Targeted release rifaximin compositions

Abstract

Presented herein are GI-specific rifaximin-releasing compositions that can be formulated for targeted delivery of rifaximin to one or more portions of the GI tract. Methods of treating diseases and disorders with the disclosed compositions are also presented.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 044,450, filed June 26, 2020, U.S. Provisional Patent Application No. 63 / 107,400, filed October 29, 2020, and U.S. Provisional Patent Application No. 63 / 190,349, filed May 19, 2021, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Rifaximin is an orally available broad-spectrum antibiotic with antibacterial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. Rifaximin is currently used for the treatment of traveler's diarrhea (TD), to maintain remission of hepatic encephalopathy (HE), and to treat irritable bowel syndrome with diarrhea (IBS-D). Other uses of rifaximin include treating, for example, C. difficile infection, infectious diarrhea, small intestinal bacterial overgrowth (SIBO), inflammatory diseases, inflammatory bowel disease (IBD), and diverticular disease. Currently, rifaximin is manufactured as 200 mg and 550 mg tablets and approved for daily administration at doses of 600 mg (for TD), 1100 mg (for HE), or 1650 mg (for IBS-D).

[0003] Rifaximin is poorly soluble in water and poorly absorbed, so systemic effects are uncommon. For example, when administered orally, less than 0.5% of rifaximin is absorbed into the bloodstream. This translates into a very favorable safety profile comparable to placebo. However, rifaximin is increasingly soluble in bile, which leads to higher luminal concentrations and enhanced antibacterial activity against intestinal flora. It also exhibits greater efficacy in the small intestine, lower microbial resistance, and minimal effect on colonic microflora. Thus, rifaximin is highly advantageous for use in conditions related to the small intestine and for long-term use (e.g., 6 months or longer, or when bacterial resistance is a concern). Summary of the Invention [Problem to be solved by the invention]

[0004] Despite these beneficial features, emerging evidence suggests that the full therapeutic potential of rifaximin has yet to be realized. [Means for solving the problem]

[0005] It is now known that the absorption of rifaximin varies through several local environments in the gastrointestinal (GI) tract. For example, as discussed in more detail below, Figure 1 and Table 1 show that the extent of rifaximin exposure in the mid-small intestine (MSB) after delivery of a 150 mg solid dispersion of rifaximin was less than half that of the proximal small intestine (PSB). The distal small intestine (DSB) is the second-lowest relative bioavailability (F) after the colon. Rel) was also found to be lowest. See id. These findings, and other data presented herein, suggest that local absorption occurs and that this may be due in part to altered permeability of rifaximin in the intestinal tract. This indicates the possibility of increasing solubilized rifaximin concentrations in targeted regions of the intestinal tract without increasing undesired systemic exposure. Furthermore, as demonstrated herein, by providing controlled rifaximin release, inconsistencies in drug dissolution and undesired side effects, such as increased systemic exposure or uncontrolled reduction of normal GI flora, can be reduced or eliminated.

[0006] Thus, provided herein are GI-specific rifaximin release compositions that can be formulated for targeted delivery of the API to one or more portions of the GI tract, e.g., the upper GI tract, the middle GI tract, the lower GI tract, and / or the colon.

[0007] In one aspect, the disclosed compositions provide targeted release of rifaximin to the upper or middle or lower GI tract. In some aspects, the disclosed compositions provide targeted release of rifaximin to the upper or middle GI tract.

[0008] In one aspect, the disclosed compositions include rifaximin and a nonpareil bead substrate, such as a sugar sphere or a cellulose sphere. Without being limited to any one theory of the invention, the use of soluble sugar spheres in the beads described herein was chosen in part to provide an osmotic pressure that helps promote dissolution of the rifaximin coated on the beads.

[0009] In one embodiment, the disclosed composition comprises rifaximin, a non-pareil bead base, such as a sugar sphere, and at least one polymer.

[0010] In some aspects, the disclosed compositions are in the form of a unit dosage form and comprise a plurality of first and second targeted-release beads, each having a unique combination of rifaximin, a non-pareil bead base, such as a sugar sphere, and at least one polymer, wherein the first and second targeted-release rifaximin beads are configured to release rifaximin at different locations in the gastrointestinal tract of a subject.

[0011] In some embodiments, the at least one polymer of the disclosed compositions is selected from a first pH-independent polymer and a second pH-independent polymer. In some embodiments, the at least one polymer of the disclosed compositions is selected from a first pH-independent polymer, a second pH-independent polymer, and a pH-dependent polymer.

[0012] In some embodiments, the first pH-independent polymer of the disclosed compositions is present in an amount of about 1% to about 20% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the second pH-independent polymer of the disclosed compositions is present in an amount of about 10% to about 50% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer of the disclosed compositions is present in an amount of about 25% to about 75% by weight, based on the total weight of rifaximin in the composition.

[0013] In one embodiment, the disclosed compositions comprise a surfactant. In some embodiments, the disclosed compositions comprise a non-ionic surfactant present in an amount of about 1% to about 30% by weight, based on the total weight of rifaximin in the composition.

[0014] In one aspect, the disclosed compositions include a pharmaceutically acceptable plasticizer.

[0015] In one aspect, the disclosed compositions include an enteric coating. In some aspects, the enteric coating further comprises a non-stick additive.

[0016] In one embodiment, the rifaximin in the disclosed compositions is crystalline, non-crystalline, and / or amorphous.

[0017] In one embodiment, rifaximin in the disclosed compositions is present in an amount of about 0.5% to about 50% by weight, based on the total weight of the composition.

[0018] Also provided herein is the use of one or more of the disclosed compositions to treat one or more diseases in a subject in need thereof. In one embodiment, the one or more diseases can include bowel-related or liver dysfunction, developmental disorders, cardiovascular conditions, disorders affecting the central nervous system, disorders associated with cognitive impairment, and cancer.

[0019] The pharmaceutical compositions described herein represent embodiments of targeted release technology that deliver rifamycin compounds, such as rifaximin, to selected regions or sites of a subject's gastrointestinal tract for the treatment of disease. In one aspect, the pharmaceutical compositions described herein are provided to increase the luminal solubility of rifaximin in the gastrointestinal tract while limiting systemic exposure. In some embodiments, the pharmaceutical compositions described herein result in less systemic rifaximin than administration of a XIFAXAN® (rifaximin) 550 mg tablet. In some embodiments, the pharmaceutical compositions described herein have a greater accumulation ratio than a XIFAXAN® (rifaximin) 550 mg tablet. In some embodiments, the pharmaceutical compositions described herein provide prolonged luminal rifaximin exposure compared to a XIFAXAN® (rifaximin) 550 mg tablet. In some embodiments, the compositions described herein are useful in treating irritable bowel syndrome (IBS) (e.g., IBS-D), diarrhea, microbial-associated diarrhea, infectious diarrhea, Clostridium difficile infections and symptoms (e.g., Clostridium difficile-associated diarrhea), traveler's diarrhea, small intestinal bacterial overgrowth (SIBO), Crohn's disease, diverticular disease, pancreatitis (including chronic), pancreatic insufficiency, enteritis, colitis (e.g., ulcerative colitis, antibiotic-associated colitis, and microscopic colitis), hepatic encephalopathy (or other diseases that increase ammonia levels) and symptoms thereof, gastric dyspepsia, cirrhosis (e.g., alcoholic cirrhosis), polycystic liver disease, pouchitis, peritonitis, short bowel syndrome, inflammatory bowel disease, rosacea, sickle cell disease, and H. pylori infection.

[0020] With respect to sickle cell disease (SCD), for example, and without being limited to any one theory of the invention, the targeted release technology described herein provides therapy in patients by (1) reducing elevated levels of circulating aged neutrophils (CANs) and / or (2) reducing or preventing the occurrence of vaso-occlusive crises (VOCs). In contrast to previous therapies and knowledge in the art, the benefits demonstrated by the invention described herein are provided at substantially reduced dosages of rifaximin while providing clinical benefit.

[0021] Patients with SCD can experience recurrent, painful vaso-occlusive crises (VOCs), which are the most common clinical manifestation of SCD. VOCs occur when a patient's microcirculation becomes blocked by sickle red blood cells (RBCs) and can lead to ischemic injury, ulcers, priapism, organ damage, and spontaneous abortion. Furthermore, patients with SCD may experience an overall poor quality of life and a shortened lifespan.

[0022] Neutrophils have been implicated in regulating VOCs in SCD patients. WBC > 15 × 10 9 SCD patients with a high CD62L / L are more likely to suffer from stroke, acute chest syndrome, and premature death. Neutrophils in SCD patients have also been shown to exhibit increased levels of activation molecules, including CD64 and CD11b / CD18, with their serum exhibiting elevated levels of soluble CD62L. A subset of neutrophils known as circulating senescent neutrophils (CANs) is substantially elevated. CANs are characterized by high cell surface expression of CXCR4 and low CD62L. Activated and senescent neutrophils can become immobilized on the endothelium in the circulatory system, forming foci for the adhesion of sickle-shaped RBCs, which can result in VOCs.

[0023] It has been reported that modulating the intestinal microbial composition may be a therapeutic option for treating SCD patients to reduce VOCs by reducing activated and senescent neutrophils. One study found that a 550 mg dose of rifaximin (i.e., XIFAXAN® 550 mg tablets) delivered BID was able to reduce CAN in SCD patients (clinical trial identifier: NCT03719729). Furthermore, when SCD patients were administered a 550 mg dose of rifaximin (i.e., XIFAXAN® 550 mg tablets) BID for 6 months, the results showed a decrease in the number of VOCs and therefore an improvement in quality of life.

[0024] In one embodiment, the invention described herein includes a method of treating sickle cell disease (SCD) in a patient in need thereof, comprising administering to the patient a disclosed targeted release composition. In some embodiments, the method of treating sickle cell disease (SCD) comprises reducing elevated levels of circulating sage neutrophils (CAN) in the patient. In some embodiments, the method of treating sickle cell disease (SCD) in a patient comprises treating a vaso-occlusive crisis (VOC) in the patient. In some embodiments, treating a vaso-occlusive crisis (VOC) in the patient comprises (1) alleviating one or more symptoms of a VOC in the patient; (2) reducing or preventing the occurrence of a VOC in the patient; (3) reducing the duration or severity of a VOC in the patient; and / or (4) mediating or otherwise reducing opioid usage in the patient during a VOC. In some embodiments, a method of treating sickle cell disease (SCD) in a patient comprises alleviating one or more symptoms of a vaso-occlusive crisis (VOC) in the patient. In some embodiments, a method of treating sickle cell disease (SCD) in a patient comprises reducing or preventing the occurrence of a vaso-occlusive crisis (VOC) in the patient. In some embodiments, a method of treating sickle cell disease (SCD) in a patient comprises reducing the duration or severity of a VOC in the patient. In some embodiments, a method of treating sickle cell disease (SCD) in a patient comprises mediating or otherwise reducing the patient's opioid utilization during a vaso-occlusive crisis (VOC) in the patient.

[0025] In some embodiments, the methods described herein further include administering an additional therapeutic agent, e.g., an SCD therapeutic agent. In some embodiments, the additional therapeutic agent is an SCD therapeutic agent. In some embodiments, the SCD therapeutic agent is selected from the group consisting of hydroxyurea, L-glutamine, hydroxycarbamide, an erythropoietin stimulator, an opioid analgesic, and combinations thereof. In some embodiments, the opioid analgesic is selected from the group consisting of morphine, codeine, hydrocodone, hydromorphone, methadone, tramadol, oxycodone, tapentadol, fentanyl, and combinations thereof. In some embodiments, the SCD therapeutic agent comprises an opioid analgesic.

[0026] Further provided is the use of the targeted release technology described herein for the delivery of poorly soluble therapeutic compounds. Thus, in one embodiment, a composition for targeted release to at least one of the upper, lower, and middle GI tract is provided, comprising a non-pareil bead base, such as a sugar sphere, and at least one polymer described herein. Additional components, such as one or more surfactants, one or more pharmaceutically acceptable plasticizers, one or more enteric coatings, and / or one or more non-stick additives, are also contemplated for this embodiment. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 shows the mean plasma concentration versus time profile of rifaximin following topical administration of 150 mg immediate release solid dispersion rifaximin capsules to the GI tract. [Figure 2] FIG. 1 shows the dissolution profiles of MGI and UGI compositions of the present invention compared to XIFXAN® 550 mg tablets under acidic and basic conditions. [Figure 3] FIG. 1 shows PK results (AUC0-24) between MGI and UGI compositions and Xifaxin 550 mg tablets in dogs. [Figure 4]FIG. 1 shows rifaximin plasma concentrations as a function of time for dogs treated with MGI and UGI compositions of the present invention compared to rifaximin. DETAILED DESCRIPTION OF THE INVENTION

[0028] Unless otherwise defined, all 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 pertains.

[0029] When ranges are used herein to describe, for example, amounts of certain compounds or ingredients, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the use of the term "about" means that the stated number or numerical range is an approximation within experimental variability (or within experimental statistical error), and therefore the number or numerical range may vary. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes embodiments "consisting of" or "consisting essentially of" the described features, e.g., embodiments of any composition, such as a material, method, or process.

[0030] 1. Description of the composition Disclosed herein are targeted-release rifaximin compositions useful for delivering rifaximin to different regions of the GI tract. See, e.g., Figure 2. It is shown herein that the disclosed compositions can be tailored to provide extended release (sustained release) in a pH-independent or pH-dependent manner. These properties are beneficial in light of the finding that rifaximin exposure differs between the colon and the mid-, proximal, and distal small intestine, suggesting that varying pH has a substantial effect on rifaximin absorption. See, e.g., Figure 1 and Table 1.

[0031] Mean PK parameters (C maxThe AUC (Area Underlying Calcium) is approximately 10 times higher for the composition of the present invention in the upper and mid-GI at 200 mg strength compared to XIFAXAN® 550 tablets. When dose normalized, the drug absorption between the composition beads of the present invention and XIFAXAN® 550 tablets is approximately 10 times higher than the AUC 0-24 It was found that there was an approximately 25-fold difference in the

[0032] In one aspect, the invention described herein includes a bead composition comprising a nonpareil bead base coated with a poorly water-soluble compound and at least one polymer. In some embodiments, the poorly water-soluble compound may be a rifamycin compound selected from the group consisting of rifaximin, rifamycin A, rifamycin B, rifamycin C, rifamycin D, rifamycin E, rifamycin S, rifamycin SV, rifampin (rifampicin), rifapentine, rifabutin, and rifalazil, and pharmaceutically acceptable salts thereof, which may be in crystalline, noncrystalline, and / or amorphous form. In some embodiments, the rifamycin compound is rifaximin. Accordingly, the invention described herein includes a rifaximin bead composition comprising rifaximin and a nonpareil bead base coated with at least one polymer.

[0033] In one embodiment, the nonpareil bead base is selected from sugar spheres or cellulose beads. In one embodiment, the nonpareil bead base is a sugar sphere. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0034] In one embodiment, the at least one polymer is selected from a pH-independent polymer and a pH-dependent polymer. In some embodiments, the pH-independent polymer comprises one or more pH-independent polymers, such as a first pH-independent polymer and a second pH-independent polymer. In some embodiments, the pH-dependent polymer comprises one or more pH-dependent polymers. In some embodiments, the at least one polymer is selected from a first pH-independent polymer, a second pH-independent polymer, and a pH-dependent polymer. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0035] In one embodiment, the at least one polymer is selected from a first pH-independent polymer and a second pH-independent polymer. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0036] In one embodiment, the first pH-independent polymer is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 6% to about 12% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 6% to about 10% by weight, based on the total weight of rifaximin in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 5% to about 9% by weight, based on the total weight of rifaximin in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 5% to about 8% by weight, based on the total weight of rifaximin in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 5% to about 7% by weight, based on the total weight of rifaximin in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 6% to about 7% by weight, based on the total weight of rifaximin in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 7% to about 10% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 0.1% to about 2.5% by weight, based on the total weight of the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 0.3% to about 2.3% by weight, based on the total weight of the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 0.3% to about 0.5% by weight, or about 1.8% to about 2.0% by weight, based on the total weight of the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 0.4% to about 0.5% by weight, or about 1.9% to about 2.0% by weight, based on the total weight of the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0037] In one embodiment, the second pH-independent polymer is present in an amount of about 15% to about 35% by weight based on the total weight of rifaximin in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 15% to about 25% by weight based on the total weight of rifaximin in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 15% to about 20% by weight based on the total weight of rifaximin in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 18% to about 20% by weight based on the total weight of rifaximin in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 19% to about 20% by weight based on the total weight of rifaximin in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 20% to about 35% by weight based on the total weight of rifaximin in the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 25% to about 30% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 26% to about 27% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 0.5% to about 4.0% by weight, or about 3.0% to about 8.0% by weight, based on the total weight of the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 0.5% to about 2.0% by weight, or about 4.0% to about 7.0% by weight, based on the total weight of the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 0.1% to about 2.0% by weight, or about 5.0% to about 6.0% by weight, based on the total weight of the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0038] In one embodiment, the rifaximin to pH-independent polymer in the composition is provided in a weight ratio of about 65:35 to about 85:15, respectively. In some embodiments, the rifaximin to pH-independent polymer in the composition is provided in a weight ratio of about 70:30 to about 80:20, respectively. In some embodiments, the rifaximin to pH-independent polymer in the composition is provided in a weight ratio of about 70:30 to about 75:25, respectively. In some embodiments, the rifaximin and pH-independent polymer that can be included in the compositions described herein are not provided in a weight ratio of 25:75, 50:50, or 75:25, respectively. In some embodiments, the compositions described herein contain more rifaximin by weight than the pH-independent polymer when such compositions contain both rifaximin and a pH-independent polymer.

[0039] In one embodiment, the pH-independent polymer comprises one or more of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), hydroxyethyl cellulose (HEC) polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid (PAA), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, and divinyl ether maleic anhydride copolymer (DIVEMA). In some embodiments, the first and second pH-independent polymers are selected from hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), hydroxyethyl cellulose (HEC) polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid (PAA), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, and divinyl ether maleic anhydride copolymer (DIVEMA). In some embodiments, the first pH-independent polymer is HPMC. In some embodiments, the second pH-independent polymer is PVP. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0040] In one embodiment, at least one polymer is a pH-dependent polymer. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0041] In one embodiment, the pH-dependent polymer is present in an amount of about 20% to about 60% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 20% to about 50% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 25% to about 45% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 30% to about 40% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 30% to about 35% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 40% to about 60% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 40% to about 50% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 43% to about 47% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 44% to about 45% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 1% to about 12% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 1% to about 4% by weight, or about 8% to about 11% by weight, based on the total weight of the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 1% to about 3% by weight, or about 8% to about 10% by weight, based on the total weight of the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 2% to about 3% by weight, or about 9% to about 10% by weight, based on the total weight of the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0042] In one embodiment, the rifaximin to pH-dependent polymer in the composition is provided in a weight ratio of about 65:35 to about 75:25, respectively. In some embodiments, the rifaximin to pH-dependent polymer in the composition is provided in a weight ratio of about 60:40 to about 70:30, respectively. In some embodiments, the rifaximin to pH-dependent polymer in the composition is provided in a weight ratio of about 65:35 to about 70:30, respectively. In some embodiments, the rifaximin and pH-dependent polymer that can be included in the compositions described herein are not provided in a weight ratio of 25:75, 50:50, or 75:25, respectively. In some embodiments, the compositions described herein, when such compositions include both rifaximin and a pH-dependent polymer, contain more rifaximin by weight than the pH-dependent polymer.

[0043] In one embodiment, the pH-dependent polymer comprises one or more of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), methacrylic acid / ethyl acrylic acid copolymer, hydroxypropyl methylcellulose acetate phthalate (HPMC-P), cellulose acetate phthalate (CAP), and cellulose acetate trimellitate (CAT). In some embodiments, the pH-dependent polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMC-AS), methacrylic acid / ethyl acrylic acid copolymer, hydroxypropyl methylcellulose acetate phthalate (HPMC-P), cellulose acetate phthalate (CAP), and cellulose acetate trimellitate (CAT). In some embodiments, at least one pH-dependent polymer is HPMC-AS. In some embodiments, at least one pH-dependent polymer is HPMC-AS Grade M. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0044] In one embodiment, the composition further comprises a surfactant. In some embodiments, the surfactant is a non-ionic surfactant. In some embodiments, the surfactant is poloxamer 407. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0045] In one embodiment, the surfactant is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the surfactant is present in an amount of about 7% to about 9% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the surfactant is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0046] In one embodiment, the composition further comprises diethyl phthalate or dibutyl phthalate. In some embodiments, the composition comprises diethyl phthalate. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0047] In one embodiment, the composition further comprises a pharmaceutically acceptable plasticizer. In some embodiments, the pharmaceutically acceptable plasticizer is an alkyl citrate. In some embodiments, the pharmaceutically acceptable plasticizer is selected from triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate (TOC), acetyl trioctyl citrate (ATOC), trihexyl citrate (THC), acetyl trihexyl citrate (ATHC), butyryl trihexyl citrate (BTHC, o-butyryl trihexyl citrate), and trimethyl citrate (TMC). In some embodiments, the pharmaceutically acceptable plasticizer is TEC. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0048] In one embodiment, the composition further comprises an enteric coating. In some embodiments, the enteric coating surrounds the rifaximin-coated nonpareil bead base and at least one polymer. In some embodiments, the enteric coating comprises a methacrylic acid-acrylate copolymer, optionally a combination of glyceryl monostearate, triethyl citrate, and polysorbate 80 (e.g., Plasacryl HTP 20). In some embodiments, the enteric coating comprises an ethyl methacrylate-acrylate copolymer (e.g., Eudragit L30D55), optionally a combination of glyceryl monostearate, triethyl citrate, and polysorbate 80 (e.g., Plasacryl HTP 20). In some embodiments, the enteric coating further comprises a non-stick additive. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0049] In one embodiment, the composition further comprises an antioxidant and / or a chelating agent. In some embodiments, the compositions described herein comprise one or more antioxidants or chelating agents selected from ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid.

[0050] In one embodiment, the rifaximin in the provided compositions is crystalline, non-crystalline, and / or amorphous. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0051] In one embodiment, the rifaximin in the provided compositions is in the form of a solid dispersion comprising at least one polymer, as described herein. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0052] In one embodiment, rifaximin is present in the provided compositions in an amount of about 1% to about 30% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 1% to about 10% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 4% to about 6% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 15% to about 25% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 20% to about 23% by weight, based on the total weight of the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0053] 2.Definition "Rifaximin" has the chemical structure depicted below:

[0054] [ka] This refers to the antibiotic 4-deoxy-4'-methylpyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV, which has the formula:

[0055] Rifaximin may exist in several different solvates, hydrates, polymorphs, and / or crystalline forms, including the α-, β-, γ-, δ-, ε-, and amorphous forms of rifaximin. In some embodiments, the rifaximin specified herein may be in the α-, β-, γ-, δ-, ε-form, amorphous form, or combinations thereof. Forms, formulations, and methods of using rifaximin are described, for example, in U.S. Patent Nos. 7,045,620; 7,906,542; 7,915,275; 8,193,196; 8,309,569; 8,518,949; 8,741,904; and 9,737,610, each of which is incorporated herein by reference in its entirety.

[0056] "Solid dispersion," as used herein, refers to a dispersion of rifaximin and an inert carrier matrix in solid form; i.e., rifaximin is homogeneously mixed with the inert carrier. The inert matrix is ​​generally hydrophilic (e.g., a polymer, e.g., HPMC-AS) and can be crystalline, non-crystalline, and / or amorphous. It is understood that it is not necessarily the method of preparation that affects the properties of a solid dispersion, but rather the molecular configuration of the dispersion's contents. Thus, unless otherwise stated or process constraints are incorporated, solid dispersions are not limited by the process by which they are made. The terms "solid dispersion," "soluble solid dispersion," and the abbreviations "SD" and "SSD" are used interchangeably and each refer to the disclosed solid dispersions of rifaximin.

[0057] The term "upper GI tract" collectively refers to the stomach and proximal small intestine.

[0058] The term "mid-GI tract" refers to the mid-small intestine.

[0059] The term "lower GI tract" refers to the distal small intestine.

[0060] "pH-independent polymer" refers to a polymer that is not overly sensitive to changes in pH of the surrounding medium (e.g., the GI tract). In one aspect, dimensionality (e.g., the ability to swell or deswell) is not dependent on the acidity or basicity of the medium to which it is exposed. As used herein, pH-independent polymer may refer to one or more of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), hydroxyethyl cellulose (HEC), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid (PAA), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, and divinyl ether maleic anhydride copolymer (DIVEMA).

[0061] A "pH-dependent" or "pH-responsive" polymer refers to a polymer that responds to changes in the pH of the surrounding medium (e.g., the GI tract), for example, by changing dimensions. In one aspect, the polymer may swell or deswell based on the pH of the environment. A pH-independent polymer may include a natural polymer block, a polyacid, or a polybase. In another aspect, the polymer may exhibit pH-dependent solubility such that it dissolves or begins to dissolve when a certain pH is achieved or exceeded. As used herein, a pH-dependent polymer may refer to one or more of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), methacrylic acid / ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate phthalate (HPMC-P), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), and methacrylic acid ethyl acrylate copolymer.

[0062] "Hepatic encephalopathy" or abbreviated "HE" is defined as an altered mental state diagnosed as HE, defined as an increase in the Conn score to a grade ≥ 2 (i.e., an increase from 0 or 1 to ≥ 2). HE can be considered "covert" or "overt" HE (CHE or OHE, respectively), depending on the severity of its associated symptoms. HE may be described as a continuum represented by the West Haven Criteria (WHC): Grade 0 - minimal hepatic encephalopathy with symptoms potentially including complex and persistent attention deficits; Grade 1 (CHE) - symptoms include subtle cognitive deficits, euphoria or anxiety, shortened attention span, impaired addition or subtraction, and altered sleep rhythms, with clinical findings including mild asterixis or tremor; Grade 2 (OHE) - symptoms include fatigue or lethargy, disorientation to time, clear personality changes, and inappropriate behavior, with clinical findings including clear asterixis, dyspraxia, and slurred speech; Grade 3 (OHE) - symptoms include somnolence to semicoma, unresponsiveness to stimuli, confusion, marked disorientation, and bizarre behavior, with clinical findings including muscle rigidity, clonus, and hyperreflexia; and Grade 4 (OHE) - symptoms include coma and clinical findings including decerebrate posturing (decerebrate rigidity). OHE can also be observed with the Hepatic Encephalopathy Grading Instrument (HEGI), which uses clinical findings (present for at least 1 hour) to measure the patient's disorientation and thereby the severity of the HE episode (on a scale of Grade 2 to Grade 4), with Grade 4 being the most severe and Grade 2 being the least severe.

[0063] "Esophageal variceal bleeding" or abbreviated "EVB" is defined as 1) bleeding from esophageal or gastric varices during endoscopy, or 2) the occurrence of clinically significant gastrointestinal bleeding defined as the presence of large varices with palpable blood in the stomach and no other identifiable cause for the bleeding observed during endoscopy, in the presence of at least one of the following criteria: i) a hemoglobin decrease of more than 2 g / dL over the first 48 hours after admission, ii) the need for transfusion of two or more units of blood within 24 hours of admission, iii) a systolic blood pressure of less than 100 mm Hg, or iv) a pulse rate of more than 100 beats / min on admission.

[0064] "Spontaneous bacterial peritonitis," or abbreviated "SBP," is defined as a condition in which there are more than 250 polymorphonuclear (PMN) cells / mm in the peritoneal fluid. 3 and / or positive single organism cultures.

[0065] "Hepatorenal syndrome" (HRS) was defined as i) a gradual rise in serum creatinine (>1.5 mg / dL) without improvement after at least 2 days of diuretic withdrawal and albumin volume expansion, ii) absence of substantial renal disease, iii) oliguria, iv) absence of shock, and v) no current or recent (within 3 months prior to randomization) treatment with nephrotoxic drugs.

[0066] As used herein, the term "treatment of sickle cell disease (SCD)" refers to the amelioration, prevention, or reduction in frequency of one or more symptoms of SCD. For example, "treatment of sickle cell disease (SCD)" can refer to the reduction of elevated levels of circulating sage neutrophils (CAN(s)) in a patient, where such levels of CAN(s) are elevated compared to, for example, the levels of CAN(s) that would be expected in a patient not diagnosed with SCD. As another example, "treating sickle cell disease (SCD)" can refer to treating a vaso-occlusive crisis (VOC) in a patient, and "treating a vaso-occlusive crisis (VOC)" or "treating vaso-occlusive crisis(s) (VOC(s))" can refer to, as the case may be, (1) alleviating one or more symptoms of a VOC in a patient; (2) reducing or preventing the occurrence of VOCs in a patient; (3) reducing the duration or severity of a VOC in a patient; and / or (4) mediating or otherwise reducing a patient's opioid utilization during a VOC. For example, symptoms of a VOC include, but are not limited to, pain, swelling, ischemic injury, ulcers, priapism, organ damage, and spontaneous abortion. "Treatment of sickle cell disease (SCD)" can refer to preventing the occurrence of a vaso-occlusive crisis (VOC) in a patient, e.g., a patient with a history of a VOC (e.g., at least one VOC within the 12 months prior to treatment). "Treatment of sickle cell disease (SCD)" can refer to reducing the occurrence or frequency of vaso-occlusive crisis (VOC) in a patient, e.g., a patient with a history of VOC. "Treatment of sickle cell disease (SCD)" can refer to reducing the severity of vaso-occlusive crisis (VOC) occurrences in a patient, e.g., a patient with a history of VOC. "Treatment of sickle cell disease (SCD)" can refer to mediating or reducing a patient's opioid utilization during a VOC. Mediating or reducing a patient's opioid utilization during a VOC can refer, for example, to mediating or reducing a patient's dependence on opioids (e.g., opioid analgesics) to manage pain during a VOC compared to a history of such opioid-dependent patients during a VOC.Alternatively, mediating or reducing opioid utilization in a patient during a VOC can refer to mediating or reducing the patient's reliance on opioids (e.g., opioid analgesics) to manage pain during a VOC compared to a patient during a VOC who does not receive a targeted release composition described herein.

[0067] The term "effective amount" or "therapeutically effective amount" refers to the amount of a composition described herein, e.g., a composition having a dosage of about 0.001 to about 100 mg / kg body weight / day of rifaximin, that elicits a biological or medical response in a subject.

[0068] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0069] "Pharmaceutically acceptable" means molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or human, as appropriate.

[0070] The terms "treatment," "treat," and "treating" refer to reversing the likelihood of developing, alleviating, reducing, or inhibiting the progression of a disease or disorder described herein or one or more symptoms thereof. In some embodiments, treatment, i.e., therapeutic treatment, may occur after one or more symptoms have developed. In other embodiments, treatment may occur in the absence of symptoms. For example, treatment, i.e., prophylactic treatment, may occur in susceptible individuals prior to the onset of symptoms (e.g., based on a history of symptoms and / or genetic or other susceptibility factors). Treatment may continue after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0071] 3. Dual release composition In one aspect, a rifaximin delivery composition is provided that includes a plurality of first targeted-release rifaximin beads and a plurality of second targeted-release rifaximin beads, wherein the first targeted-release rifaximin beads include sugar spheres coated with a combination comprising rifaximin, a first pH-independent polymer (e.g., HPMC), and a second pH-independent polymer (e.g., PVP), and the second targeted-release rifaximin beads include sugar spheres coated with a combination comprising rifaximin and a pH-dependent polymer (e.g., HPMC-AS), and the first and second targeted-release rifaximin beads are configured to release rifaximin at different locations in the gastrointestinal tract of a subject.

[0072] In the embodiments described herein, the first targeted-release rifaximin beads may be referred to as upper gastrointestinal (UGI) beads or extended-release (ER) beads. As used herein, the terms "UGI beads" and "ER beads" are interchangeable.

[0073] In embodiments described herein, the second targeted-release rifaximin beads may be referred to as mid-gastrointestinal (MGI) beads or delayed extended-release (DER) beads. As used herein, the terms "MGI beads" and "DER beads" are interchangeable. In some embodiments, the MGI beads may be prepared to target the mid-GI tract, or may also be prepared to target the mid-GI tract and lower GI tract. In some embodiments, the MGI beads may be prepared to target the mid-GI tract, lower GI tract, and colon.

[0074] In one embodiment, the rifaximin delivery composition further comprises at least one surfactant. In some embodiments, the surfactant is a non-ionic surfactant. In some embodiments, the surfactant is poloxamer 407. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0075] In one embodiment, the rifaximin delivery composition further comprises diethyl phthalate or dibutyl phthalate. In some embodiments, the composition comprises diethyl phthalate. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0076] In one embodiment, the rifaximin delivery composition further comprises a pharmaceutically acceptable plasticizer. In some embodiments, the pharmaceutically acceptable plasticizer is an alkyl citrate. In some embodiments, the pharmaceutically acceptable plasticizer is selected from triethyl citrate (TEC), acetyltriethyl citrate (ATEC), tributyl citrate (TBC), acetyltributyl citrate (ATBC), trioctyl citrate (TOC), acetyltrioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryltrihexyl citrate (BTHC, o-butyryltrihexyl citrate), and trimethyl citrate (TMC). In some embodiments, the pharmaceutically acceptable plasticizer is TEC. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0077] In one embodiment, the rifaximin delivery composition further comprises an enteric coating. In some embodiments, the rifaximin delivery composition further comprises an enteric coating surrounding the sugar spheres coated with a combination comprising rifaximin and HPMC-AS of the second targeted-release beads. In some embodiments, the enteric coating comprises a methacrylic acid-acrylate copolymer and, optionally, a combination of glycerol monostearate, triethyl citrate, and polysorbate 80 (e.g., Plasacryl HTP 20). In some embodiments, the enteric coating comprises an anionic methacrylic acid-acrylate copolymer. In some embodiments, the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate (e.g., Eudragit L30D55), and, optionally, a combination of glycerol monostearate, triethyl citrate, and polysorbate 80 (e.g., Plasacryl HTP 20). In some embodiments, the enteric coating further comprises a non-stick additive. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0078] In one embodiment, the rifaximin of the first targeted release bead combination is crystalline, non-crystalline, and / or amorphous. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0079] In one embodiment, the rifaximin of the second targeted release bead combination is crystalline, non-crystalline, and / or amorphous. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0080] In one embodiment, the first targeted-release bead is configured to release rifaximin in the upper GI tract. In some embodiments, the first targeted-release bead is configured to release rifaximin in the initial portion of the small intestine. In some embodiments, the second targeted-release bead is configured to release rifaximin in the mid-GI tract. In some embodiments, the second targeted-release bead is configured to release rifaximin in the mid-GI tract and the lower GI tract. In some embodiments, the second targeted-release bead is configured to release rifaximin in the mid-GI tract, the lower GI tract, and the colon. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0081] In one embodiment, the second targeted release bead is configured to provide release in the mid-GI tract. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0082] 4. Upper GI targeting composition Provided are rifaximin compositions (herein referred to as UGI beads or ER beads) formulated to deliver rifaximin to the upper GI tract. Such compositions include a rifaximin targeted-release composition comprising sugar spheres coated with a combination of rifaximin and a pH-independent polymer, the combination comprising a first pH-independent polymer (e.g., hypromellose (HPMC)) and a second pH-independent polymer (e.g., PVP). In some embodiments, the first pH-independent polymer is HPMC (2910 50 mPa*s USP). In some embodiments, the second pH-independent polymer is povidone (PVP) K-90 (e.g., Plasdone™ K-90 USP, EP, JP).

[0083] In one embodiment, the rifaximin to pH-independent polymer in the composition is provided in a weight ratio of about 65:35 to about 85:15, respectively. In some embodiments, the rifaximin to pH-independent polymer in the composition is provided in a weight ratio of about 70:30 to about 80:20, respectively. In some embodiments, the rifaximin to pH-independent polymer in the composition is provided in a weight ratio of about 70:30 to about 75:25, respectively. In some embodiments, the rifaximin and pH-independent polymer that may be included in the compositions described herein are not provided in a weight ratio of 25:75, 50:50, or 75:25, respectively. In some embodiments, the compositions described herein, when such compositions include both rifaximin and a pH-independent polymer, contain more rifaximin by weight than the pH-independent polymer.

[0084] In one embodiment, HPMC is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 6% to about 12% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 6% to about 10% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 5% to about 9% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 5% to about 8% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 5% to about 7% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 6% to about 7% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 6.5% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 7% to about 10% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the combination. In some embodiments, HPMC is present in an amount of about 0.1% to about 2.5% by weight, based on the total weight of the composition. In some embodiments, HPMC is present in an amount of about 0.3% to about 2.3% by weight, based on the total weight of the composition. In some embodiments, HPMC is present in an amount of about 0.3% to about 0.5% by weight, or about 1.8% to about 2.0% by weight, based on the total weight of the composition. In some embodiments, HPMC is present in an amount of about 0.4% to about 0.5% by weight, or about 1.9% to about 2.0% by weight, based on the total weight of the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0085] In one embodiment, PVP is present in an amount of about 15% to about 35% by weight, based on the total weight of rifaximin in the combination. In some embodiments, PVP is present in an amount of about 15% to about 25% by weight, based on the total weight of rifaximin in the combination. In some embodiments, PVP is present in an amount of about 15% to about 20% by weight, based on the total weight of rifaximin in the combination. In some embodiments, PVP is present in an amount of about 18% to about 20% by weight, based on the total weight of rifaximin in the combination. In some embodiments, PVP is present in an amount of about 19% to about 20% by weight, based on the total weight of rifaximin in the combination. In some embodiments, PVP is present in an amount of about 19.7% by weight, based on the total weight of rifaximin in the combination. In some embodiments, PVP is present in an amount of about 20% to about 35% by weight, based on the total weight of rifaximin in the combination. In some embodiments, PVP is present in an amount of about 25% to about 30% by weight, based on the total weight of rifaximin in the combination. In some embodiments, PVP is present in an amount of about 26% to about 27% by weight, based on the total weight of rifaximin in the combination. In some embodiments, PVP is present in an amount of about 0.5% to about 4.0% by weight, or about 3.0% to about 8.0% by weight, based on the total weight of the composition. In some embodiments, PVP is present in an amount of about 0.5% to about 2.0% by weight, or about 4.0% to about 7.0% by weight, based on the total weight of the composition. In some embodiments, PVP is present in an amount of about 0.1% to about 2.0% by weight, or about 5.0% to about 6.0% by weight, based on the total weight of the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0086] In one embodiment, the combination further comprises a surfactant. In some embodiments, the surfactant is a combination further comprising a non-ionic surfactant. In some embodiments, the combination further comprises poloxamer 407. In some embodiments, the poloxamer 407 is Pluronic F127. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0087] In one embodiment, the surfactant is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the surfactant is present in an amount of about 7% to about 9% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the surfactant is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0088] In one embodiment, the composition further comprises diethyl phthalate or dibutyl phthalate. In some embodiments, the composition comprises diethyl phthalate. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0089] In one embodiment, rifaximin is present in an amount of about 1% to about 30% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 1% to about 10% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 4% to about 6% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 15% to about 25% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 20% to about 23% by weight, based on the total weight of the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0090] In one embodiment, the composition is a pH-independent release composition. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0091] In one embodiment, the composition is for release in the upper gastrointestinal tract. In some embodiments, the composition is for release in the initial portion of the small intestine. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0092] 5. Middle GI targeting composition Provided are rifaximin compositions (referred to herein as MGI beads or DER beads) formulated to deliver rifaximin to the mid-GI tract, lower GI tract, and / or colon. Such compositions include rifaximin targeted-release compositions comprising sugar spheres coated with a combination comprising rifaximin and a pH-dependent polymer (e.g., HPMC-AS). In some embodiments, the pH-dependent polymer comprises hypromellose acetate succinate (HPMC-AS) (e.g., Ashland HPMC-AS MF, NF, JP).

[0093] In one embodiment, the rifaximin to pH-dependent polymer in the composition is provided in a weight ratio of about 65:35 to about 75:25, respectively. In some embodiments, the rifaximin to pH-dependent polymer in the composition is provided in a weight ratio of about 60:40 to about 70:30, respectively. In some embodiments, the rifaximin to pH-dependent polymer in the composition is provided in a weight ratio of about 65:35 to about 70:30, respectively. In some embodiments, the rifaximin and pH-dependent polymer that may be included in the compositions described herein are not provided in a weight ratio of 25:75, 50:50, or 75:25, respectively. In some embodiments, the compositions described herein, when such compositions include both rifaximin and a pH-dependent polymer, contain more rifaximin by weight than the pH-dependent polymer.

[0094] In one embodiment, the HPMC-AS is Grade M. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0095] In one embodiment, HPMC-AS is present in an amount of about 20% to about 60% by weight, based on the total weight of rifaximin in the composition. In some embodiments, HPMC-AS is present in an amount of about 20% to about 50% by weight, based on the total weight of rifaximin in the composition. In some embodiments, HPMC-AS is present in an amount of about 25% to about 45% by weight, based on the total weight of rifaximin in the composition. In some embodiments, HPMC-AS is present in an amount of about 30% to about 40% by weight, based on the total weight of rifaximin in the composition. In some embodiments, HPMC-AS is present in an amount of about 30% to about 35% by weight, based on the total weight of rifaximin in the composition. In some embodiments, HPMC-AS is present in an amount of about 31% by weight, based on the total weight of rifaximin in the composition. In some embodiments, HPMC-AS is present in an amount of about 40% to about 60% by weight, based on the total weight of rifaximin in the mixture. In some embodiments, HPMC-AS is present in an amount of about 40% to about 50% by weight, based on the total weight of rifaximin in the mixture. In some embodiments, HPMC-AS is present in an amount of about 43% to about 47% by weight, based on the total weight of rifaximin in the mixture. In some embodiments, HPMC-AS is present in an amount of about 44% to about 45% by weight, based on the total weight of rifaximin in the mixture. In some embodiments, HPMC-AS is present in an amount of about 1% to about 4% by weight, or about 8% to about 11% by weight, based on the total weight of the composition. In some embodiments, HPMC-AS is present in an amount of about 1% to about 3% by weight, or about 8% to about 10% by weight, based on the total weight of the composition. In some embodiments, HPMC-AS is present in an amount of about 2% to about 3% by weight, or about 9% to about 10% by weight, based on the total weight of the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0096] In one embodiment, the combination further comprises a surfactant. In some embodiments, the combination further comprises a non-ionic surfactant. In some embodiments, the combination further comprises poloxamer 407. In some embodiments, the poloxamer 407 is Pluronic F127. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0097] In one embodiment, the surfactant is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the surfactant is present in an amount of about 7% to about 9% by weight, based on the total weight of rifaximin in the composition. In some embodiments, the surfactant is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0098] In one embodiment, the composition further comprises diethyl phthalate or dibutyl phthalate. In some embodiments, the composition comprises diethyl phthalate. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0099] In one embodiment, the composition further comprises a pharmaceutically acceptable plasticizer. In some embodiments, the pharmaceutically acceptable plasticizer is an alkyl citrate. In some embodiments, the pharmaceutically acceptable plasticizer is selected from triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate (TOC), acetyl trioctyl citrate (ATOC), trihexyl citrate (THC), acetyl trihexyl citrate (ATHC), butyryl trihexyl citrate (BTHC, o-butyryl trihexyl citrate), and trimethyl citrate (TMC). In some embodiments, the pharmaceutically acceptable plasticizer is TEC. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0100] In one embodiment, the composition further comprises an enteric coating. In some embodiments, the composition further comprises an enteric coating around the combination and the sugar spheres. In some embodiments, the enteric coating comprises a methacrylic acid-acrylate copolymer and, optionally, a combination of glycerol monostearate, triethyl citrate, and polysorbate 80 (i.e., Plasacryl HTP 20). In some embodiments, the enteric coating comprises an ethyl methacrylate-acrylate copolymer (e.g., Eudragit L30D55) and, optionally, a combination of glycerol monostearate, triethyl citrate, and polysorbate 80 (e.g., Plasacryl HTP 20). In some embodiments, the enteric coating further comprises a non-stick additive. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0101] In one embodiment, rifaximin is present in an amount of about 1% to about 30% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 1% to about 10% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 4% to about 6% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 15% to about 25% by weight, based on the total weight of the composition. In some embodiments, rifaximin is present in an amount of about 20% to about 23% by weight, based on the total weight of the composition. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0102] In one embodiment, the composition is a pH dependent release composition. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0103] In one embodiment, the composition is for release in the mid-gastrointestinal tract. Elements from this embodiment may be combined with one or more of the additional embodiments and / or aspects described herein.

[0104] 5. Dosage In one embodiment, the total amount of rifaximin in the disclosed compositions is less than about 250 mg (e.g., less than about 240 mg, less than about 230 mg, less than about 220 mg, less than about 210 mg, less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 110 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 70 mg, less than about 60 mg, less than about 50 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, or less than about 10 mg). In some embodiments, the total amount of rifaximin is in the range of about 2.5 mg to about 250 mg (e.g., about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 125 mg, about 10 mg to about 125 mg, about 10 mg to about 100 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 30 mg to about 70 mg, about 35 mg to about 65 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 75 mg to about 125 mg, about 80 mg to about 120 mg, 85 mg to about 115 mg, about 90 mg to about 110 mg, or about 95 mg to about 105 mg). In some embodiments, the total amount of rifaximin (in milligrams) in the disclosed compositions ranges from about 10 mg to about 30 mg, about 15 mg to about 25 mg, about 30 mg to about 50 mg, about 35 mg to about 45 mg, about 70 mg to about 90 mg, or about 75 to about 85 mg; in some embodiments, the total amount of rifaximin (in milligrams) in the disclosed compositions ranges from about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82,about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 110, about 111, about 112, about 113, about 114, about 115, about 116, about 117, about 118, about 119, about 120, about 121, about 122, about 123, about 124, or about 125 mg, or about 126, or about 127, or about 128, or about 129, or about 130, or about 131, or about 13 2, or about 133, or about 134, or about 135, or about 140, or about 145, or about 150, or about 155, or about 160, or about 165, or about 170, or about 175, or about 180, or about 185, or about 190, or about 195, or about 200, or about 205, or about 210, or about 215, or about 220, or about 225, or about 230, or about 235, or about 240, or about 245, or about 250 mg; or at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, at least about 50, at least about 51, at least about 52, at least about 53, at least about 54, at least about 55, at least about 56, at least about 57, at least about 58, at least about 59, at least about 60, at least about 61, at least about 62, at least about 63, at least about 64, at least about 65, at least about 66, at least about 67,at least about 68, at least about 69, at least about 70, at least about 71, at least about 72, at least about 73, at least about 74, at least about 75, at least about 76, at least about 77, at least about 78, at least about 79, at least about 80, at least about 81, at least about 82, at least about 83, at least about 84, at least about 85, at least about 86, at least about 87, at least about 88, at least about 89, at least about 90, at least about 91, at least about 92, at least about 93, at least about 94, at least about 95, at least about 96, at least about 97, at least about 98, at least about 99, at least about 100, at least about 101, at least about 102, at least about 103, at least about 104, at least about 105, at least about 106, at least about 107, at least about 108, at least about 109, at least about 110, at least about 111, at least about 112, at least about 113, at least about 114, at least about 115, at least about 116, at least about 117, at least about 118, at least about 119, at least about 120, at least about 121, at least about 122, at least about 123, at least about 124, or at least about 125, or at least about 126 , or at least about 127, or at least about 128, or at least about 129, or at least about 130, or at least about 131, or at least about 132, or at least about 133, or at least about 134, or at least about 135, or at least about 140, or at least about 145, or at least about 150, or at least about 155, or at least about 160, or at least about 165, or at least about 170, or at least about 175, or at least about 180 , or at least about 185, or at least about 190, or at least about 195, or at least about 200, or at least about 205, or at least about 210, or at least about 215, or at least about 220, or at least about 225, or at least about 230, or at least about 235, or at least about 240, or at least about 245, or at least about 250 mg; or at most about 5, at most about 6, at most about 7, at most about 8, at most about 9, at most about 10,at most about 11, at most about 12, at most about 13, at most about 14, at most about 15, at most about 16, at most about 17, at most about 18, at most about 19, at most about 20, at most about 21, at most about 22, at most about 23, at most about 24, at most about 25, at most about 26, at most about 27, at most about 28, at most about 29, at most about 30, at most about 31, at most about 32, at most about 33, at most about 34, at most about 35, at most about 36, at most about 37, at most about 38, at most about 39, at most about 40, at most about 41, at most about 42, at most about 43, at most about 44, at most about 45, at most about 46, at most about 47, at most about 48, at most about 49, at most about 50, at most about 51, at most about 52, at most about 53, at most about 54, at most about 55, at most about 56, at most about 57, at most about 58, at most about 59, at most about 60, at most about 61, at most about 62, at most about 63, at most about 64, at most about 65, at most about 66, at most about 67, at most about 68, at most about 69, at most about 70, at most about 71, at most about 72, at most about 73, at most about 74, at most about 75, at most about 76, at most about 77, at most about 78, at most about 79, at most about 80, at most about 81, at most about 82, at most about 83, at most about 84, at most about 85, at most about 86, at most about 87, at most about 88, at most about 89, at most about 90, at most about 91, at most about 92, at most about 93, at most about 94, at most about 95, at most about 96, at most about 97, at most about 98, at most about 99, at most about 100, at most about 101, at most about 102, at most about 103, at most about 104, at most about 105, at most about 106, at most about 107, at most about 108, at most about 109, at most about 110, at most about 111, at most about 112, at most about 113, at most about 114, at most about 115, at most about 116, at most about 117, at most about 118, at most about 119, at most about 120, at most about 121, at most about 122, at most about 123, at most about 124, or at most about 125, or at most about 126, or at most about 127, or at most about 128, or at most about 129,or at most about 130, or at most about 131, or at most about 132, or at most about 133, or at most about 134, or at most about 135, or at most about 140, or at most about 145, or at most about 150, or at most about 155, or at most about 160, or at most about 165, or at most about 170, or at most about 175, or at most about 180, or at most about 185, or at most about 190, or at most about 195, or at most about 200, or at most about 205, or at most about 210, or at most about 215, or at most about 220, or at most about 225, or at most about 230, or at most about 235, or at most about 240, or at most about 245, or at most about 250 mg. In some aspects, the total amount (in milligrams) of rifaximin in the disclosed compositions is about 20 mg, about 40 mg, or about 80 mg. Elements from these embodiments may be combined with one or more of the additional embodiments and / or aspects described herein.

[0105] 7. Use for poorly water-soluble drugs This technology can also be applied to other therapeutic compounds that can benefit from targeted release to one or more of the upper, lower, or middle GI tract. Such compounds include, for example, those that have poor water solubility in one or more of the upper, middle, and lower GI tract. In some embodiments, such compounds can be rifamycin compounds. In some embodiments, the rifamycin compounds can be selected from the group consisting of rifaximin, rifamycin A, rifamycin B, rifamycin C, rifamycin D, rifamycin E, rifamycin S, rifamycin SV, rifampin (rifampicin), rifapentine, rifabutin, rifalazil, and pharmaceutically acceptable salts thereof. In some embodiments, the rifamycin compound is rifaximin.

[0106] So in some cases: a. a first targeted release bead comprising a sugar sphere coated with a combination comprising a rifamycin compound, a first pH-independent polymer, and a second pH-independent polymer, the first targeted release bead configured to release the rifamycin compound to the upper GI tract; and / or b. A second targeted release bead comprising a sugar sphere coated with a combination comprising a rifamycin compound and a pH-dependent polymer, the second targeted release bead configured to release the rifamycin compound to the mid-GI tract, lower GI tract, and / or colon. A composition for providing targeted release to one or more of the upper GI tract, middle GI tract, and lower GI tract is provided, comprising:

[0107] In some embodiments, the first pH-independent polymer and the second pH-independent polymer are selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), hydroxyethyl cellulose (HEC), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid (PAA), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, and divinyl ether maleic anhydride copolymer (DIVEMA). In some embodiments, the first pH-independent polymer is HPMC. In some embodiments, the second pH-independent polymer is PVP.

[0108] In some embodiments, the pH-dependent polymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), methacrylic acid / ethyl acrylic acid copolymer, hydroxypropyl methylcellulose acetate phthalate (HPMC-P), cellulose acetate phthalate (CAP), and cellulose acetate trimellitate (CAT). In some embodiments, the pH-dependent polymer is HPMC-AS.

[0109] In some embodiments, the first and / or second targeted release beads may further comprise a surfactant. In some embodiments, the surfactant is a non-ionic surfactant. In some embodiments, the surfactant is poloxamer 407.

[0110] In some embodiments, the first and / or second targeted release beads may comprise a pharmaceutically acceptable plasticizer. In some embodiments, the pharmaceutically acceptable plasticizer is an alkyl citrate. In some embodiments, the pharmaceutically acceptable plasticizer is selected from triethyl citrate (TEC), acetyltriethyl citrate (ATEC), tributyl citrate (TBC), acetyltributyl citrate (ATBC), trioctyl citrate (TOC), acetyltrioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryltrihexyl citrate (BTHC, o-butyryltrihexyl citrate), and trimethyl citrate (TMC). In some embodiments, the pharmaceutically acceptable plasticizer is TEC. In some embodiments, the first and / or second targeted release beads may further comprise diethyl phthalate and / or dibutyl phthalate. In some embodiments, the first and / or second targeted release beads comprise diethyl phthalate.

[0111] In some embodiments, the second targeted-release beads comprise an enteric coating. In some embodiments, the enteric coating surrounds the rifamycin compound-coated sugar spheres and the pH-dependent polymer. In some embodiments, the enteric coating comprises a methacrylic acid-acrylate copolymer and, optionally, a combination of glycerol monostearate, triethyl citrate, and polysorbate 80 (e.g., Plasacryl HTP 20). In some embodiments, the enteric coating comprises an ethyl methacrylate-acrylate copolymer (e.g., Eudragit L30D55) and, optionally, a combination of glycerol monostearate, triethyl citrate, and polysorbate 80 (e.g., Plasacryl HTP 20). In some embodiments, the enteric coating further comprises a non-stick additive.

[0112] In one embodiment, the first pH-independent polymer is present in an amount of about 5% to about 15% by weight based on the total weight of the rifamycin compounds in the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 6% to about 12% by weight based on the total weight of the rifamycin compounds in the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 6% to about 10% by weight based on the total weight of the rifamycin compounds in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 5% to about 9% by weight based on the total weight of the rifamycin compounds in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 5% to about 8% by weight based on the total weight of the rifamycin compounds in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 5% to about 7% by weight based on the total weight of the rifamycin compounds in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 6% to about 7% by weight based on the total weight of the rifamycin compounds in the combination. In some embodiments, the first pH-independent polymer is present in an amount of about 7% to about 10% by weight, based on the total weight of the rifamycin compound in the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 8% to about 9% by weight, based on the total weight of the rifamycin compound in the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 0.1% to about 2.5% by weight, based on the total weight of the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 0.3% to about 2.3% by weight, based on the total weight of the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 0.3% to about 0.5% by weight, or about 1.8% to about 2.0% by weight, based on the total weight of the composition. In some embodiments, the first pH-independent polymer is present in an amount of about 0.4% to about 0.5% by weight, or about 1.9% to about 2.0% by weight, based on the total weight of the composition.

[0113] In one embodiment, the second pH-independent polymer is present in an amount of about 15% to about 35% by weight, based on the total weight of the rifamycin compounds in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 15% to about 25% by weight, based on the total weight of the rifamycin compounds in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 15% to about 20% by weight, based on the total weight of the rifamycin compounds in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 18% to about 20% by weight, based on the total weight of the rifamycin compounds in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 19% to about 20% by weight, based on the total weight of the rifamycin compounds in the combination. In some embodiments, the second pH-independent polymer is present in an amount of about 20% to about 35% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 25% to about 30% by weight, based on the total weight of the rifamycin compound in the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 26% to about 27% by weight, based on the total weight of the rifamycin compound in the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 0.5% to about 4.0% by weight, or about 3.0% to about 8.0% by weight, based on the total weight of the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 0.5% to about 2.0% by weight, or about 4.0% to about 7.0% by weight, based on the total weight of the composition. In some embodiments, the second pH-independent polymer is present in an amount of about 0.1% to about 2.0% by weight, or about 5.0% to about 6.0% by weight, based on the total weight of the composition.

[0114] In one embodiment, the pH-dependent polymer is present in an amount of about 20% to about 60% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 20% to about 50% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 25% to about 45% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 30% to about 40% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 30% to about 35% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 40% to about 60% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 40% to about 50% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 43% to about 47% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 44% to about 45% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 1% to about 12% by weight, based on the total weight of the rifamycin compounds in the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 1% to about 4% by weight, or about 8% to about 11% by weight, based on the total weight of the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 1% to about 3% by weight, or about 8% to about 10% by weight, based on the total weight of the composition. In some embodiments, the pH-dependent polymer is present in an amount of about 2% to about 3% by weight, or about 9% to about 10% by weight, based on the total weight of the composition.

[0115] In one embodiment, the rifamycin compound to the pH-independent polymer in the composition is provided in a weight ratio of about 65:35 to about 85:15, respectively. In some embodiments, the rifamycin compound to the pH-independent polymer in the composition is provided in a weight ratio of about 70:30 to about 80:20, respectively. In some embodiments, the rifamycin compound to the pH-independent polymer in the composition is provided in a weight ratio of about 70:30 to about 75:25, respectively. In some embodiments, the rifamycin compound and pH-independent polymer that can be included in the compositions described herein are not provided in a weight ratio of 25:75, 50:50, or 75:25, respectively. In some embodiments, the compositions described herein, when such compositions include both a rifamycin compound and a pH-independent polymer, contain more rifamycin compound by weight than the pH-independent polymer.

[0116] In one embodiment, the rifamycin compound to pH-dependent polymer in the composition is provided in a weight ratio of about 65:35 to about 75:25, respectively. In some embodiments, the rifamycin compound to pH-dependent polymer in the composition is provided in a weight ratio of about 60:40 to about 70:30, respectively. In some embodiments, the rifamycin compound to pH-dependent polymer in the composition is provided in a weight ratio of about 65:35 to about 70:30, respectively. In some embodiments, the rifamycin compound and pH-dependent polymer that can be included in the compositions described herein are not provided in a weight ratio of 25:75, 50:50, or 75:25, respectively. In some embodiments, the compositions described herein, when such compositions include both a rifamycin compound and a pH-dependent polymer, contain more rifamycin compound by weight than pH-dependent polymer.

[0117] In one embodiment, the surfactant is present in an amount of about 5% to about 15% by weight based on the total weight of the rifamycin compounds in the composition. In some embodiments, the surfactant is present in an amount of about 7% to about 9% by weight based on the total weight of the rifamycin compounds in the composition. In some embodiments, the surfactant is present in an amount of about 8% to about 9% by weight based on the total weight of the rifamycin compounds in the composition.

[0118] In one embodiment, the rifamycin compound provided in the composition is present in an amount of about 1% to about 30% by weight, based on the total weight of the composition. In some embodiments, the rifamycin compound is present in an amount of about 1% to about 10% by weight, based on the total weight of the composition. In some embodiments, the rifamycin compound is present in an amount of about 4% to about 6% by weight, based on the total weight of the composition. In some embodiments, the rifamycin compound is present in an amount of about 15% to about 25% by weight, based on the total weight of the composition. In some embodiments, the rifamycin compound is present in an amount of about 20% to about 23% by weight, based on the total weight of the composition.

[0119] In some embodiments, the composition comprising the first and / or second targeted release beads may comprise a rifamycin compound according to any of the following dosages: In one embodiment, the total amount of the rifamycin compound in the disclosed composition is less than about 250 mg (e.g., less than about 240 mg, less than about 230 mg, less than about 220 mg, less than about 210 mg, less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 110 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 70 mg, less than about 60 mg, less than about 50 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, or less than about 10 mg). In some embodiments, the total amount of the rifamycin compound is in the range of about 2.5 mg to about 250 mg (e.g., about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 125 mg, about 10 mg to about 125 mg, about 10 mg to about 100 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 30 mg to about 70 mg, about 35 mg to about 65 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 75 mg to about 125 mg, about 80 mg to about 120 mg, 85 mg to about 115 mg, about 90 mg to about 110 mg, or about 95 mg to about 105 mg). In some embodiments, the total amount (in milligrams) of rifamycin compounds in the disclosed compositions is about 5, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46 , about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95,about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 110, about 111, about 112, about 113, about 114, about 115, about 116, about 117, about 118, about 119, about 120, about 121, about 122, about 123, about 124, or about 125 mg, or about 126 mg, or about 127 mg, or about 128 mg, or about 129 mg, or about 130 mg, or about 131 mg, or about 132 mg, or about 133 mg, or about 134 mg, or about 135 mg, or about 140 mg, or about 145 mg, or about 150 mg, or about 155 mg, or about 160 mg, or about 165 mg, or about 170 mg, or about 175 mg, or about 180 mg, or about 185 mg, or about 190 mg, or about 195 mg, or about 200 mg, or about 205 mg, or about 210 mg, or about 215 mg, or about 220 mg, or about 225 mg, or about 230 mg, or about 235 mg, or about 240 mg, or about 245 mg, or about 250 mg; or at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, at least about 50, at least about 51, at least about 52, at least about 53, at least about 54, at least about 55, at least about 56, at least about 57, at least about 58, at least about 59, at least about 60, at least about 61, at least about 62, at least about 63, at least about 64, at least about 65, at least about 66, at least about 67, at least about 68, at least about 69, at least about 70,at least about 71, at least about 72, at least about 73, at least about 74, at least about 75, at least about 76, at least about 77, at least about 78, at least about 79, at least about 80, at least about 81, at least about 82, at least about 83, at least about 84, at least about 85, at least about 86, at least about 87, at least about 88, at least about 89, at least about 90, at least about 91, at least about 92, at least about 93, at least about 94, at least about 95, at least about 96, at least about 97, at least about 98, at least about 99, at least about 100, at least about 101, at least about 102, at least about 103, at least about 104, at least about 105, at least about 106, at least about 107, at least about 108, at least about 109, at least about 110, at least about 111, at least about 112, at least about 113, at least about 114, at least about 115, at least about 116, at least about 117, at least about 118, at least about 119, at least about 120, at least about 121, at least about 122, at least about 123, 23, at least about 124, or at least about 125 mg, or at least about 126 mg, or at least about 127 mg, or at least about 128 mg, or at least about 129 mg, or at least about 130 mg, or at least about 131 mg, or at least about 132 mg, or at least about 133 mg, or at least about 134 mg, or at least about 135 mg, or at least about 140 mg, or at least about 145 mg, or at least about 150 mg, or at least about 155 mg, or at least about 160 mg, or at least about 165 mg g, or at least about 170 mg, or at least about 175 mg, or at least about 180 mg, or at least about 185 mg, or at least about 190 mg, or at least about 195 mg, or at least about 200 mg, or at least about 205 mg, or at least about 210 mg, or at least about 215 mg, or at least about 220 mg, or at least about 225 mg, or at least about 230 mg, or at least about 235 mg, or at least about 240 mg, or at least about 245 mg, or at least about 250 mg; or at most about 10,at most about 11, at most about 12, at most about 13, at most about 14, at most about 15, at most about 16, at most about 17, at most about 18, at most about 19, at most about 20, at most about 21, at most about 22, at most about 23, at most about 24, at most about 25, at most about 26, at most about 27, at most about 28, at most about 29, at most about 30, at most about 31, at most about 32, at most about 33, at most about 34, at most about 35, at most about 36, at most about 37, at most about 38, at most about 39, at most about 40, at most about 41 , at most about 42, at most about 43, at most about 44, at most about 45, at most about 46, at most about 47, at most about 48, at most about 49, at most about 50, at most about 51, at most about 52, at most about 53, at most about 54, at most about 55, at most about 56, at most about 57, at most about 58, at most about 59, at most about 60, at most about 61, at most about 62, at most about 63, at most about 64, at most about 65, at most about 66, at most about 67, at most about 68, at most about 69, at most about 70, at most about 71, at most about 7 2, at most about 73, at most about 74, at most about 75, at most about 76, at most about 77, at most about 78, at most about 79, at most about 80, at most about 81, at most about 82, at most about 83, at most about 84, at most about 85, at most about 86, at most about 87, at most about 88, at most about 89, at most about 90, at most about 91, at most about 92, at most about 93, at most about 94, at most about 95, at most about 96, at most about 97, at most about 98, at most about 99, at most about 100, at most about 101, at most about 102, at most about at most about 103, at most about 104, at most about 105, at most about 106, at most about 107, at most about 108, at most about 109, at most about 110, at most about 111, at most about 112, at most about 113, at most about 114, at most about 115, at most about 116, at most about 117, at most about 118, at most about 119, at most about 120, at most about 121, at most about 122, at most about 123, at most about 124, or at most about 125 mg, or at most about 126 mg, or at most about 127 mg, or at most about 128 mg,or at most about 129 mg, or at most about 130 mg, or at most about 131 mg, or at most about 132 mg, or at most about 133 mg, or at most about 134 mg, or at most about 135 mg, or at most about 140 mg, or at most about 145 mg, or at most about 150 mg, or at most about 155 mg, or at most about 160 mg, or at most about 165 mg, or at most about 170 mg, or at most about 175 mg, or is at most about 180 mg, or at most about 185 mg, or at most about 190 mg, or at most about 195 mg, or at most about 200 mg, or at most about 205 mg, or at most about 210 mg, or at most about 215 mg, or at most about 220 mg, or at most about 225 mg, or at most about 230 mg, or at most about 235 mg, or at most about 240 mg, or at most about 245 mg, or at most about 250 mg.

[0120] 8. Dosage Form For administration purposes, in some embodiments, the compositions described herein may be administered directly or may be formulated as an alternative dosage form, for example, for oral delivery. Formulations for oral delivery may be in the form of lozenges, aqueous or oily suspensions, emulsions, capsules, syrups, or elixirs. Orally administered compositions may contain one or more optional agents to obtain a pharmaceutically acceptable preparation, such as sweeteners, for example, fructose, aspartame, or saccharin; flavoring agents, for example, peppermint, wintergreen oil, or cherry; coloring agents; and preservatives. The compositions may be coated to delay disintegration and absorption in the digestive tract, thereby providing a sustained effect over a long period of time.

[0121] In some embodiments, the disclosed compositions are formulated in capsule form. In some embodiments, the disclosed compositions are formulated in soft or hard capsule form. In some embodiments, the disclosed compositions are formulated in soft or hard gelatin capsule form.

[0122] It should be noted that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.

[0123] 9. Antioxidants / chelating agents In some embodiments, the compositions described herein may further comprise an antioxidant and / or a chelating agent.

[0124] In some embodiments, the compositions described herein further comprise an antioxidant and / or chelating agent selected from ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid. Without being limited to any one theory of the invention, BHT and citric acid can be used, for example, as antioxidants and / or chelating agents to minimize potential degradation of rifaximin via oxidation.

[0125] In some embodiments, the compositions described herein comprise an antioxidant and / or a chelating agent in an amount of from about 0.001% to about 3% by weight of the composition.

[0126] In some embodiments, the compositions described herein comprise an antioxidant and / or chelating agent in an amount of about 0.05% to about 3%, or about 0.1% to about 3%, or about 0.1% to about 1%, or about 0.1% to about 0.5% by weight of the composition, hi some embodiments, the compositions described herein comprise an antioxidant and / or chelating agent in an amount of at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, or 3% by weight of the composition. In some embodiments, the compositions described herein comprise an antioxidant and / or chelating agent in an amount of at most about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, or 3% by weight of the composition. In some embodiments, the compositions described herein comprise an antioxidant and / or chelating agent in an amount of at most about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, or 3% by weight of the composition.

[0127] In some embodiments, the compositions described herein include BHA, BHT, and / or Vitamin E TPGS in an amount of about 0.05% to about 3%, or about 0.1% to about 2%, or about 0.1% to about 1%, or about 0.1% to about 0.5% by weight of the composition. In some embodiments, the compositions described herein include BHA, BHT, and / or Vitamin E TPGS in an amount of at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, or 3% by weight of the composition. In some embodiments, the compositions described herein include BHA, BHT, and / or Vitamin E TPGS in an amount of at most about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, or 3% by weight of the composition. In some embodiments, the compositions described herein include BHA, BHT, and / or Vitamin E TPGS in an amount of at most about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, or 3% by weight of the composition.

[0128] In some embodiments, the compositions described herein comprise BHA in an amount of about 0.05% to about 1%, or about 0.1% to about 0.5%, or about 0.1% to about 0.4%, or about 0.1% to about 0.3% by weight of the composition. In some embodiments, the compositions described herein comprise BHA in an amount of at least about 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% by weight of the composition. In some embodiments, the compositions described herein comprise BHA in an amount of at most about 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% by weight of the composition. In some embodiments, the compositions described herein comprise BHA in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% by weight of the composition.

[0129] In some embodiments, the compositions described herein comprise BHT in an amount of about 0.05% to about 1%, or about 0.1% to about 0.5%, or about 0.1% to about 0.4%, or about 0.1% to about 0.3% by weight of the composition. In some embodiments, the compositions described herein comprise BHT in an amount of at least about 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% by weight of the composition. In some embodiments, the compositions described herein comprise BHT in an amount of at most about 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% by weight of the composition. In some embodiments, the compositions described herein comprise BHT in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% by weight of the composition.

[0130] In some embodiments, the compositions described herein include Vitamin E TPGS in an amount of about 0.1% to about 3%, or about 0.5% to about 3%, or about 0.5% to about 1%, or about 1% to about 3% by weight of the composition. In some embodiments, the compositions described herein include Vitamin E TPGS in an amount of at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, or 3% by weight of the composition. In some embodiments, the compositions described herein include Vitamin E TPGS in an amount of at most about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, or 3% by weight of the composition. In some embodiments, the compositions described herein comprise Vitamin E TPGS in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, or 3% by weight of the composition.

[0131] 10. Methods and Uses The compositions described herein can be used in methods for treating diseases. For example, the present disclosure includes methods for treating a disease or disorder in a subject in need thereof. Such methods can include administering to the subject a therapeutically effective amount of any one or more of the aforementioned compositions, which can be in unit dosage form.

[0132] The compositions described herein are useful for treating one or more disorders involving gut-related or liver dysfunction, including, for example, irritable bowel syndrome (IBS) (e.g., IBS-D), diarrhea, microbial-associated diarrhea, infectious diarrhea, Clostridium difficile infection and symptoms (e.g., Clostridium difficile-associated diarrhea), traveler's diarrhea, small intestinal bacterial overgrowth (SIBO), Crohn's disease, diverticular disease, pancreatitis (including chronic), pancreatic insufficiency, enteritis, colitis (e.g., ulcerative colitis, antibiotic-associated colitis, microscopic colitis), hepatic encephalopathy (or other diseases causing elevated ammonia levels) and symptoms thereof, gastric dyspepsia, cirrhosis (e.g., alcoholic cirrhosis), polycystic liver disease, pouchitis, peritonitis, short bowel syndrome, inflammatory bowel disease, rosacea, sickle cell disease, and H. pylori infection.

[0133] The compositions described herein are useful for treating and / or preventing hepatic encephalopathy.For example, the compositions described herein can be useful for treating recurrent hepatic encephalopathy, and / or for treating overt hepatic encephalopathy, and / or for preventing overt hepatic encephalopathy.

[0134] The compositions described herein are useful in liver transplant preparations.

[0135] The compositions described herein are useful for treating cardiovascular conditions (eg, atherosclerotic cardiovascular disease).

[0136] The compositions described herein are useful for treating disorders affecting the central nervous system and those associated with cognitive impairment, such as Parkinson's disease, Alzheimer's disease, and autism.

[0137] The compositions described herein are useful in the treatment of certain cancers, such as acute myeloid leukemia.

[0138] The compositions described herein are useful for treating sickle cell disease and / or its associated conditions.

[0139] In certain embodiments, the inventions described herein include methods of treating sickle cell disease (SCD) in a patient in need thereof, comprising administering to the patient a disclosed targeted release composition. In some embodiments, the method of treating sickle cell disease (SCD) comprises reducing elevated levels of circulating serotonin-associated neutrophils (CANs) in the patient. In some embodiments, the method of treating sickle cell disease (SCD) in a patient comprises treating a vaso-occlusive crisis (VOC) in the patient.

[0140] In some embodiments, treating a vaso-occlusive crisis (VOC) in a patient comprises (1) alleviating one or more symptoms of a VOC in the patient, (2) reducing or preventing the occurrence of VOCs in the patient, (3) reducing the duration or severity of a VOC in the patient, and / or (4) mediating or otherwise reducing the patient's opioid utilization during a VOC. In some embodiments, a method of treating sickle cell disease (SCD) in a patient comprises alleviating one or more symptoms of a vaso-occlusive crisis (VOC) in the patient. In some embodiments, a method of treating sickle cell disease (SCD) in a patient comprises reducing or preventing the occurrence of vaso-occlusive crises (VOCs) in the patient. In some embodiments, a method of treating sickle cell disease (SCD) in a patient comprises reducing the duration or severity of a VOC in the patient. In some embodiments, a method of treating sickle cell disease (SCD) in a patient includes mediating or otherwise reducing the patient's opioid utilization during a vaso-occlusive crisis (VOC) in the patient. Without being limited to any one theory of the invention, the ER and DER bead formulations described herein are understood to have greater benefit in SCD patients compared to XIFXAN® 550 mg tablets because (1) the ER and DER bead formulations extend rifaximin exposure, in part due to the release profile, (2) the ER and DER bead formulations have lower Cmax values ​​for comparable systemic exposure (i.e., AUC), and (3) the ER and DER bead formulations have higher accumulation ratios for comparable systemic exposure (i.e., AUC).

[0141] In some embodiments, the rifaximin compositions described herein can be administered with an additional SCD therapeutic agent in the treatment methods. In some embodiments, the additional SCD therapeutic agent can be, for example, hydroxyurea, L-glutamine, hydroxycarbamide, an erythropoietin stimulator, and / or an opioid analgesic. In some embodiments, the opioid analgesic can be selected from the group consisting of morphine, codeine, hydrocodone, hydromorphone, methadone, tramadol, oxycodone, tapentadol, fentanyl, and combinations thereof.

[0142] Provided are methods of treating one or more of the diseases or disorders described herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the disclosed compositions. Also provided are uses of the disclosed compositions for the manufacture of a medicament for treating one or more of the diseases or disorders described herein. Further provided are uses of the disclosed compositions for treating one or more of the diseases or disorders described herein.

[0143] In accordance with the above, methods include administering a composition described herein to administer a dose of a rifamycin compound, e.g., rifaximin, to a patient in need thereof in an amount of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 505, 510, The invention may include administering to a subject an amount (in milligrams) of 45, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg. In some embodiments, such methods include administering a composition described herein to administer a dose of a rifamycin compound, e.g., rifaximin, to a patient in need thereof in an amount of at most about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, The invention may include administering to a subject an amount (in milligrams) of 40, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg.In some embodiments, such methods include administering a composition described herein to administer a dose of a rifamycin compound, e.g., rifaximin, to a patient in need thereof, in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 250, 260, 270, 280, 290, 310, 320, 330, 340, 350, 360, 370, 380, 390, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 690, 710, 720, 730, 740, 750, 760, 770, 7 , 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg (in milligrams) of the compound of formula (I) to the subject.

[0144] In accordance with the above, the methods include administering a composition described herein once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID) to provide a daily dose of a rifamycin compound, e.g., rifaximin, of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, , 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 4 70, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755 , 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1000 mg (in milligrams) of the compound of formula (I) to the subject.In some embodiments, the methods include administering a composition described herein once daily, twice daily, three times daily, or four times daily to provide a daily dose of a rifamycin compound, e.g., rifaximin, of at most about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 , 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 4 80, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760 , 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1000 mg (in milligrams) of the compound of formula (I) to the subject.In some embodiments, the methods include administering a composition described herein once daily, twice daily, three times daily, or four times daily to provide a daily dose of a rifamycin compound, e.g., rifaximin, of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 4 0, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480 , 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, The invention may include administering to a subject an amount (in milligrams) of 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1000 mg.

[0145] In some embodiments, the methods may include administering a composition described herein once daily, twice daily, three times daily, or four times daily to provide the subject with a daily dose of a rifamycin compound, e.g., rifaximin, in an amount (in milligrams) of about 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 200 mg, 240 mg, 280 mg, or 320 mg.

[0146] In some embodiments, the method may include administering a composition described herein twice daily to provide the subject with a daily dose of a rifamycin compound, e.g., rifaximin, in an amount (in milligrams) of about 80 mg or about 160 mg.

[0147] For example, the method may involve administering to a subject in need thereof a unit dose of an ER bead or DER bead formulation containing 40 mg of rifaximin twice daily to provide a daily dose of 80 mg of rifaximin.

[0148] In another example, the method may involve administering to a subject in need thereof a unit dose of an ER bead or DER bead formulation containing 80 mg of rifaximin twice daily to provide a daily dose of 160 mg of rifaximin.

[0149] In some embodiments, the dose or daily dose, as the case may be, may be obtained by administering to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms of the composition (e.g., capsules) per dose or per day. In some embodiments, the dose or daily dose, as the case may be, may be obtained by administering to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms of the composition (e.g., capsules) per dose or per day. In some embodiments, the dose or daily dose, as the case may be, may be obtained by administering to the subject about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dosage forms of the composition (e.g., capsules) per dose or per day.

[0150] For example, the method may involve administering two unit doses (capsules) of an ER bead or DER bead formulation containing 20 mg of rifaximin each (i.e., 40 mg total) twice daily to a subject in need thereof to provide a daily dose of 80 mg of rifaximin.

[0151] In another example, the method may involve administering four unit doses (capsules) of an ER bead or DER bead formulation containing 20 mg of rifaximin each (i.e., 80 mg total) twice daily to a subject in need thereof to provide a daily dose of 160 mg of rifaximin.

[0152] While certain embodiments of the present invention have been described and / or illustrated above, various other embodiments will be apparent to those skilled in the art from this disclosure. The present invention, therefore, is not limited to the specific embodiments described and / or illustrated, but is capable of considerable variation and modification without departing from the scope and spirit of the appended claims. [Example]

[0153] Example The representative examples presented below are intended to help illustrate the disclosure and are not intended to, and should not be construed as, limiting the scope of the invention.

[0154] [Example 1] Topical bioavailability of rifaximin An open-label, five-way, non-randomized, single-sequence crossover study in healthy male subjects was conducted to investigate the local bioavailability of rifaximin when delivered to target sites in the gastrointestinal (GI) tract. In Period 1, subjects received 150 mg of rifaximin formulated as immediate-release (IR) solid dispersion capsules. Solid dispersion forms of rifaximin can be found, for example, in WO 2018 / 064472, WO 2012 / 009388, US 9,737,610, and US 10,874,647, the entire contents of which are incorporated herein by reference. In Period 2, subjects received 150 mg of rifaximin formulated as immediate-release (IR) solid dispersion capsules to the proximal small intestine (PSB), distal small intestine (DSB), colon, and mid-small intestine (MSB). Blood samples were collected pre-dose and at specific time points post-dose for PK analysis.

[0155] As shown in Figure 1 and Table 1, the extent of rifaximin exposure was greatest after delivery to the proximal small intestine and decreased with distance along the intestinal tract. Absorption from the colon was negligible (plasma samples provided by most subjects failed to contain quantifiable rifaximin after delivery to the colon). This trend was reflected in the mean estimates of Frel, which were 36.4%, 7.08%, 2.09%, and 0.216% in the proximal, mid, and distal small intestine.

[0156] [Table 1]

[0157] [Example 2] UGI and MGI Composition Two compositions were prepared according to the invention described above. The first composition was prepared as an upper GI targeted or ER formulation. The second composition was prepared as a mid and / or lower GI targeted or DER formulation.

[0158] The upper GI (UGI)-targeted ER composition contained rifaximin-layered sucrose sugar spheres, in which rifaximin was amorphous and encapsulated in two polymers (povidone K-90 and hypromellose 2910) along with a surfactant (poloxamer 407) and a plasticizer (diethyl phthalate). The amount of rifaximin was adjusted appropriately to accommodate various dosages. The beads were filled into opaque Swedish orange size 0EL hard gelatin capsule shells. Specifically, high and low drug-loading beads were prepared and investigated.

[0159] The mid-GI (MGI)-targeting, DER composition contains rifaximin-layered sucrose sugar spheres, in which rifaximin is amorphous and encapsulated in an enteric polymer (hypromellose acetate succinate) along with a surfactant (poloxamer 407) and plasticizers (diethyl phthalate and triethyl citrate). The drug-layered spheres are then coated with a methacrylic acid and ethyl acrylate copolymer (Eudragit L30 D55) plasticized with polysorbate 80 and triethyl citrate. Glycerol monostearate is included in the functional coating application as an anti-adherent agent. The amount of rifaximin was adjusted appropriately to accommodate various dosages. The beads were filled into opaque Swedish orange size 0EL hard gelatin capsule shells. High and low drug-loading beads were prepared and investigated as described above.

[0160] With respect to dissolution, the beads are designed to have an extended release profile (UGI beads) and the release is pH independent. The MGI formulation is designed as delayed release (no release at pH < 4.5) and has an extended release profile when the pH conditions reach pH 6.8.

[0161] In fact, the UGI formulation is designed for pH-independent extended release, with the majority of the drug released over a 2-3 hour period. Rifaximin release from this dosage form is intended for delivery to the upper gastrointestinal tract, where the pH can vary from 1 to 6 as the beads travel through the stomach, duodenum, and jejunum segments. The amount released can be modified with each dose increase; doubling the dose from 20 mg to 40 mg doubles the amount released.

[0162] Experimental UGI formulations containing different ratios of HPMC AS to povidone K90 established that HPMC AS-containing formulations did not provide favorable pH-independent drug release. Such formulations resulted in slower dissolution at lower pH. Without being limited to any one theory, this behavior is attributed to the characteristics of the HPMC-AS polymer, which requires a higher pH to ionize and hydrate. Furthermore, such formulations exhibited relatively slow release. To match drug release with small intestinal transit time, a faster release was targeted, with 60–80% of the drug released within 2–3 hours. Therefore, HPMC-AS was not preferred for use in UGI formulations, and HPMC was developed as the preferred polymer in such formulations.

[0163] In summary, the choice of polymer for the dissolution behavior of the UGI formulation was important from both a dissolution and processing standpoint. Povidone K90 was identified as the preferred polymer, providing good drug layering properties. The incorporation of HPMC-AS into the povidone polymer system did not provide the desired release characteristics for the UGI beads because this polymer has some "enteric" properties and does not hydrate sufficiently at pH < 6. The dissolution profiles in these formulation studies also demonstrated that hypromellose may provide some solubility enhancement or inhibition of rifaximin precipitation, helping to keep rifaximin solubilized.

[0164] Incorporation of hypromellose into the bead composition produced beads in which rifaximin release was more pH independent. Composition testing further supported that lower levels, or approximately 25% of the total polymer, with povidone K90 as the remainder, produced suitable beads. Higher concentrations of hypromellose were produced at a development scale, but because hypromellose is poorly soluble in the methanol solvent used for the drug layering step, a lower concentration of hypromellose was desired to ensure that the polymer allowed for further intermolecular interactions of rifaximin with the polymer in solution, as well as to avoid any solids in the spray solution that could result in processing challenges (nozzle clogging or uneven polymer deposition).

[0165] Other factors evaluated included sugar sphere size and drug loading to determine their effect on release. Sugar sphere sizes derived from 14 / 18 mesh (largest), 20 / 25 mesh (medium), and 30 / 35 mesh (smallest) were evaluated in batches 4224-120, 3669154, and 4224-155, respectively. For the UGI formulation, dissolution profiles performed at pH 4.5 demonstrated that drug release increased as sugar sphere size decreased. This is expected since, at a given dose, smaller bead sizes have a larger surface area. For the UGI formulation, 20 / 25 mesh spheres were chosen due to increased processing risks (sticking / twinning) with smaller sugar spheres. Additionally, beads with lower drug loading exhibited faster release, with >80% of the drug released within 1-2 hours at such a dose level (i.e., 5% rifaximin drug loading) compared to higher drug loading formulations (i.e., 22% rifaximin drug loading), where less than 50% was released within the same time frame.

[0166] The MGI formulation was designed to release rifaximin in the mid-intestinal tract, specifically the jejunum and ileum. The drug release profile was achieved using several compositional design features. First, the drug-layered beads were formulated to contain HPMC-AS, an enteric polymer designed to hydrate at approximately pH 6. Second, the beads were coated with a methacrylate-ethyl acrylate copolymer (Eudragit L30 D55). The pH sensitivity of this polymer protects the beads when exposed to low pH and does not allow the coating to hydrate. When pH conditions approach 5.5, the polymer hydrates and dissolves, allowing the inner beads to begin releasing the drug.

[0167] Furthermore, testing of MGI formulations demonstrated that HPMC-AS was preferred over povidone / HPMC-based systems. The grade of HPMC-AS proved relevant, as the M grade showed improved performance compared to the H grade with respect to friction during processing. Furthermore, MGI formulations benefited from the use of a soluble enteric polymer, as opposed to a water-insoluble enteric polymer (e.g., Eudragit RL / RS) with pH-dependent hydration properties. Furthermore, drug loading was demonstrated to play a role in the release profile, with lower drug loading resulting in a faster release rate for the same dose.

[0168] Examples of UGI and MGI compositions are listed in Tables 2-4 below.

[0169] [Table 2]

[0170] [Table 3]

[0171] [Example 3] In vitro dissolution testing of UGI and MGI compositions Figure 2 shows the dissolution profiles of 80 mg strength MGI and UGI compositions compared to XIFAXAN® 550 mg tablets under acidic and basic conditions. The data from this figure establish the pH-dependent nature of the rifaximin MGI delivery composition (e.g., it is designed for delayed release (no release at pH < 4.5) and has an extended release profile when pH conditions reach pH 6.8) and the pH-independent nature of the UGI composition. XIFAXAN® 550 mg tablets have essentially negligible release for both acidic and buffered conditions compared to the compositions of the present invention.

[0172] [Example 4] In vivo pharmacokinetic study of UGI and MGI compositions Male and female dogs were pretreated with pentagastrin to stimulate gastric acid secretion and closely mimic human gastric pH. Dogs were administered a 200 mg strength UGI composition, a 200 mg strength MGI composition, or a Xifaxin 550 mg tablet. Mean PK parameters (C max The AUC (Areas per Unit of Measure) is approximately 10-fold higher for the 200 mg strength UGI (labeled IR beads) and MGI (labeled ER-DC-5.5 beads) targeting compositions of the present invention compared to XIFAXAN® 550 tablets. When dose-normalized, the drug absorption between the UGI and MGI compositions of the present invention and XIFAXAN® 550 tablets is approximately 10-fold higher for the 200 mg strength UGI (labeled IR beads) and MGI (labeled ER-DC-5.5 beads) targeting compositions of the present invention compared to XIFAXAN® 550 tablets. 0-24 It was found that there was an approximately 25-fold difference in the β-glucan concentration. See, for example, Figure 3.

[0173] Figure 4 shows rifaximin plasma concentrations as a function of time. The MGI composition (labeled ER-DC-5.5 beads) exhibits a delayed release of approximately 1 hour, indicating absent or minimal dissolution in the upper GI tract. The UGI composition (labeled IR beads) exhibits a faster release, indicating its pH-independent design.

[0174] [Example 5] A randomized, placebo-controlled study evaluating the safety, tolerability, and pharmacokinetics of a novel rifaximin formulation in healthy volunteers A Phase 1, randomized, placebo-controlled, safety, tolerability, and PK study of the disclosed 10 mg, 40 mg, and 80 mg rifaximin ER and DER compositions was conducted in healthy volunteers. The study was divided into two phases: a single ascending dose (SAD) phase and a multiple dose (MD) phase.

[0175] A. Single Ascending Dose (SAD) For the SAD study, four single doses were tested: low dose, medium dose, high dose, and maximum dose (one daily high BID dose). The daily BID dose was incorporated into the SAD phase to provide safety data for the single maximum BID dose to support the selection of the BID dose to be evaluated in the multiple dose phase. Two cohorts were enrolled for each composition, and enrollment was staggered with appropriate safety assessments and washout periods to facilitate dose escalation. Participants were randomized in a 6:2 ratio (active:placebo) within each of the following six dose escalation cohorts. Participants maintained their initial randomization (active or placebo) throughout the SAD phase.

[0176] Formulation 2: Rifaximin ER Capsules Cohort 1: low dose (10 mg rifaximin) followed by high dose (80 mg rifaximin) Cohort 2: Medium dose (40 mg rifaximin), then maximum dose (80 mg rifaximin BID)

[0177] Formulation 3: Rifaximin DER Capsules Cohort 1: low dose (10 mg rifaximin) followed by high dose (80 mg rifaximin) Cohort 2: Medium dose (40 mg rifaximin), then maximum dose (80 mg rifaximin BID)

[0178] B. Multiple Ascending Dose (MAD) Approximately 2 weeks after completion of the SAD phase, a decision was made to proceed to the MAD phase for each formulation, and an appropriate dose for BID dosing was selected based on safety, tolerability, and PK data. For formulations continuing into the MD phase, safety, tolerability, and PK of BID dosing for 14 days were evaluated. Eight (8) new participants were randomized into Cohort 3 per formulation (6 active: 2 placebo) as follows:

[0179] Formulation 1: Rifaximin ER Capsules Cohort 3: 80mg BID

[0180] Formulation 2: Rifaximin DER Capsules Cohort 3: 80mg BID

[0181] result A. Serious Adverse Events (SAEs) and Treatment-Emergent Adverse Events (TEAEs) For the ER composition, there were no TEAEs or SAEs with a severity of ≧Grade 3 (i.e., severe), and the majority of reported TEAEs were Grade 1 (mild). For the DER composition, there were no SAEs, TEAEs with a severity of ≧Grade 3 (i.e., severe), or TEAEs that led to discontinuation of study drug or discontinuation of the study reported. All TEAEs reported for the DER composition were Grade 1 (mild). Similar results were observed in the MAD study.

[0182] B. Pharmacokinetics SAD dose rifaximin ER composition Administration of the ER composition resulted in similar rifaximin concentrations within 5 hours of dosing for 10 mg and 40 mg (median Tmax ranged from 2.5 to 3.5 hours) (Table 4). Peak rifaximin concentrations occurred over a wider range (up to 5 hours post-dose) for low, medium, high, and maximum ER dose levels. BID dosing (2 x 80 mg) resulted in a higher rifaximin concentration (AUC last and AUC infwere 6.78 and 7.05 h.ng / mL, respectively), whereas AUC last (18.9h.ng / mL) and AUC inf There was a greater than proportional increase in rifaximin exposure for 19.5 h ng / mL (Table 5). The t (5.9-13 h) after administration of the ER formulation was variable (CV% up to 38%), indicating that sufficient plasma levels were available to adequately determine the terminal elimination phase. After up to 80 mg BID ER formulation, significantly higher mean rifaximin levels were observed after administration of the second dose (approximately 1.1 ng / mL) than after the first dose (approximately 0.4 ng / mL).

[0183] [Table 4]

[0184] SAR Dose Rifaximin DER Composition Administration of DER showed an increase in mean rifaximin concentrations (Cmax) according to the following order: 10 mg (0.22 ng / mL) < 40 mg (0.36 ng / mL) < 80 mg (0.65 ng / mL) < 80 mg BID (0.72 ng / mL; Table 5). The t1 / 2 (9.7-15.7 hours) after administration of the DER formulations was variable (geometric CV% up to 33%) but similar to that obtained with the ER composition.

[0185] [Table 5]

[0186] MAD dose rifaximin ER composition After administration of the rifaximin ER composition, a short lag time was observed on Day 1 (median 0.25 hours), after which Cmax was reached approximately 2 hours after administration. On Day 14, Cmax was approximately 3.5 hours, with a lag time of 0. Higher mean rifaximin plasma concentration levels were observed on Day 14 (Day 14: 1.33 ng / mL) compared to Day 1 (0.82 ng / mL) due to an absorption phase of up to 6 hours. Where it was possible to determine this, the t on Day 1 was an underestimate of 3.6 hours (n=3), but when determined on Day 14, the t of 17.9 hours reflected potential accumulation over time (Tables 6A and 6B). The trough rifaximin plasma concentration was approximately 0.5 ng / mL. Comparison of Cmax (Day 14 / Day 1) showed a moderate mean accumulation ratio of 1.6 (CV% 79%), which may have been influenced by the observed two-phase absorption phase occurring at 1.5 and 5 hours after the first dose. However, AUC 0-12 When determined using (day 14 / day 1), the time dependence was reduced and thus the formulation specific characteristics were more accurate ratios, which were determined to be 2.0 (CV 55%) (Table 7).

[0187] MAD dose rifaximin DER composition After administration of rifaximin DER capsules, a slightly longer median Tlag was observed on Day 1 (1 hour) (Tables 6A and 6B). Furthermore, the Cmax and AUC parameters on Day 1 were lower than those observed for ER (Tables 6A and 6B). However, by Day 14, Cmax and AUC reached steady-state levels that were approximately 5-fold higher than those observed on Day 1. The mean (CV%) Cavg was 0.138 ng / mL (37.4%) on Day 1 and 0.594 ng / mL (18.2%) on Day 14, confirming accumulation. Trough rifaximin levels from Days 4 to 13 were approximately 0.5 ng / mL. The accumulation ratios for DER were 4.1 and 4.3 for Cmax and AUCtau, respectively (Table 7).

[0188] Compared to the pharmacokinetics of 80 mg ER (BID) and 80 mg DER (BID), XIFAXAN® 550 mg tablets (TID) have been shown to exhibit a Cmax of 2.39±1.28 ng / mL, a Tmax of 5.63±5.27 h, and an AUCtau of 9.3±2.7 ng.hr / mL at Day 14 in healthy patients.

[0189] [Table 6]

[0190] [Table 7]

[0191] [Table 8]

[0192] [Example 6] Exemplary antioxidant-containing rifaximin ER and DER compositions. In addition to the above, Tables 8-14 include high BHA, low BHA, and TPGS-containing rifaximin ER and DER formulations.

[0193] [Table 9]

[0194] [Table 10]

[0195] [Table 11]

[0196] [Table 12]

[0197] [Table 13]

[0198] [Table 14]

[0199] [Table 15]

[0200] [Example 7] A proposed randomized, double-blind, placebo-controlled study to characterize the safety, efficacy, pharmacokinetics, and pharmacodynamics of a rifaximin composition in sickle cell disease patients with vaso-occlusive crisis. The objective of this study was to evaluate the safety, efficacy, and pharmacokinetics of rifaximin after oral administration of one or more of the disclosed rifaximin compositions in sickle cell disease (SCD) patients with a history of vaso-occlusive crisis (VOC). Any potential pharmacokinetic-pharmacodynamic (PK / PD) relationships between rifaximin systemic exposure and potential biomarkers of microbial-associated induction of VOC were also evaluated. Previous clinical studies have shown rifaximin treatment (i.e., XIFAXAN® 550 mg tablets) to have potential benefit in reducing the number of VOCs and the use of intravenous opioid analgesia (IOA). One potential explanation for this benefit may be through modulation of the gut microbial composition in SCD patients. Significant increases in circulating senescent neutrophils (CANs), with high CXCR4 and low CD62L surface expression, have been observed during VOC and have been implicated in the development of the condition. It is proposed that this may occur in response to increased translocation of intestinal bacteria and bacterial products, which can be controlled using administration of rifaximin.

[0201] This study evaluates the safety, efficacy, and PK of rifaximin in patients with SCD, as well as the PK / PD relationship between rifaximin and several putative biomarkers associated with the proposed mechanism.

[0202] the goal The primary goal of this study is to evaluate the effectiveness of the disclosed compositions in reducing VOCs in SCD patients.

[0203] The secondary objectives of this study are: (1) evaluate the effectiveness of the disclosed composition(s) in reducing VOC subcategories in SCD patients; (2) evaluate the impact of the disclosed composition(s) on IOA utilization during VOCs; (3) evaluate the impact of the disclosed composition(s) on outpatient opioid utilization; (4) evaluate the safety and tolerability of the disclosed composition(s) in SCD patients; and (5) characterize the PK and PK / PD relationships between the disclosed rifaximin compositions tested herein and potential biomarkers of microbial-associated VOCs.

[0204] Endpoints The primary efficacy endpoint of this study will be measured by the annualized rate of VOCs (total and resulting in medical visits).

[0205] Secondary efficacy endpoints of the study will be measured by the annualized rate of subcategorical VOCs (total and resulting in a medical visit); the annualized rate of SCD-related medical visits and / or hospitalizations; and the duration of SCD-related medical visits and / or hospitalizations.

[0206] Secondary endpoints of the impact on IOA use for this study will be measured by the annualized percentage of days using IOA; the time from first use of IOA during VOC to preparation for discharge; the cumulative IOA consumption during VOC; and the time to discontinuation of IOA use during VOC.

[0207] Secondary endpoints of assessing the impact of rifaximin compositions on outpatient opioid utilization will be measured in MME units.

[0208] Secondary safety endpoints will be measured by AEs, vital signs, and clinical labs.

[0209] Secondary endpoints of PK (rifaximin and 25-desacetylrifaximin in plasma) were assessed in subjects with intensive PK sampling (Day 1): max , T max , AUC last、 AUC 0-12 , AUC inf , λz,t 1 / 2 , CL / F, Vz / F, MR_ AUCinf ;Subjects with intensive PK sampling (Day 29): C trough , C max,ss , T max,ss , AUC tau , C ss,av λz,t 1 / 2 , CL / F ss , Vz / F ss , R AUC , R Cmax , MR_AUC tau and subjects with sparse sampling: (Day 1, Day 8 [± 1 day], Day 15 [± 1 day], Day 29 [± 1 day], Month 3, and Month 6): C trough , C max , measured by AUC.

[0210] Secondary PD endpoints will be measured by the counts and changes from baseline for total neutrophils and CAN, serum CD62L, urinary 3-indoxyl sulfate, LPS, zonulin, serum citrulline, and intestinal fatty acid binding protein (iFABP) on Day 1 (Day 8 [± 1 day], Day 15 [± 1 day], Day 29 [± 1 day], Month 3, and Month 6).

[0211] Secondary PK / PD endpoints will be measured by assessing the PK / PD relationship between the PK of rifaximin and each PD endpoint.

[0212] Proposed exploratory endpoints include use of the FANLTC questionnaire; examination of the relative taxonomic abundance of the fecal microbiota at baseline (screening window), day 29, and month (Month); examination of iFABP levels; assessment of CAN levels; assessment of zonulin levels; and assessment of serum LPS levels.

[0213] Patient population SCD patients who had experienced at least one VOC in the 12 months prior to enrollment.

[0214] Key inclusion and exclusion criteria Inclusion Criteria: Obtain informed consent. · Have SCD of any genotype (HbSS, HbSC, HbS β-thalassemia). · 18 to 70 years of age (inclusive) on the date of consent. Have experienced at least one VOC within the 12 months prior to screening. Previous VOCs should include the occurrence of appropriate symptoms, visits to a medical facility and / or medical professional, and receipt of parenteral opioid or NSAID analgesia or oral opioids. If receiving hydroxyurea or hydroxycarbamide (HU / HC) or an erythropoietin-stimulating agent, patients must have been on treatment for at least 6 months prior to screening and on a plan to maintain the same dose and schedule throughout the study. The following laboratory values ​​must be met at screening: Absolute neutrophil count ≥ 1.0 × 10 9 / L Platelets ≥ 75 x 10 9 / L Hemoglobin (Hgb) ≥ 4.0 g / dL Glomerular filtration rate using the CKD-EPI formula ≥ 45 mL / min / 1.73 m 2 Direct (conjugated) bilirubin ≦2.0 × ULN Alanine transaminase (ALT) ≦3.0 × ULN INR ≥ 2.0 ·ECOG activity status ≦2

[0215] Exclusion criteria: · History of stem cell transplant. - Acute VOC has ended within 7 days prior to the first day of medication. - Received any blood products within 30 days from the first day of medication. Uncontrolled liver or kidney disease, colitis, or inflammatory bowel disease. Prior to screening, had received active treatment in another investigational trial or had received penicillin prophylaxis or antibiotics for the treatment of an infection within 30 days or 5 half-lives of treatment, whichever is longer. ·A significant medical condition requiring hospitalization (other than SCD with VOC) within 2 months prior to screening. Participating in a chronic transfusion program (a pre-planned series of transfusions for preventive purposes). Exchange transfusions are scheduled for the duration of the study; intermittent transfusions are permitted in response to worsening anemia or VOCs. Hypersensitivity to rifaximin, rifampin, rifamycin antimicrobial agents, or any component of the rifaximin composition. Use of therapeutic anticoagulation (at permitted prophylactic doses) or antiplatelet therapy (other than aspirin or NSAIDs) within 10 days prior to Day 1 of dosing. Pregnant or breastfeeding women. · Women of childbearing potential, defined as all women who are physiologically capable of becoming pregnant unless they have a negative serum pregnancy test at screening and consent to standard prophylaxis. · A history of substance abuse, either substantiated or in the opinion of the investigator. ·Requirements for the use of any medicines on the prohibited medicines list (CYP3A4 inhibitors / inducers, PPIs, PgP bases). Any prior gastrointestinal surgery that alters the anatomy of the esophagus, stomach, or small / large intestine (exceptions include appendectomy, cholecystectomy, and fundoplication). Colonoscopy or sigmoidoscopy, or any other use of bowel prep, laxatives, or enemas within 30 days prior to Day 1, or plans to undergo such procedures during the study. Any documented history of clinical stroke or intracranial hemorrhage, or unexplored neurological findings, within 12 months prior to screening. Silent infarctions present only on imaging are allowed. Patients with bleeding disorders. -Patients who are scheduled to undergo major surgery during this study ·HIV positivity or other concurrent immunodeficiency. Active hepatitis B infection (HBsAg positive). Prior infection, but inactive (i.e., anti-HBc positive, HBsAg and HBV-DNA negative) is also considered. Hepatitis C (HCV RNA) positivity. Prior infection that resolves spontaneously or persistently (i.e., HCV RNA is undetectable) after antiviral treatment for ≥ 6 months (with IFN-free treatment) or ≥ 12 months (with the use of IFN treatment) after cessation of antiviral drugs is considered. Malignant disease. Exceptions include malignancies that have been curatively treated and have not recurred within 2 years prior to study treatment, completely excised basal cell and squamous cell skin cancers, and any completely excised carcinoma in situ. Serious mental or physical illness that, in the opinion of the investigator, may compromise participation in this study. Any condition that, in the opinion of the investigator, may interfere with the successful collection of measurements required for this study. Resting QTcF ≥ 470 msec at screening. Cardiac abnormalities or cardiac repolarization abnormalities, including any of the following: History of myocardial infarction (MI), angina, coronary artery bypass graft (CABG), or uncontrolled congestive heart failure within 6 months prior to Day 1. Clinically significant arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-degree atrioventricular block (e.g., bifascicular block, Mobitz type II, and third-degree atrioventricular block). Family history of long QT syndrome, idiopathic sudden death, or congenital long QT syndrome, or any of the following: Risk factors for torsades de pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, a history of heart failure, or a history of clinically significant / symptomatic bradycardia. • Concomitant medications with a known risk of TdP that cannot be discontinued or replaced by a safe alternative (within 5 half-lives before starting the study drug). ●QTcF interval cannot be determined. · Inability to understand or follow test instructions and requirements. For subjects in the intensive PK group, subjects with hepatic impairment (pediatric - Pugh class A, B, or C) should be excluded.

[0216] Subject evaluation Efficacy assessments performed include: Number of VOCs during treatment and their history in the 12 months prior to treatment. Crises identified by the investigator will be adjudicated in a blinded manner by an independent crisis-review committee. Number of VOCs by treatment subcategory (uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, priapism) and their history in the 12 months prior to treatment. Crises identified by the investigator will be adjudicated in a blinded manner by an independent crisis review committee. Number of SCD-related hospitalizations and ER visits during treatment and their history in the 12 months prior to treatment. Dates and durations for each start and stop of IOA use in the VOC. Duration of hospitalization during each VOC, date / duration of first use of IOA, and date / duration of discharge preparation. Cumulative consumption of IOA in each VOC during treatment and its history during the 12 months prior to treatment. · Cumulative duration of IOA use in each VOC.

[0217] Safety and tolerability assessments include AEs, vital signs, clinical laboratory values, and ECGs.

[0218] Other evaluations include: Pre-treatment Functional Analysis of Non-Life-Threatening Conditions (FANLTC) questionnaire at Day 1, Day 29, Month 3, and Month 6 Fecal samples for microbiome profiling during the day 29 and 6-month screening windows.

[0219] PK assessment is presented as follows: For intensive PK subjects (Days 1 and 29): Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 12 hours post-dose (the 12 hour time point should be prior to the second dose). For all other scheduled visits, pre-dose and up to three additional post-dose samples (as determined by the pharmacometrician (TBD)). For subjects with sparse sampling: Pre-dose and up to three additional post-dose samples (as determined by the pharmacometrist) at Days 1, 8, 15, 29, 3 months, and 6 months. · For all subjects: If possible, during a visit to a health care facility for VOCs by estimated time of last dose. A medication diary was kept with the time of the dose recorded.

[0220] PD assessment is indicated as follows: Pre-dose, Day 1, Day 8, Day 15, Day 29, Month 3, and Month 6 visits, and during visits to the healthcare facility for VOCs, if available Neutrophil markers: total neutrophils (count and WBC%), CAN (count and neutrophil%), serum CD62L. ○Intestinal permeability markers: zonulin, serum citrulline, iFABP. ○Intestinal bacterial markers: LPS, urinary 3-indoxyl sulfate.

[0221] Data analysis The primary efficacy endpoint is the annualized rate of VOCs, calculated as follows: total number of adjudicated VOCs × 365 ÷ (end date - randomization date + 1), where end date is defined as the date of the last dose + 14 days. Differences in annual VOC rates for each rifaximin group versus placebo group will be analyzed with a Wilcoxon rank-sum test stratified by the use of a categorized history of crises in the previous year (<5; >=5 POV).

[0222] Changes from baseline in rate of VOC, days with IOA, SCD-related hospitalization and ER events and duration will be summarized by treatment and compared to placebo.

[0223] The time from first use of an IOA during each VOC to preparation for discharge and the time to discontinuation of IOA use during the VOC are summarized by treatment group using descriptive statistics and presented as Kaplan-Meier plots.

[0224] Cumulative use of IOA consumption during VOC will be summarized by treatment group using descriptive statistics and compared to placebo.

[0225] AEs summarized by MedDRA System Organ Class (SOC) and Preferred Term (PT) and reported by relationship to treatment group and treatment. Observed and change from baseline in vital signs, laboratory, and ECG parameters (RR, PR, QTcF, QRS).

[0226] PK will be evaluated in a population of subjects using non-compartmental analysis. A population PK model will be developed using data from all subjects providing quantifiable samples post-dose. C values ​​will be measured for all subjects at Days 8, 15, and 29. trough Measurements can be used to assess steady state and can be simulated using population PK models.

[0227] PD endpoints will be summarized by treatment using substance volume at each visit and change from baseline.

[0228] The association between rifaximin PK parameters and each PD endpoint will be assessed using ANOVA models. Population PK / PD models can be developed as separate analyses if warranted.

[0229] Changes from baseline in FANLTC questionnaire scores will be summarized by treatment and compared to placebo.

[0230] Changes from baseline in gut microbiome composition can be summarized by treatment and compared to placebo.

[0231] [Example 8] A proposed phase 1b randomized, double-blind, placebo-controlled study to characterize the pharmacokinetics and pharmacodynamics of a novel formulation of rifaximin in patients with sickle cell disease The goals of this study were to characterize the pharmacokinetic properties of rifaximin ER and DER in subjects with sickle cell disease (SCD), evaluate the safety and tolerability of rifaximin ER and DER, and assess the response to treatment of pharmacodynamic markers associated with VOCs, including total neutrophils, CAN, serum CD62L, the intestinal permeability biomarker iFABP, and the gut bacterial biomarker urinary 3-indoxyl sulfate.

[0232] Subjects will be enrolled and randomized 2:2:1:2:2:1 to one of the following six parallel dosing arms and will receive oral treatment twice daily (BID) for approximately 29 days: Group 1: 40 mg rifaximin ER, BID Group 2: 40 mg rifaximin DER, BID Group 3: Placebo with 40 mg rifaximin, BID Group 4: 80 mg rifaximin ER, BID Group 5: 80 mg rifaximin DER, BID Group 6: Placebo with 80 mg rifaximin, BID

[0233] The above-mentioned dosing arms cited herein can be designated as follows: 40 mg rifaximin ER, BID (can be provided as one 40 mg rifaximin ER capsule BID or two 20 mg rifaximin ER capsules BID); 40 mg rifaximin DER, BID (can be provided as one 40 mg rifaximin DER capsule BID or two 20 mg rifaximin DER capsules BID); 80 mg rifaximin ER, twice daily (alternatively, it can be provided as one 80 mg rifaximin ER capsule twice daily, four 20 mg rifaximin ER capsules twice daily, or two 40 mg rifaximin ER capsules twice daily); and 80 mg rifaximin DER, twice daily (alternatively, it can be provided as one 80 mg rifaximin DER capsule twice daily, four 20 mg rifaximin DER capsules twice daily, or two 40 mg rifaximin DER capsules twice daily).

[0234] The rifaximin ER capsules for use in this study can be described as a controlled-release solid oral dosage form for oral administration designed to deliver rifaximin to the proximal small intestine. The formulation contains drug and polymer-layered beads in a hard gelatin capsule (bovine and / or porcine). The drug product contains 20 mg of the active ingredient, rifaximin, and the following inactive ingredients: sucrose, gelatin, hypromellose, povidone, poloxamer 407, diethyl phthalate, titanium dioxide, and iron oxide.

[0235] The rifaximin DER capsules used in this study can be described as a controlled-release solid oral dosage form designed to target delivery of rifaximin to the mid-small intestine. The formulation contains drug and polymer-layered beads with an enteric coating in a hard gelatin capsule (bovine and / or porcine). The drug product contains 20 mg of the active ingredient, rifaximin, and the following inactive ingredients: sucrose, gelatin, hypromellose acetate succinate, methacrylic acid and ethyl acrylate copolymer, poloxamer 407, glycerol monostearate, triethyl citrate, diethyl phthalate, polysorbate 80, titanium dioxide, and iron oxide.

[0236] The target population included men and non-pregnant, non-lactating women aged 18-70 years with SCD and at least two VOCs in the past 12 months.

[0237] Subject participation will be for up to 9 weeks, including a 21-day screening period, a 4-week treatment period, and a 2-week follow-up. Outcomes will be assessed.

[0238] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated by reference in their entirety.

[0239] Further embodiments Embodiment 1. A rifaximin delivery composition for use in a unit dosage form comprising a plurality of first targeted-release rifaximin beads and a plurality of second targeted-release rifaximin beads, wherein the first targeted-release rifaximin beads comprise sugar spheres coated with a combination comprising rifaximin, HPMC, and PVP; and the second targeted-release rifaximin beads comprise sugar spheres coated with a combination comprising rifaximin and HPMC-AS, wherein the first and second targeted-release rifaximin beads are configured to release rifaximin at different locations in the gastrointestinal tract of a subject.

[0240] Embodiment 2. The rifaximin delivery composition of embodiment 1, further comprising a surfactant.

[0241] Embodiment 3. The rifaximin delivery composition of embodiment 1 or 2, further comprising a non-ionic surfactant.

[0242] Embodiment 4. A rifaximin delivery composition according to any one of embodiments 1 to 3, further comprising poloxamer 407.

[0243] Embodiment 5. The rifaximin delivery composition of any one of embodiments 1 to 4, further comprising at least one pharmaceutically acceptable plasticizer and / or at least one agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid.

[0244] Embodiment 6. The rifaximin delivery composition of embodiment 5, wherein the at least one pharmaceutically acceptable plasticizer is selected from alkyl citrates and phthalates, or combinations thereof.

[0245] Embodiment 7. The rifaximin delivery composition of embodiment 5 or 6, wherein the at least one pharmaceutically acceptable plasticizer is selected from triethyl citrate (TEC), acetyltriethyl citrate (ATEC), tributyl citrate (TBC), acetyltributyl citrate (ATBC), trioctyl citrate (TOC), acetyltrioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryltrihexyl citrate (BTHC, o-butyryltrihexyl citrate), trimethyl citrate (TMC), diethyl phthalate, or dibutyl phthalate.

[0246] Embodiment 8. A rifaximin delivery composition according to any one of embodiments 5 to 7, wherein the at least one pharmaceutically acceptable plasticizer is selected from TEC and diethyl phthalate, or a combination thereof.

[0247] Embodiment 9. A rifaximin delivery composition according to any one of embodiments 5 to 8, wherein at least one pharmaceutically acceptable plasticizer is TEC.

[0248] Embodiment 10. A rifaximin delivery composition according to any one of embodiments 5 to 8, wherein the at least one pharmaceutically acceptable plasticizer is a combination of TEC and diethyl phthalate.

[0249] Embodiment 11. A rifaximin delivery composition according to any one of embodiments 1 to 10, further comprising an enteric coating.

[0250] Embodiment 12. A rifaximin delivery composition according to any one of embodiments 1 to 11, further comprising an enteric coating surrounding the sugar spheres coated with a combination comprising rifaximin and HPMC-AS of a second targeted release bead.

[0251] Embodiment 13. A rifaximin delivery composition according to embodiment 11 or 12, wherein the enteric coating comprises a methacrylic acid-acrylate copolymer.

[0252] Embodiment 14. A rifaximin delivery composition according to any one of embodiments 11 to 13, wherein the enteric coating comprises an anionic methacrylic acid-acrylate copolymer.

[0253] Embodiment 15. A rifaximin delivery composition according to any one of embodiments 11 to 14, wherein the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate.

[0254] Embodiment 16. A rifaximin delivery composition according to any one of embodiments 11 to 15, wherein the enteric coating further comprises a non-stick additive.

[0255] Embodiment 17. A rifaximin delivery composition according to any one of embodiments 1 to 16, wherein the rifaximin of the first targeted release bead combination is crystalline, non-crystalline, and / or amorphous.

[0256] Embodiment 18. A rifaximin delivery composition according to any one of embodiments 1 to 16, wherein the rifaximin of the second targeted release bead combination is crystalline, non-crystalline, and / or amorphous.

[0257] Embodiment 19. A rifaximin delivery composition according to any one of embodiments 1 to 18, wherein the first targeted release bead is configured to provide release in the upper gastrointestinal tract.

[0258] Embodiment 20. A rifaximin delivery composition according to any one of embodiments 1 to 19, wherein the first targeted release bead is configured to provide release in the initial part of the small intestine.

[0259] Embodiment 21. A rifaximin delivery composition according to any one of embodiments 1 to 20, wherein the second targeted release bead is configured to provide release in the mid-gastrointestinal tract.

[0260] Embodiment 22. A rifaximin composition for use in targeted release comprising sugar spheres coated with a combination comprising rifaximin, HPMC, and PVP.

[0261] Embodiment 23. A rifaximin composition according to embodiment 22, wherein HPMC is present in an amount of about 5% to about 15% by weight, based on the total weight of the rifaximin in the combination.

[0262] Embodiment 24. A rifaximin composition according to embodiment 22 or 23, wherein HPMC is present in an amount of about 6% to about 12% by weight, based on the total weight of the rifaximin in the combination.

[0263] Embodiment 25. A rifaximin composition according to any one of embodiments 22 to 24, wherein HPMC is present in an amount of about 6% to about 10% by weight, based on the total weight of the rifaximin in the combination.

[0264] Embodiment 26. A rifaximin composition according to any one of embodiments 22 to 25, wherein HPMC is present in an amount of about 6% to about 9% by weight, based on the total weight of the rifaximin in the combination.

[0265] Embodiment 27. A rifaximin composition according to any one of embodiments 22 to 26, wherein HPMC is present in an amount of about 0.1% to about 2.5% by weight, based on the total weight of the composition.

[0266] Embodiment 28. A rifaximin composition according to any one of embodiments 22 to 27, wherein HPMC is present in an amount of about 0.3% to about 2.3% by weight, based on the total weight of the composition.

[0267] Embodiment 29. A rifaximin composition according to any one of embodiments 22 to 28, wherein HPMC is present in an amount of about 0.3% to about 0.5% by weight or about 1.8% to about 2.0% by weight, based on the total weight of the composition.

[0268] Embodiment 30. A rifaximin composition according to any one of embodiments 22 to 29, wherein HPMC is present in an amount of about 0.4% to about 0.5% by weight or about 1.9% to about 2.0% by weight, based on the total weight of the composition.

[0269] Embodiment 31. A rifaximin composition according to any one of embodiments 22 to 30, wherein the PVP is present in an amount of about 15% to about 35% by weight, based on the total weight of the rifaximin in the combination.

[0270] Embodiment 32. A rifaximin composition according to any one of embodiments 22 to 31, wherein the PVP is present in an amount of about 15% to about 30% by weight, based on the total weight of the rifaximin in the combination.

[0271] Embodiment 33. A rifaximin composition according to any one of embodiments 22 to 32, wherein the PVP is present in an amount of about 20% to about 30% by weight, based on the total weight of the rifaximin in the combination.

[0272] Embodiment 34. A rifaximin composition according to any one of embodiments 22 to 33, wherein the PVP is present in an amount of from about 0.5% to about 4.0% by weight or from about 3.0% to about 8.0% by weight, based on the total weight of the composition.

[0273] Embodiment 35. A rifaximin composition according to any one of embodiments 22 to 34, wherein the PVP is present in an amount of from about 0.5% to about 2.0% by weight or from about 4.0% to about 7.0% by weight, based on the total weight of the composition.

[0274] Embodiment 36. A rifaximin composition according to any one of embodiments 22 to 35, wherein the PVP is present in an amount of about 0.1% by weight to about 2.0% by weight or about 5.0% by weight to about 6.0% by weight, based on the total weight of the composition.

[0275] Embodiment 37. A rifaximin composition according to any one of embodiments 22 to 36, wherein the combination further comprises a surfactant.

[0276] Embodiment 38. A rifaximin composition according to any one of embodiments 22 to 37, wherein the combination further comprises a non-ionic surfactant.

[0277] Embodiment 39. A rifaximin composition according to any one of embodiments 22 to 38, wherein the combination further comprises poloxamer 407.

[0278] Embodiment 40. The rifaximin composition of any one of embodiments 37 to 39, wherein the surfactant is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition.

[0279] Embodiment 41. A rifaximin composition according to any one of embodiments 37 to 40, wherein the surfactant is present in an amount of about 7% to about 9% by weight, based on the total weight of rifaximin in the composition.

[0280] Embodiment 42. A rifaximin composition according to any one of embodiments 37 to 41, wherein the surfactant is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the composition.

[0281] Embodiment 43. A rifaximin composition according to any one of embodiments 22 to 42, wherein the combination comprises crystalline, non-crystalline, and / or amorphous rifaximin.

[0282] Embodiment 44. The rifaximin composition of any one of embodiments 22 to 43, further comprising at least one plasticizer and / or at least one agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid.

[0283] Embodiment 45. The rifaximin composition of embodiment 44, wherein the at least one plasticizer is selected from diethyl phthalate and dibutyl phthalate.

[0284] Embodiment 46. A rifaximin composition according to embodiment 44 or 45, wherein at least one plasticizer is diethyl phthalate.

[0285] Embodiment 47. A rifaximin composition according to any one of embodiments 22 to 46, wherein the rifaximin is present in an amount of about 1% to about 30% by weight, based on the total weight of the composition.

[0286] Embodiment 48. A rifaximin composition according to any one of embodiments 22 to 47, wherein the rifaximin is present in an amount of about 1% to about 10% by weight, based on the total weight of the composition.

[0287] Embodiment 49. A rifaximin composition according to any one of embodiments 22 to 48, wherein the rifaximin is present in an amount of about 4% to about 6% by weight, based on the total weight of the composition.

[0288] Embodiment 50. A rifaximin composition according to any one of embodiments 22 to 47, wherein the rifaximin is present in an amount of about 15% to about 25% by weight, based on the total weight of the composition.

[0289] Embodiment 51. A rifaximin composition according to any one of embodiments 22 to 47 and 50, wherein the rifaximin is present in an amount of about 20% to about 23% by weight, based on the total weight of the composition.

[0290] Embodiment 52. A rifaximin composition according to any one of embodiments 22 to 51, which is a pH-independent release composition.

[0291] Embodiment 53. A rifaximin composition according to any one of embodiments 22 to 52, for release in the upper gastrointestinal tract.

[0292] Embodiment 54. A rifaximin composition according to any one of embodiments 22 to 53, for providing release in the initial part of the small intestine.

[0293] Embodiment 55. A rifaximin composition for use in targeted release comprising sugar spheres coated with a combination comprising rifaximin and HPMC-AS.

[0294] Embodiment 56. A rifaximin composition according to embodiment 55, wherein the HPMC-AS is grade M.

[0295] Embodiment 57. A rifaximin composition according to embodiment 55 or 56, wherein the HPMC-AS is present in an amount of about 20% to about 60% by weight, based on the total weight of rifaximin in the mixture.

[0296] Embodiment 58. A rifaximin composition according to any one of embodiments 55 to 57, wherein the HPMC-AS is present in an amount of about 25% to about 50% by weight, based on the total weight of rifaximin in the mixture.

[0297] Embodiment 59. A rifaximin composition according to any one of embodiments 55 to 58, wherein the HPMC-AS is present in an amount of about 30% to about 47% by weight, based on the total weight of rifaximin in the mixture.

[0298] Embodiment 60. A rifaximin composition according to any one of embodiments 55 to 59, wherein the HPMC-AS is present in an amount of about 30% to about 45% by weight, based on the total weight of rifaximin in the mixture.

[0299] Embodiment 61. A rifaximin composition according to any one of embodiments 55 to 60, wherein the HPMC-AS is present in an amount of from about 1% to about 4% by weight or from about 8% to about 11% by weight, based on the total weight of the composition.

[0300] Embodiment 62. A rifaximin composition according to any one of embodiments 55 to 61, wherein the HPMC-AS is present in an amount of about 1% to about 3% by weight, or about 8% to about 10% by weight, based on the total weight of the composition.

[0301] Embodiment 63. A rifaximin composition according to any one of embodiments 55 to 62, wherein the HPMC-AS is present in an amount of about 2% by weight to about 3% by weight or about 9% by weight to about 10% by weight, based on the total weight of the composition.

[0302] Embodiment 64. A rifaximin composition according to any one of embodiments 55 to 63, wherein the combination further comprises a surfactant.

[0303] Embodiment 65. A rifaximin composition according to any one of embodiments 55 to 64, wherein the combination further comprises a non-ionic surfactant.

[0304] Embodiment 66. A rifaximin composition according to any one of embodiments 55 to 65, wherein the combination further comprises poloxamer 407.

[0305] Embodiment 67. A rifaximin composition according to any one of embodiments 55 to 66, wherein the surfactant is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition.

[0306] Embodiment 68. A rifaximin composition according to any one of embodiments 55 to 67, wherein the surfactant is present in an amount of about 7% to about 9% by weight, based on the total weight of rifaximin in the composition.

[0307] Embodiment 69. A rifaximin composition according to any one of embodiments 55 to 68, wherein the surfactant is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the composition.

[0308] Embodiment 70. The rifaximin composition of any one of embodiments 52 to 69, further comprising at least one pharmaceutically acceptable plasticizer and / or at least one agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid.

[0309] Embodiment 71. A rifaximin composition according to embodiment 70, wherein the at least one pharmaceutically acceptable plasticizer is selected from alkyl citrates and phthalates, or a combination thereof.

[0310] Embodiment 72. A rifaximin composition according to embodiment 70 or 71, wherein the at least one pharmaceutically acceptable plasticizer is selected from triethyl citrate (TEC), acetyltriethyl citrate (ATEC), tributyl citrate (TBC), acetyltributyl citrate (ATBC), trioctyl citrate (TOC), acetyltrioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryltrihexyl citrate (BTHC, o-butyryltrihexyl citrate), trimethyl citrate (TMC), diethyl phthalate, or dibutyl phthalate.

[0311] Embodiment 73. A rifaximin composition according to any one of embodiments 70 to 72, wherein the at least one pharmaceutically acceptable plasticizer is selected from TEC, diethyl phthalate, diethyl phthalate, or a combination thereof.

[0312] Embodiment 74. A rifaximin composition according to any one of embodiments 70 to 73, wherein the at least one pharmaceutically acceptable plasticizer is selected from TEC and diethyl phthalate, or a combination thereof.

[0313] Embodiment 75. A rifaximin composition according to any one of embodiments 70 to 74, wherein at least one pharmaceutically acceptable plasticizer is TEC.

[0314] Embodiment 76. A rifaximin composition according to any one of embodiments 70 to 74, wherein the at least one pharmaceutically acceptable plasticizer is a combination of TEC and diethyl phthalate.

[0315] Embodiment 77. A rifaximin composition according to any one of embodiments 55 to 76, further comprising an enteric coating.

[0316] Embodiment 78. A rifaximin composition according to any one of embodiments 55 to 77, further comprising an enteric coating around the combination and sugar spheres.

[0317] Embodiment 79. A rifaximin composition according to embodiment 77 or 78, wherein the enteric coating comprises a methacrylic acid-acrylate copolymer.

[0318] Embodiment 80. A rifaximin composition according to any one of embodiments 77 to 79, wherein the enteric coating comprises an anionic methacrylic acid-acrylate copolymer.

[0319] Embodiment 81. A rifaximin composition according to any one of embodiments 77 to 80, wherein the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate.

[0320] Embodiment 82. A rifaximin composition according to any one of embodiments 77 to 81, wherein the enteric coating further comprises a non-stick additive.

[0321] Embodiment 83. A rifaximin composition according to any one of embodiments 55 to 82, wherein the rifaximin is present in an amount of about 1% to about 30% by weight, based on the total weight of the composition.

[0322] Embodiment 84. A rifaximin composition according to any one of embodiments 55 to 83, wherein the rifaximin is present in an amount of about 1% to about 10% by weight, based on the total weight of the composition.

[0323] Embodiment 85. A rifaximin composition according to any one of embodiments 55 to 84, wherein the rifaximin is present in an amount of about 4% to about 6% by weight, based on the total weight of the composition.

[0324] Embodiment 86. A rifaximin composition according to any one of embodiments 55 to 83, wherein the rifaximin is present in an amount of about 15% to about 25% by weight, based on the total weight of the composition.

[0325] Embodiment 87. A rifaximin composition according to any one of embodiments 55 to 83 and 86, wherein the rifaximin is present in an amount of about 20% to about 23% by weight, based on the total weight of the composition.

[0326] Embodiment 88. A rifaximin composition according to any one of embodiments 55 to 87, which is a pH-dependent release composition.

[0327] Embodiment 89. A rifaximin targeted release composition according to any one of embodiments 55 to 88, for providing release in the mid-gastrointestinal tract.

[0328] Embodiment 90. A composition as described herein, particularly a composition as described in any one of claims 1 to 148 or any one of embodiments 1 to 89, for use in a method for treating one or more disorders in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition to the subject.

[0329] Embodiment 91. The composition of embodiment 90, wherein the one or more disorders are selected from irritable bowel syndrome (IBS), diarrhea, microbial-associated diarrhea, infectious diarrhea, Clostridium difficile infection and symptoms, traveler's diarrhea, small intestinal bacterial overgrowth (SIBO), Crohn's disease, sickle cell disease, diverticular disease, pancreatitis, pancreatic insufficiency, enteritis, colitis, antibiotic-associated colitis, hepatic encephalopathy, gastric dyspepsia, cirrhosis, polycystic liver disease, pouchitis, peritonitis, short bowel syndrome, inflammatory bowel disease, rosacea, and H. pylori infection.

[0330] Embodiment 92. The composition of embodiment 90, wherein the one or more disorders are selected from Parkinson's disease, Alzheimer's disease, autism, and acute myeloid leukemia.

[0331] Embodiment 93. The composition of embodiment 90, wherein the one or more disorders are selected from Clostridium difficile-associated diarrhea, chronic pancreatitis, ulcerative colitis, antibiotic-associated colitis, microscopic colitis, and alcoholic cirrhosis.

[0332] Embodiment 94. The composition of embodiment 90, wherein the one or more disorders is atherosclerotic cardiovascular disease.

[0333] Embodiment 95. The composition of embodiment 90, wherein the one or more disorders is sickle cell disease.

[0334] Embodiment 96. A composition as described herein, particularly a composition as described in any one of claims 1 to 148 or any one of embodiments 1 to 89, for use in a method of treating sickle cell disease (SCD) in a patient in need thereof, the method comprising administering to the patient an amount of the composition.

[0335] Embodiment 97. A composition as described herein, particularly a composition as described in any one of claims 1 to 148 or any one of embodiments 1 to 89, for use in a method for reducing elevated levels of circulating senescent neutrophils (CANs) in a patient in need thereof, the method comprising administering to the patient an amount of the composition.

[0336] Embodiment 98. A composition as described herein, particularly a composition as described in any one of claims 1 to 148 or any one of embodiments 1 to 89, for use in a method of treating vaso-occlusive crises (VOCs) in a patient in need thereof, the method comprising administering to the patient an amount of the composition.

[0337] Embodiment 99. The composition for use of any one of embodiments 96 to 98, further comprising administering to the patient an additional SCD therapeutic agent.

[0338] Embodiment 100. The composition for use of embodiment 99, wherein the additional SCD therapeutic comprises hydroxyurea, L-glutamine, hydroxycarbamide, an erythropoietin stimulator, an opioid analgesic, or a combination thereof.

[0339] Embodiment 101. A composition for use according to embodiment 100, wherein the opioid analgesic comprises morphine, codeine, hydrocodone, hydromorphone, methadone, tramadol, oxycodone, tapentadol, fentanyl, or a combination thereof.

[0340] Embodiment 102. A composition for use according to any one of embodiments 98 to 101, wherein the method of treating vaso-occlusive crises (VOCs) in a patient in need thereof comprises alleviating one or more symptoms of VOCs in the patient.

[0341] Embodiment 103. A composition for use according to any one of embodiments 98 to 101, wherein the method of treating vaso-occlusive crises (VOCs) in a patient in need thereof comprises reducing or preventing the occurrence of VOCs in the patient.

[0342] Embodiment 104. A composition for use according to any one of embodiments 98 to 101, wherein the method of treating vaso-occlusive crises (VOCs) in a patient in need thereof comprises reducing the duration or severity of VOCs in the patient.

[0343] Embodiment 105. A composition for use according to any one of embodiments 98 to 101, wherein the method of treating vaso-occlusive crises (VOCs) in a patient in need thereof comprises mediating or otherwise reducing the patient's opioid utilization during VOCs.

[0344] Embodiment 106. A composition for use according to any one of embodiments 96 to 101, wherein the step of administering to the patient an amount of a composition described herein, in particular an amount of a composition described in any one of claims 1 to 148 or any one of embodiments 1 to 89, comprises administering a dose of the composition to the patient once a day, twice a day, three times a day, or four times a day.

[0345] Embodiment 107. A composition for use according to any one of embodiments 96 to 101, wherein the step of administering to the patient an amount of a composition described herein, in particular an amount of a composition described in any one of claims 1 to 148 or any one of embodiments 1 to 89, comprises administering a dose of the composition to the patient twice daily.

[0346] Embodiment 108. A composition for use according to any one of embodiments 96 to 101, wherein the step of administering to the patient an amount of a composition described herein, in particular an amount of a composition described in any one of claims 1 to 148 or any one of embodiments 1 to 89, comprises administering a dose of the composition to the patient twice daily, wherein the dose comprises about 20, 40, 60, or 80 mg of rifaximin.

[0347] Embodiment 109. A composition for use according to any one of embodiments 96 to 101, wherein the step of administering to the patient an amount of a composition described herein, in particular an amount of a composition described in any one of claims 1 to 148 or any one of embodiments 1 to 89, comprises administering about 20, 40, 60, or 80 mg of rifaximin provided in an ER bead formulation.

[0348] Embodiment 110. A composition for use according to any one of embodiments 96 to 101, wherein the step of administering to the patient an amount of a composition described herein, in particular an amount of a composition described in any one of claims 1 to 148 or any one of embodiments 1 to 89, comprises administering about 20, 40, 60, or 80 mg of rifaximin provided in a DER bead formulation.

[0349] Embodiment 111. A composition for use in targeted release to the upper, middle or lower gastrointestinal tract, in particular a composition as described herein, preferably a composition as described in any one of claims 1 to 148 or any one of embodiments 1 to 89, comprising sugar spheres encapsulated with a combination comprising a poorly soluble therapeutic compound layered with at least one pH-independent or pH-dependent polymer as defined herein, or both. Some embodiments are given below. Item 1 A rifaximin bead composition comprising a non-pareil bead base coated with rifaximin and at least one polymer. Section 2 Item 1. A rifaximin bead composition according to Item 1, wherein the non-pareil bead base is a sugar sphere or a cellulose bead. Section 3 Item 3. The rifaximin bead composition according to Item 1 or 2, wherein the non-pareil bead base is a sugar sphere. Section 4 4. The rifaximin bead composition of any one of paragraphs 1 to 3, wherein at least one polymer is selected from a first pH-independent polymer, a second pH-independent polymer, and a pH-dependent polymer. Section 5 5. The rifaximin bead composition of any one of paragraphs 1 to 4, wherein at least one polymer is selected from a first pH-independent polymer and a second pH-independent polymer. Section 6 Item 6. The rifaximin bead composition according to item 4 or 5, wherein the first pH-independent polymer is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition. Section 7 7. The rifaximin bead composition of any one of paragraphs 4 to 6, wherein the first pH-independent polymer is present in an amount of about 6% to about 12% by weight, based on the total weight of rifaximin in the composition. Item 8 8. The rifaximin bead composition of any one of paragraphs 4 to 7, wherein the first pH-independent polymer is present in an amount of about 6% to about 10% by weight, based on the total weight of rifaximin in the composition. Section 9 9. The rifaximin bead composition of any one of paragraphs 4 to 8, wherein the first pH-independent polymer is present in an amount of about 6% to about 9% by weight, based on the total weight of rifaximin in the composition. Section 10 10. The rifaximin bead composition of any one of paragraphs 4 to 9, wherein the first pH-independent polymer is present in an amount of about 0.1% by weight to about 2.5% by weight, based on the total weight of the composition. Section 11 11. The rifaximin bead composition of any one of paragraphs 4 to 10, wherein the first pH-independent polymer is present in an amount of about 0.3% to about 2.3% by weight, based on the total weight of the composition. Item 12 12. The rifaximin bead composition according to any one of paragraphs 4 to 11, wherein the first pH-independent polymer is present in an amount of about 0.3% to about 0.5% by weight or about 1.8% to about 2.0% by weight, based on the total weight of the composition. Section 13 13. The rifaximin bead composition of any one of paragraphs 4 to 12, wherein the first pH-independent polymer is present in an amount of about 0.4% to about 0.5% by weight or about 1.9% to about 2.0% by weight, based on the total weight of the composition. Section 14 14. The rifaximin bead composition of any one of paragraphs 4 to 13, wherein the second pH-independent polymer is present in an amount of about 15% to about 35% by weight, based on the total weight of rifaximin in the composition. Section 15 15. The rifaximin bead composition of any one of paragraphs 4 to 14, wherein the second pH-independent polymer is present in an amount of about 15% to about 30% by weight, based on the total weight of rifaximin in the composition. Section 16 16. The rifaximin bead composition of any one of paragraphs 4 to 15, wherein the second pH-independent polymer is present in an amount of about 20% to about 30% by weight, based on the total weight of rifaximin in the composition. Section 17 17. The rifaximin bead composition of any one of paragraphs 4 to 16, wherein the second pH-independent polymer is present in an amount of about 0.5% to about 4.0% by weight or about 3.0% to about 8.0% by weight, based on the total weight of the composition. Section 18 18. The rifaximin bead composition of any one of paragraphs 4 to 17, wherein the second pH-independent polymer is present in an amount of about 0.5% to about 2.0% by weight or about 4.0% to about 7.0% by weight, based on the total weight of the composition. Section 19 19. The rifaximin bead composition of any one of paragraphs 4 to 18, wherein the second pH-independent polymer is present in an amount of about 0.1% to about 2.0% by weight or about 5.0% to about 6.0% by weight, based on the total weight of the composition. Section 20 20. The rifaximin bead composition of any one of paragraphs 4 to 19, wherein the first and second pH-independent polymers are selected from hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), hydroxyethyl cellulose (HEC), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid (PAA), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, and divinyl ether maleic anhydride copolymer (DIVEMA). Section 21 21. The rifaximin bead composition of any one of paragraphs 4 to 13 and 20, wherein the first pH-independent polymer is HPMC. Section 22 21. The rifaximin bead composition of any one of paragraphs 4, 5, and 15 to 20, wherein the second pH-independent polymer is PVP. Section 23 5. The rifaximin bead composition of any one of paragraphs 1 to 4, wherein at least one polymer is a pH-dependent polymer. Section 24 Item 24. The rifaximin bead composition according to item 4 or 23, wherein the pH-dependent polymer is present in an amount of about 20% to about 60% by weight, based on the total weight of rifaximin in the composition. Section 25 25. The rifaximin bead composition of any one of paragraphs 4, 23, and 24, wherein the pH-dependent polymer is present in an amount of about 20% to about 50% by weight, based on the total weight of rifaximin in the composition. Section 26 26. A rifaximin bead composition according to any one of paragraphs 4 and 23 to 25, wherein the pH-dependent polymer is present in an amount of about 25% to about 45% by weight or about 43% to about 47% by weight, based on the total weight of rifaximin in the composition. Section 27 27. A rifaximin bead composition according to any one of paragraphs 4 and 23 to 26, wherein the pH-dependent polymer is present in an amount of about 30% to about 35% by weight or about 44% to about 45% by weight, based on the total weight of rifaximin in the composition. Section 28 28. The rifaximin bead composition of any one of paragraphs 4 and 23 to 27, wherein the pH-dependent polymer is present in an amount of about 1% to about 12% by weight, based on the total weight of rifaximin in the composition. Section 29 29. The rifaximin bead composition of any one of paragraphs 4 and 23 to 28, wherein the pH-dependent polymer is present in an amount of about 1% to about 4% by weight or about 8% to about 11% by weight, based on the total weight of the composition. Section 30 30. The rifaximin bead composition of any one of paragraphs 4 and 23 to 29, wherein the pH-dependent polymer is present in an amount of about 1% to about 3% by weight or about 8% to about 10% by weight, based on the total weight of the composition. Section 31 31. A rifaximin bead composition according to any one of paragraphs 4 and 23 to 30, wherein the pH-dependent polymer is present in an amount of about 2% by weight to about 3% by weight or about 9% by weight to about 10% by weight, based on the total weight of the composition. Section 32 32. The rifaximin bead composition of any one of paragraphs 4 and 23 to 31, wherein the pH-dependent polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose acetate phthalate (HPMC-P), cellulose acetate phthalate (CAP), and cellulose acetate trimellitate (CAT). Item 33 33. The rifaximin bead composition of any one of paragraphs 4 and 23 to 32, wherein at least one pH-dependent polymer is HPMC-AS. Section 34 34. The rifaximin bead composition of any one of paragraphs 4 and 23 to 33, wherein at least one pH-dependent polymer is HPMC-AS Grade M. Section 35 35. The rifaximin bead composition of any one of paragraphs 1 to 34, further comprising a surfactant. Section 36 36. The rifaximin bead composition of any one of paragraphs 1 to 35, further comprising a non-ionic surfactant. Section 37 37. The rifaximin bead composition of any one of paragraphs 1 to 36, further comprising poloxamer 407. Section 38 38. The rifaximin bead composition of any one of paragraphs 35 to 37, wherein the surfactant is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition. Section 39 39. The rifaximin bead composition of any one of paragraphs 35 to 38, wherein the surfactant is present in an amount of about 7% to about 9% by weight, based on the total weight of rifaximin in the composition. Section 40 40. The rifaximin bead composition of any one of paragraphs 35 to 39, wherein the surfactant is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the composition. Section 41 41. The rifaximin bead composition of any one of paragraphs 1 to 40, further comprising at least one pharmaceutically acceptable plasticizer and / or at least one agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid. Section 42 42. The rifaximin bead composition of claim 41, wherein the at least one pharmaceutically acceptable plasticizer is selected from alkyl citrates and phthalates, or a combination thereof. Section 43 43. The rifaximin bead composition according to paragraph 41 or 42, wherein the at least one pharmaceutically acceptable plasticizer is selected from triethyl citrate (TEC), acetyltriethyl citrate (ATEC), tributyl citrate (TBC), acetyltributyl citrate (ATBC), trioctyl citrate (TOC), acetyltrioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryltrihexyl citrate (BTHC, o-butyryltrihexyl citrate), trimethyl citrate (TMC), diethyl phthalate or dibutyl phthalate. Section 44 44. The rifaximin bead composition of any one of paragraphs 41 to 43, wherein the at least one pharmaceutically acceptable plasticizer is selected from TEC, diethyl phthalate, and dibutyl phthalate, or a combination thereof. Section 45 44. The rifaximin bead composition of any one of paragraphs 41 to 43, wherein the at least one pharmaceutically acceptable plasticizer is selected from TEC and diethyl phthalate, or a combination thereof. Section 46 46. ​​The rifaximin bead composition of any one of paragraphs 41 to 45, wherein at least one pharmaceutically acceptable plasticizer is TEC. Section 47 46. ​​The rifaximin bead composition of any one of paragraphs 41 to 45, wherein the at least one pharmaceutically acceptable plasticizer is a combination of TEC and diethyl phthalate. Section 48 48. The rifaximin bead composition of any one of paragraphs 1 to 47, further comprising an enteric coating. Section 49 49. A rifaximin bead composition according to paragraph 48, wherein an enteric coating surrounds the rifaximin-coated nonpareil bead base and at least one polymer. Section 50 50. The rifaximin bead composition of paragraph 48 or 49, wherein the enteric coating comprises a methacrylic acid-acrylate copolymer. Section 51 51. The rifaximin bead composition of any one of paragraphs 48 to 50, wherein the enteric coating comprises an anionic methacrylic acid-acrylate copolymer. Section 52 52. The rifaximin bead composition of any one of paragraphs 48 to 51, wherein the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate. Section 53 53. The rifaximin bead composition of any one of paragraphs 48 to 52, wherein the enteric coating further comprises a non-stick additive. Section 54 54. The rifaximin bead composition of any one of paragraphs 1 to 53, wherein the rifaximin is crystalline, non-crystalline, and / or amorphous. Section 55 55. The rifaximin bead composition of any one of paragraphs 1 to 54, wherein the rifaximin is present in an amount of about 1% to about 30% by weight, based on the total weight of the composition. Section 56 56. The rifaximin bead composition of any one of paragraphs 1 to 55, wherein the rifaximin is present in an amount of about 1% to about 10% by weight, based on the total weight of the composition. Section 57 57. The rifaximin bead composition of any one of paragraphs 1 to 56, wherein the rifaximin is present in an amount of about 4% to about 6% by weight, based on the total weight of the composition. Section 58 56. The rifaximin bead composition of any one of paragraphs 1 to 55, wherein the rifaximin is present in an amount of about 15% to about 25% by weight, based on the total weight of the composition. Section 59 59. The rifaximin bead composition of any one of paragraphs 1 to 55 and 58, wherein the rifaximin is present in an amount of about 20% to about 23% by weight, based on the total weight of the composition. Item 60 1. A rifaximin delivery composition in unit dosage form comprising a plurality of first targeted-release rifaximin beads and a plurality of second targeted-release rifaximin beads, the first targeted release rifaximin beads comprise sugar spheres coated with a combination comprising rifaximin, HPMC, and PVP; the second targeted release rifaximin beads comprise sugar spheres coated with a combination comprising rifaximin and HPMC-AS; wherein the first and second targeted-release rifaximin beads are configured to release rifaximin at different locations in the gastrointestinal tract of the subject. Section 61 61. The rifaximin delivery composition of claim 60, further comprising a surfactant. Section 62 62. The rifaximin delivery composition of claim 60 or 61, further comprising a non-ionic surfactant. Section 63 63. The rifaximin delivery composition of any one of paragraphs 60 to 62, further comprising poloxamer 407. Section 64 64. The rifaximin delivery composition of any one of paragraphs 60 to 63, further comprising at least one pharmaceutically acceptable plasticizer and / or at least one agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid. Section 65 65. The rifaximin delivery composition of paragraph 64, wherein the at least one pharmaceutically acceptable plasticizer is selected from alkyl citrates and phthalates, or a combination thereof. Section 66 66. The rifaximin delivery composition of claim 64 or 65, wherein the at least one pharmaceutically acceptable plasticizer is selected from triethyl citrate (TEC), acetyltriethyl citrate (ATEC), tributyl citrate (TBC), acetyltributyl citrate (ATBC), trioctyl citrate (TOC), acetyltrioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryltrihexyl citrate (BTHC, o-butyryltrihexyl citrate), trimethyl citrate (TMC), diethyl phthalate, or dibutyl phthalate. Section 67 67. The rifaximin delivery composition of any one of paragraphs 64 to 66, wherein the at least one pharmaceutically acceptable plasticizer is selected from TEC and diethyl phthalate, or a combination thereof. Section 68 68. The rifaximin delivery composition of any one of paragraphs 64 to 67, wherein at least one pharmaceutically acceptable plasticizer is TEC. Section 69 68. The rifaximin bead composition of any one of paragraphs 64 to 67, wherein at least one pharmaceutically acceptable plasticizer is a combination of TEC and diethyl phthalate. Section 70 70. The rifaximin delivery composition of any one of paragraphs 60 to 69, further comprising an enteric coating. Section 71 71. The rifaximin delivery composition of any one of paragraphs 60 to 70, further comprising an enteric coating surrounding the sugar spheres coated with a combination comprising rifaximin and HPMC-AS of the second targeted release bead. Section 72 72. The rifaximin delivery composition of paragraph 70 or 71, wherein the enteric coating comprises a methacrylic acid-acrylate copolymer. Section 73 73. The rifaximin delivery composition of any one of paragraphs 70 to 72, wherein the enteric coating comprises an anionic methacrylic acid-acrylate copolymer. Section 74 74. The rifaximin delivery composition of any one of paragraphs 70 to 73, wherein the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate. Section 75 75. The rifaximin delivery composition of any one of paragraphs 70 to 74, wherein the enteric coating further comprises a non-stick additive. Section 76 76. The rifaximin delivery composition of any one of paragraphs 60 to 75, wherein the rifaximin of the first targeted release bead combination is crystalline, non-crystalline, and / or amorphous. Section 77 76. The rifaximin delivery composition of any one of paragraphs 60 to 75, wherein the rifaximin of the second targeted release bead combination is crystalline, non-crystalline, and / or amorphous. Section 78 78. The rifaximin delivery composition of any one of paragraphs 60 to 77, wherein the first targeted release bead is configured to provide release in the upper gastrointestinal tract. Section 79 79. The rifaximin delivery composition of any one of paragraphs 60 to 78, wherein the first targeted release bead is configured to provide release in the initial part of the small intestine. Section 80 80. The rifaximin delivery composition of any one of paragraphs 60 to 79, wherein the second targeted release bead is configured to provide release in the mid-gastrointestinal tract. Section 81 A rifaximin targeted release composition comprising sugar spheres coated with a combination comprising rifaximin, HPMC, and PVP. Section 82 Item 82. The rifaximin targeted release composition of paragraph 81, wherein HPMC is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the combination. Section 83 83. The rifaximin targeted release composition of paragraph 81 or 82, wherein HPMC is present in an amount of about 6% to about 12% by weight, based on the total weight of rifaximin in the combination. Section 84 84. The rifaximin targeted release composition of any one of paragraphs 81 to 83, wherein HPMC is present in an amount of about 6% to about 10% by weight, based on the total weight of rifaximin in the combination. Section 85 85. The rifaximin targeted release composition of any one of paragraphs 81 to 84, wherein HPMC is present in an amount of about 6% to about 9% by weight, based on the total weight of rifaximin in the combination. Section 86 86. The rifaximin targeted release composition of any one of paragraphs 81 to 85, wherein HPMC is present in an amount of about 0.1% to about 2.5% by weight, based on the total weight of the composition. Section 87 87. The rifaximin targeted release composition of any one of paragraphs 81 to 86, wherein HPMC is present in an amount of about 0.3% to about 2.3% by weight, based on the total weight of the composition. Section 88 88. The rifaximin targeted release composition of any one of paragraphs 81 to 87, wherein HPMC is present in an amount of about 0.3% to about 0.5% by weight or about 1.8% to about 2.0% by weight, based on the total weight of the composition. Section 89 89. The rifaximin targeted release composition of any one of paragraphs 81 to 88, wherein HPMC is present in an amount of about 0.4% to about 0.5% by weight or about 1.9% to about 2.0% by weight, based on the total weight of the composition. Section 90 89. The rifaximin targeted release composition of any one of paragraphs 81 to 89, wherein the PVP is present in an amount of about 15% to about 35% by weight, based on the total weight of the rifaximin in the combination. Section 91 91. The rifaximin targeted release composition of any one of paragraphs 81 to 90, wherein the PVP is present in an amount of about 15% to about 30% by weight, based on the total weight of the rifaximin in the combination. Section 92 92. The rifaximin targeted release composition of any one of paragraphs 81 to 91, wherein the PVP is present in an amount of about 20% to about 30% by weight, based on the total weight of the rifaximin in the combination. Section 93 93. The rifaximin targeted release composition of any one of paragraphs 81 to 92, wherein the PVP is present in an amount of about 0.5% to about 4.0% by weight or about 3.0% to about 8.0% by weight, based on the total weight of the composition. Section 94 94. The rifaximin targeted release composition of any one of paragraphs 81 to 93, wherein the PVP is present in an amount of about 0.5% to about 2.0% by weight or about 4.0% to about 7.0% by weight, based on the total weight of the composition. Section 95 95. The rifaximin targeted release composition of any one of paragraphs 81 to 94, wherein the PVP is present in an amount of about 0.1% to about 2.0% by weight or about 5.0% to about 6.0% by weight, based on the total weight of the composition. Section 96 96. The rifaximin targeted release composition of any one of paragraphs 81 to 95, wherein the combination further comprises a surfactant. Section 97 97. The rifaximin targeted release composition of any one of paragraphs 81 to 96, wherein the combination further comprises a non-ionic surfactant. Section 98 98. The rifaximin targeted release composition of any one of paragraphs 81 to 97, wherein the combination further comprises poloxamer 407. Section 99 99. The rifaximin targeted release composition of any one of paragraphs 96 to 98, wherein the surfactant is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition. Item 100 99. The rifaximin targeted release composition of any one of paragraphs 96 to 99, wherein the surfactant is present in an amount of about 7% to about 9% by weight, based on the total weight of rifaximin in the composition. Section 101 101. The rifaximin targeted release composition of any one of paragraphs 96 to 100, wherein the surfactant is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the composition. Section 102 102. The rifaximin targeted release composition of any one of paragraphs 81 to 101, wherein the combination comprises crystalline, non-crystalline, and / or amorphous rifaximin. Section 103 103. The rifaximin targeted-release composition of any one of paragraphs 81 to 102, further comprising at least one plasticizer and / or at least one agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid. Section 104 Item 104. The rifaximin targeted release composition of paragraph 103, wherein the at least one plasticizer is selected from diethyl phthalate and dibutyl phthalate. Section 105 105. The rifaximin targeted release composition of paragraph 103 or 104, wherein at least one plasticizer is diethyl phthalate. Section 106 106. The rifaximin targeted release composition of any one of paragraphs 81 to 105, wherein the rifaximin is present in an amount of about 1% to about 30% by weight, based on the total weight of the composition. Section 107 107. The rifaximin targeted release composition of any one of paragraphs 81 to 106, wherein the rifaximin is present in an amount of about 1% to about 10% by weight, based on the total weight of the composition. Section 108 108. The rifaximin targeted release composition of any one of paragraphs 81 to 107, wherein the rifaximin is present in an amount of about 4% to about 6% by weight, based on the total weight of the composition. Section 109 107. The rifaximin targeted release composition of any one of paragraphs 81 to 106, wherein the rifaximin is present in an amount of about 15% to about 25% by weight, based on the total weight of the composition. Section 110 110. The rifaximin targeted release composition of any one of paragraphs 81 to 106 and 109, wherein the rifaximin is present in an amount of about 20% to about 23% by weight, based on the total weight of the composition. Section 111 111. The rifaximin targeted release composition of any one of paragraphs 81 to 110, which is a pH-independent release composition. Section 112 112. The rifaximin targeted release composition of any one of paragraphs 81 to 111, for providing release in the upper gastrointestinal tract. Section 113 113. The rifaximin targeted release composition of any one of paragraphs 81 to 112, for effecting release in the initial part of the small intestine. Section 114 A rifaximin targeted release composition comprising sugar spheres coated with a combination comprising rifaximin and HPMC-AS. Section 115 115. The rifaximin targeted release composition of clause 114, wherein the HPMC-AS is grade M. Section 116 116. The rifaximin targeted-release composition of paragraph 114 or 115, wherein the HPMC-AS is present in an amount of about 20% to about 60% by weight, based on the total weight of rifaximin in the mixture. Section 117 117. The rifaximin targeted-release composition of any one of paragraphs 114 to 116, wherein the HPMC-AS is present in an amount of about 25% to about 50% by weight, based on the total weight of rifaximin in the mixture. Section 118 118. The rifaximin targeted release composition of any one of paragraphs 114 to 117, wherein the HPMC-AS is present in an amount of about 30% to about 47% by weight, based on the total weight of rifaximin in the mixture. Section 119 119. The rifaximin targeted release composition of any one of paragraphs 114 to 118, wherein the HPMC-AS is present in an amount of about 30% to about 45% by weight, based on the total weight of rifaximin in the mixture. Section 120 120. The rifaximin targeted release composition of any one of paragraphs 114 to 119, wherein the HPMC-AS is present in an amount of about 1% to about 4% by weight or about 8% to about 11% by weight, based on the total weight of the composition. Section 121 121. The rifaximin targeted release composition of any one of paragraphs 114 to 120, wherein the HPMC-AS is present in an amount of about 1% to about 3% by weight or about 8% to about 10% by weight, based on the total weight of the composition. Section 122 122. The rifaximin targeted release composition of any one of paragraphs 114 to 121, wherein the HPMC-AS is present in an amount of about 2% to about 3% by weight or about 9% to about 10% by weight, based on the total weight of the composition. Section 123 123. The rifaximin targeted release composition of any one of paragraphs 114 to 122, wherein the combination further comprises a surfactant. Section 124 124. The rifaximin targeted release composition of any one of paragraphs 114 to 123, wherein the combination further comprises a non-ionic surfactant. Section 125 125. The rifaximin targeted release composition of any one of paragraphs 114 to 124, wherein the combination further comprises poloxamer 407. Section 126 126. The rifaximin targeted release composition of any one of paragraphs 114 to 125, wherein the surfactant is present in an amount of about 5% to about 15% by weight, based on the total weight of rifaximin in the composition. Section 127 127. The rifaximin targeted release composition of any one of paragraphs 114 to 126, wherein the surfactant is present in an amount of about 7% to about 9% by weight, based on the total weight of rifaximin in the composition. Section 128 128. The rifaximin targeted release composition of any one of paragraphs 114 to 127, wherein the surfactant is present in an amount of about 8% to about 9% by weight, based on the total weight of rifaximin in the composition. Section 129 129. The rifaximin targeted-release composition of any one of paragraphs 111 to 128, further comprising at least one pharmaceutically acceptable plasticizer and / or at least one agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid. Section 130 Item 130. The rifaximin targeted release composition of item 129, wherein the at least one pharmaceutically acceptable plasticizer is selected from alkyl citrates and phthalates, or a combination thereof. Section 131 131. The rifaximin targeted release composition according to paragraph 129 or 130, wherein the at least one pharmaceutically acceptable plasticizer is selected from triethyl citrate (TEC), acetyltriethyl citrate (ATEC), tributyl citrate (TBC), acetyltributyl citrate (ATBC), trioctyl citrate (TOC), acetyltrioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryltrihexyl citrate (BTHC, o-butyryltrihexyl citrate), trimethyl citrate (TMC), diethyl phthalate or dibutyl phthalate. Section 132 132. The rifaximin targeted release composition of any one of paragraphs 129 to 131, wherein the at least one pharmaceutically acceptable plasticizer is selected from TEC, diethyl phthalate, diethyl phthalate, or a combination thereof. Section 133 133. The rifaximin targeted release composition of any one of paragraphs 129 to 132, wherein the at least one pharmaceutically acceptable plasticizer is selected from TEC and diethyl phthalate, or a combination thereof. Section 134 134. The rifaximin targeted release composition of any one of paragraphs 129 to 133, wherein at least one pharmaceutically acceptable plasticizer is TEC. Section 135 134. The rifaximin targeted release composition of any one of paragraphs 129 to 133, wherein the at least one pharmaceutically acceptable plasticizer is a combination of TEC and diethyl phthalate. Section 136 136. The rifaximin targeted release composition of any one of paragraphs 114 to 135, further comprising an enteric coating. Section 137 137. The rifaximin targeted release composition of any one of paragraphs 114 to 136, further comprising an enteric coating around the combination and sugar spheres. Section 138 138. The rifaximin targeted release composition of paragraph 136 or 137, wherein the enteric coating comprises a methacrylic acid-acrylate copolymer. Section 139 139. The rifaximin targeted release composition of any one of paragraphs 136 to 138, wherein the enteric coating comprises an anionic methacrylic acid-acrylate copolymer. Section 140 140. The rifaximin targeted release composition of any one of paragraphs 136 to 139, wherein the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate. Section 141 141. The rifaximin targeted release composition of any one of paragraphs 136 to 140, wherein the enteric coating further comprises a non-stick additive. Section 142 142. The rifaximin targeted release composition of any one of paragraphs 114 to 141, wherein the rifaximin is present in an amount of about 1% to about 30% by weight, based on the total weight of the composition. Section 143 143. The rifaximin targeted release composition of any one of paragraphs 114 to 142, wherein the rifaximin is present in an amount of about 1% by weight to about 10% by weight, based on the total weight of the composition. Section 144 144. The rifaximin targeted release composition of any one of paragraphs 114 to 143, wherein the rifaximin is present in an amount of about 4% to about 6% by weight, based on the total weight of the composition. Section 145 143. The rifaximin targeted release composition of any one of paragraphs 114 to 142, wherein the rifaximin is present in an amount of about 15% to about 25% by weight, based on the total weight of the composition. Section 146 146. The rifaximin targeted release composition of any one of paragraphs 114 to 142 and 145, wherein the rifaximin is present in an amount of about 20% to about 23% by weight, based on the total weight of the composition. Section 147 147. The rifaximin targeted release composition of any one of paragraphs 114 to 146, which is a pH dependent release composition. Section 148 148. The rifaximin targeted release composition of any one of paragraphs 114 to 147, for providing release in the mid-gastrointestinal tract. Section 149 A method for treating one or more disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition described in any one of paragraphs 1 to 148. Section 150 150. The method of clause 149, wherein the one or more disorders are selected from irritable bowel syndrome (IBS), diarrhea, microbial-associated diarrhea, infectious diarrhea, Clostridium difficile infection and symptoms, traveler's diarrhea, small intestinal bacterial overgrowth (SIBO), Crohn's disease, sickle cell disease, diverticular disease, pancreatitis, pancreatic insufficiency, enteritis, colitis, antibiotic-associated colitis, hepatic encephalopathy, gastric dyspepsia, cirrhosis, polycystic liver disease, pouchitis, peritonitis, short bowel syndrome, inflammatory bowel disease, rosacea, and H. pylori infection. Section 151 150. The method of paragraph 149, wherein the one or more disorders is selected from Parkinson's disease, Alzheimer's disease, autism, and acute myeloid leukemia. Section 152 150. The method of clause 149, wherein the one or more disorders are selected from Clostridium difficile-associated diarrhea, chronic pancreatitis, ulcerative colitis, antibiotic-associated colitis, microscopic colitis, and alcoholic cirrhosis. Section 153 150. The method of paragraph 149, wherein the one or more disorders is atherosclerotic cardiovascular disease. Section 154 150. The method of paragraph 149, wherein the one or more disorders is sickle cell disease. Section 156 149. A method of treating sickle cell disease (SCD) in a patient in need thereof, comprising administering to the patient an amount of the composition of any one of paragraphs 1 to 148. Section 157 149. A method for reducing elevated levels of circulating senolytic neutrophils (CANs) in a patient in need thereof, comprising administering to the patient an amount of the composition of any one of paragraphs 1 to 148. Section 158 A method for treating vaso-occlusive crises (VOCs) in a patient in need thereof, comprising administering to the patient an amount of a composition described in any one of paragraphs 1 to 148. Section 159 159. The method of any one of paragraphs 156 to 158, further comprising administering to the patient an additional SCD therapeutic agent. Section 160 160. The method of paragraph 159, wherein the additional SCD therapeutic agent comprises hydroxyurea, L-glutamine, hydroxycarbamide, an erythropoietin stimulator, an opioid analgesic, or a combination thereof. Section 161 161. The method of paragraph 160, wherein the opioid analgesic comprises morphine, codeine, hydrocodone, hydromorphone, methadone, tramadol, oxycodone, tapentadol, fentanyl, or a combination thereof. Section 162 162. The method of any one of paragraphs 158 to 161, wherein the method of treating vaso-occlusive crises (VOCS) in a patient in need thereof comprises alleviating one or more symptoms of VOCS in the patient. Section 163 162. The method of any one of paragraphs 158 to 161, wherein the method of treating vaso-occlusive crises (VOCs) in a patient in need thereof comprises reducing or preventing the occurrence of VOCs in the patient. Section 164 162. The method of any one of paragraphs 158 to 161, wherein the method of treating vaso-occlusive crises (VOCs) in a patient in need thereof comprises reducing the duration or severity of VOCs in the patient. Section 165 162. The method of any one of paragraphs 158 to 161, wherein the method of treating vaso-occlusive crises (VOCs) in a patient in need thereof comprises mediating or otherwise reducing the patient's opioid utilization during VOCs. Section 166 162. The method of any one of clauses 156 to 161, wherein administering to the patient an amount of the composition of any one of clauses 1 to 148 comprises administering a composition dose to the patient once daily, twice daily, three times daily, or four times daily. Section 167 162. The method of any one of clauses 156 to 161, wherein administering to the patient an amount of the composition of any one of clauses 1 to 148 comprises administering a dose of the composition to the patient twice daily. Section 168 162. The method of any one of clauses 156 to 161, wherein administering to the patient an amount of the composition of any one of clauses 1 to 148 comprises administering a composition dose to the patient twice daily, wherein the dose comprises about 20, 40, 60, or 80 mg of rifaximin. Section 169 162. The method of any one of clauses 156 to 161, wherein administering to the patient an amount of the composition of any one of clauses 1 to 148 comprises administering approximately 20, 40, 60, or 80 mg of rifaximin provided in an ER bead formulation. Section 170 162. The method of any one of clauses 156 to 161, wherein administering to the patient an amount of the composition of any one of clauses 1 to 148 comprises administering approximately 20, 40, 60, or 80 mg of rifaximin provided in a DER bead formulation. Section 171 A composition for targeted release to the upper, middle, or lower gastrointestinal tract comprising sugar spheres encapsulated with a combination comprising a poorly soluble therapeutic compound layered with at least one pH-independent or pH-dependent polymer, or both, as defined above.

Claims

1. 1. A rifaximin targeted release composition comprising sugar spheres coated with a coating comprising rifaximin, hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP), HPMC, about 5% to about 15% by weight, about 6% to about 12% by weight, about 6% to about 10% by weight, or about 6% to about 9% by weight, based on the total weight of rifaximin in the composition; about 0.1 wt. % to about 2.5 wt. %, about 0.3 wt. % to about 2.3 wt. %, about 0.3 wt. % to about 0.5 wt. %, about 0.4 wt. % to about 0.5 wt. %, about 1.8 wt. % to about 2.0 wt. %, or about 1.9 wt. % to about 2.0 wt. %, based on the total weight of the composition is present in an amount of PVP, about 15% to about 35% by weight, about 15% to about 30% by weight, or about 20% to about 30% by weight, based on the total weight of rifaximin in the composition; or about 0.5% to about 4.0%, about 0.5% to about 2.0%, or about 0.1% to about 2.0% by weight, based on the total weight of the composition; or About 3.0% to about 8.0%, about 4.0% to about 7.0%, or about 5.0% to about 6.0% by weight, based on the total weight of the composition 10. The rifaximin targeted release composition, wherein the rifaximin targeted release composition is present in an amount of

2. A rifaximin targeted release composition as described in claim 1, further comprising a surfactant.

3. A rifaximin targeted release composition described in claim 1 or 2, further comprising a nonionic surfactant.

4. A rifaximin targeted release composition described in any one of claims 1 to 3, further comprising poloxamer 407.

5. 5. The rifaximin targeted release composition of claim 2, wherein the surfactant is present in an amount of about 5% to about 15% by weight, about 7% to about 9% by weight, or about 8% to about 9% by weight, based on the total weight of rifaximin in the composition.

6. A rifaximin targeted release composition described in any one of claims 1 to 5, comprising crystalline, non-crystalline, and / or amorphous rifaximin.

7. 7. The rifaximin targeted-release composition of any one of claims 1 to 6, further comprising at least one plasticizer and / or at least one agent selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, cysteine, potassium metabisulfite, propyl gallate, sodium thiosulfate, vitamin E (e.g., vitamin E TPGS), and 3,4-dihydroxybenzoic acid.

8. 8. The rifaximin targeted release composition of claim 7, wherein the at least one plasticizer is selected from diethyl phthalate and dibutyl phthalate, preferably the at least one plasticizer is diethyl phthalate.

9. 9. The rifaximin targeted-release composition of any one of claims 1 to 8, wherein the rifaximin is present in an amount of about 1% to about 30% by weight, about 1% to about 10% by weight, about 4% to about 6% by weight, about 15% to about 25% by weight, or about 20% to about 23% by weight, based on the total weight of the composition.

10. 10. The rifaximin targeted release composition of any one of claims 1 to 9, which is a pH-independent release composition.

11. 11. A rifaximin targeted release composition according to any one of claims 1 to 10, for providing release in the upper gastrointestinal tract.

12. 12. A rifaximin targeted release composition according to any one of claims 1 to 11, for providing release in the initial part of the small intestine.

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