as diluents, pharmaceutically acceptable carriers, syringes, pipetting or measuring tools, or other useful supplies readily recognizable by those skilled in the art.

[0144] Materials or components assembled in kit form can be stored and provided to a physician in any convenient and appropriate manner that maintains their operability and usefulness. For example, the components may be in dissolved, dehydrated, or lyophilized form; they can be provided at room temperature, refrigerated temperature, or frozen temperature. The components are typically contained within suitable packaging materials. As used herein, the phrase "packaging material" refers to one or more physical structures used to contain the contents of the kit, such as the inventive composition, etc. The packaging material is preferably constructed by well-known methods so as to provide a sterile, contaminant-free environment. The packaging materials used in the kits are those customarily utilized in treating gastrointestinal disorders. As used herein, the term "packaging" refers to a suitable solid matrix or material, such as glass, plastic, paper, foil, etc., that can hold the individual kit components. Thus, for example, the packaging may be a bottle used to contain a suitable dosage of a formulation comprising NAC and rifaximin as described herein. The packaging material generally has an external label indicating the contents and / or purpose of the kit and / or its components.

[0145] Treatment method Various aspects of the present invention provide for the treatment of irritable bowel syndrome (IBS) comprising administering to a subject in need thereof a formulation of one or more doses of rifaximin and N-acetylcysteine (NAC) as described herein. In various aspects, the IBS is diarrhea-predominant IBS (IBS-D). In various aspects, the IBS is H 2 S-positive IBS. That is, the subject was positive in the hydrogen sulfide test.

[0146] Various aspects of the present invention provide for the treatment of small intestinal bacterial overgrowth (SIBO) comprising administering to a subject in need thereof a formulation of one or more doses of rifaximin and N-acetylcysteine (NAC) as described herein.

[0147] Various aspects of the present invention provide a reduction in the Escherichia coli load, Klebsiella load, and total bacterial load in the small intestine, including the step of administering to a subject in need thereof a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses as described herein. In various aspects, the reduction in the Escherichia coli load, Klebsiella load, and total bacterial load occurs in the ileum. In various aspects, the reduction in the Escherichia coli load, Klebsiella load, and total bacterial load occurs in the duodenum.

[0148] Various aspects of the present invention provide a method of improving stool hardness, including the step of administering to a subject in need thereof a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses as described herein.

[0149] Various aspects of the present invention provide a method of reducing systemic inflammation, including the step of administering to a subject in need thereof a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses as described herein.

[0150] Various aspects of the present invention provide a method of improving stool hardness and reducing systemic inflammation, including the step of administering to a subject in need thereof a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses as described herein.

[0151] In various aspects, the subject was positive in an H 2 S test, for example, based on a breath test. Thus, the subject may have H 2 S positivity. Methods of testing for H 2 S are known in the art. Methods of testing for H 2 S are also described in International Application No. PCT / US2018 / 019490, filed February 23, 2018, the contents of which are hereby incorporated by reference in their entirety as if fully set forth herein.

[0152] The subject may be a mammalian subject, preferably a human subject.

[0153] In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses is via oral administration.

[0154] In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses includes the step of administering a formulation in more than two doses per day to a subject in need thereof. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses includes the step of administering a dosage of three times per day to a subject in need thereof.

[0155] In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses includes the step of administering one or more doses for about 7 to 14 days. The step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses includes the step of administering one or more doses for about 7 to 10 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses includes the step of administering one or more doses for about 10 to 14 days. The step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses includes the step of administering one or more doses for about 5 to 10 days.

[0156] In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises the step of administering one dose per day to a subject in need thereof for about 7 to 14 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises the step of administering one dose per day to a subject in need thereof for about 7 to 10 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises the step of administering one dose per day to a subject in need thereof for about 10 to 14 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises the step of administering one dose per day to a subject in need thereof for about 5 to 10 days.

[0157] In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises the step of administering two doses per day to a subject in need thereof for about 7 to 14 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises the step of administering two doses per day to a subject in need thereof for about 7 to 10 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises the step of administering two doses per day to a subject in need thereof for about 10 to 14 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises the step of administering two doses per day to a subject in need thereof for about 5 to 10 days.

[0158] In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises administering a dosage three times a day to a subject in need thereof for about 7 to 14 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises administering a dosage three times a day to a subject in need thereof for about 7 to 10 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises administering a dosage three times a day to a subject in need thereof for about 10 to 14 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises administering a dosage three times a day to a subject in need thereof for about 5 to 10 days.

[0159] In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises administering a dosage four times a day to a subject in need thereof for about 7 to 14 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises administering a dosage four times a day to a subject in need thereof for about 7 to 10 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises administering a dosage four times a day to a subject in need thereof for about 10 to 14 days. In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or more doses comprises administering a dosage four times a day to a subject in need thereof for about 5 to 10 days.

[0160] In various embodiments, the step of administering a formulation of rifaximin and N-acetylcysteine (NAC) in one or multiple doses comprises administering one, two, three, or four doses per day over a long-term treatment. The long-term treatment can be a treatment that lasts for about 30 days, about 60 days, about 90 days, about 120 days, about 150 days, about 180 days, or longer than 180 days. In various embodiments, the long-term treatment can be a treatment that lasts for about 15 - 30 days, 30 - 60 days, about 60 - 90 days, about 90 - 120 days, or about 120 - 180 days. The long-term treatment can also be a cycle of treatment; for example, treatment is administered for a certain number of days and then there is a period without treatment with rifaximin. Examples of cycles include, but are not limited to, administering treatment for about 10 days followed by about 1 - 3 months without treatment. Then, in a second cycle, treatment can be administered for another 10 days and there may be another 1 - 3 months without treatment. Another example of a cycle is administering treatment for about 14 days followed by about 1 - 3 months without treatment.

[0161] Administration of the formulation according to an embodiment of the present invention can be achieved by oral administration.

[0162] In various embodiments, the formulation of rifaximin and N-acetylcysteine (NAC) administered according to these methods comprises a shell containing a first solid composition comprising an amount of rifaximin and a plurality of second solid compositions comprising an amount of NAC.

[0163] In various embodiments, the formulation of rifaximin and N-acetylcysteine (NAC) administered according to these methods comprises a shell containing a first solid composition comprising an amount of rifaximin and a plurality of coated second solid compositions comprising an amount of NAC.

[0164] In various embodiments, the amount of rifaximin is about 66 mg. In various embodiments, the amount of rifaximin is about 66.5 mg. In various embodiments, the amount of rifaximin is about 62 - 70 mg. In various embodiments, the amount of rifaximin is about 59 - 73 mg.

[0165] In various embodiments, the amount of rifaximin is about 132 mg. In various embodiments, the amount of rifaximin is about 133 mg. In various embodiments, the amount of rifaximin is about 125 - 139 mg. In various embodiments, the amount of rifaximin is about 118 - 146 mg.

[0166] In various embodiments, the amount of NAC is about 560 mg. In various embodiments, the amount of NAC is about 561.3. In various embodiments, the amount of NAC is about 532 - 588 mg. In various embodiments, the amount of NAC is about 504 - 616 mg. In various embodiments, the amount of NAC is about 450 - 560 mg. In various embodiments, the amount of NAC is about 427 - 588 mg. In various embodiments, the amount of NAC is about 405 - 616 mg.

[0167] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a shell comprising a first solid composition comprising about 66 mg of rifaximin and a plurality of second solid compositions comprising about 560 mg of NAC.

[0168] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a shell comprising a first solid composition comprising about 66.5 mg of rifaximin and a plurality of second solid compositions comprising about 561.3 mg of NAC.

[0169] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a shell comprising a first solid composition comprising about 132 mg of rifaximin and a plurality of second solid compositions comprising about 560 mg of NAC.

[0170] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a shell comprising a first solid composition comprising about 133 mg of rifaximin and a plurality of second solid compositions comprising about 561.3 mg of NAC.

[0171] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a shell comprising a first solid composition comprising from about 59 to 73 mg or 62 to 70 mg of rifaximin and a plurality of second solid compositions comprising from about 405 to 616 mg or 427 to 588 mg or 450 to 560 mg or 504 to 616 mg or 532 to 588 mg of NAC.

[0172] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a shell comprising a first solid composition comprising from about 118 to 146 mg or 125 to 139 mg of rifaximin and a plurality of second solid compositions comprising from about 405 to 616 mg or 427 to 588 mg or 450 to 560 mg or 504 to 616 mg or 532 to 588 mg of NAC.

[0173] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a shell comprising a first solid composition comprising about 66 mg of rifaximin and a plurality of coated second solid compositions comprising about 560 mg of NAC.

[0174] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a shell comprising a first solid composition comprising about 66.5 mg of rifaximin and a plurality of coated second solid compositions comprising about 561.3 mg of NAC.

[0175] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a shell comprising a first solid composition comprising about 132 mg of rifaximin and a plurality of coated second solid compositions comprising about 560 mg of NAC.

[0176] In various embodiments, a formulation of rifaximin and N-acetylcysteine (NAC) administered according to these methods comprises a shell comprising a first solid composition comprising about 133 mg of rifaximin and a plurality of coated second solid compositions comprising about 561.3 mg of NAC.

[0177] In various embodiments, a formulation of rifaximin and N-acetylcysteine (NAC) administered according to these methods comprises a shell comprising a first solid composition comprising about 59 - 73 mg or 62 - 70 mg of rifaximin and a plurality of coated second solid compositions comprising about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC.

[0178] In various embodiments, a formulation of rifaximin and N-acetylcysteine (NAC) administered according to these methods comprises a shell comprising a first solid composition comprising about 118 - 146 mg or 125 - 139 mg of rifaximin and a plurality of coated second solid compositions comprising about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC.

[0179] In various embodiments, the first solid composition in a formulation of rifaximin and N-acetylcysteine (NAC) further comprises one or more excipients. In various embodiments, the second solid composition in a formulation of rifaximin and N-acetylcysteine (NAC) further comprises one or more excipients.

[0180] In various embodiments, the first solid composition in a formulation of rifaximin and N-acetylcysteine (NAC) is in tablet form.

[0181] In various embodiments, the second solid composition in the formulation of rifaximin and N-acetylcysteine (NAC) is in the form of crystals, pellets, beads, or mini-tablets. In various embodiments, the crystals, pellets, beads, or mini-tablets have a size with the longest dimension of 3 mm or less. In various embodiments, the crystals, pellets, beads, or mini-tablets have a size with the longest dimension of 2 mm or less. In various embodiments, the crystals, pellets, beads, or mini-tablets have a size with the longest dimension of up to 1 mm.

[0182] In various embodiments, the coating of the second solid composition comprises a polymer.

[0183] In various embodiments, the coating of the second solid composition comprises at least one polymer that is insoluble at a pH lower than 5. In various embodiments, the coating of the second solid composition comprises at least one polymer that is insoluble at a pH lower than 3.5. In various embodiments, the coating of the second solid composition comprises at least one polymer that is insoluble at a pH between 1.5 and 3.5.

[0184] In various embodiments, the shell does not contain gelatin. In various embodiments, the shell contains hypromellose.

[0185] In various embodiments, the first solid composition containing rifaximin is not substantially dissolved after 1 hour in a Type 2 dissolution bath containing about 0.1 N hydrochloric acid.

[0186] In various embodiments, the first solid composition containing rifaximin is completely dispersed or substantially dispersed in simulated intestinal fluid in a fed state.

[0187] In various aspects of these methods, a formulation of rifaximin and N-acetylcysteine (NAC) is orally administered to a subject in need thereof, the formulation comprising a shell containing a first solid composition comprising an amount of rifaximin and a plurality of coated second solid compositions comprising an amount of NAC, the first solid composition comprising rifaximin being a tablet comprising rifaximin and one or more excipients, the plurality of coated second solid compositions comprising NAC being a plurality of mini-tablets comprising NAC and one or more excipients, and the coating comprising at least one polymer that is substantially insoluble at a pH lower than 3.5.

[0188] Unless otherwise specified, rifaximin provided in these formulations can be rifaximin base, rifaximin polymorphs (e.g., rifaximin-α), amorphous rifaximin, pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, or enantiomers thereof. In certain aspects, rifaximin provided in these formulations is rifaximin base. In other certain aspects, rifaximin provided in these formulations is polymorph-α. In other certain aspects, rifaximin provided in these formulations is amorphous rifaximin.

[0189] By way of non-limiting example, rifaximin is provided in a form that is at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. For example, if rifaximin is provided in the rifaximin-α form, at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the rifaximin is considered to be in the rifaximin-α form. If rifaximin is provided as rifaximin base, at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the rifaximin is considered to be in the rifaximin base form. In various aspects, the rifaximin base form is not purified with respect to polymorphs.

[0190] In various embodiments, the amount of rifaximin in the formulation of rifaximin and NAC administered is not 200 mg. In various embodiments, the amount of NAC in the formulation of rifaximin and NAC is not 600 mg of NAC. In various embodiments, the amount of rifaximin and the amount of NAC in the formulation of rifaximin and NAC administered are not 200 mg of rifaximin and 600 mg of NAC.

[0191] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a solid core composition comprising an amount of rifaximin and an amount of NAC and a coating surrounding the solid core composition.

[0192] In various embodiments, the amount of rifaximin is about 66 mg. In various embodiments, the amount of rifaximin is about 66.5 mg. In various embodiments, the amount of rifaximin is about 62 - 70 mg. In various embodiments, the amount of rifaximin is about 59 - 73 mg.

[0193] In various embodiments, the amount of rifaximin is about 132 mg. In various embodiments, the amount of rifaximin is about 133 mg. In various embodiments, the amount of rifaximin is about 125 - 139 mg. In various embodiments, the amount of rifaximin is about 118 - 146 mg.

[0194] In various embodiments, the amount of NAC is about 560 mg. In various embodiments, the amount of NAC is about 561.3. In various embodiments, the amount of NAC is about 532 - 588 mg. In various embodiments, the amount of NAC is about 504 - 616 mg. In various embodiments, the amount of NAC is about 450 - 560 mg. In various embodiments, the amount of NAC is about 427 - 588 mg. In various embodiments, the amount of NAC is about 405 - 616 mg.

[0195] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a solid core composition containing about 66 mg of rifaximin and about 560 mg of NAC and a coating surrounding the solid core composition.

[0196] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a solid core composition containing about 66.5 mg of rifaximin and about 561.3 mg of NAC and a coating surrounding the solid core composition.

[0197] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a solid core composition containing about 132 mg of rifaximin and about 560 mg of NAC.

[0198] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a solid core composition containing about 133 mg of rifaximin and about 561.3 mg of NAC.

[0199] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a solid core composition containing about 59 - 73 mg or 62 - 70 mg of rifaximin and about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC.

[0200] In various embodiments, formulations of rifaximin and N-acetylcysteine (NAC) administered according to these methods include a solid core composition containing about 118 - 146 mg or 125 - 139 mg of rifaximin and about 405 - 616 mg or 427 - 588 mg or 450 - 560 mg or 504 - 616 mg or 532 - 588 mg of NAC.

[0201] In various embodiments, the solid core composition in a formulation of rifaximin and N-acetylcysteine (NAC) further comprises one or more excipients.

[0202] In various embodiments, the solid core composition in a formulation of rifaximin and N-acetylcysteine (NAC) is in tablet form.

[0203] In various embodiments, the coating around the solid core composition comprises a polymer.

[0204] In various embodiments, the coating around the solid core composition comprises at least one polymer that is insoluble at a pH lower than 5. In various embodiments, the coating of the second solid composition comprises at least one polymer that is insoluble at a pH lower than 3.5. In various embodiments, the coating of the second solid composition comprises at least one polymer that is insoluble at a pH between 1.5 and 3.5.

[0205] In various embodiments, the coating around the solid core composition does not contain gelatin. In various embodiments, the coating around the solid core composition comprises hypromellose.

[0206] In various embodiments, the solid core composition comprising rifaximin and NAC is not substantially dissolved after 1 hour in a Type 2 dissolution bath containing about 0.1 N hydrochloric acid.

[0207] In various embodiments, the solid core composition comprising rifaximin and NAC completely disperses or substantially disperses in simulated intestinal fluid in a fed state.

[0208] In various embodiments of these methods, a formulation of rifaximin and N-acetylcysteine (NAC) is orally administered to a subject in need thereof, the formulation comprising a solid core composition comprising an amount of rifaximin and an amount of NAC and a coating around the solid core composition, the solid core composition constituting a single layer that is uniform or substantially uniform in composition.

[0209] Refaximin provided in these formulations can be, unless otherwise specified, refaximin base, refaximin polymorphs (e.g., refaximin-α), amorphous refaximin, pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, or enantiomers thereof. In certain embodiments, refaximin provided in these formulations is refaximin base. In other certain embodiments, refaximin provided in these formulations is refaximin polymorph-α. In other certain embodiments, refaximin provided in these formulations is amorphous form of refaximin.

[0210] By way of non-limiting example, refaximin is provided in a form where at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% is present. For example, if refaximin is provided in the refaximin-α form, at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the refaximin is considered to be in the refaximin-α form. If refaximin is provided as refaximin base, at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the refaximin is considered to be in the refaximin base form. In various embodiments, the refaximin base form is not purified with respect to the polymorphs.

[0211] In various embodiments, the amount of refaximin in the formulation of refaximin and NAC administered is not 200 mg. In various embodiments, the amount of NAC in the formulation of refaximin and NAC is not 600 mg of NAC. In various embodiments, the amount of refaximin and the amount of NAC in the formulation of refaximin and NAC administered are not 200 mg of refaximin and 600 mg of NAC.

Examples

[0212] The following examples are provided to better illustrate the claimed invention and should not be construed as limiting the scope of the invention. To the extent that specific materials are recited, this is for illustrative purposes only and is not intended to limit the invention. One of ordinary skill in the art can develop equivalent means or reactants without exercising inventive faculty and without departing from the scope of the invention.

[0213] Example 1 In vitro dilution growth / bactericidal experiments were performed against Escherichia coli and Klebsiella to determine the doses of rifaximin and NAC, including the minimum doses of rifaximin and NAC. Based on the experiments, the indicated NAC concentration of 0.125 mg / mL improves the minimum inhibitory concentration (MIC) of 4 μg / mL of rifaximin.

[0214] Dosing conversions for use in a rat model and for human use were calculated and are shown in FIG. 1. A rifaximin dose of 66 mg three times daily orally, along with an NAC dose of 560 three times daily orally, results in a total daily dose of 1680 mg NAC and 198 mg rifaximin in humans.

[0215] To calculate human doses for NAC and rifaximin, the FDA Guidance for Industry (Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers - www.fda.gov / media / 72309 / download) was used, and the conversion of animal doses to human equivalent doses was based on body surface area (Table 1 of the guideline). The rat dose of NAC of approximately 58 mg / kg (14 mg of NAC per rat with an average body weight of 0.24 kg) was divided by a conversion factor of 6.2 and multiplied by 60 kg (the average body weight of an adult recommended by the FDA), resulting in a dose of 561.3 mg per dose. The rat dose of rifaximin of approximately 6.87 mg / kg (1.65 mg of rifaximin per rat with an average body weight of 0.24 kg) was divided by a conversion factor of 6.2 and multiplied by 60 kg (the average body weight of an adult recommended by the FDA), resulting in a dose of 66.5 mg per dose.

[0216] Example 2 A validated rat model of IBS-D was used in the experiment to test the dosages of NAC and rifaximin. The research plan is shown in Figure 2. As shown in Figure 2, the control vehicle (1 ml of 1×PBS), rifaximin, or rifaximin + NAC was given to the rats by gavage.

[0217] The results show that the therapy with rifaximin + NAC can reduce the Escherichia coli load and total bacterial load in the small intestine (Figures 3A and 3B); the therapy with rifaximin + NAC can improve stool hardness (Figure 4); the therapy with rifaximin + NAC can reduce systemic inflammation (Figures 5A and 5B).

[0218] In conclusion, NAC improves the effectiveness of rifaximin in the killing of Escherichia coli and Klebsiella. Since this effect is very strong, it becomes possible to reduce the dosage of rifaximin with higher effectiveness. The effective amount of the combination in humans was estimated to be 66 mg of rifaximin + 560 mg of NAC, both three times a day.

[0219] Rifaximin with NAC is superior to rifaximin alone in the treatment of IBS and the reduction of Escherichia coli in the small intestine (Sprague-Dawley rats do not have Klebsiella). The rats treated with the combination had a greater reduction in the wet weight of feces.

[0220] The cytokine profile was seen in this study and predicted the observed response.

[0221] Example 3 Figure 6 depicts an exemplary embodiment of the formation of rifaximin and NAC described herein. Figure 6 shows a capsule containing a solid tablet containing rifaximin and a mini-tab containing NAC.

[0222] Figure 7 shows the percentage dissolution of rifaximin and NAC over a period of 0 to 175 minutes and the change from an acidic solution of pH 1 to a neutral solution.

[0223] Figure 8 shows the dissolution of NAC mini-tabs over a period of 0 to 45 minutes in buffer only (100 mM sodium phosphate pH 7.4 containing 0.45% sodium lauryl sulfate) and an acidic solution without surfactant (pH 1 (0.1 N HCl)), followed by the buffer. Percent dissolution is based on the stated amount of drug in the dosage form. In this example, due to variability between units, some dosage form units containing more than the target dose are produced, and as a result, the dissolution values may appear to exceed 100%.

[0224] Example 4 FIG. 9 depicts an exemplary embodiment of the formation of rifaximin and NAC described herein. FIG. 9 shows a solid core composition comprising rifaximin and NAC surrounded by a coating.

[0225] Various aspects of the present invention are described above in detail. While these descriptions directly describe the above aspects, it will be understood that those skilled in the art may conceive of modifications and / or variations to the specific aspects shown and described herein. Any such modifications or variations that fall within the scope of this description are similarly intended to be included within the scope of this description. Unless otherwise specified, the words and phrases in the specification and claims are intended to be given their ordinary and customary meaning to those skilled in the art.

[0226] The foregoing descriptions of the various aspects of the present invention as known to the applicant at the time of filing of this application are presented for purposes of illustration and explanation. This specification is not intended to be exhaustive or to limit the invention to the precise form disclosed, and many modifications and variations are possible in light of the above teachings. The described aspects are intended to explain the principles of the invention and its practical application and to enable others skilled in the art to utilize the invention with various modifications suited to the particular uses contemplated in various aspects. Accordingly, the invention is not intended to be limited to the specific aspects disclosed for carrying out the invention.

[0227] Certain aspects of the invention described herein are shown and described, but based on the teachings herein, changes and modifications can be made without departing from the invention and its broader aspects, and thus it will be apparent to those skilled in the art that the appended claims are intended to cover all such changes and modifications as being within the true spirit and scope of the invention. As used herein, the term "comprising" or "comprises" is used in connection with compositions, methods, and respective components thereof that are useful, but the inclusion of elements not specified is opened, whether useful or not. Generally, the terms used herein are usually intended as "open" terms (e.g., the term "including" should be construed as "including but not limited to", the term "having" should be construed as "having at least", the term "includes" should be construed as "includes but is not limited to", etc.), as will be understood by those skilled in the art. For purposes of describing and claiming the invention, the open-ended term "comprising" is used herein as a synonym for synonyms such as "including", "containing", or "having", but the invention or aspects thereof described herein can alternatively be described using alternative terms such as "consisting of" or "consisting essentially of".

[0228] Unless otherwise indicated, the terms "a", "an", "the", and similar references used in the context of describing particular aspects of the present application (especially in the context of the claims) can be construed to cover both the singular and the plural. The description of a range of values herein is merely intended to serve as a concise way of referring individually to each separate value within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly precluded by the context. The use of any examples or exemplary language provided herein with respect to a particular aspect (e.g., "such as") is merely intended to better clarify the present application and is not intended to limit the scope of the present application as otherwise claimed. The abbreviation "e.g." is derived from the Latin exempli gratia and is used herein to indicate non-limiting examples. Thus, the abbreviation "e.g." is synonymous with the term "for example". No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present application.

[0229] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and thus that the description includes examples of the circumstance occurring and examples of the circumstance not occurring.

[0230] The classification of alternative elements or aspects of the present disclosure disclosed herein should not be construed as limiting. Members of each group may be referred to and claimed individually, or in any combination with other members of the group or other elements found herein. One or more members of a group may be included in or deleted from the group for reasons of convenience and / or patentability. If any such inclusion or deletion occurs, this specification is considered herein to include the group so modified and thus to satisfy the written description of all Markush groups used in the appended claims.

Claims

1. A shell; A first solid composition contained within the shell and comprising a certain amount of rifaximin; and A plurality of coated second solid compositions contained within the shell and comprising a certain amount of NAC A formulation of rifaximin and N-acetylcysteine (NAC) comprising the same.

2. A solid core composition comprising a certain amount of rifaximin and a certain amount of NAC; and A coating surrounding the solid core composition A formulation of rifaximin and N-acetylcysteine (NAC) comprising the same.

3. The formulation according to claim 1 or claim 2, wherein the amount of rifaximin is about 66 mg.

4. The formulation according to claim 1 or claim 2, wherein the amount of rifaximin is about 62 to 70 mg.

5. The formulation according to claim 1 or claim 2, wherein the amount of rifaximin is about 59 to 73 mg.

6. The formulation according to claim 1 or claim 2, wherein the amount of rifaximin is about 132 mg.

7. The formulation according to claim 1 or claim 2, wherein the amount of rifaximin is about 125 to 139 mg.

8. The formulation according to claim 1 or claim 2, wherein the amount of rifaximin is about 118 to 146 mg.

9. The formulation according to any one of claims 1 to 8, wherein the amount of NAC is about 560 mg.

10. The formulation according to any one of claims 1 to 8, wherein the amount of NAC is about 532 to 588 mg.

11. The formulation according to any one of claims 1 to 8, wherein the amount of NAC is about 504 to 616 mg.

12. The formulation according to any one of claims 1 to 8, wherein the amount of NAC is about 450 to 560 mg.

13. The formulation according to any one of claims 1 to 8, wherein the amount of NAC is about 427 to 588 mg.

14. The formulation according to any one of claims 1 to 8, wherein the amount of NAC is about 405 to 616 mg.

15. The formulation according to claim 1 or any one of claims 3 to 14, wherein the first solid composition further comprises one or more excipients.

16. The formulation according to claim 1 or any one of claims 3 to 15, wherein the second solid composition further comprises one or more excipients.

17. The formulation according to claim 1 or any one of claims 3 to 16, wherein the first solid composition is in tablet form.

18. The preparation according to any one of claims 1 or 3 to 17, wherein the second solid composition is in the form of a mini-tablet, crystal, pellet, or bead.

19. The preparation according to any one of claims 1 or 3 to 18, wherein the coating of the second solid composition comprises at least one polymer.

20. The preparation according to any one of claims 1 or 3 to 18, wherein the coating of the second solid composition comprises at least one polymer that is insoluble at a pH lower than 5.

21. The preparation according to any one of claims 1 or 3 to 18, wherein the coating of the second solid composition comprises at least one polymer that is insoluble at a pH lower than 3.

5.

22. The preparation according to any one of claims 1 or 3 to 18, wherein the coating of the second solid composition comprises at least one polymer that is insoluble at a pH between 1.5 and 3.

5.

23. The preparation according to any one of claims 1 or 3 to 22, wherein the shell does not contain gelatin.

24. The preparation according to any one of claims 1 or 3 to 22, wherein the shell contains hypromellose.

25. The preparation according to any one of claims 1 or 3 to 24, wherein the first solid composition containing rifaximin is not substantially dissolved after 1 hour in a Type 2 dissolution bath containing about 0.1 N hydrochloric acid.

26. The preparation according to any one of claims 1 or 3 to 25, wherein the first solid composition containing rifaximin is substantially dispersed in simulated intestinal fluid in a fed state.

27. The preparation according to any one of claims 2 to 14, wherein the solid core composition constitutes a monolayer that is uniform or essentially uniform in composition state.

28. The preparation according to any one of claims 2 to 14, wherein the NAC in the solid core composition enhances the dissolution of rifaximin as compared to a solid core composition without NAC.

29. The first solid composition containing rifaximin is a tablet containing rifaximin and one or more excipients; The plurality of coated second solid compositions containing NAC are a plurality of mini-tablets containing NAC and one or more excipients; and The coating comprises at least one polymer that is substantially insoluble at a pH lower than 3.

5. The preparation according to claim 1.

30. A method for treating irritable bowel syndrome (IBS) comprising the step of administering to a subject in need thereof one or more doses of a formulation according to any one of claims 1 to 29.

31. The method according to claim 30, wherein the IBS is diarrhea-predominant IBS (IBS-D).

32. The method according to claim 30, wherein the IBS is hydrogen sulfide (H 2 S)-positive IBS.

33. A method for treating small intestinal bacterial overgrowth (SIBO) comprising the step of administering to a subject in need thereof one or more doses of a formulation according to any one of claims 1 to 29.

34. A method for reducing the load of Escherichia coli (E. Coli), Klebsiella, and total bacteria in the small intestine, comprising the step of administering to a subject in need thereof one or more doses of a formulation according to any one of claims 1 to 29.

35. The method according to claim 34, wherein the reduction of the load of Escherichia coli, Klebsiella, and total bacteria occurs in the ileum.

36. The method according to claim 34, wherein the reduction of the load of Escherichia coli, Klebsiella, and total bacteria occurs in the duodenum.

37. A method for improving stool hardness, reducing systemic inflammation, or both, comprising the step of administering to a subject in need thereof one or more doses of a formulation according to any one of claims 1 to 29.

38. The method according to any one of claims 33 to 37, wherein the step of administering one or more doses of the formulation comprises administering to the subject in need thereof a dosage three times a day.

39. The method according to any one of claims 33 to 37, wherein the step of administering one or more doses of the formulation comprises administering to the subject in need thereof a dosage three times a day for about 7 to 10 days.

40. The method according to any one of claims 30 to 39, wherein the step of administering is via oral administration.

Images