Ridinilazole solid tablet dosage form

Abstract

The present invention relates to solid tablet oral dosage forms of 2,2'-di(pyridin-4-yl)-1H,1'H-5,5'-bibenzo[d]imidazole (2,2'-di-4-pyridinyl-6,6'-bi-1H-benzimidazole; 5,5'-bis[2-(4-pyridinyl)-1H-benzimidazole]; 2,2'-bis(4-pyridyl)-3H,3'H-5,5'-bibenzimidazole; or 2-pyridin-4-yl-6-(2-pyridin-4-yl-3H-benzimidazol-5-yl)-1H-benzimidazole), referred to herein by the INN name Ridinilazole, and pharma- ceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites, or prodrugs thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to UK Patent Application Publication No. 2100470.0, filed January 14, 2021, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to solid tablet oral dosage forms of 2,2'-di(pyridin-4-yl)-1H,1'H-5,5'-bibenzo[d]imidazole (sometimes known as 2,2'-di-4-pyridinyl-6,6'-bi-1H-benzimidazole, 5,5'-bis[2-(4-pyridinyl)-1H-benzimidazole], 2,2'-bis(4-pyridyl)-3H,3'H-5,5'-bibenzimidazole, or 2-pyridin-4-yl-6-(2-pyridin-4-yl-3H-benzimidazol-5-yl)-1H-benzimidazole), referred to herein by the INN name Ridinilazole, and pharma- ceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites, or prodrugs thereof. [Background technology]

[0003] 2. Background of the Invention Infection with Clostridioides difficile (formerly Clostridium difficile) (CDI) causes Clostridioides difficile-associated disease (CDAD). More than 450,000 cases of CDI occur annually in the United States, with more than 80,000 first recurrences and approximately 29,000 deaths. The most common precipitating factor is antibiotic use, which leads to loss of colonization resistance and potentially the establishment of a long-lasting, species-poor microbiota that is susceptible to pathogen invasion. Oral treatment with vancomycin and metronidazole is associated with a high CDI recurrence rate, possibly due to adverse effects on the resident colonic flora. Recurrences are costly in terms of both clinical burden and healthcare resource utilization. In one study, hospital readmission was required in approximately one-third of recurrent cases.

[0004] Presumably, both the biomass and composition of the microbiota at the gut-bacteria interface influence the C. difficile colonization niche. Although colonization resistance is associated with specific taxa, perhaps a different, yet diverse, microbiota community structure can confer protection. Consistent characteristics of CDI-susceptible communities are low diversity levels and reduced metabolic function, with reduced relative viability of members of the phyla Bacteroidetes and Firmicutes and increased that of Proteobacteria. Fecal microbiota transplantation (FMT) normalizes these characteristics and disrupts the CDI relapse cycle.

[0005] Overall, these data support a role for CDI agents in minimizing their effect on the resident microbiota to reduce the risk of relapse.

[0006] Ridinilazole (also known as SMT19969 and variously referred to in the literature as 2,2'-di(pyridin-4-yl)-1H,1'H-5,5'-bibenzo[d]imidazole or 5,5'-bis[2-(4-pyridinyl)-1H-benzimidazole]) is a narrow-spectrum, poorly absorbed, and potent antibacterial agent that targets C. difficile. Ridinilazole can be represented by the formula:

[0007] [ka]

[0008] In a recent phase 2 randomized controlled double-blind clinical trial comparing the efficacy of ridinilazole with vancomycin (Vickers et al. (2017) Lancet Infect Dis 17: 735-744), ridinilazole was associated with a significant reduction in disease recurrence rates (14.3% vs. 34.8%). Ridinilazole showed improved preservation of the human gut microbiota compared to vancomycin, which may contribute to the reduction in CDI recurrence observed in the phase 2 trial.

[0009] Ridinilazole is a BCS class IV orally administered locally acting (lower gut) GI antibiotic that exhibits minimal systemic exposure and very low solubility over physiologically relevant pH. BCS class IV drugs are known to present particular formulation challenges, especially for oral formulations (see e.g. Ghadi and Dand (2017) BCS class IV drugs: Highly notorious candidates for formulation development Journal of Controlled Release, 248: 71-95).

[0010] Existing clinical ridinilazole formulations include an aqueous suspension used in Phase 1 trials. Individual doses (2 mg-2000 mg) were prepared extemporaneously and administered within 24 hours. The drug substance (2 mg-2000 mg) was suspended in 30 ml of water for injection (WFI) with additional WFI given as a rinse. Prior to preparation of unit doses, the drug substance was deagglomerated in a pestle and mortar for organoleptic reasons. This formulation was successful in delivering the powdered drug substance through the gastrointestinal tract to the colon.

[0011] In a Phase 2 study, ridinilazole was formulated as an immediate release liquid-filled hard gelatin capsule with a strength of 200 mg. This dosage form also allowed for easy dispersion of the powdered drug substance in the stomach and delivery through the gastrointestinal tract to the colon. The ridinilazole capsules were manufactured by liquid-filling a semi-solid blend of ridinilazole and Vitamin E polyethylene glycol succinate (Vitamin E TPGS). Prior to filling, ridinilazole was uniformly dispersed in Vitamin E TPGS through high shear mixing. Vitamin E TPGS was selected based on its ability to efficiently disperse the active ingredient in a volume compatible with the drug load, unit dose, and capsule size, its compatibility with the manufacturing process, and its compatibility with the active ingredient and capsule shell.

[0012] However, suspension and liquid-filled capsule ridinilazole formulations have significant drawbacks. Suspension formulations are disadvantageous because they may need to be prepared extemporaneously just before use or, if prepared, may need to be physically treated (e.g., by thorough shaking) before administration, otherwise there is a risk that a non-uniform formulation will be used when measuring the actual dose to be administered. In fact, with suspension formulations, the risk posed by the lack of uniformity is serious. For example, the dose must be measured out of the liquid bottle with a spoon or oral administration syringe, which usually results in inaccurate dosing of each dose. Moreover, even ready-to-use suspensions are disadvantageous because the entire process of the necessary procedures is contained in the liquid bottle, which the patient must handle and store appropriately.

[0013] Liquid-filled capsule formulations also have risks associated with non-uniform dosing, as the fluid suspension can settle unless great (and costly) attention is paid to temperature control and agitation during capsule filling. Capsule filling also requires great care to ensure that the correct dose of fluid is metered into each capsule, necessitating specialized equipment for commercial manufacture that is not widely available.

[0014] Therefore, a solid tablet oral dosage form of ridinilazole is highly desirable. However, the therapeutic dose of ridinilazole is 200 mg twice a day (BID), resulting in a daily dose of 400 mg. Thus, a relatively high drug loading is required in any oral tablet that is appropriately sized for safe and convenient administration with good patient compliance. As a result, the bulk and surface properties of ridinilazole significantly affect manufacturability and processability. Thus, as an electrostatically charged micronized material with very low water solubility, low wettability, low bulk density, and low flowability, formulation of ridinilazole as a solid oral tablet with an appropriate size presents a significant challenge. Summary of the Invention

[0015] The inventors have now discovered that the challenges posed by these characteristics can be overcome by selection of a specific particle size of ridinilazole tetrahydrate crystal aggregates in the intragranular solid phase that enables the production, by wet or dry granulation processes, of ridinilazole granules having physical properties (including particle size, density, morphology, and microstructure) that unexpectedly confer utility in solid tablet oral dosage forms.

[0016] As a result, a tablet comprising ridinilazole tetrahydrate as an active ingredient can now be provided to further improve the treatment of CDI, which overcomes the challenges associated with the existing Phase I and Phase II liquid formulations described above, while exhibiting superior delivery properties compared to Phase II capsule formulations.

[0017] Summary of the Invention The present invention generally comprises: (i) ridinilazole crystalline aggregates; and (ii) an intragranular solid phase embedded in an extragranular solid phase Including, (a) The intragranular phase is a granular phase having a particle size D of less than 30 μm dispersed in a first pharma- ceutically acceptable excipient system. 90 The crystalline aggregates of ridinilazole having the formula: (b) the extragranular phase comprises a second pharma- ceutically acceptable excipient system; Includes tablet formulations.

[0018] In certain embodiments, the intragranular and extragranular phases are different.

[0019] In a particular embodiment, the ridinilazole crystalline aggregates comprise ridinilazole tetrahydrate, preferably ridinilazole tetrahydrate crystalline aggregates.

[0020] In certain embodiments, the ridinilazole crystalline aggregates have a particle size D of about 7 to about 25 μm. 90 has.

[0021] In certain embodiments, the ridinilazole crystalline aggregates have a particle size D of about 10 to about 20 μm. 90has.

[0022] In certain embodiments, the ridinilazole crystalline aggregates comprise ridinilazole tetrahydrate Form A.

[0023] In certain embodiments, ridinilazole tetrahydrate is present in the tablet in an amount of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% wt / wt.

[0024] In certain embodiments, ridinilazole tetrahydrate is present in the tablet at a concentration of about 40% wt / wt or greater.

[0025] In certain embodiments, the intragranular phase is present in the tablet at a concentration of about 65 to about 95% wt / wt.

[0026] In certain embodiments, the extragranular phase is present in the tablet at a concentration of about 5 to about 35% wt / wt.

[0027] In certain embodiments, the first excipient system is present in the tablet at a concentration of up to about 40% wt / wt.

[0028] In certain embodiments, the first excipient system comprises a first diluent, wherein the first diluent is present in the tablet at a concentration of up to 35% wt / wt.

[0029] In certain embodiments, the first diluent comprises lactose monohydrate and / or microcrystalline cellulose; Here, lactose monohydrate is present in the tablet at a concentration of up to 30% wt / wt and microcrystalline cellulose is present in the tablet at a concentration of up to 10% wt / wt.

[0030] In certain embodiments, the first excipient system comprises a first disintegrant; wherein the first disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch.

[0031] In certain embodiments, the first disintegrant is present in the tablet at a concentration of up to 2% wt / wt.

[0032] In certain embodiments, the first excipient system comprises a binder; wherein the binder is selected from the group consisting of polyvinylpyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ethers, wherein the cellulose ethers are selected from hydroxypropyl cellulose (HPC), methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC), and sodium carboxymethyl cellulose (NaCMC).

[0033] In certain embodiments, the binder is present in the tablet at a concentration of up to 3% wt / wt.

[0034] In certain embodiments, the second excipient system is present in the tablet at a concentration of up to 10% wt / wt.

[0035] In certain embodiments, the second excipient system comprises a second diluent and / or a second disintegrant and / or a lubricant.

[0036] In certain embodiments, the second diluent is present in the tablet at a concentration of up to 6% wt / wt.

[0037] In certain embodiments, the second diluent comprises lactose monohydrate and / or microcrystalline cellulose, Lactose monohydrate is present in the tablet at a concentration of up to 5% wt / wt and microcrystalline cellulose is present in the tablet at a concentration of up to 2% wt / wt.

[0038] In certain embodiments, the second excipient system comprises a second disintegrant; wherein the second disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch.

[0039] In certain embodiments, the second disintegrant is present in the tablet at a concentration of up to 3% wt / wt.

[0040] In certain embodiments, the second excipient system comprises a lubricant; wherein the lubricant is selected from (a) fatty acids; (b) metal salts of fatty acids; (c) combinations of fatty acids and their metal salts; (d) fatty acid esters; (e) metal salts of fatty acid esters; and (f) inorganic materials and inorganic polymers.

[0041] In certain embodiments, the lubricant comprises: (i) a fatty acid selected from the group consisting of stearic acid, palmitic acid, and myristic acid; (ii) a metal salt of a fatty acid selected from magnesium stearate, calcium stearate, and zinc stearate; (iii) a combination of stearic acid and magnesium stearate; (iv) fatty acid esters selected from glyceride esters and sugar esters; (v) a glyceride ester selected from glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate; (vi) a sugar ester selected from sorbitan monostearate and sucrose monopalmitate; and / or (vii) sodium stearyl fumarate or lysine, Or a combination of both.

[0042] In certain embodiments, the lubricant is present in the tablet at a concentration of up to 1% wt / wt.

[0043] In certain embodiments, the second excipient system comprises lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, and magnesium stearate.

[0044] In certain embodiments, the formulation is substantially anhydrous.

[0045] In certain embodiments, the tablet contains about 100 to about 400 mg of ridinilazole tetrahydrate.

[0046] In a particular embodiment, the tablet contains about 200 mg of ridinilazole tetrahydrate (equivalent to 169 mg of ridinilazole on an anhydrous basis).

[0047] In certain embodiments, the tablet formulation comprises or consists of:

[0048] [Table 1]

[0049] In certain embodiments, some or all of the intragranular phase takes the form of inclusions embedded within the matrix formed by the extragranular phase.

[0050] In certain embodiments, the tablet formulation has a T of ridinilazole tetrahydrate in the ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model. MAX indicates less than 3 hours.

[0051] In certain embodiments, the tablet formulation has a T of ridinilazole tetrahydrate in the ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model. MAX indicates less than 2 hours.

[0052] According to another embodiment of the present invention, there is provided a ridinilazole tetrahydrate tablet comprising an intragranular solid phase incorporated in an extragranular solid phase, wherein (a) the intragranular phase has a particle size D of about 4 μm to about 30 μm. 90 (b) the extragranular phase comprises ridinilazole tetrahydrate agglomerates dispersed within a first Pharmaceutically Acceptable Excipient System having the formula:

[0053] In embodiments, ridinilazole is in the form of ridinilazole tetrahydrate, preferably in the form of ridinilazole tetrahydrate crystalline aggregates, more preferably ridinilazole tetrahydrate Form A (as defined herein).

[0054] In some embodiments, the lysinilazole tetrahydrate crystalline aggregates have a particle size D of about 7 to about 25 μm. 90 and preferably has a particle size D of about 10 to about 20 μm. 90 In various embodiments, the crystalline aggregates have a particle size D of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, or about 50 μm. 90 In other embodiments, the crystal aggregates may have a particle size D of less than 40 μm. 90 has.

[0055] In some embodiments, ridinilazole tetrahydrate is present in any suitable concentration, for example at least 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, or 70% wt / wt. Preferably, ridinilazole is present in the tablet at a concentration of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% wt / wt. More preferably, ridinilazole tetrahydrate is present in the tablet at a concentration of 40% wt / wt or more, for example about 50% wt / wt.

[0056] In some embodiments, the intragranular phase is preferably present in the tablet at a concentration of about 65 to about 95% wt / wt, e.g., about 90% wt / wt. In some embodiments, the extragranular phase is preferably present in the tablet at a concentration of about 5 to about 35% wt / wt, e.g., about 10% wt / wt.

[0057] In some embodiments, the first excipient system is preferably present in the tablet at a concentration of up to about 40% wt / wt, for example about 40% wt / wt. In some embodiments, the first excipient system is preferably lubricant-free. In some embodiments, the first excipient system may include a first diluent and / or a first disintegrant and / or a binder.

[0058] Preferably, the first excipient system comprises a first diluent or a combination of first diluents. Any pharma- ceutically acceptable diluent or combination of diluents can be used. In some embodiments, the first diluent can be present in the tablet at a concentration of up to 35% wt / wt, e.g., about 35% wt / wt. The first diluent can comprise, consist of, or consist essentially of lactose monohydrate and / or microcrystalline cellulose. Preferably, the first diluent consists of, or consists essentially of, lactose monohydrate and microcrystalline cellulose, e.g., lactose monohydrate 200M and Avicel PH101®. In a more preferred embodiment, lactose monohydrate is present in the tablet at a concentration of up to 30% wt / wt, e.g., about 25% wt / wt, and microcrystalline cellulose is present in the tablet at a concentration of up to 10% wt / wt, e.g., about 9% wt / wt.

[0059] In some embodiments, the first excipient system may include a first disintegrant or a combination of first disintegrants. Any pharma- ceutically acceptable disintegrant or combination of disintegrants may be used. Suitable disintegrants may be selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch. In a preferred embodiment, the first disintegrant comprises, consists of, or consists essentially of croscarmellose sodium, such as Ac Di Sol® or Primellose®. In some embodiments, the first disintegrant may be present in the tablet at a concentration of up to 2% wt / wt, for example about 2% wt / wt.

[0060] In embodiments, the first excipient system may include a binder. Any pharma- ceutically acceptable binder, or combination of binders, may be used. A suitable binder may include, consist of, or consist essentially of a hydrophilic polymer. For example, the binder may be selected from polyvinylpyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ethers. Thus, in embodiments, the binder may include a cellulose ether selected from hydroxypropylcellulose (HPC), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), and sodium carboxymethylcellulose (NaCMC). In a preferred embodiment, the binder comprises, consists of, or consists essentially of hydroxypropylcellulose. In embodiments, the binder is preferably present in the tablet at a concentration of up to 3% wt / wt, for example about 3% wt / wt.

[0061] Preferably, the first excipient system consists essentially of a first diluent, a first disintegrant, and a binder. In these embodiments, the first excipient system preferably consists essentially of lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, and croscarmellose sodium, e.g., lactose monohydrate 200M, Avicel PH101, hydroxypropyl cellulose, and croscarmellose sodium.

[0062] In some embodiments, the second excipient system may be present in the tablet at a concentration of up to 10% wt / wt, for example about 10% wt / wt. In some embodiments, the second excipient system preferably does not include a binder. In some embodiments, the second excipient system may include a second diluent and / or a second disintegrant and / or a lubricant.

[0063] Preferably, the second excipient system comprises a second diluent or a combination of second diluents. Any pharma- ceutically acceptable diluent or combination of diluents can be used. In some embodiments, the second diluent can be present in the tablet at a concentration of up to 6% wt / wt, for example, about 6% wt / wt. In some embodiments, the second diluent can preferably comprise, consist of, or consist essentially of lactose monohydrate and / or microcrystalline cellulose, more preferably consist of, consist essentially of lactose monohydrate 100M and Avicel PH102®. In these embodiments, lactose monohydrate is preferably present in the tablet at a concentration of up to 5% wt / wt, for example, about 4.5% wt / wt, and microcrystalline cellulose is present in the tablet at a concentration of up to 2% wt / wt, for example, about 1.5% wt / wt.

[0064] In some embodiments, the second excipient system may include a second disintegrant. Any pharma- ceutically acceptable disintegrant or combination of disintegrants may be used as the second disintegrant. In some embodiments, the second disintegrant may be selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch. The second disintegrant may include, consist of, or consist essentially of croscarmellose sodium, such as Ac Di Sol® or Primellose®. The second disintegrant is preferably present in the tablet at a concentration of up to 3% wt / wt, for example about 3% wt / wt.

[0065] In some embodiments, the second excipient system may include a lubricant. Any pharma- ceutically acceptable lubricant or combination of lubricants may be used. For example, the lubricant may be selected from (a) fatty acids; (b) metal salts of fatty acids; (c) combinations of fatty acids and their metal salts; (d) fatty acid esters; (e) metal salts of fatty acid esters; and (f) inorganic materials and inorganic polymers. For example, the lubricant may include a fatty acid selected from stearic acid, palmitic acid, and myristic acid. The lubricant may include a metal salt of a fatty acid selected from magnesium stearate, calcium stearate, and zinc stearate. Other suitable lubricants include a combination of stearic acid and magnesium stearate. The lubricant may also include a fatty acid ester selected from a glyceride ester and a sugar ester. For example, the lubricant may include a glyceride ester selected from glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate. Other suitable lubricants include sugar esters selected from sorbitan monostearate and sucrose monopalmitate. The lubricant may also include sodium stearyl fumarate or lysine. In a preferred embodiment, the lubricant comprises, consists of, or consists essentially of magnesium stearate. The lubricant is preferably present at a concentration of up to 1% wt / wt, for example about 1% wt / wt.

[0066] Preferably, the second excipient system consists essentially of a second diluent, a second disintegrant, and a lubricant. In these embodiments, the second excipient system preferably consists essentially of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, such as lactose monohydrate 100M, Avicel PH102®, and magnesium stearate.

[0067] In embodiments, tablets of the invention are preferably dry or substantially anhydrous, e.g., having a moisture content of less than 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 5%, 4%, 3%, 2%, or 1% by weight.

[0068] In some embodiments, the tablets of the invention contain ridinilazole tetrahydrate in an amount sufficient to produce a therapeutic effect in a human subject, with tablets containing about 100 to about 400 mg of ridinilazole tetrahydrate, preferably about 200 mg of ridinilazole tetrahydrate (equivalent to 169 mg of anhydrous ridinilazole).

[0069] Part or all of the intragranular phase may take the form of inclusions embedded within the matrix formed by the extragranular phase.

[0070] In embodiments, the tablets of the present invention preferably have a T for ridinilazole in the ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model described herein (and known to those of skill in the art). MAX More preferably, the tablet of the present invention exhibits a T for ridinilazole in the ileal effluent measured using the TIM-1 dynamic in vitro gastrointestinal model of less than 3 hours. MAX Most preferably, the tablet of the present invention exhibits a T for ridinilazole in the ileal effluent measured using the TIM-1 dynamic in vitro gastrointestinal model of less than 2 hours. MAX Indicates approximately 1 hour to approximately 2 hours.

[0071] In some embodiments, the tablet of the present invention preferably further comprises a coating. Any suitable coating can be used, and preferred coatings provide protection from contamination, improved stability, organoleptic properties, and swallowability. Preferred coatings include pharma- ceutically acceptable water-soluble polymer films.

[0072] In another embodiment of the present invention, the particle size D of about 4 to about 30 μm 90A composition is provided comprising granules comprising ridinilazole tetrahydrate, optionally in the form of aggregates, dispersed within a first pharma- ceutically acceptable excipient system having the formula: and an extragranular second pharma-ceutically acceptable excipient system, the first excipient system and the second excipient system being different. The granules may be dispersed, preferably uniformly, within the second pharma-ceutically acceptable excipient system.

[0073] The composition of this embodiment is preferably a tableting composition suitable for compression into tablets. Alternatively, or in addition, the composition of this aspect of the invention may be suitable for other uses. Such uses include processes for the formulation of any type of oral and parenteral ridinilazole pharmaceutical composition. For example, the composition of the second aspect of the invention may take the form of, or be applied to the preparation of, pharmaceutical formulations other than tablets, including liquid suspensions, granule-filled capsules, and granule-filled sachets (or other containers).

[0074] In embodiments, the ridinilazole tetrahydrate aggregate is preferably in the form of a ridinilazole tetrahydrate crystalline aggregate, more preferably ridinilazole tetrahydrate Form A (as defined herein).

[0075] In some embodiments, the granules may be dispersed in a second pharma- ceutically acceptable excipient system. Preferably, the granules are homogeneously dispersed in the second pharma- ceutically acceptable excipient system. The granules are dry, e.g., having a moisture content of less than 10%, 5%, 2%, or 1% by weight.

[0076] In embodiments, the second pharma- ceutically acceptable excipient system can be particulate and can be dry, e.g., having a moisture content of less than 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 5%, 4%, 3%, 2%, or 1% by weight.

[0077] In some embodiments, the crystal aggregates have a particle size D of about 5 μm to about 40 μm. 90 and preferably has a particle size D of about 10 to about 20 μm. 90In other embodiments, the crystalline aggregates have a particle size D of less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 5 μm. 90 may have.

[0078] In embodiments, ridinilazole tetrahydrate may be present in the composition at a concentration of at least 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, or 70% wt / wt, preferably at a concentration of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% wt / wt, more preferably at a concentration of 40% wt / wt or greater, e.g., about 50% wt / wt.

[0079] In embodiments, the granules may be present in the composition at a concentration of 65-95% wt / wt, preferably about 90% wt / wt.

[0080] In embodiments, the second excipient system may be present in the composition at a concentration of about 5 to about 35% wt / wt, preferably about 10% wt / wt.

[0081] In embodiments, the first and second excipient systems are preferably as defined above for the tablets of the present invention.

[0082] In embodiments, the tableting composition is preferably dry, e.g., having a moisture content of less than 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 5%, 4%, 3%, 2%, or 1% by weight.

[0083] More preferred is a tableting composition suitable for compression into tablets according to the invention as defined according to the first aspect of the invention above.

[0084] In another aspect of the present invention, there is provided a method for producing a granular ridinilazole tetrahydrate composition, comprising the steps of: (a) Particle size D of about 4 to about 30 μm90 providing a ridinilazole tetrahydrate aggregate having (b) mixing the agglomerates of step (a) with a first Pharmaceutically acceptable intragranular excipient system to form a pre-granulation mixture; (c) granulating the pre-granulation mixture to form granules comprising said crystalline agglomerates dispersed within said first pharma- ceutically acceptable excipient system; and (d) blending the granules of step (c) with a second pharma- ceutically acceptable extragranular excipient system to form a granular ridinilazole composition, optionally suitable for compression into tablets.

[0085] In some embodiments, the method is preferably suitable for producing a granular ridinilazole composition as defined in accordance with the second aspect of the present invention above. The granular ridinilazole tetrahydrate composition of step (d) is preferably suitable for compression into the tablet of the present invention as defined in accordance with the first aspect of the present invention above. Alternatively, or in addition, the granular ridinilazole tetrahydrate composition of step (d) may also be suitable for other uses, including processes for the formulation of any kind of oral and parenteral pharmaceutical ridinilazole tetrahydrate composition. For example, the ridinilazole tetrahydrate composition of step (d) may take the form of, or be applied to the preparation of, pharmaceutical formulations other than tablets, including liquid suspensions, granular filled capsules, and granular filled sachets (or other containers).

[0086] In embodiments, the ridinilazole tetrahydrate aggregates are preferably in the form of ridinilazole tetrahydrate crystalline aggregates, more preferably ridinilazole tetrahydrate Form A (as defined herein). The crystalline aggregates have a particle size D of about 7 to about 25 μm. 90 and preferably has a particle size D of about 10 to about 20 μm. 90 has.

[0087] In some embodiments, ridinilazole tetrahydrate may be present in the granules at a concentration of at least 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, or 70% wt / wt, such as up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% wt / wt. Preferably, ridinilazole tetrahydrate is present in the granules at a concentration of 40% wt / wt or more, such as about 50% wt / wt.

[0088] In embodiments, the granules are preferably present in the granular ridinilazole tetrahydrate composition of step (d) at a concentration of about 65 to about 95% wt / wt, for example about 90% wt / wt.

[0089] In embodiments, the second excipient system may be present in the granular ridinilazole composition of step (d) at a concentration of about 5 to about 35% wt / wt, for example about 10% wt / wt.

[0090] In embodiments, the first and second excipient systems are preferably as defined above for the tablets and tableting compositions of the present invention.

[0091] In several embodiments, providing step (a) preferably includes a step of reducing the particle size of the crystalline ridinilazole, for example by micronization and / or by a process including the steps of milling, grinding, sieving, and / or screening, for example by air jet milling.

[0092] In some embodiments, the mixing step (b) may further comprise screening or sieving the first excipient system prior to mixing with the agglomerates.

[0093] In some embodiments, the mixing step (b) comprises the steps of: (b1) mixing the agglomerates of step (a) with a first portion of a first Pharmaceutically acceptable intragranular excipient system to form an initial pre-granulation mixture; (b2) passing the pre-granulation mixture of step (b1) through a screen or sieve to form a screened initial pre-granulation mixture; (b3) passing a second portion of the first Pharmaceutically Acceptable Intragranular Excipient System through the screen or sieve of step (b2) to form a screened second portion; followed by (b4) mixing the screened initial pre-granulation blend of step (b2) with the screened second excipient portion of step (b3) to form a final pre-granulation blend for granulation according to step (c).

[0094] In the above embodiments, the first portion of the first pharma- ceutically acceptable intragranular excipient system may be a subset of the constituent excipients of the first excipient system described herein, for example, the first portion may comprise all of the constituent excipients of the first excipient system as described herein except for some or all of the first diluent (e.g., microcrystalline cellulose, which is the first diluent in the preferred embodiment above).

[0095] Also, in the above embodiments, the agglomerates of step (a) may include reagglomerated ridinilazole tetrahydrate particles, in these cases, steps (b1) and (b2) break down and remove the reagglomerated ridinilazole particles, such that the screened initial pre-granulation mixture of step (b2) contains uniformly distributed ridinilazole tetrahydrate crystal agglomerates.

[0096] The particle size of the API can be analyzed by any convenient method, including sedimentation field flow fractionation, photon correlation spectroscopy, light scattering (e.g., laser diffraction), and disc centrifugation. Dry laser diffraction methods, as described herein, are preferred.

[0097] The mixing step (b) preferably involves high shear dry blending.

[0098] The granulation step (c) may comprise dry granulation, however, preferably, the granulation step (c) comprises wet granulation, more preferably high shear wet granulation.

[0099] In a fourth aspect of the present invention, there is provided a method for making ridinilazole tetrahydrate tablets comprising the steps of: (a) providing a granular ridinilazole composition by the method of the third aspect of the present invention; followed by (b) preparing ridinilazole tablets by compressing the granular composition.

[0100] In some embodiments, the tableting method may further include coating the ridinilazole tablets to form coated ridinilazole tetrahydrate tablets. It may also further include packaging a plurality of the ridinilazole tablets to form a ridinilazole patient pack, or bottle or other container, containing sufficient tablets for one course of treatment (e.g., about 20 tablets).

[0101] In a fifth aspect of the present invention, there is provided a granular ridinilazole tetrahydrate composition suitable for compression into tablets obtainable by the process of the third aspect of the present invention.

[0102] In another aspect of the invention there is provided a ridinilazole tetrahydrate tablet, patient pack or container obtainable by the process of the fourth aspect of the invention.

[0103] In another aspect of the invention, there is provided a tablet of the invention for use in the treatment, therapy or prevention of CDI or CDAD.

[0104] In another aspect of the invention there is provided the use of a tablet of the invention for the manufacture of a medicament for use in the treatment, therapy or prevention of CDI or CDAD.

[0105] In another aspect of the invention, there is provided a method for treating, treating or preventing CDI or CDAD in a patient in need thereof, comprising orally administering to said patient a tablet of the invention.

[0106] In another embodiment of the invention, there is provided a tablet formulation comprising: (i) ridinilazole tetrahydrate; and (ii) an intragranular solid phase incorporated into an extragranular solid phase; where (a) The granular phase has a particle size D of about 4 to about 30 μm. 90 a first soluble crystalline agglomerate of ridinilazole dispersed within a first pharma- ceutically acceptable excipient system having the formula: (b) the extragranular phase comprises a second pharma- ceutically acceptable excipient system; Here, unlike the first excipient system and the second excipient system, the lidinilazole tetrahydrate crystal aggregates have a particle size D of about 7 to about 25 μm. 90 has.

[0107] In some embodiments, the crystal aggregates have a particle size D of about 5 μm to about 40 μm. 90 and preferably has a particle size D of about 10 to about 20 μm. 90 In other embodiments, the crystalline aggregates have a particle size D of less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 5 μm. 90 may have.

[0108] In embodiments, the ridinilazole crystalline aggregates comprise ridinilazole tetrahydrate.

[0109] In embodiments, the ridinilazole tetrahydrate crystalline aggregate comprises ridinilazole tetrahydrate Form A.

[0110] In embodiments, ridinilazole is present in the tablet in an amount up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% wt / wt.

[0111] In some embodiments, ridinilazole is present in the tablet at a concentration of 40% wt / wt or more, for example about 50% wt / wt.

[0112] In embodiments, the intragranular phase is present in the tablet at a concentration of about 65 to about 95% wt / wt, for example about 90% wt / wt.

[0113] In embodiments, the extragranular phase is present in the tablet at a concentration of about 5 to about 35% wt / wt, for example about 10% wt / wt.

[0114] In embodiments, the first excipient system is present in the tablet at a concentration of up to 40% wt / wt, for example about 40% wt / wt.

[0115] In embodiments, the first excipient system comprises a first diluent, wherein the first diluent is present in the tablet at a concentration of up to 35% wt / wt.

[0116] In several embodiments, the first diluent comprises, consists of, or consists essentially of lactose monohydrate and / or microcrystalline cellulose, where lactose monohydrate is present in the tablet at a concentration of up to 30% wt / wt and microcrystalline cellulose is present in the tablet at a concentration of up to 10% wt / wt.

[0117] In embodiments, the first excipient system comprises a first disintegrant, where the first disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch.

[0118] In embodiments, the first disintegrant is present in the tablet at a concentration of up to 2% wt / wt, for example about 2% wt / wt.

[0119] In embodiments, the first excipient system comprises a binder, where the binder is selected from polyvinylpyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and a cellulose ether, where the cellulose ether is selected from hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), and sodium carboxymethylcellulose (NaCMC).

[0120] In embodiments, the binder is present in the tablet at a concentration of up to 3% wt / wt, for example about 3% wt / wt.

[0121] In embodiments, the second excipient system is present in the tablet at a concentration of up to 10% wt / wt, for example about 10% wt / wt.

[0122] In embodiments, the second excipient system comprises a second diluent and / or a second disintegrant and / or a lubricant.

[0123] In some embodiments, the second diluent is present in the tablet at a concentration of up to 6% wt / wt.

[0124] In several embodiments, the second diluent comprises lactose monohydrate and / or microcrystalline cellulose, where the lactose monohydrate is present in the tablet at a concentration of up to 5% wt / wt and the microcrystalline cellulose is present in the tablet at a concentration of up to 2% wt / wt.

[0125] In embodiments, the second excipient system comprises a second disintegrant, optionally wherein the second disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch.

[0126] In embodiments, the second disintegrant is present in the tablet at a concentration of up to 3% wt / wt, for example about 3% wt / wt.

[0127] In embodiments, the second excipient system comprises a lubricant, where the lubricant is selected from (a) fatty acids; (b) metal salts of fatty acids; (c) combinations of fatty acids and their metal salts; (d) fatty acid esters; (e) metal salts of fatty acid esters; and (f) inorganic materials and inorganic polymers.

[0128] In embodiments, the lubricant comprises a fatty acid selected from stearic acid, palmitic acid, and myristic acid; a metal salt of a fatty acid selected from magnesium stearate, calcium stearate, and zinc stearate; a combination of stearic acid and magnesium stearate; a fatty acid ester selected from a glyceride ester and a sugar ester; a glyceride ester selected from glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate; a sugar ester selected from sorbitan monostearate and sucrose monopalmitate; sodium stearyl fumarate or lysine.

[0129] In embodiments, the lubricant is present in the tablet at a concentration of up to 1% wt / wt.

[0130] In embodiments, the second excipient system comprises lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, and magnesium stearate, e.g., lactose monohydrate 100M, Avicel PH102®, and magnesium stearate.

[0131] In some embodiments, the tablet contains about 100 to about 400 mg of ridinilazole tetrahydrate.

[0132] In some embodiments, the tablet contains about 200 mg of ridinilazole tetrahydrate.

[0133] In embodiments, some or all of the intragranular phase takes the form of inclusions embedded within the matrix formed by the extragranular phase.

[0134] In embodiments, the tablet formulation has a T for ridinilazole in the ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model. MAX Shows less than 3 hours.

[0135] In embodiments, the tablet formulation has a T for ridinilazole in the ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model. MAX Shows less than 2 hours. [Brief description of the drawings]

[0136] [Figure 1] 1 shows a representative X-ray powder diffraction pattern of ridinilazole tetrahydrate form A. [Diagram 2] 1 shows an ORTEP plot of the A-form structure of ridinilazole molecule and water molecules. [Diagram 3] FIG. 1 shows a packing diagram of the ridinilazole tetrahydrate form A structure along each crystallographic axis. [Figure 4] FIG. 1 shows a packing diagram of the ridinilazole tetrahydrate form A structure along each crystallographic axis. [Diagram 5] FIG. 1 shows a packing diagram of the ridinilazole tetrahydrate form A structure along each crystallographic axis. [Figure 6] A representative X-ray powder diffraction pattern of ridinilazole anhydrate form D is shown. [Figure 7] 1 shows an ORTEP plot of the D-shaped conformation of the ridinilazole molecule. [Figure 8] A packing diagram of the ridinilazole D-form structure along each crystallographic axis is shown. [Figure 9] A packing diagram of the ridinilazole D-form structure along each crystallographic axis is shown. [Figure 10] A packing diagram of the ridinilazole D-form structure along each crystallographic axis is shown. [Figure 11] Hydrogen bonds between lysinilazole D-form molecules are shown which give rise to a two-dimensional network structure along the ab plane (i.e., viewed along the c-axis). [Figure 12]1 shows an XRPD overlay of ridinilazole tablet (top trace), placebo (middle trace), and Form A (bottom trace) from about 10° 2θ to about 25° 2θ. [Figure 13] 1 shows comparative ileal effluent profiles for ridinilazole tetrahydrate 200 mg capsules and ridinilazole tetrahydrate 200 mg tablets (each equivalent to 169 mg anhydrous ridinilazole) in the TIM-1 intestinal system model. The plot shows the amount of ridinilazole measured in the ileal effluent at each 60 minute time point over the experimental period. The ileal effluent is equal to the amount of material delivered to the colon. [Figure 14] 4 shows the dissolution profile of tablets with drug substance at the limit of particle size specification. [Figure 15] Bristol stool form chart and various types of stool forms. [Figure 16-1] 1 shows an exemplary manufacturing process for ridinilazole tetrahydrate 200 mg tablets. [Figure 16-2] 1 shows an exemplary manufacturing process for ridinilazole tetrahydrate 200 mg tablets. [Figure 17] 1 shows the dissolution profiles of ridinilazole tetrahydrate tablets in micronized and non-micronized tablets and caplets. [Figure 18] 4 shows the dissolution profiles of ridinilazole tetrahydrate tablets for non-micronized tablet-incomplete granulation, non-micronized tablet-complete granulation, and micronized tablet. [Figure 19] 1 shows an exemplary manufacturing process for the tablets of the present invention. [Figure 20] Dissolution at four different hardness targets is shown. [Figure 21] Dissolution at three different hardness targets is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0137] Detailed Description All publications, patents, patent applications, and other references mentioned herein are incorporated by reference in their entirety for all purposes as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference and as if the contents were set forth in full.

[0138] Definition and general preference The following terms, as used herein, and unless specifically indicated otherwise, are intended to have the following meanings, in addition to any broader (or narrower) meaning that such terms may have in the art.

[0139] Unless the context requires otherwise, the use of the singular herein should be read to include the plural and vice versa. The terms "a" or "an" used in reference to an entity should be read to mean one or more of that entity. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0140] The term "about" as used herein with respect to a numerical value or numerical range should be interpreted as being as accurate as the method used to measure it. The term may also be used synonymously with the term "at or near" in this context, and thus, reference to "about" with respect to a particular numerical value or numerical range may also be interpreted as defining that particular numerical value or numerical range, or near it. Thus, a reference to "about x" may be interpreted as "x, or about x", while a reference to "about x to y" may be interpreted as "x to y, or about x to about y, or about x to y". The term may also be interpreted as defining a ±10% error limit for the numerical value referred to, or for the upper and lower limits of the range referred to. In certain embodiments, the term "about" when referring to a value includes ±10% of the stated value. For example, about 50% includes a range of 45% to 55%, while about 20 molar equivalents includes a range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to ±10% of the respective stated value at each end of the range.

[0141] The term "administering" refers to administration of a composition of the present invention to a subject.

[0142] The term "aggregate" means two or more primary particles tightly bound together by strong chemical bonds resulting from sintering or cementation. Primary particles are inorganic or organic structures held together by atomic or molecular bonds. Primary particles are the "basic" particles. Primary particles cannot be broken down into smaller particles except by application of very high energy. In any sample, they usually only represent a fraction of a percent. Aggregates are the fusion of particles by processes other than heat / pressure, i.e., deposition of ionic salts on the surface during manufacture. Aggregates usually form when powders are heated, compressed, or dried from suspension. Aggregates have a large interfacial contact area between each particle, and the forces required to break these bonds are substantial. Aggregates constitute, for all practical purposes, the largest single fraction of any particle size distribution (PSD) one may wish to achieve in a formulation.

[0143] The term "agglomerates" refers to collections of aggregates held together loosely at two-point contacts by weak electromagnetic forces, van der Waals forces, mechanical friction, and interlocking. Agglomerates form when particulates are handled, shaken, rolled, or stored undisturbed in one location. They are readily disintegrable by appropriate dispersion techniques.

[0144] The term bioisostere (or simply isostere) is a term used in the art to define drug analogues in which one or more atoms (or groups of atoms) are replaced by alternative atoms (or groups of alternative atoms) that have similar steric and / or electronic characteristics to the atom in question. Substitution of hydrogen atoms or hydroxyl groups by fluorine atoms is a commonly used bioisosteric replacement. Silasubstitution (C / Si exchange) is a relatively recent technique for producing isosteres. This approach involves replacing one or more specific carbon atoms in a compound with silicon (for a review, see the article by Tacke and Zilch in Endeavour, New Series, 1986, 10, 191-197). Silasubstitution isosteres (silicon isosteres) may exhibit improved pharmacological properties, such as improved tolerability, extended half-life, or increased potency (see, for example, the article by Englebienne in Med. Chem., 2005, 1(3), 215-226). Similarly, replacement of an atom with one of its isotopes, e.g., hydrogen with deuterium, may also improve pharmacological properties, e.g., increase half-life (see, e.g., Kushner et al (1999) Can J Physiol Pharmacol. 77(2):79-88). In its broadest aspects, the present invention contemplates all bioisosteres of the compounds of the present invention, particularly all silicon bioisosteres.

[0145] The term "composition" as used herein is intended to encompass formulations comprising a specified active pharmaceutical ingredient (API) as described herein (e.g., ridinilazole tetrahydrate, preferably form A) as well as pharma- ceutically acceptable excipients, carriers, or diluents in specified amounts, e.g., as provided throughout the disclosure as originally filed, obtained by combining specific ingredients, e.g., combining the specified ingredients as described herein in the specified amounts as described herein.

[0146] The term "comprise", or variations thereof, such as "comprises" or "comprising", as used herein, should be read to indicate the inclusion of any recited integer (e.g., feature, element, characteristic, property, method / process step, or limitation) or group of integers (e.g., features, elements, characteristics, properties, method / process steps, or limitations) and not the exclusion of any other integer or group of integers. Thus, the term "comprising" as used herein is inclusive or non-exclusive and does not exclude additional, unrecited integers or method / process steps.

[0147] As used herein, the phrase "consisting essentially of" is used to require specified integers or steps, and integers or steps that do not materially affect the nature or function of the claimed invention.

[0148] As used herein, the term "consisting of" is used to indicate the presence of only a recited integer (e.g., feature, element, characteristic, property, method / process step, or limitation) or group of integers (e.g., features, elements, characteristics, properties, method / process steps, or limitations).

[0149] The term "disintegrant" refers to a pharmaceutical excipient incorporated into a composition to promote its disintegration when the composition comes into contact with liquid.For example, disintegrants are pharma- ceutically acceptable agents used in the preparation of tablets to make the tablet disintegrate and release pharmaceutical ingredients when it comes into contact with moisture.Examples of disintegrants include, but are not limited to, cross-linked polymers, including cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), modified starch, sodium starch glycolate, etc.

[0150] As used herein, the term "D # " means distribution particle size distribution. For example, the unit D 10 D represents the particle size that 10% of the particles in the powder are smaller than. It is usually measured in μm. A laser particle sizer measures the particles using a laser at different angles, and then obtains a diffraction pattern from an image sensor. Finally, by performing addition, subtraction, or cross analysis calculations, the instrument determines the statistical proportion of the particle size. 90 means that 90% of the total particles are smaller than the particle size. For example, D 10 is 2.557 μm, and D 90 The particle size D of these two particles is 46.88 μm. 10 and D. 90 D encompasses the range of particle sizes of the sample powder. Particle sizes beyond this range can be ignored due to the small number of particles. 50 means that 50% of the total particles are smaller than the particle size, or 50% of the particles are larger than the particle size. D 50 is the median of the particle size distribution, and we sometimes refer to this value as the "median."

[0151] As used herein, the term "disposed on" refers to the placement of one layer or coating on top of another layer or coating. Such placement may conform to the shape of the underlying layer or coating, such that the stacking of layers and coatings does not result in substantial gaps between them.

[0152] As used herein, the term "extragranular phase" refers to the bulk portion of the core structure that exists between the internal phase and the outer coating of the composition. Although the extragranular phase may be considered a coating in its own right, it is generally thicker than a simple coating and provides significant structure / dimension to the composition.

[0153] As used herein, the term "Form A" of ridinilazole refers to a crystalline form of ridinilazole tetrahydrate characterized by a powder X-ray diffractogram containing characteristic peaks at 2θ angles of (11.02±0.2)°, (16.53±0.2)°, and (13.0±0.2)°.

[0154] As used herein, "Form D" of ridinilazole means a crystalline form of ridinilazole tetrahydrate characterized by a powder X-ray diffractogram containing characteristic peaks at 2θ angles of (12.7±0.2)°, (23.18±0.2)°, and (27.82±0.2)°, and in some cases containing characteristic peaks at 2θ angles of (12.7±0.2)°, (23.18±0.2)°, (27.82±0.2)°, (19.5±0.2)°, and (22.22±0.2)°.

[0155] As used herein, the term "Form N" of ridinilazole refers to a crystalline form of ridinilazole tetrahydrate characterized by a powder X-ray diffractogram containing characteristic peaks at 2θ angles of (10.82±0.2)°, (13.35±0.2)°, and (19.15±0.2)°, and in some cases containing characteristic peaks at 2θ angles of (10.82±0.2)°, (13.35±0.2)°, (19.15±0.2)°, (8.15±0.2)°, and (21.74±0.2)°.

[0156] Those skilled in the art will recognize that XRPD patterns may be obtained with measurement errors due to the measurement conditions used. In particular, it is generally known that the intensities of XRPD patterns may vary depending on the measurement conditions used. Relative intensities may also vary depending on the experimental conditions, and therefore, relative intensities should not be considered as definitive. Furthermore, the measurement error of the diffraction angle of a typical XRPD pattern is usually about 5% or less, and such measurement error should be taken into consideration when considering the diffraction angles described. It will be recognized that the various crystal forms described herein are not limited to crystal forms that produce X-ray diffraction patterns completely identical to those shown in the accompanying drawings. Rather, crystal forms of ridinilazole that produce X-ray diffraction patterns substantially in accordance (as defined above) with those shown in the drawings are within the scope of the present invention.

[0157] The term "glidant" refers to a substance added to a powder to improve the flow and / or lubricity of the powder. Examples of glidants include, but are not limited to, magnesium stearate, fumed silica, starch, and talc.

[0158] The term "granulated mixture" refers to a mixture of two or more drugs that is made by mixing and granulating the two or more drugs together into a particulate form, resulting in a particulate material comprised of the two or more drugs.

[0159] The term "hydrophilic silica" refers to a pharmaceutical excipient that can be used as a flow agent (anti-caking agent), adsorbent, and desiccant in solid dosage forms. Hydrophilic silica may also be used to increase the mechanical stability and disintegration rate of a composition. The hydrophilic silica may be fumed silica, i.e., manufactured through a pyrogenic process to produce fine silica particles. The fumed silica particles may vary in size, for example, from 5 nm to 100 nm, or from 5 to 50 nm. The particles are non-porous and have a surface area of ​​50 to 1,000 m. 2 / g or 50~600m 2An example of a hydrophilic silica may have a specific surface area of ​​about 200 m 2 An example of such a material is Aerosil 200 having a viscosity of 1 / g.

[0160] The term "intragranular phase" refers to the central most part of the composition. In this embodiment, the intragranular phase is the location where the active ingredient ridinilazole tetrahydrate is present.

[0161] The term "lubricant" refers to a substance added to a formulation to reduce friction. Compounds that act as lubricants may also have properties as glidants. Examples of lubricants include, but are not limited to, talc, silica, and fats such as vegetable stearin, magnesium stearate, or stearic acid.

[0162] The term "microcrystalline cellulose" or "MCC" refers to pharmaceutical grade cellulose produced from refined wood pulp. MCC may be unmodified or modified, such as silicified microcrystalline cellulose (SMCC). MCC may function as a bulking agent and may facilitate tablet formation due to its favorable compressibility.

[0163] The terms "patient" or "subject" are used interchangeably and refer to an organism, including but not limited to a human subject, suffering from or susceptible to a disease or condition treatable by administration of the pharmaceutical compositions provided herein. Further non-limiting examples include, but are not limited to, humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cows, deer, horses, and other mammals. In some embodiments, the patient is a human.

[0164] The term "pharmaceutical pack" as used herein defines a series of one or more ridinilazole tetrahydrate tablets, optionally contained within a common outer packaging. The tablets may be contained within a blister pack. The pharmaceutical pack may further comprise instructions for use. The ridinilazole tetrahydrate tablet composition of the present invention may be included in a pharmaceutical pack or a patient pack.

[0165] The term "patient pack" as used herein defines a package prescribed to a patient that contains a pharmaceutical composition throughout a course of treatment. A patient pack will usually include one or more blister packs, but may conveniently take the form of a small bottle or other container that contains enough tablets for one or more courses of treatment. For example, the container may contain about 20 to about 60 tablets, e.g., about 20 tablets or about 60 tablets (the former being particularly suitable for a single course of treatment, while the latter being particularly suitable for multiple courses of treatment). Patient packs have an advantage over traditional prescriptions, in which a pharmacist divides a patient supply of a drug from a bulk supply, in that the patient can always refer to the packaging insert contained in the patient pack, which is usually absent from the patient prescription. The inclusion of a packaging insert has been shown to improve patient compliance with the physician's instructions.

[0166] The term pharma- ceutically acceptable derivatives, as applied to ridinilazole tetrahydrate, defines compounds obtained (or obtainable) by chemical derivatization of ridinilazole tetrahydrate. Thus, pharma- ceutically acceptable derivatives are suitable for use in administration to or in contact with mammalian tissues and are free of undue toxicity, irritation, or allergic responses (i.e., commensurate with a reasonable benefit / risk ratio). Preferred derivatives are those obtained (or obtainable) by alkylation, esterification, or acylation of ridinilazole tetrahydrate. The derivatives may be active per se or inactive until processed in vivo. In the latter case, the derivatives of the invention act as prodrugs. Particularly preferred prodrugs are ester derivatives that are esterified at one or more free hydroxyls and are activated by hydrolysis in vivo. Other preferred prodrugs are covalently bonded compounds that release the active parent drug of formula (I) after cleavage of the covalent bond in vivo.

[0167] The pharma- ceutically acceptable derivatives of the present invention retain some or all of the activity of the parent compound. In some cases, the activity is increased by derivatization. Derivatization may also increase other biological activities of the compound, such as bioavailability.

[0168] The term pharma- ceutically acceptable salt as applied to ridinilazole tetrahydrate defines any non-toxic organic or inorganic acid addition salt of the free base compound that is suitable for use in contact with mammalian tissue, without undue toxicity, irritation, or allergic response, and commensurate with a reasonable benefit / risk ratio. Suitable pharma- ceutically acceptable salts are well known in the art. Examples include salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid), organic carboxylic acids (e.g., acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, and mandelic acid), and organic sulfonic acids (e.g., methanesulfonic acid and p-toluenesulfonic acid). The compounds of the present invention can be converted into their salts (monobasic or dibasic) by reaction with a suitable base, e.g., an alkali metal hydroxide, methoxide, ethoxide, or tert-butoxide, e.g. selected from NaOH, NaOMe, KOH, KOtBu, LiOH, and BuLi, or an alkyl lithium; pharma- ceutically acceptable salts of ridinilazole tetrahydrate can also be prepared in this manner.

[0169] These salts and free base compounds may exist in solvated, hydrated or substantially anhydrous form. Crystalline forms of the compounds of the invention are also contemplated, and generally, the acid addition salts of the compounds of the invention are crystalline materials.

[0170] The term pharma- ceutically acceptable solvate as applied to ridinilazole tetrahydrate defines any pharma- ceutically acceptable solvate form of the specified compound that retains the biological effectiveness of the compound. Examples of solvates include combinations of the compounds of the present invention with water (hydrates), short chain alcohols (including isopropanol, ethanol, and methanol), dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine, acetone, dimethylformamide (DMF), dimethylacetamide (DMAc), pyrrolidones (e.g., N-methyl-2-pyrrolidone (NMP)), tetrahydrofuran (THF), and ethers (e.g., tertiary butyl methyl ether (TBME)).

[0171] Also included are miscible formulations of solvated mixtures, such as a combination of a compound of the invention with an acetone-ethanol mixture. In a preferred embodiment, the solvate comprises a compound of the invention in a combination of about 20% ethanol and about 80% acetone. Thus, the structural formulas include compounds having the indicated structure, including hydrated and non-hydrated forms.

[0172] The term pharma- ceutically acceptable prodrug as applied to ridinilazole tetrahydrate defines any pharma- ceutically acceptable compound that is convertible in vivo, under physiological conditions or by solvolysis, to ridinilazole tetrahydrate, to a pharma- ceutically acceptable salt of the compound, or to a compound that shares at least some of the antibacterial activity of the compound (e.g., exhibits activity against Clostridioides difficile).

[0173] The term pharma- ceutically acceptable metabolite as applied to ridinilazole tetrahydrate defines a pharmacologically active product produced through metabolism in the body of ridinilazole tetrahydrate or a salt thereof.

[0174] Prodrugs and active metabolites of the compounds of the invention can be identified using routine techniques known in the art (see, e.g., Bertolini et al., J. Med. Chem., 1997, 40, 2011-2016).

[0175] The term pharma- ceutically acceptable complexes, as applied to ridinilazole tetrahydrate, defines compounds or compositions in which the compounds of the invention form a moiety. Thus, complexes of the invention include derivatives in which the compounds of the invention are physically bound (e.g., by covalent or non-covalent bonds) to one or more other moieties. Thus, the term includes multimeric forms of the compounds of the invention. These multimers can be produced by linking or placing multiple copies of the compounds of the invention in close proximity to each other (e.g., through a scaffold or carrier moiety). The term includes cyclodextrin complexes.

[0176] In its broadest aspect, the present invention contemplates all tautomeric forms, optical isomers, racemic forms, and diastereoisomers of the compounds described herein. Those skilled in the art will recognize that due to the asymmetrically substituted carbon atoms present in the compounds of the present invention, the compounds can be produced in optically active and racemic forms. When a chiral or otherwise isomeric center is present in a compound of the present invention, all forms of that isomer or isomers, including enantiomers and diastereoisomers, are intended to be encompassed herein. Compounds of the present invention that contain one chiral center (or multiple chiral centers) may be used as racemic mixtures, enantiomerically enriched mixtures, or racemic mixtures may be separated using well-known techniques to use individual enantiomers alone. Thus, reference to the compounds of the present invention includes products as diastereomeric mixtures, as individual diastereoisomers, as enantiomeric mixtures, and in the form of individual enantiomers.

[0177] Thus, the present invention contemplates all optical isomers of the compounds of the present invention as well as their racemic forms, and unless otherwise indicated (e.g., by use of a dashed wedge structural formula), the compounds depicted herein are intended to encompass all possible optical isomers of the compounds as depicted. In cases where the stereochemical form of a compound is important to its pharmaceutical utility, the present invention contemplates the use of isolated eutomers.

[0178] As used herein, the term "ridinilazole" is used to define the active ingredient in the present formulation, which is the compound 2,2'-di(pyridin-4-yl)-1H,1'H-5,5'-bibenzo[d]imidazole (sometimes known as 2,2'-di-4-pyridinyl-6,6'-bi-1H-benzimidazole; 5,5'-bis[2-(4-pyridinyl)-1H-benzimidazole]; 2,2'-bis(4-pyridyl)-3H,3'H-5,5'-bibenzimidazole; or 2-pyridin-4-yl-6-(2-pyridin-4-yl-3H-benzimidazol-5-yl)-1H-benzimidazole). This term also includes pharma- ceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites, or prodrugs of ridinilazole as defined herein. Lisdinilazole tetrahydrate (i.e., Form A), the active ingredient in the drug formulation, has the following structure:

[0179] [ka]

[0180] The abbreviation "XRPD" means X-ray powder diffraction (or, where the context permits, X-ray powder diffractogram).

[0181] "Siliconized microcrystalline cellulose" or "SMCC" refers to a particulate aggregate of co-processed microcrystalline cellulose and silicon dioxide. SMCC suitable for use in the present invention may contain silicon dioxide in an amount of about 0.1% to about 20% by weight of the microcrystalline cellulose, where the silicon dioxide may have a particle size of about 1 nanometer (nm) to about 100 microns (μm) based on the average primary particle size. For example, the silicon dioxide may be present at about 0.5% to about 10% by weight of the silicified microcrystalline cellulose, or at about 1.25% to about 5% by weight of the microcrystalline cellulose. Additionally, the silicon dioxide may have a particle size of about 5 nm to about 40 μm, or about 5 nm to about 50 μm. The silicon dioxide may have a surface area of ​​about 10 m 2 / g~about 500m 2 / g, or about 50m 2 / g~about 500m 2 / g, or about 175m 2 / g ~ approx. 350m 2 / g. Silicified microcrystalline cellulose is commercially available from several sources known to those skilled in the art, such as Penwest Pharmaceuticals, Inc. under the trademark PROSOLV®. PROSOLV® is available in several grades including, for example, PROSOLV® SMCC 50, PROSOLV® SMCC 90, and PROSOLV® HD. Other products include, but are not limited to, SMCC 50LD, SMCC HD90, and SMCC 90LM.

[0182] The term "substantially identical" with respect to XRPD diffraction patterns means that variability in peak positions and relative intensities of peaks is allowed for. The ability to ascertain substantial identity of X-ray diffraction patterns is within the understanding of one of ordinary skill in the art. For example, typical accuracy of 2θ values ​​is in the range of ±0.2°2θ. Thus, a diffraction peak that normally appears at 14.9°2θ may appear at 14.7°-15.1°2θ on most X-ray diffractometers under standard conditions. In addition, variability may also arise due to the particular instrument used, as well as the degree of crystallinity in the sample, orientation, sample preparation, and other factors. Typically, XRPD measurements are performed at room temperature, e.g., at a temperature of 20° C., and preferably at a relative humidity of 40%.

[0183] As used herein, the term "substantially pure" with respect to a particular crystalline form (polymorph) of ridinilazole is used to define a form that contains less than 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, and most preferably less than 1% by weight of any other physical form of ridinilazole.

[0184] The term "room temperature" (RT) as used herein relates to a temperature between 15°C and 25°C.

[0185] D 90 Particle size is the parameter for which 90% by volume of the particles are smaller than that parameter in their longest dimension as measured by any conventional particle size measurement technique known to those skilled in the art, including, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering (e.g., laser diffraction), and disc centrifugation.

[0186] Composition D 50 Particle size is the parameter for which 50% by volume of the particles in the composition are smaller than that parameter in question in terms of their longest dimension, as measured by any conventional particle size measuring technique known to those skilled in the art (and as described above). Thus, D 50 Particle size is a measure of the volume median particle size, but is sometimes also referred to as the "average" or "mean" particle size.

[0187] Composition D 10 Particle size is the parameter such that 10% by volume of the particles in the composition are smaller than that parameter in question in terms of their longest dimension, as measured by any conventional particle size measuring technique known to those of skill in the art (and as described above).

[0188] As used herein, the term "tabletting composition" as used in reference to the compositions of the invention defines a composition comprising ridinilazole tetrahydrate suitable for compression into tablets. Typically, the tableting composition of the invention is suitable as feed for a tablet press, such as a stamp or rotary tablet press. In a preferred embodiment, the tableting composition of the invention is suitable for compression into ridinilazole tetrahydrate tablets comprising an intragranular solid phase embedded in an extragranular solid phase, wherein (a) the intragranular phase has a particle size D of 4 to 30 μm. 90 (b) the extragranular phase comprises ridinilazole tetrahydrate crystalline agglomerates dispersed within a first Pharmaceutically Acceptable Excipient System having the formula:

[0189] "Therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" further includes within its meaning a non-toxic but sufficient amount of a particular drug that is said to exhibit a desired therapeutic effect. The exact amount required will vary from subject to subject, depending on factors such as the patient's general health, the patient's age, etc. The exact amount will depend on the purpose of the treatment and can be ascertained by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0190] "Treat", "treating", and "treatment" refer to any evidence of success in treating or ameliorating an injury, pathology, or condition, including any objective or subjective parameter, such as remission; remission; reduction in symptoms or increasing the patient's tolerance to the injury, pathology, or condition; slowing the rate of decline or decline; less debilitating to the point of ultimate failure; improving the patient's physical or mental health. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical exam, a neuropsychiatric exam, and / or a psychiatric evaluation.

[0191] The abbreviation "(w / w)" refers to the phrase "weight by weight," i.e., the proportion of a particular substance in a mixture measured by weight or mass, or the weight amount of one component of the composition relative to the total weight amount of the composition disclosed herein. Thus, the amount is unitless and represents the weight amount of one component relative to the total weight of the composition. For example, a 2% (w / w) solution means that 2 grams of solute are dissolved in 100 grams of solution.

[0192] However, it should be understood that the tableting compositions of the invention as defined herein may also be suitable for other applications, in particular they may be suitable for use as the basis for dosage forms other than tablets, including liquid suspensions, granule-filled capsules, and granule-filled sachets (or other containers).

[0193] Method for producing ridinilazole tetrahydrate tablets Both the small scale synthesis (approximately 1 kg granulation, 6 liter granulator) and the large scale synthesis (approximately 3 kg, 25 liter granulator and 9 kg granulation, 65 liter granulator) are essentially the same and are described in the manufacturing process shown in FIG. 15.

[0194] Overall, the process development studies demonstrated the importance of the wet agglomeration step, including the use of micronized API, as well as the appropriate ratio of intragranular to extragranular phase in the final blend to be compressed into tablets exhibiting suitable hardness and disintegration time.

[0195] Prototype tablet process manufacturing trials showed that the wet agglomeration step was critical to the product, as the granulation endpoint was reached within a short wetting rate window. Attempts to use lower granulation water levels (20% and 15%) to produce lower density granules confirmed that lower water levels could be effective in the granulation step and could produce granules with good morphology. However, reducing the amount of purified water added during the granulation process did not always result in core tablets with good hardness and short disintegration times. Also, one product lot evaluated using this process did not produce good granules and tableting could not proceed.

[0196] It was deemed that agglomerated particles in the API and the predominance of API in the blend in the granulator during wet agglomeration of the prototype tablet process (approximately 65% ​​by weight of the granulated blend) may have contributed to the poor granulation reproducibility. Therefore, tests were conducted to try to improve the granulation latitude and the granulation and dissolution reproducibility for the tablet process.

[0197] To recognize the presence of varying amounts of aggregates in the API, it was decided to use micronized API. This would ensure that the API particle characteristics are more consistent from lot to lot, e.g., in terms of particle size distribution, and may facilitate the reproducibility of the wet granulation step. To increase the flexibility of the wet granulation step, an additional portion of the excipients (other than magnesium stearate) was transferred from the external phase to the internal phase of the wet granulation step, such that the internal phase constituted 90% by weight of the final blend.

[0198] Small scale testing (approximately 200 g granulation in a 1 L granulation bowl) confirmed improved latitude in granulation end points. Granules with good morphology were produced over a range of 30% to 37% by weight of water added during wet granulation, producing tablets that exhibited good hardness (approximately 170 N) with short disintegration times (approximately 5 minutes). The identified tableting manufacturing process was adapted to 6 L (approximately 1 Kg granulation), 25 L (approximately 3 Kg granulation), and 65 L (approximately 9 Kg granulation) granulation bowls, and the process was advanced to the production of larger scale feeds.

[0199] To avoid flow issues observed during initial investigations of the dry granulation options of direct compression and roller compaction, a conventional wet granulation approach to product manufacturing was pursued. Initial studies, described here as tablet development, focused on excipient selection and amounts, as well as initial wet granulation parameters (e.g., water addition rate). Subsequent studies were conducted to validate the process for the clinical trial formulation in order to improve the performance of the granulation process.

[0200] After initial development and compatibility testing, a prototype wet granulation tablet formulation was identified. Compatibility of ridinilazole tetrahydrate active substance with a range of excipients routinely utilized in tablet formulations was effectively demonstrated. The wet granulation formulation screening identified a lead formulation that produced granules that exhibited good flowability and acceptable tablet processability at low compression forces on a small scale. The prototype tablet formulation showed rapid disintegration and complete dispersion in less than 4 minutes. This was scaled up to proceed with a pilot run of 1,000 tablets that allowed samples to be subjected to 6-month stability testing. No significant changes in appearance, assay, related substances, hardness, moisture content, or disintegration time were observed under long-term (25°C / 60% RH) or accelerated (40°C / 75% RH) conditions, thus confirming the stability of the prototype tablet formulation.

[0201] Further development and optimization was then pursued using small scale prototype tablet formulations with the goal of identifying a manufacturing process that would allow for the production of robust tablets suitable for large scale high speed tablet presses. The prototype formulations were investigated in studies evaluating changes in lactose:crystalline cellulose ratio, amount of disintegrant, amount of binder, and amount of water. Eleven formulations were produced and tested. Extreme and central points across the compression curves were also tested to understand compaction behavior. Key outputs were run through a statistical software package to identify any trends in critical property attributes. However, tablets from these studies were found to exhibit longer disintegration times compared to the original process prototype tablets, thus necessitating further investigation.

[0202] Therefore, a second study was then conducted employing a "one variable at a time" approach to establish a process for a prototype formulation capable of producing tablets that meet the desired target formulation profile regarding disintegration, dissolution, manufacturability, and ability to produce a robust formulation for scale-up. The amount of binder, the amount of water, the lactose distribution ratio (intragranular / extragranular), and the disintegrant distribution ratio (intragranular / extragranular) were further evaluated to try to establish the final optimization process. However, these tablets showed problems with granule endpoint detection and, as a result, problems with flowability in the tablet press on the one hand, and tablet crushing strength / disintegrability on the other hand. Despite the challenges with the granulation process, it was possible to produce tablets that were subjected to stability testing.

[0203] Therefore, further development of the granulation was carried out to further ensure tablet manufacturing process acceptability at a larger scale and suitable for manufacturing. It was developed without changing the quantitative and qualitative composition from the one already developed by transferring most of the excipients in the tablet to the intragranular phase and optimizing the particle size of the excipients remaining in the extragranular phase. Furthermore, the use of micronized and particle size controlled ridinilazole tetrahydrate drug substance to enhance the reproducibility of drug substance properties during wet granulation resulted in a process that showed acceptable latitude for granulation endpoint based on water requirement and good flowability in the tablet press.

[0204] Excipients The tablets and tableting compositions of the present invention comprise two separate pharma- ceutically acceptable excipient systems, referred to herein as the first and second pharma- ceutically acceptable excipient systems.

[0205] In the case of the ridinilazole tetrahydrate tablets of the present invention, the first pharma- ceutically acceptable excipient system forms part of the intragranular phase along with dispersed ridinilazole tetrahydrate crystal agglomerates, while the second pharma-ceutically acceptable excipient system constitutes the extragranular phase relative to the intragranular phase comprising the API and the first excipient system.

[0206] Similarly, in the case of the tableting composition of the present invention, the first Pharmaceutically Acceptable Excipient System is present intragranularly along with dispersed ridinilazole tetrahydrate crystal agglomerates, and these granules are surrounded by the second Pharmaceutically Acceptable Excipient System (the second excipient system is therefore extragranular).

[0207] Each excipient system comprises at least one pharma- ceutically acceptable excipient, although in preferred embodiments, both excipient systems comprise two or more chemically and / or functionally distinct excipients.

[0208] The two excipient systems of the tablets and tableting compositions of the present invention are distinct or different, and may differ in particular (a) with respect to the nature of the excipient or excipients present, (b) with respect to the number of chemically and / or functionally distinct excipients present, (c) with respect to the concentration of the excipients present, (d) with respect to the relative concentrations of two or more excipients present, and / or (e) with respect to the presence or absence of distinct functional classes of excipients.

[0209] In a preferred embodiment, both the first and second pharma- ceutically acceptable excipient systems include a diluent. In this specification, the diluent may be referred to as a "first diluent" when present in the first pharma- ceutically acceptable excipient system, and may be referred to as a "second diluent" when present in the second pharma- ceutically acceptable excipient system. Preferably, two distinct diluents are used in one or both of the first and second pharma- ceutically acceptable excipient systems, which may be referred to herein as a first diluent and a second diluent, respectively.

[0210] In a preferred embodiment, both the first and second pharma- ceutically acceptable excipient systems contain a disintegrant. In this specification, the disintegrant may be referred to as "first disintegrant" when present in the first pharma- ceutically acceptable excipient system, and may be referred to as "second disintegrant" when present in the second pharma- ceutically acceptable excipient system. Preferably, one disintegrant is used in one or both of the first and second pharma- ceutically acceptable excipient systems, which may be referred to as the first disintegrant and the second disintegrant, respectively, in this specification. The first and second disintegrants may be the same or different, and in a preferred embodiment, the first and second disintegrants are the same.

[0211] In a preferred embodiment, the first pharma- ceutically acceptable excipient system comprises a binder, while the second pharma- ceutically acceptable excipient system does not comprise a binder.

[0212] In a preferred embodiment, the first pharma- ceutically acceptable excipient system does not include a lubricant, while the second pharma- ceutically acceptable excipient system includes a lubricant.

[0213] Thus, in certain preferred embodiments, the two excipient systems differ with respect to the presence / absence of two specific functional classes of excipients: binders and lubricants. Specifically, it is particularly preferred that (a) the first pharmaceutically acceptable excipient system comprises binders, and this class of excipients is absent in the second excipient system, while (b) the second pharmaceutically acceptable excipient system comprises lubricants, and this class of excipients is absent in the first excipient system.

[0214] In various embodiments, depending on the first and second excipient systems used, the tablet formulation may be delivered as immediate release, sustained release, extended release, delayed release, or a combination thereof.

[0215] Functional classes of excipients Diluent As described above, both the first and second pharmaceutically acceptable excipient systems can include a diluent.Any suitable pharmaceutically acceptable diluent or its combination can be used.These include the diluent that comprises, consists of, or essentially consists of lactose monohydrate and / or microcrystalline cellulose, for example the combination of lactose monohydrate and microcrystalline cellulose.

[0216] In a preferred embodiment, the first diluent comprises, consists of, or consists essentially of a combination of lactose monohydrate 200M and Avicel PH101®. In another preferred embodiment, the second diluent comprises, consists of, or consists essentially of a combination of lactose monohydrate 100M and Avicel PH102®.

[0217] Disintegrants As described above, both the first and second pharma- ceutically acceptable excipient systems can include a disintegrant.Any suitable pharma- ceutically acceptable disintegrant or combinations thereof can be used.These include disintegrants selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch.

[0218] Croscarmellose sodium, e.g., Ac Di Sol® or Primellose®, is particularly preferred as the first and second disintegrants. Croscarmellose sodium has been found to be unexpectedly advantageous as a disintegrant in the tablets and tableting compositions of the present invention. Without wishing to be bound by theory, it is believed that ionic interactions between ridinilazole tetrahydrate and croscarmellose sodium occur with the formation of an anionic hydrogel upon contact with water (see, e.g., Huang et al. (2006) Elimination of meformin-croscarmellose sodium interaction by competition Int J Pharm 311(1-2): 33-39). In particular, the inventors have unexpectedly found that when croscarmellose sodium is used as a disintegrant, disintegration times are improved compared to otherwise identical tablets in which crospovidone is used as a disintegrant.

[0219] Binder As explained above, the first pharma- ceutically acceptable excipient system may include a binder (whereas the second pharma- ceutically acceptable excipient system preferably does not include a binder). Any suitable pharma- ceutically acceptable binder or combinations thereof may be used. Preferred binders include, consist of, or consist essentially of hydrophilic polymers.

[0220] Suitable binders may be selected from polyvinylpyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ethers. For example, the binder may include a cellulose ether selected from hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), and sodium carboxymethylcellulose (NaCMC).

[0221] In a preferred embodiment, the binder comprises, consists of, or consists essentially of hydroxypropylcellulose, which is present only in the first pharma- ceutically acceptable excipient system (the second pharma-ceutically acceptable excipient system does not comprise a binder).

[0222] lubricant As explained above, the second pharma- ceutically acceptable excipient system may include a lubricant (whereas the first pharma- ceutically acceptable excipient system is preferably lubricant-free).Any suitable pharma- ceutically acceptable lubricant or combinations thereof may be used.

[0223] Preferred lubricants may be selected from (a) fatty acids; (b) metal salts of fatty acids; (c) combinations of fatty acids and their metal salts; (d) fatty acid esters; (e) metal salts of fatty acid esters; and (f) inorganic materials and inorganic polymers.

[0224] Suitable fatty acid lubricants may be selected from stearic acid, palmitic acid, and myristic acid. Suitable metal salts of fatty acids may be selected from magnesium stearate, calcium stearate, and zinc stearate. Combinations of the above are also suitable, for example, the lubricant may include a combination of stearic acid and magnesium stearate.

[0225] The lubricant comprises a fatty acid ester selected from glyceride esters and sugar esters. For example, the lubricant comprises a glyceride ester selected from glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate. Also suitable are sugar esters selected from sorbitan monostearate and sucrose monopalmitate. The lubricant may also comprise, consist of, or consist essentially of sodium stearyl fumarate and / or lysine.

[0226] In a preferred embodiment, the lubricant comprises, consists of, or consists essentially of magnesium stearate, more preferably it is present only in the second pharma- ceutically acceptable excipient system (the first pharma-ceutically acceptable excipient system does not comprise a lubricant).

[0227] Active Pharmaceutical Ingredients (API) The API present in the tablet and tableting composition of the present invention is ridinilazole tetrahydrate.The term ridinilazole as used herein is used to define the compound 2,2'-di(pyridin-4-yl)-1H,1'H-5,5'-bibenzo[d]imidazole (also known as 2,2'-di-4-pyridinyl-6,6'-bi-1H-benzimidazole; 5,5'-bis[2-(4-pyridinyl)-1H-benzimidazole]; 2,2'-bis(4-pyridyl)-3H,3'H-5,5'-bibenzimidazole; or 2-pyridin-4-yl-6-(2-pyridin-4-yl-3H-benzimidazol-5-yl)-1H-benzimidazole). The term also includes pharma- ceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites, or prodrugs of ridinilazole as defined herein, such as ridinilazole tetrahydrate.

[0228] The ridinilazole tetrahydrate present in the tablets and tableting compositions of the present invention is preferably in the form of ridinilazole tetrahydrate crystalline aggregates. Ridinilazole tetrahydrate Form A (as defined herein) is particularly preferred.

[0229] Thus, in the above ridinilazole tetrahydrate tablet formulation, the ridinilazole tetrahydrate API is preferably present in the form of ridinilazole tetrahydrate crystalline Form A, characterized by an X-ray powder diffractogram containing characteristic peaks at 2θ angles of (11.02±0.2)°, (16.53±0.2)°, and (13.0±0.2)°.

[0230] particle size Ridinilazole tetrahydrate exhibits very low water solubility and relatively low wettability, and the inventors have unexpectedly discovered that control of API particle size is important in controlling variability in the processability and performance of the tablets, tableting compositions, and processes of the present invention that directly or indirectly affect granule structure and thereby tablet quality.

[0231] In particular, D outside the range of about 10 to about 20 μm 90 (especially D less than 4 μm or more than 30 μm 90 It has been found that ridinilazole tetrahydrate tablets manufactured using a drug substance having crystalline agglomerate particles (having a crystal structure of at least 100 μm) yield tablets with properties that are unsuitable for the manufacture and performance of a drug formulation (see Example 9 below).

[0232] In some embodiments, the crystal aggregates have a particle size D of about 5 μm to about 40 μm. 90 and preferably has a particle size D of about 10 to about 20 μm. 90 In other embodiments, the crystalline aggregates have a particle size D of less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 5 μm. 90 may have.

[0233] Thus, ridinilazole tetrahydrate API is formulated in the tablets, tableting compositions, and methods of the present invention to have a particle size D of about 4 to about 30 μm. 90 , preferably 7 to 25 μm D 90 , more preferably 10 to 20 μm D 90 Ridinilazole tetrahydrate exists in the form of aggregates having the formula:

[0234] Size reduction of ridinilazole tetrahydrate API (e.g., when provided in the form of crystalline ridinilazole tetrahydrate Form A) can be accomplished by any convenient method, including milling, grinding, sieving, and / or screening. Particle size reduction by air jet milling is preferred.

[0235] API particle size can be determined using any convenient and well documented analytical technique, including sedimentation field flow fractionation, photon correlation spectroscopy, light scattering (e.g. laser diffraction), and disc centrifugation. Dry laser diffraction methods, as described herein, are preferred.

[0236] Secondary flocculation, pre-blending, and API distribution Bulk solids at rest (i.e., aggregates) such as dry powders or granules tend to form agglomerates driven by more or less strong attractive forces. The strength of these forces depends on the material properties, surface conditions, residual moisture, and particle size, and may include van der Waals forces, capillary forces, and / or electrostatic and magnetic forces. In general, the smaller the particles, the greater the tendency to bind.

[0237] The inventors unexpectedly found that the desired particle size D of 4 to 30 μm was obtained. 90 It has been discovered that APIs having reduced particle size exhibit a significant tendency to re-agglomerate to form secondary "soft agglomerates." Specifically, ridinilazole tetrahydrate API that has undergone a particle size reduction operation (e.g., air jet milling or other micronization methods) is a highly cohesive, poorly flowing powder that exhibits static charge and a tendency to recombine to form secondary "soft agglomerates."

[0238] These secondary agglomerates are problematic in that they prevent efficient blending with the first excipient system of the present invention. Therefore, it has been found important to break down the agglomerates before combining ridinilazole tetrahydrate into the first excipient blend for granulation to ensure that no agglomerates remain after the wet granulation and drying processes. This avoids the presence of "hot spots" due to poor distribution of ridinilazole tetrahydrate in the finished granules and tablets, which results in undesirable variability in the uniformity of the API in the tablets and tableting compositions.

[0239] The soft agglomerates of ridinilazole tetrahydrate particles cause blockage and clogging of sieve and screen openings and oozing over their surfaces, so that the particle size D of 4 to 30 μm 90 Sieving or screening the reduced particle size ridinilazole tetrahydrate having a particle size of 0.01 to 0.01 mm is a very difficult and time-consuming operation, whether done manually or mechanically (e.g. using a cone mill or oscillator). Ultimately, this leads to blockages, which entail interrupting the process allowing cleaning / clearing, and also to incomplete and time-consuming transfer of the powder through the sieve. Sieving and screening is therefore difficult, time-consuming, and even impossible.

[0240] This problem is caused by the particle size D of 4 to 30 μm. 90 This can be overcome by preparing a pre-blend of ridinilazole tetrahydrate crystalline aggregate particles having a first granular excipient system (e.g., a subset of the constituent excipients of the first excipient system as defined herein) with a portion of the first pharma- ceutically acceptable intragranular excipient system having a first diluent having a first diluent content of 0.01 to 0.01% by weight (e.g., 0.01 to 0.01%). For example, it has been found that blending ridinilazole tetrahydrate particles with all of the first excipients except for some or all of the first diluent (e.g., microcrystalline cellulose in preferred embodiments) to form an initial intermediate blend allows for efficient and easy sieving of the intermediate blend, allowing for effective disintegration of all soft agglomerates of ridinilazole tetrahydrate.

[0241] The screen can then be "washed" or "flushed" with the retained excipient (e.g., microcrystalline cellulose in the preferred embodiment), which has been found to be effective in transferring any granular blend of first excipient and API remaining on the surface of the screen into the final blend (e.g., the microcrystalline cellulose or other first diluent that passes through the screen can be combined with the remaining ridinilazole tetrahydrate mixture already screened, and then the entire material can be mixed at the end to obtain the final blend for granulation).

[0242] These processes ensure good and uniform distribution of ridinilazole tetrahydrate API within the intragranular phase of the tablets of the present invention and within the granules of the various compositions of the present invention.

[0243] The above findings are applicable to the method for producing the composition of the present invention. For example, it is applicable to the method for producing the granulated ridinilazole tetrahydrate composition according to the third aspect of the present invention described above. In these cases, the ridinilazole tetrahydrate aggregates are first mixed with a first portion of a first pharma- ceutically acceptable intragranular excipient system to form an initial pre-granulation mixture, then the pre-granulation mixture is screened or sieved to form a screened initial pre-granulation mixture, and then a second portion of the first pharma- ceutically acceptable intragranular excipient system is passed through the same screen or sieve to form a screened second portion. The screened initial pre-granulation mixture and the screened second excipient portion can then be mixed to form a final pre-granulation mixture for granulation according to step (c) of the third aspect of the present invention. In this way, "hot spots" caused by soft agglomerates of ridinilazole tetrahydrate can be avoided, resulting in more uniform distribution of ridinilazole tetrahydrate API in the tableting composition (and ultimately the ridinilazole tetrahydrate tablet).

[0244] Pre-blending and API distribution in other particulate or granular ridinilazole tetrahydrate compositions As explained above, the tableting compositions of the present invention may also be suitable for use as the basis for dosage forms other than tablets, including liquid suspensions, granule-filled capsules, and granule-filled sachets (or other containers). Thus, the recognition of the potential problems caused by reagglomeration in reduced size ridinilazole tetrahydrate particulate compositions, and the discovery of the advantages associated with effective means to prevent, remove, or break up secondary soft agglomerates (e.g., by the pre-blending step described above), also applies to the manufacture of ridinilazole tetrahydrate compositions that share the composition of the tableting compositions of the present invention, but are suitable for applications other than tableting, including other oral dosage forms such as liquid suspensions, granule-filled capsules, and granule-filled sachets.

[0245] The above findings therefore have broad application to the preparation of granular or particulate ridinilazole tetrahydrate compositions that are substantially free of secondary soft agglomerates (formed by the above-mentioned re-agglomeration of reduced particle size API). The present invention therefore provides a method for producing granular or particulate ridinilazole tetrahydrate compositions having a particle size D of 4 to 30 μm that are substantially free of secondary soft agglomerates resulting from the re-agglomeration of crystalline aggregates. 90 Also contemplated is a granular or particulate ridinilazole tetrahydrate composition comprising crystalline agglomerates of crystalline ridinilazole tetrahydrate having the formula:

[0246] These granular or particulate ridinilazole tetrahydrate compositions are preferably, but not necessarily, suitable for compression into tablets. For example, they may be suitable for applications other than tableting. These applications include oral and parenteral ridinilazole tetrahydrate pharmaceutical compositions. For example, the granular or particulate ridinilazole tetrahydrate compositions of the present invention may take the form of, or be adapted for the preparation of, pharmaceutical formulations other than tablets, including liquid suspensions, granular-filled capsules, and granular-filled sachets (or other containers).

[0247] Tablet formulation The ridinilazole tetrahydrate tablet of the present invention comprises an intragranular solid phase incorporated in an extragranular solid phase, wherein (a) the intragranular phase has a particle size D of about 4 to about 30 μm. 90(b) the extragranular phase comprises ridinilazole tetrahydrate aggregates dispersed within a first pharma- ceutically acceptable excipient system having the following composition: (a) the extragranular phase comprises a second pharma- ceutically acceptable excipient system, wherein the first excipient system and the second excipient system are different. A preferred ridinilazole tetrahydrate tablet of the present invention has the following composition:

[0248] [Table 2]

[0249] A more preferred ridinilazole tetrahydrate tablet of the present invention has the following composition:

[0250] [Table 3]

[0251] A more preferred ridinilazole tetrahydrate tablet of the present invention has the following composition:

[0252] [Table 4]

[0253] A more preferred ridinilazole tetrahydrate tablet of the present invention has the following composition:

[0254] [Table 5]

[0255] A more preferred ridinilazole tetrahydrate tablet of the present invention has the following composition:

[0256] [Table 6]

[0257] A more preferred ridinilazole tetrahydrate tablet of the present invention has the following composition:

[0258] [Table 7]

[0259] A more preferred ridinilazole tetrahydrate tablet of the present invention has the following composition:

[0260] [Table 8]

[0261] In the above exemplary tablet formulations, the tablet preferably further comprises a coating, such as a water-soluble polymer film.

[0262] In the above exemplary tablet formulations, the tablet preferably contains about 100 to about 400 mg of ridinilazole tetrahydrate, more preferably about 100 to about 300 mg of ridinilazole tetrahydrate, even more preferably about 150 to about 250 mg of ridinilazole tetrahydrate, and most preferably about 200 mg of ridinilazole tetrahydrate. One skilled in the art could calculate, for example, that about 200 mg of ridinilazole tetrahydrate is equivalent to 169 mg of ridinilazole on an anhydrous basis.

[0263] A particularly preferred tablet formulation has the following composition:

[0264] [Table 9]

[0265] In the above ridinilazole tetrahydrate tablet formulation, ridinilazole tetrahydrate API is preferably present in the form of ridinilazole tetrahydrate crystalline Form A, characterized by an X-ray powder diffractogram containing characteristic peaks at 2θ angles of (11.02±0.2)°, (16.53±0.2)°, and (13.0±0.2)°.

[0266] The most preferred tablet formulations have one of the following compositions:

[0267] [Table 10]

[0268] [Table 11]

[0269] Treatment The described formulations comprising ridinilazole tetrahydrate (e.g., ridinilazole tetrahydrate form A) can be utilized to treat or eliminate Clostridium difficile infection (CDI) and / or one or more Clostridioides difficile associated diseases (CDAD). In some embodiments, CDI comprises toxin A and / or toxin B C. difficile in the feces. In some embodiments, a subject in need is administered a composition comprising ridinilazole tetrahydrate. In some embodiments, the composition comprises a ridinilazole tetrahydrate tablet as described herein. The administration can be effective to reduce or eliminate CDI and / or CDAD in a subject in need.

[0270] In some embodiments, a subject in need thereof is treated with a therapeutically effective amount of ridinilazole tetrahydrate (e.g., ridinilazole tetrahydrate form A). In some embodiments, a subject in need thereof is treated with a therapeutically effective amount of ridinilazole tetrahydrate, where a therapeutically effective amount is an amount sufficient to reduce or eliminate at least one symptom of CDI and / or CDAD. In some embodiments, a therapeutically effective amount comprises at least about 200 mg, at most about 200 mg, or about 200 mg of ridinilazole tetrahydrate, one or more times per day. In embodiments, the therapeutically effective amount comprises about 10, 25, 50, 75, 100, 120, 140, 160, 180, 185, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 275, 300, 350, 400, 450, or 500 mg of ridinilazole tetrahydrate (e.g., ridinilazole tetrahydrate Form A).

[0271] One of ordinary skill in the art will appreciate that, for example, about 100 mg of ridinilazole tetrahydrate is equivalent to 84.5 mg of ridinilazole on an anhydrous basis (and that about 200 mg of ridinilazole tetrahydrate is equivalent to 169 mg of anhydrous ridinilazole).

[0272] Thus, in certain embodiments, administering one amount of ridinilazole tetrahydrate Form A is equivalent to administering to a subject about 8.45, 17, 25.5, 43, 76, 84.5, 93, 101, 110, 118, 126.5, 135, 143.5, 152, 160.5, 169, 178.5, 190, 200, 210, 220, 230, 240, 250, 275, 300, 350, 400, 450 mg of ridinilazole content on an anhydrous basis.

[0273] In some embodiments, ridinilazole tetrahydrate is administered to a subject in need thereof for any number of days. In some embodiments, ridinilazole tetrahydrate is administered for about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or up to 30 days. In some embodiments, ridinilazole tetrahydrate is administered for about 10 days. In some embodiments, ridinilazole tetrahydrate is administered for about 5-10 days. In some embodiments, ridinilazole tetrahydrate is administered for about 5-20 days. In some embodiments, ridinilazole tetrahydrate is administered multiple times per day. For example, ridinilazole tetrahydrate can be administered once, twice, three times, four times, five times, or six times a day, preferably twice a day. In some embodiments, ridinilazole tetrahydrate is administered every 12 hours. In some embodiments, ridinilazole tetrahydrate is administered until CDI and / or CDAD are resolved. In some embodiments, ridinilazole tetrahydrate is administered until symptoms of ridinilazole tetrahydrate are reduced or eliminated.

[0274] In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing CDI and / or CDAD as determined by a reduction or elimination of symptoms associated with CDI, including, but not limited to, diarrhea (e.g., irregular stool), fever, stomach tenderness, loss of appetite, nausea, and combinations thereof. In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing symptoms of CDI and / or CDAD for at least about 1 day compared to another comparable subject not administered the drug. In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing symptoms of CDI and / or CDAD for at least about 1 day, 2 days, 3 days, 4 days, or 5 consecutive days compared to another comparable subject not administered the drug.

[0275] In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing CDI and / or CDAD, as determined by a reduction in the frequency of unformed bowel movements (UBM) by the subject compared to pre-administration. In some embodiments, administration of ridinilazole tetrahydrate is effective in eliminating CDI and / or CDAD in a subject in need thereof, as determined by elimination of unformed bowel movements (UBM). In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing detection of UBM for at least about one day, compared to an otherwise matched subject not administered. In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing detection of UBM for at least about one day, two days, three days, four days, or five consecutive days, compared to an otherwise matched subject not administered. In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing the recurrence of diarrhea episodes (e.g., more than about three UBM) for one day. In some embodiments, the subject in need shows clinical response after administration of ridinilazole tetrahydrate.In some embodiments, the subject in need does not show recurrence of CDI and / or CDAD for about 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 160 days, 170 days, 180 days, 190 days, or 200 days after treatment.In some embodiments, the subject in need does not show recurrence of CDI and / or CDAD for at least about 30 days or 90 days after treatment.

[0276] In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing CDI and / or CDAD, as determined by a reduction in the frequency of unformed bowel movements (UBM) by the subject compared to an otherwise comparable subject receiving vancomycin. In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing detection of UBM compared to another otherwise comparable subject receiving vancomycin for at least about 1 day. In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing detection of UBM compared to an otherwise comparable subject receiving vancomycin for at least about 1 day, 2 days, 3 days, 4 days, or 5 consecutive days. In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing recurrence of diarrheal episodes (e.g., more than about 3 UBM) compared to an otherwise comparable subject receiving vancomycin for 1 day.

[0277] UBM can be determined by the Bristol Stool Form Chart. See FIG. 16. In some embodiments, UBM comprises stool types 5, 6, or 7 on the Bristol Stool Form Chart. In some embodiments, administration of ridinilazole tetrahydrate is effective in reducing the frequency (time frequency) or detection of UBM in a subject in need thereof. In some embodiments, administration of ridinilazole tetrahydrate is effective in changing the stool type of a subject in need from type 5, 6, or 7 to a type selected from the group consisting of 1, 2, 3, and 4. In some embodiments, administration of ridinilazole tetrahydrate is effective in changing the stool type by at least about 1, 2, 3, 4, 5, or 6 types based on the Bristol Stool Form Chart compared to an otherwise comparable subject not receiving the treatment.

[0278] In some embodiments, the subject in need is already receiving an antibiotic. In some embodiments, the antibiotic is selected from the group consisting of ampicillin, amoxicillin, cephalosporin, and clindamycin. However, any antibiotic is contemplated. In some embodiments, the subject is co-treated with ridinilazole tetrahydrate and at least one additional therapeutic agent. In some embodiments, the one additional therapeutic agent comprises an antibiotic. In some embodiments, the subject in need is already receiving an antibiotic that is not ridinilazole tetrahydrate. In some embodiments, the subject in need is already receiving vancomycin.

[0279] In some embodiments, the subject in need has been hospitalized or is currently hospitalized. In some embodiments, the subject in need has antibiotic-resistant C. difficile. In some embodiments, the subject in need is immunosuppressed. In some embodiments, the subject in need is undergoing cancer chemotherapy.

[0280] In some embodiments, CDI is detected using an in vitro assay, including, but not limited to, ELISA, latex agglutination assay, cell cytotoxicity assay, PCR, C. difficile culture, and combinations thereof. EXAMPLES

[0281] Working Example The present invention will now be described with reference to specific examples, which are merely exemplary and for illustrative purposes only, and are in no way intended to limit the scope of the claimed exclusivity or the scope of the invention described. These examples constitute the best modes currently contemplated for carrying out the invention.

[0282] method Water activity (A w ) Water activity coefficients and water activities were calculated using the UNIFAC activity coefficient calculator (Choy, B.; Reible, D. (1996). UNIFAC Activity Coefficient Calculator (Version 3.0, 1996) [Software]. University of Sydney, Australia and Louisiana State University, USA).

[0283] X-ray powder diffraction (XRPD) XRPD analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detection system. Isothermal samples were analyzed in transmission mode and held between low density polyethylene films. The XRPD program used a range of 3-40°2θ, a step size of 0.013°, a count time of 99 s, and a run time of approximately 22 min. XRPD patterns were screened using HighScore Plus 2.2c software.

[0284] Carbon (Norit®) Treatment: Crude ridinilazole is dissolved in methanol + 30% sodium methoxide, the resulting solution is treated with Norit® SX Plus (0-0.5 wt), and the mixture is stirred. The Norit® is then filtered off through a filter aid. Water is then added to the filtrate, followed by acetic acid to precipitate the purified ridinilazole.

[0285] In vitro dissolution assay Determined by HPLC using 2.5% sodium lauryl sulfate (SLS) in 0.01N HCl with the solubility parameters shown in the table below.

[0286] Degassed dissolution medium (1 liter) is placed in the dissolution vessel and equilibrated to 37±0.5°C. The tablet to be analyzed is dropped into the dissolution vessel and allowed to sink to the bottom of the vessel. Paddle rotation (100 rpm) is then started. Using a syringe fitted with a stainless steel cannula and full-flow filter, 5 mL of solution is removed from the area midway between the surface of the dissolution medium and the top of the paddle, at least 1 cm from the vessel wall, at 15, 30, 45, and 60 minutes. After 60 minutes, the rotation speed is increased to 250 rpm, and after 15 minutes of rotation, 5 mL of solution is removed from the vessel. The solution is then filtered through an Acrodisc 25 mm syringe filter with a 1 μm glass fiber membrane, the first 3 mL of filtrate is discarded, and the remaining filtrate is collected in an HPLC vial for analysis.

[0287] Ridinilazole Crystalline Agglomerate Particle Sizing This was done by laser diffraction using a Malvern 2000 dry dispersion instrument. The settings used for sizing are described below. Equipment: Malvern Mastersizer dry dispersion equipment Balancing: Min. 2 faces equipment method Accessory name: Scirocco 2000 Mode: General purpose Calculation sensitivity: Normal (select "Fine Power" for finely powdered samples only) Sample refractive index: 1.704 Particle Absorption: 0.01 Obscuration limits: 0.1% to 6.0% (if achievable) Vibration supply rate: 45% Mesh size: large mesh, 1.6mm Sample measurement time: 20 seconds Dispersion air pressure: 2bar Sample tray: General purpose (<200g) Aliquots: 3 per method Measurement: 1 per aliquot Background Time: 3 seconds Measurement snaps: 20,000 Background snap: 3,000

[0288] Sample preparation – triplicate Invert the sample jar or vial 10 times. Weigh out approximately 2 g of sample and transfer to the sample tray. Distribute the sample evenly on the sample tray.

[0289] Example 1: Preparation of ridinilazole form A tetrahydrate crystalline aggregates Reaction: A reaction flask was charged with 4-cyano-pyridine (0.85 kg) and MeOH (5.4 kg) followed by NAM-30 (NaOMe as a 30 wt% solution in MeOH; 0.5 eq; 0.15 kg). The resulting mixture was heated at 60° C. for 10 min and then cooled. This solution was added to a mixture of 3,3'-diaminobenzidine (DAB) (0.35 kg) and acetic acid (0.25 kg) in MeOH (1 L) at 60° C. over 1 h. The mixture was then heated for 2 h. The reaction mixture was allowed to cool to ambient temperature overnight. The crystalline mass was filtered, washed with MeOH (1.4 L) and sucked dry on the filter.

[0290] Purification: Norit treatment was performed four times.

[0291] Polymorph Formation: The desired polymorph was obtained by reslurrying in 20 volumes of 1:3 WFI water:MeOH and drying was carried out in a vacuum drying oven at ambient temperature and under a nitrogen purge for 6 days.

[0292] XRPD analysis showed that this process yielded crystalline aggregates of hydrated ridinilazole form A (see Figure 1). The reflections are shown in Table 1 below.

[0293] [Table 12-1]

[0294] [Table 12-2]

[0295] The crystal aggregates are then divided into those with the target particle size (D 90About 4 to about 30 μm, preferably D 90 About 7 to about 25 μm, more preferably D 90 The mixture was air jet milled to a particle size of about 10 to about 20 μm.

[0296] Example 2: Crystal structure of ridinilazole tetrahydrate form A Single crystals of ridinilazole form A were grown by liquid diffusion at room temperature from a solution of ridinilazole in NMP / dioxane using chloroform as the antisolvent. A needle-shaped crystal specimen with approximate dimensions of 0.380 mm × 0.015 mm × 0.010 mm was used for X-ray crystallography at beamline 119 at the Diamond Light Source.

[0297] The atomic numbering scheme of ridinilazole molecules and water molecules is shown as an ORTEP plot in Figure 2. Packing diagrams of the ridinilazole A-form structure are shown in Figures 3-5 along each crystal axis. Hydrogen bonds between ridinilazole molecules cannot be described, since only one hydrogen bond can be clearly located between N24-H24...N51. Other hydrogen bonds occurring in the structure are formed between water molecules and the imidazole hydrogen and pyridine nitrogen atoms. Due to the large disorder of the water molecules and their hydrogen atoms, the hydrogen bond network cannot be fully resolved.

[0298] Example 3: Preparation of ridinilazole form D Reaction: A reaction flask was charged with 4-cyano-pyridine (0.85 kg) and MeOH (5.4 kg) followed by NaOMe as a 30 wt% solution in MeOH; 0.5 eq; 0.15 kg (NAM-30). The resulting mixture was heated at 60° C. for 10 min and then cooled. This solution was added to a mixture of DAB (0.35 kg) and acetic acid (0.25 kg) in MeOH (1 L) at 60° C. over 1 h. The mixture was then heated for 2 h. The reaction mixture was allowed to cool to ambient temperature overnight. The crystalline mass was filtered, washed with MeOH (1.4 L) and sucked dry on the filter.

[0299] Purification: Norit® treatment was performed four times.

[0300] XRPD analysis showed that this process yielded crystalline aggregates of ridinilazole anhydrate form D (see FIG. 6). The reflections are shown in Table 2 below.

[0301] [Table 13-1]

[0302] [Table 13-2]

[0303] Example 4: Crystal structure of ridinilazole anhydrate form D Single crystals of ridinilazole form D were grown by vapor diffusion at room temperature from an ethanolic solution of ridinilazole using water as the antisolvent and subjected to single crystal structure determination. Prismatic crystal samples of approximate dimensions 0.3 mm × 0.2 mm × 0.1 mm were used for X-ray crystallography.

[0304] The structure was solved by routine automated direct methods and refined by least-squares refinement on all unique F2 measurements. The numbering scheme used in the refinement is shown in Figure 7. The atomic numbering scheme for the ridinilazole molecule is shown as an ORTEP plot in Figure 7. Packing diagrams of the ridinilazole D-form structure are shown in Figures 8-10 along each crystallographic axis. Hydrogen bonds between ridinilazole molecules give rise to a two-dimensional network along the ab plane. Hydrogen bonds are formed between the donor hydrogen imidazole nitrogen atom and the acceptor pyridine nitrogen atom. The network is extended in the third direction through relatively weak interactions between hydrogen atoms and the pi electrons of the aromatic carbons.

[0305] Example 5: Conversion of ridinilazole form D to form A Ridinilazole form D is prepared as described in Example 3. Ridinilazole form A is prepared as described in Example 1. Seed crystals were prepared by manual grinding and sieving. The conversion was carried out as follows: 1) Add D shape. 2) Add MeOH. 3) Heat to 60° C. Stir at 300 rpm. 4) Hold for 15 minutes. 5) Add water over 30 minutes. w Approximately 0.47. 6) Cool to 40°C over 2 hours. 7) Seed with 2 wt. % Form A (or 2 wt. % Form A in a slurry prepared in MeOH / H2O (80 / 20 v / v) and slurried for 2.5 hours prior to addition). 8) Wait 1 hour. Thick slurry, limited mobility. 9) Cool to 20°C over 2 hours. 10) Heat to 40°C for 4 hours. 11) Cool to 20°C over 10 hours. 12) Wait 2.5 hours. Thick mobile slurry. 13) VF. Filtration time: 15 seconds. 14) Wash the reactor three times with 1 volume of MeOH / H2O (80 / 20 v / v). 3 ml each wash. Wash the wet cake with 1 volume of MeOH / H2O (80 / 20 v / v) 3 ml.

[0306] Example 6: Lidinilazole 200mg Oral Tablet Preferred tablet formulations are set forth in Tables 3 and 4 below.

[0307] [Table 14]

[0308] [Table 15]

[0309] XRPD analysis was performed on ridinilazole tablets to confirm that no morphological changes occurred after tableting. One tablet was crushed in a mortar and pestle and analyzed by transmission XRPD. It was not possible to completely separate the small amount of sample coating from the crushed sample.

[0310] The XRPD traces showed a small amount of peak shift when comparing the sample to Form A, but the presence of additional peaks at about 12.5° 2θ and at about 19-24° 2θ. XRPD analysis of ridinilazole tablets, ridinilazole Form A, and the placebo blend confirmed that these additional peaks were due to the placebo mixture (FIG. 12), i.e., the additional peaks were present in the placebo mixture and therefore due to the excipients.

[0311] Stability of ridinilazole crystalline forms in tablets packaged in the intended commercial packaging configuration. Evaluation was performed using a validated specialized X-ray powder diffraction (XRPD) method developed as a limit test for detection of forms D and N in drug formulations. No conversion of forms was detected and therefore form A is stable in the tablets in the proposed commercial packaging configuration and under the proposed storage conditions.

[0312] Example 7: Comparison of release and colonic delivery profiles of ridinilazole capsule and tablet formulations in the in vitro dynamic GI model TIM-1 We also compared the release and colonic delivery profiles of ridinilazole 200 mg capsule and 200 mg tablet formulations in the in vitro dynamic GI model TIM-1. TIM-1 is a dynamic, multicompartmental, and predictive in vitro system that mimics digestive conditions in the intestinal lumen (Minekus M. (2015) The TNO Gastro-Intestinal Model (TIM). In: Verhoeckx K. et al. (eds) The Impact of Food Bioactives on Health. Springer, Cham. https: / / doi.org / 10.1007 / 978-3-319-16104-4_5). Simulated conditions include gastric and small intestinal transit, flow rate and composition of digestive fluids, pH, and removal of water and metabolites. TIM-1 consists of four compartments (stomach, duodenum, jejunum, and ileum) and can mimic fed or fasted conditions.

[0313] Both ridinilazole formulations were tested under simulated fasting conditions and analyzed from each compartment and ileal effluent throughout the time course of the experiment. For compartmental analysis, dialysate samples were obtained from each compartment (stomach, jejunum, ileum) at 60 min intervals.

[0314] Surprisingly, the capsule formulation disintegrated more slowly than the tablet formulation, which resulted in a lower T of ridinilazole measured in the ileal effluent. MAX was found to be delayed compared to the tablet formulation (Figure 13). In the tablet formulation, the maximum amount of ridinilazole was measured within the period of 60 to 120 minutes, whereas in the capsule formulation, it was measured within the period of 120 to 180 minutes.

[0315] Example 8: Comparison of in vivo release profiles of ridinilazole capsule and tablet formulations A single dose pharmacokinetic (PK) study was performed to evaluate the ridinilazole Phase II liquid capsule formulation and the ridinilazole solid tablet formulation of the present invention in dogs. Groups of three animals were administered the test article as a single dose (200 mg) and blood samples were taken 8 hours after administration. All bioanalytical results were below the limit of quantification and there were no adverse effects of either formulation in the study subjects.

[0316] Example 9: Particle size As a material that exhibits very low water solubility and relatively low wettability, control of drug substance particle size is important to control process processability and performance variability, thereby providing control of granule structure and therefore tablet quality.

[0317] The particle size of ridinilazole is controlled within the drug substance, and size reduction of ridinilazole crystalline aggregates is performed as a final step in drug substance manufacture (see Example 1), which not only ensures batch-to-batch consistency of particle size distribution within the drug substance, but also ensures batch-to-batch consistency in both the manufacture and quality of the ridinilazole drug formulation.

[0318] Proposed commercial specification range for reduced particle size drug substance (D 90The suitability of the 10-20 μm diameter granules for manufacturing and performance of the drug formulation was evaluated. Ridinilazole tablets were manufactured using drug substance batches at the limits of the proposed specification (Table 4). Figure 14 shows that the dissolution profiles from these batches exhibiting the limits of the proposed drug substance particle size specification are suitable for manufacturing and performance of the drug formulation.

[0319] [Table 16]

[0320] D outside the range of 10 to 20 μm 90 (especially D less than 4 μm or more than 30 μm 90 and especially D of more than 40 μm 90 Ridinilazole tablets manufactured using drug substances having crystalline agglomerate particles (having crystalline agglomerates) resulted in tableting materials with unsuitable properties for the manufacture and performance of drug formulations.

[0321] Further studies were completed to evaluate the particle size of micronized ridinilazole tetrahydrate used in tablet formulations, and the data are shown in Table 6 below.

[0322] [Table 17]

[0323] According to one embodiment of the present invention, the ridinilazole tetrahydrate crystalline aggregates used to prepare ridinilazole tetrahydrate 200 mg tablets are D 90 Approx. 10μm~Approx. 20μm, D 50 Approximately 2 μm to approximately 9 μm, and D 10 According to another embodiment, the lysinilazole tetrahydrate crystalline aggregates have a particle size in the range of less than 2 μm. 90 Approximately 8μm~approximately 15μm, D 50 Approximately 2 μm to approximately 8 μm, and D 10 It has a particle size in the range of less than 2 μm.

[0324] Example 10: Manufacturing Process Lidinilazole tablets (200 mg) were prepared as described below.

[0325] Wet granulation After screening into a high shear granulation bowl, the batch amounts of ridinilazole (Form A), lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, and croscarmellose sodium for the wet granulation internal phase are subjected to an initial brief premixing at 80 revolutions per minute (rpm) for approximately 1 minute.

[0326] Purified water is added while mixing continues. At 12% water addition and 24% water addition, the wet mass is manually moved through a 2000 μm screen to improve water distribution, returning each time to the granulation bowl to continue granulation. At approximately 35% water addition, the wet granulation is transferred into a fluid bed dryer.

[0327] Drying The wet milled granules are then transferred to a fluid bed dryer with an inlet air temperature of about 60° C. until the target limit of detection (LOD) is achieved. Upon completion of drying, the dried granules are transferred through a Comil equipped with a 1143 μm screen into an appropriately sized blender bin.

[0328] Final Blending The dry milled granules are combined with lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium for the outer granule phase.

[0329] Lubrication The calculated batch amount of magnesium stearate is added to the dry blend and then manually transferred through a 250 μm screen into the 20 L bin containing the final blend. Lubrication is achieved by tumbling the 20 L bin in the blender at 30 rpm for 2 minutes.

[0330] compression Tablets are compressed using oval tooling. Dust removal and metal inspection are performed during line post compression.

[0331] coating The tablet cores are coated with Opadry® II Yellow in a pan coater. The target weight gain of the coated tablets is 3-4%.

[0332] Example 11 Effect of micronization on the tabletting characteristics of ridinilazole API The effect of micronization on the tableting properties of ridinilazole API was investigated on two separate occasions during the development process.

[0333] Initially, during formulation development studies, tablets made with micronized API were compared to tablets made with non-micronized API. Tablets were compressed with both round and capsule tooling and the dissolution profiles were compared (Figure 16).

[0334] Tablets made with non-micronized API showed slower and incomplete dissolution. Disintegration times were also extended.

[0335] During the process understanding campaign, a second test on the effect of micronization was conducted. In this test, a batch of tablets was manufactured using the finished formulation and process. The non-micronized material behaved differently during the wet granulation process. In the standard process, 945g of water is added to the powder at a rate of 200g / min. Four minutes after the water addition, the granules appeared to already be fully granulated. A portion of the granulation was removed at this stage for evaluation, and the remainder of the granulation was allowed to complete.

[0336] Differences were noted during compression. Typically, tablets are compressed to a target hardness of 17.5 kp. It was not possible to achieve this target hardness using the maximum compression pressure of the benchtop machine. Tablets were produced at hardnesses of 7.7 kp and 12.9 kp for two sublots.

[0337] The dissolution profile of the non-micronized batch mirrored that in the previous study: both the rate and extent of dissolution were significantly reduced when compared to batches manufactured by the same process using micronized API (Figure 17).

[0338] Example 12 - Formulation Development The objective of this study was to develop a formulation and process for ridinilazole tetrahydrate drug substance compressed into tablets at 200 mg strength. Table 7 outlines the ingredients to produce tablets that meet the desired specification targets for disintegration, dissolution, and manufacturability, as well as producing a robust formulation for scale-up.

[0339] [Table 18]

[0340] Batches were manufactured using wet granulation, an exemplary process is shown in Figure 19.

[0341] A batch (1801A) was compressed to produce two different hardness targets (150-170N, 170-190N, 200-220N, and 250N). Figure 20 reveals the effect of hardness on drug release at 5 minutes, with the harder tablets releasing slower. However, tablets of all four hardness levels release the drug completely by 50 minutes.

[0342] An increased disintegration time was expected at a hardness of 250N because the harder the tablet, the less porous it is and therefore the longer it takes for moisture to enter. This production produced tablets that exhibited low friability relative to the hardness target.

[0343] Drug release at hardness values ​​of 200-220N and 250N follows a similar pattern, reaching completion by 75 minutes. In contrast, drug release at hardness values ​​of 170-190N reaches 103% at 30 minutes. The results are shown in Figure 21.

[0344] The above description details presently preferred embodiments of the present invention. It is expected that those skilled in the art will, upon consideration of these descriptions, be aware of numerous modifications and variations in its implementation. These modifications and variations are intended to be encompassed within the scope of the claims appended hereto.

Claims

1. (i) Lidinirazole crystal aggregates; and (ii) Granule solid phase incorporated into granule outer solid phase Includes, The granular inner phase consists of particles with a particle size of 4 to 30 μm, dispersed within a first pharmaceutically acceptable excipient system. ９０ It contains lysinirazole crystal aggregates having; The granular outer phase is a tablet formulation comprising a second pharmaceutically acceptable excipient system, The lysinirazole crystal aggregate comprises lysinirazole type A, characterized by a powder X-ray diffractogram (XRPD) containing characteristic peaks at 2θ angles (9.82±0.2)°, (11.02±0.2)°, (16.53±0.2)°, (13.0±0.2)°, and (25.77±0.2)°. The first pharmaceutically acceptable excipient system is, A first diluent comprising lactose monohydrate and / or crystalline cellulose; and / or A first disintegrant selected from croscarmellose sodium, crospovidone, polaritrin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch, and / or A first binder selected from the group consisting of polyvinylpyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ether, wherein the cellulose ether is selected from hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), and sodium carboxymethylcellulose (NaCMC). Includes, The second pharmaceutically acceptable excipient system comprises a second diluent and / or a second disintegrant and / or lubricant, The second diluent comprises lactose monohydrate and / or crystalline cellulose, and / or The second disintegrant is selected from croscarmellose sodium, crospovidone, polaritrin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch, and / or The lubricant is selected from (a) fatty acids; (b) metal salts of fatty acids; (c) combinations of fatty acids and their metal salts; (d) fatty acid esters; (e) metal salts of fatty acid esters; and (f) inorganic materials and polymers. Tablet formulation.

2. The ridinirazole crystal aggregates have a particle size D of approximately 7 to approximately 25 μm. ９０ A tablet formulation according to claim 1, having the following characteristics.

3. The lysinirazole crystal aggregates have a particle size D of approximately 10 to approximately 20 μm. ９０ A tablet formulation according to claim 1, having the following characteristics.

4. The tablet formulation according to claim 1, wherein the ridinirazole type A is present in the tablet in an amount of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% wt / wt.

5. The tablet formulation according to claim 1, wherein the lidinirazole type A is present in the tablet at a concentration of 40% wt / wt or more.

6. The tablet formulation according to claim 1, wherein the granular internal phase is present in the tablet at a concentration of about 65 to about 95% wt / wt.

7. The tablet formulation according to claim 1, wherein the granular outer phase is present in the tablet at a concentration of about 5 to about 35% wt / wt.

8. The tablet formulation according to claim 1, wherein the first excipient system is present in the tablet at a maximum concentration of approximately 40% wt / wt.

9. The tablet formulation according to claim 8, wherein the first excipient system comprises a first diluent, the first diluent present in the tablet at a maximum concentration of 35% wt / wt.

10. The first diluent comprises lactose monohydrate and / or crystalline cellulose, The tablet formulation according to claim 9, wherein the lactose monohydrate is present in the tablet at a maximum concentration of 30% wt / wt, and the crystalline cellulose is present in the tablet at a maximum concentration of 10% wt / wt.

11. The tablet formulation according to claim 1, wherein the first disintegrant is present in the tablet at a maximum concentration of 2% wt / wt.

12. The tablet formulation according to claim 1, wherein the binder is present in the tablet at a maximum concentration of 3% wt / wt.

13. The tablet formulation according to claim 1, wherein the second excipient system is present in the tablet at a maximum concentration of 10% wt / wt.

14. The tablet formulation according to claim 1, wherein the second diluent is present in the tablet at a maximum concentration of 6% wt / wt.

15. The second diluent comprises lactose monohydrate and / or crystalline cellulose, The tablet formulation according to claim 1, wherein the lactose monohydrate is present in the tablet at a maximum concentration of 5% wt / wt, and the crystalline cellulose is present in the tablet at a maximum concentration of 2% wt / wt.

16. The tablet formulation according to claim 1, wherein the second disintegrant is present in the tablet at a maximum concentration of 3% wt / wt.

17. The tablet formulation according to claim 1, wherein the lubricant comprises the following: (i) Fatty acids selected from the group consisting of stearic acid, palmitic acid, and myristic acid; (ii) Metal salts of fatty acids selected from magnesium stearate, calcium stearate, and zinc stearate; (iii) Combination of stearic acid and magnesium stearate; (iv) Fatty acid esters selected from glyceride esters and sugar esters; (v) Glyceride esters selected from glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate; (vi) Sugar esters selected from sorbitan monostearate and sucrose monopalmitate; and / or (vii) Sodium stearyl fumarate or lysine, Or a combination of those.

18. The tablet formulation according to claim 1, wherein the lubricant is present in the tablet at a maximum concentration of 1% wt / wt.

19. The tablet formulation according to claim 1, wherein the second excipient system comprises lactose monohydrate, crystalline cellulose, croscarmellose sodium, and magnesium stearate.

20. The tablet formulation according to claim 1, wherein the tablet contains about 100 to about 400 mg of lidinirazole type A.

21. The tablet formulation according to claim 1 or 20, wherein the tablet contains about 200 mg of lidinirazole type A.

22. A tablet formulation according to claim 1, having the following composition. Table 1

23. The tablet formulation according to claim 22, wherein part or all of the granular inner phase takes the form of an inclusion embedded in a matrix formed by the granular outer phase.

24. When measured using the TIM-1 dynamic in vitro gastrointestinal model, the T2 concentration of lysinirazole tetrahydrate in ileal effluent was measured. ＭＡＸ The tablet formulation according to claim 1, wherein the duration is less than 3 hours.

25. When measured using the TIM-1 dynamic in vitro gastrointestinal model, the T2 concentration of lysinirazole tetrahydrate in ileal effluent was measured. ＭＡＸ A tablet formulation according to claim 22 or 24, wherein the time is less than 2 hours.

26. A tablet formulation according to any one of claims 1 to 25 for use in the treatment, therapy, or prevention of Clostridioides difficile infection (CDI) or Clostridioides difficile-associated disease (CDAD).

27. ​​A tablet formulation according to any one of claims 1 to 25 for the manufacture of a medicament for use in the treatment, therapy, or prevention of Clostridioides difficile infection (CDI) or Clostridioides difficile-associated disease (CDAD).

28. The tablet formulation according to claim 26 or 27, wherein 200 mg of lidinirazole type A is administered.

29. A tablet formulation according to any one of claims 26, 27, or 28, wherein lidinirazole type A is administered once or more times a day, preferably twice a day.

30. A tablet formulation according to any one of claims 26, 27, 28, or 29, wherein lidinirazole type A is administered for about 5 to 20 days, preferably for about 10 days.

31. The tablet formulation according to claim 1, wherein the lysinirazole A type is lysinirazole tetrahydrate A type.

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