Lidinirazole in solid tablet 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 the priority of UK Patent Application Publication No. 2100470.0 filed on January 14, 2021, the entire content of which is incorporated herein by reference.

[0002] Field of the Invention The present invention relates to solid tablet oral dosage forms of 2,2'-di(pyridin - 4 - yl)-1H,1'H - 5,5'-bibenzimidazole (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 - benzimidazole - 5 - yl)-1H - benzimidazole, which is also known by the INN name ridinilazole in this specification), and its pharmaceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites, or prodrugs.

Background Art

[0003] Background of the Invention Clostridioides difficile (formerly Clostridium difficile) (CDI) infection causes Clostridioides difficile-associated disease (CDAD). In the United States, there are over 450,000 cases of CDI annually, with over 80,000 initial relapses and approximately 29,000 deaths. The most common contributing factor is antibiotic use. Antibiotics cause a loss of colonization resistance and potentially establish a long-lasting, species-poor microbiota susceptible to pathogen invasion. Oral treatment with vancomycin and metronidazole is associated with a high CDI relapse rate, likely due to adverse effects on the normal colonic microbiota. Relapses are costly in terms of both clinical burden and healthcare resource utilization. One study found that approximately one-third of relapsed cases required readmission.

[0004] Presumably, both the biomass and composition of the microbiome at the intestinal-bacterial interface influence the colonization niche of C. difficile. While colonization resistance is associated with specific taxa, perhaps different, but diverse, colonial structures of the microbiome can achieve protection. Consistent characteristics of colonies susceptible to CDI are low diversity levels and reduced metabolic function, due to decreased relative viability of members of the Bacteroidetes and Firmicutes phyla, as well as an increase in that of Proteobacteria. Fecal microbiota transplantation (FMT) normalizes these characteristics and disrupts the CDI relapse cycle.

[0005] Overall, these data support the idea that CDI agents play a role in reducing the risk of recurrence by minimizing their impact on the normal microbiome.

[0006] Lidinirazole (also known as SMT19969, and sometimes referred to in the literature as 2,2'-di(pyridinyl-4-yl)-1H,1'H-5,5'-bibenzo[d]imidazole or 5,5'-bis[2-(4-pyridinyl)-1H-benzimidazole]) is a narrow-spectrum, low-absorption, potent antimicrobial agent targeting C. difficile. Lidinirazole can be represented by the following formula:

[0007] [ka]

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

[0009] Ridinirazole is an orally administered, locally acting (lower intestinal) GI antibiotic of BCS class IV, exhibiting minimal systemic exposure and very low solubility across physiologically relevant pH ranges. BCS class IV drugs are known to present certain formulation problems, particularly in oral formulations (see, for example, Ghadi and Dand (2017) BCS class IV drugs: Highly notorious candidates for formulation development Journal of Controlled Release, 248: 71-95).

[0010] Existing clinically used ridinirazole formulations include aqueous suspensions used in Phase 1 trials. Individual doses (2 mg to 2000 mg) were prepared in situ and administered within 24 hours. The active pharmaceutical ingredient (2 mg to 2000 mg) was suspended in 30 ml of sterile water for injection (WFI), and additional WFI was given as a rinse. Before preparing unit doses, the active pharmaceutical ingredient was deaggregated in a mortar and pestle for functional reasons. This formulation successfully delivered the powdered active pharmaceutical ingredient to the colon through the gastrointestinal tract.

[0011] In Phase 2 trials, ridinirazole was formulated as 200 mg strength immediate-release liquid-filled hard gelatin capsules. This dosage form allowed for easy dispersion of the powdered active ingredient in the stomach and delivery to the colon via the gastrointestinal tract. The ridinirazole capsules were manufactured by liquid filling of a semi-solid blend of ridinirazole and vitamin E polyethylene glycol succinate (vitamin E TPGS). Prior to filling, the ridinirazole was uniformly dispersed in the vitamin E TPGS through high-shear mixing. Vitamin E TPGS was selected based on its ability to efficiently disperse the active ingredient within a volume appropriate to 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, suspensions and liquid-filled capsule formulations of ridinirazole have significant drawbacks. Suspension formulations are inconvenient for the following reasons: they may need to be prepared immediately before use, or if prepared, they may need to be physically handled (e.g., by thorough shaking) before administration, otherwise there is a risk of using a non-uniform formulation when measuring the actual dose to be administered. In fact, with respect to suspension formulations, the risks arising from the lack of uniformity are serious. For example, the dose must be measured from the liquid bottle with a spoon or oral syringe, which usually results in inaccurate administration for each dose. Furthermore, even prepared suspension formulations are inconvenient for the following reasons: the entire process of the necessary treatment is contained in the liquid bottle, which the patient must handle and store properly.

[0013] Liquid-filled capsule formulations also carry risks associated with non-uniform dosage. This is because the fluid suspension can settle unless meticulous (and costly) care is taken regarding temperature control and agitation during capsule filling. Capsule filling also requires careful measurement to ensure that the correct amount of fluid is placed in each capsule, which necessitates specialized equipment for commercial manufacturing that is not widely available.

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

[0015] The inventors hereby discovered that the challenges arising from these properties can be overcome by selecting a specific particle size of lysinirazole tetrahydrate crystal aggregates in the solid phase of the granules, enabling the production of lysinirazole granules with physical properties (including particle size, density, morphology, and microstructure) that unexpectedly yield usefulness in solid tablet oral dosage forms, through wet or dry granulation processes.

[0016] As a result, we can now provide a tablet containing lidinirazole tetrahydrate as the active ingredient, which exhibits superior delivery characteristics compared to Phase II capsule formulations while overcoming the challenges associated with the existing Phase I and Phase II liquid formulations described above, in order to further improve the treatment of CDI.

[0017] Summary of the Invention The present invention generally, (i) Lidinirazole crystal aggregates; and (ii) Granule internal solid phase incorporated into granule external solid phase Includes, (a) The granular inner phase consists of particles with a particle size of less than 30 μm, dispersed within a first pharmaceutically acceptable excipient system. 90 It contains lysinirazole crystal aggregates having; (b) The granular outer phase includes a second pharmaceutically acceptable excipient system. It includes tablet formulations.

[0018] In certain embodiments, the granular inner phase and the granular outer phase are different.

[0019] In certain embodiments, the lysinirazole crystal aggregates include lysinirazole tetrahydrate, preferably lysinirazole tetrahydrate crystal aggregates.

[0020] In certain embodiments, the lysinirazole crystal aggregates have a particle size D of approximately 7 to approximately 25 μm. 90 It holds.

[0021] In certain embodiments, the lysinirazole crystal aggregates have a particle size D of approximately 10 to approximately 20 μm. 90It holds.

[0022] In certain embodiments, the lysinirazole crystal aggregates contain lysinirazole tetrahydrate A.

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

[0024] In certain embodiments, lidinirazole tetrahydrate is present in the tablet at a concentration of approximately 40% wt / wt or higher.

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

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

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

[0028] In certain embodiments, the first excipient system comprises a first diluent, which 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 crystalline cellulose. Here, lactose monohydrate is present in the tablet at a maximum concentration of 30% wt / wt, and crystalline cellulose is present in the tablet at a maximum concentration of 10% wt / wt.

[0030] In certain embodiments, the first excipient system includes a first disintegrant. Here, the first disintegrant is selected from croscarmellose sodium, crospovidone, crystalline cellulose, polaritrin 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 includes a binder. Here, the binder is selected from the group consisting of polyvinylpyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ether, where the cellulose ether is selected from hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), and sodium carboxymethylcellulose (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 includes a second diluent and / or a second disintegrant and / or 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 crystalline cellulose, where Lactose monohydrate is present in the tablets at a maximum concentration of 5% wt / wt, and crystalline cellulose is present at a maximum concentration of 2% wt / wt.

[0038] In certain embodiments, the second excipient system includes a second disintegrant. Here, the second disintegrant is selected from croscarmellose sodium, crospovidone, crystalline cellulose, polaritrin 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 includes a lubricant. Here, the lubricants are (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. bipo Selected from Rimmer.

[0041] In certain embodiments, the lubricant includes: (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.

[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, crystalline cellulose, croscarmellose sodium, and magnesium stearate.

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

[0045] In certain embodiments, the tablets contain approximately 100 to 400 mg of lysinirazole tetrahydrate.

[0046] In certain embodiments, the tablets contain approximately 200 mg of ridinirazole tetrahydrate (equivalent to 169 mg of ridinirazole on an anhydrous basis).

[0047] In certain embodiments, the tablet formulation includes or comprises the following:

[0048] [Table 1]

[0049] In certain embodiments, part or all of the granular inner phase takes the form of inclusions embedded within a matrix formed by the granular outer phase.

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

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

[0052] According to another embodiment of the present invention, a lysinirazole tetrahydrate tablet is provided, comprising an inner granular solid phase incorporated into an outer granular solid phase, wherein (a) the inner granular phase has a particle size D of about 4 μm to about 30 μm. 90 (b) comprising lysinirazole tetrahydrate aggregates dispersed in a first pharmaceutically acceptable excipient system having; (b) the granular outer phase comprising a second pharmaceutically acceptable excipient system, wherein the first and second excipient systems are different.

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

[0054] In multiple embodiments, the rilginirazole tetrahydrate crystal aggregates can have a particle size D of about 7 to about 25 μm 90 and preferably have a particle size D of about 10 to about 20 μm 90 In various embodiments, the crystal aggregates can 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 have a particle size D that is less than 40 μm 90 In multiple embodiments, rilginirazole tetrahydrate is present at any suitable concentration, for example, 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, rilginirazole 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, rilginirazole tetrahydrate is present in the tablet at a concentration of 40% wt / wt or more, for example, at about 50% wt / wt.

[0056] In multiple embodiments, the inner phase of the granules is preferably present in the tablet at a concentration of about 65 to about 95% wt / wt, for example, at about 90% wt / wt. In multiple embodiments, the outer phase of the granules is preferably present in the tablet at a concentration of about 5 to about 35% wt / wt, for example, at 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 preferably does not contain a lubricant. In some embodiments, the first excipient system may include a first diluent and / or a first disintegrant and / or binder.

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

[0059] In some embodiments, the first excipient system may include a first disintegrant or a combination of first disintegrants. Any pharmaceutically acceptable disintegrant or combination of disintegrants may be used. Preferred disintegrants can be selected from croscarmellose sodium, crospovidone, crystalline cellulose, polariline potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch. In preferred embodiments, the first disintegrant includes, consists of, or is essentially croscarmellose sodium, e.g., 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 some embodiments, the first excipient system may include a binder. Any pharmaceutically acceptable binder or combination of binders may be used. Preferred binders may include, consist of, or be essentially a hydrophilic polymer. For example, binders may be selected from polyvinylpyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ethers. Thus, in some embodiments, the binder may include a cellulose ether selected from hydroxypropyl cellulose (HPC), methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC), and sodium carboxymethyl cellulose (NaCMC). In preferred embodiments, the binder includes, consists of, or is essentially a hydroxypropyl cellulose. In some 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 of or is essentially composed of a first diluent, a first disintegrant, and a binder. In these embodiments, the first excipient system preferably consists of or is essentially composed of lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, and croscarmellose sodium, for example, 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 contain a binder. In some embodiments, the second excipient system may include a second diluent and / or a second disintegrant and / or lubricant.

[0063] Preferably, the second excipient system includes a second diluent or a combination of second diluents. Any pharmaceutically acceptable diluent or combination of diluents can be used. In some embodiments, the second diluent may 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 may preferably consist of, or be essentially, lactose monohydrate and / or crystalline cellulose, more preferably consisting of, or essentially, lactose monohydrate 100M and Avicel PH102®. In these embodiments, the 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 the crystalline cellulose is present in the tablet at a concentration of up to 2% wt / wt, for example, about 1.5% wt / wt.

[0064] In several embodiments, the second excipient system may include a second disintegrant. Any pharmaceutically acceptable disintegrant, or combination of disintegrants, can be used as the second disintegrant. In several embodiments, the second disintegrant can be selected from croscarmellose sodium, crospovidone, crystalline cellulose, polariline potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch. The second disintegrant may include, be, or essentially consist of croscarmellose sodium, e.g., 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 several embodiments, the second excipient system may include a lubricant. Any pharmaceutically acceptable lubricant or combination of lubricants can be used. For example, the lubricant may be (a) a fatty acid; (b) a metal salt of a fatty acid; (c) a combination of a fatty acid and its metal salt; (d) a fatty acid ester; (e) a metal salt of a fatty acid ester; and (f) an inorganic material. bipoLubricants can be selected from rimers. For example, the lubricant may contain fatty acids selected from stearic acid, palmitic acid, and myristic acid. The lubricant may contain metal salts of fatty acids 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 contain fatty acid esters selected from glyceride esters and sugar esters. For example, the lubricant may contain glyceride esters 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 contain sodium stearyl fumarate or lysine. In preferred embodiments, the lubricant contains, consists of, or is essentially composed 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 of or is essentially composed of a second diluent, a second disintegrant, and a lubricant. In these embodiments, the second excipient system preferably consists of or is essentially composed of lactose monohydrate, crystalline cellulose, croscarmellose sodium, and magnesium stearate, for example, lactose monohydrate 100M, Avicel PH102®, and magnesium stearate.

[0067] In several embodiments, the tablets of the present invention are preferably dry or substantially anhydrous, and have a water content of, for example, 10% by weight, 9.5% by weight, 9% by weight, 8.5% by weight, 8% by weight, 7.5% by weight, 7% by weight, 5% by weight, 4% by weight, 3% by weight, 2% by weight, or less than 1% by weight.

[0068] In several embodiments, the tablets of the present invention contain lysinirazole tetrahydrate in an amount sufficient to produce a therapeutic effect in human subjects. Tablets containing about 100 to about 400 mg of lysinirazole tetrahydrate, preferably about 200 mg of lysinirazole tetrahydrate [equivalent to 169 mg of anhydrous lysinirazole], are preferred.

[0069] Part or all of the granular inner phase may take the form of inclusions embedded within the matrix formed by the granular outer phase.

[0070] In several embodiments, the tablets of the present invention preferably measure the T150 liginirazole in ileal effluent using the T150 liginirazole-1 dynamic in vitro gastrointestinal model described herein (and known to those skilled in the art). MAX It shows less than 3 hours. More preferably, the tablets of the present invention have a T of liginirazole in ileal effluent, as measured using the TIM-1 dynamic in vitro gastrointestinal model. MAX It shows less than 2 hours. Most preferably, the tablets of the present invention have a T of liginirazole in ileal effluent, as measured using the TIM-1 dynamic in vitro gastrointestinal model. MAX This indicates approximately 1 to 2 hours.

[0071] In several embodiments, the tablets of the present invention preferably further include a coating. Any suitable coating can be used, and preferred coatings provide protection from contamination, improved stability, functional properties, and swallowability. Preferred coatings include pharmaceutically acceptable water-soluble polymer films.

[0072] In another aspect of the present invention, particle size D is approximately 4 to approximately 30 μm. 90 A composition is provided comprising granules containing ridinirazole tetrahydrate, possibly in the form of aggregates, dispersed within a first pharmaceutically acceptable excipient system, and a second pharmaceutically acceptable excipient system outside the granules, wherein the first and second excipient systems are different. The granules can preferably be uniformly dispersed within the second pharmaceutically acceptable excipient system.

[0073] The compositions of this embodiment are preferably tableting compositions suitable for compression into tablets. Alternatively, or even further, the compositions of this embodiment of the present invention may be suitable for other uses. Such uses include processes for formulating any type of oral and parenteral ridinirazole pharmaceutical compositions. For example, the compositions of the second embodiment of the present invention may take the form of pharmaceutical formulations other than tablets, including liquid suspensions, granule-filled capsules, and granule-filled sachets (or other containers), or may be applied to the preparation thereof.

[0074] In several embodiments, the lysinirazole tetrahydrate aggregates are preferably in the form of lysinirazole tetrahydrate crystalline aggregates, more preferably lysinirazole tetrahydrate type A (as defined herein).

[0075] In several embodiments, the granules may be dispersed within a second pharmaceutically acceptable excipient system. Preferably, the granules are uniformly dispersed within the second pharmaceutically acceptable excipient system. The granules are dry and have, for example, a water content of 10% by weight, 5% by weight, 2% by weight, or less than 1% by weight.

[0076] In several embodiments, the second pharmaceutically acceptable excipient system may be particulate and may also be dry and have a water content of, for example, 10% by weight, 9.5% by weight, 9% by weight, 8.5% by weight, 8% by weight, 7.5% by weight, 7% by weight, 5% by weight, 4% by weight, 3% by weight, 2% by weight, or less than 1% by weight.

[0077] In several embodiments, the crystal aggregates have a particle size D of approximately 5 μm to approximately 40 μm. 90 It may have 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 It may have.

[0078] In several embodiments, lysinirazole 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 maximum concentration of 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% wt / wt, more preferably at a concentration of 40% wt / wt or higher, for example, about 50% wt / wt.

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

[0080] In some 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 some embodiments, the first and second excipient systems are preferably as defined above with respect to the tablets of the present invention.

[0082] In several embodiments, the tablet composition is preferably dry and has a water content of, for example, 10% by weight, 9.5% by weight, 9% by weight, 8.5% by weight, 8% by weight, 7.5% by weight, 7% by weight, 5% by weight, 4% by weight, 3% by weight, 2% by weight, or less than 1% by weight.

[0083] A tableting composition suitable for compression into tablets, as defined in the first aspect of the present invention described above, is more preferable.

[0084] In another aspect of the present invention, a method for producing a granular lysinirazole tetrahydrate composition is provided, comprising the following steps: (a) Particle size D of approximately 4 to 30 μm 90 A step of providing a lysinirazole tetrahydrate aggregate having; (b) A step of forming a pre-granulation mixture by mixing the aggregate from step (a) with a first pharmaceutically acceptable granular excipient system; (c) Granulating the pre-granulation mixture to form granules containing the crystalline aggregates dispersed within the first pharmaceutically acceptable excipient system; and (d) A step of blending the granules from step (c) with a second pharmaceutically acceptable extragranular excipient system to form a granular ridinirazole composition which may be suitable for compression into tablets.

[0085] In several embodiments, the method is preferably suitable for producing granular lysinirazole compositions as defined according to the second aspect of the present invention described above. The granular lysinirazole tetrahydrate composition of step (d) is preferably suitable for compression into tablets of the present invention as defined according to the first aspect of the present invention described above. Alternatively, or furthermore, the granular lysinirazole tetrahydrate composition of step (d) may also be suitable for other applications, including processes for the formulation of any type of oral and parenteral pharmaceutically active lysinirazole tetrahydrate composition. For example, the lysinirazole tetrahydrate composition of step (d) may take the form of pharmaceutical formulations other than tablets, including liquid suspensions, granule-filled capsules, and granule-filled sachets (or other containers), or may be applied to the preparation thereof.

[0086] In several embodiments, the lysinirazole tetrahydrate aggregates are preferably in the form of lysinirazole tetrahydrate crystalline aggregates, more preferably lysinirazole tetrahydrate type A (as defined herein). The crystalline aggregates have a particle size D of about 7 to about 25 μm. 90 It may have a particle size D of about 10 to about 20 μm. 90 It holds.

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

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

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

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

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

[0092] In some embodiments, the mixing step (b) may further include a step of screening or sieving the first excipient system before mixing it with the aggregates.

[0093] In some embodiments, mixing step (b) includes the following steps: (b1) A step of forming an initial pre-granulation mixture by mixing the aggregate from step (a) with the first portion of a first pharmaceutically acceptable granular excipient system; (b2) A step in which the pre-granulation mixture from step (b1) is passed through a screen or sieve to form a screened initial pre-granulation mixture; (b3) The second portion of the first pharmaceutically acceptable granular excipient system is passed through the screen or sieve of step (b2) to form a screened second portion; followed by (b4) A step in which the screened initial pre-granulation mixture from step (b2) and the screened second excipient portion from step (b3) are mixed to form the final pre-granulation mixture for granulation in step (c).

[0094] In the embodiments described above, the first portion of the first pharmaceutically acceptable granular excipient system may be a subset of the constituent excipients of the first excipient system described herein. For example, the first portion may constitute all of the constituent excipients of the first excipient system as described herein, except for some or all of the first diluent (e.g., crystalline cellulose, which is the first diluent in the preferred embodiments described above).

[0095] Furthermore, in the embodiments described above, the aggregates in step (a) may contain re-aggregated ridinirazole tetrahydrate particles. In these cases, the re-aggregated ridinirazole particles are decomposed and removed by steps (b1) and (b2), so that the screened initial pre-granulation mixture in step (b2) contains uniformly distributed ridinirazole tetrahydrate crystalline aggregates.

[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 separation plate centrifugation. The dry laser diffraction method described herein is preferred.

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

[0098] The granulation step (c) may include dry granulation. However, the granulation step (c) preferably includes wet granulation, more preferably high-shear wet granulation.

[0099] A fourth aspect of the present invention provides a method for preparing lysinirazole tetrahydrate tablets, comprising the following steps: (a) A step of providing a granular lysinirazole composition by a method according to a third aspect of the present invention; followed by (b) A step of producing ridinirazole tablets by compressing the granular composition.

[0100] In several embodiments, the tableting method may further include the step of forming coated ridinirazole tetrahydrate tablets by coating the ridinirazole tablets. The method may further include the step of packaging a plurality of ridinirazole tablets to form a ridinirazole patient pack, or a bottle or other container containing enough tablets for a single treatment procedure (e.g., about 20 tablets).

[0101] A fifth aspect of the present invention provides a granular lysinirazole tetrahydrate composition suitable for compression into tablets, which can be obtained by the method of the third aspect of the present invention.

[0102] In another aspect of the present invention, a lysinirazole tetrahydrate tablet, patient pack, or container is provided that can be obtained by the method of the fourth aspect of the present invention.

[0103] In another aspect of the present invention, tablets of the present invention are provided for use in the treatment, therapy, or prevention of CDI or CDAD.

[0104] In another aspect of the present invention, the use of the tablets of the present invention is provided for the manufacture of a pharmaceutical product for use in the treatment, therapy, or prevention of CDI or CDAD.

[0105] Another aspect of the present invention provides a method for treating, curing, or preventing CDI or CDAD in a patient who requires such treatment, the treatment, or prevention, the method comprising the step of orally administering a tablet of the present invention to the patient.

[0106] In another embodiment of the present invention, a tablet formulation comprising the following is provided: (i) Ridinirazole tetrahydrate; and (ii) The solid phase inside the granules incorporated into the solid phase outside the granules, Here (a) The granular inner phase has a particle size D of approximately 4 to 30 μm. 90 It comprises lysinirazole crystal aggregates dispersed in a first pharmaceutically acceptable excipient system having; (b) The granular outer phase comprises a second pharmaceutically acceptable excipient system, Unlike the first and second excipient systems, the lysinirazole tetrahydrate crystal aggregates have a particle size of approximately 7 to 25 μm. 90 It holds.

[0107] In several embodiments, the crystal aggregates have a particle size D of approximately 5 μm to approximately 40 μm. 90 It may have 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 It may have.

[0108] In several embodiments, the lysinirazole crystal aggregates contain lysinirazole tetrahydrate.

[0109] In several embodiments, the lysinirazole tetrahydrate crystal aggregate contains lysinirazole tetrahydrate type A.

[0110] In several embodiments, lidinirazole is present in the tablet in amounts of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% wt / wt.

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

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

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

[0114] In several 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 several embodiments, the first excipient system comprises a first diluent, which 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 is essentially composed of, lactose monohydrate and / or crystalline cellulose, wherein the lactose monohydrate is present in the tablet at a concentration of up to 30% wt / wt and the crystalline cellulose is present in the tablet at a concentration of up to 10% wt / wt.

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

[0118] In some 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 several 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 cellulose ether, where the cellulose ether is selected from hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), and sodium carboxymethylcellulose (NaCMC).

[0120] In several 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 several 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 some embodiments, the second excipient system includes a second diluent and / or a second disintegrant and / or lubricant.

[0123] In several 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 crystalline cellulose, where lactose monohydrate is present in the tablet at a concentration of up to 5% wt / wt and crystalline cellulose is present in the tablet at a concentration of up to 2% wt / wt.

[0125] In several embodiments, the second excipient system comprises a second disintegrant, which may be selected from croscarmellose sodium, crospovidone, crystalline cellulose, polaritrin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch.

[0126] In several 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 several embodiments, the second excipient system comprises a lubricant, where the lubricant is (a) a fatty acid; (b) a metal salt of a fatty acid; (c) a combination of a fatty acid and its metal salt; (d) a fatty acid ester; (e) a metal salt of a fatty acid ester; and (f) an inorganic material. bipo Selected from Rimmer.

[0128] In several 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 glyceride esters and sugar esters; a glyceride ester selected from glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate; a sugar ester selected from sorbitan monostearate and sucrose monopalmitate; or sodium stearyl fumarate or lysine.

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

[0130] In several embodiments, the second excipient system includes lactose monohydrate, crystalline cellulose, croscarmellose sodium, and magnesium stearate, and magnesium stearate, such as lactose monohydrate 100M, Avicel PH102®, and magnesium stearate.

[0131] In several embodiments, the tablets contain approximately 100 to 400 mg of lysinirazole tetrahydrate.

[0132] In several embodiments, the tablet contains approximately 200 mg of lysinirazole tetrahydrate.

[0133] In several embodiments, part or all of the granular inner phase takes the form of inclusions embedded within a matrix formed by the granular outer phase.

[0134] In several embodiments, the tablet formulation is measured using the TIM-1 dynamic in vitro gastrointestinal model for lysinirazole in ileal effluent. MAX This indicates less than 3 hours.

[0135] In several embodiments, the tablet formulation is measured using the TIM-1 dynamic in vitro gastrointestinal model for lysinirazole in ileal effluent. MAX This indicates less than 2 hours. [Brief explanation of the drawing]

[0136] [Figure 1] This shows a typical X-ray powder diffraction pattern of lysinirazole tetrahydrate type A. [Figure 2] The ORTEP plots for lysinirazole molecules and water molecules in the A-structure are shown. [Figure 3] The packing diagrams of the lysinirazole tetrahydrate form A structure along each crystal axis are shown. [Figure 4] The packing diagrams of the lysinirazole tetrahydrate form A structure along each crystal axis are shown. [Figure 5] The packing diagrams of the lysinirazole tetrahydrate form A structure along each crystal axis are shown. [Figure 6] This shows a typical X-ray powder diffraction pattern of lysinirazole anhydride type D. [Figure 7] The ORTEP plot for lysinirazole molecules with a D-shape is shown. [Figure 8] The packing diagrams of the lysinirazole D-form structure along each crystal axis are shown. [Figure 9] The packing diagrams of the lysinirazole D-form structure along each crystal axis are shown. [Figure 10] The packing diagrams of the lysinirazole D-form structure along each crystal axis are shown. [Figure 11] This exhibits hydrogen bonding between lysinirazole D-type molecules, creating a two-dimensional network structure along the ab plane (i.e., viewed along the c-axis). [Figure 12]The image shows XRPD overlays of ridinirazole tablets (upper trace), placebo (middle trace), and type A (lower trace) at approximately 10°2θ to 25°2θ. [Figure 13] This shows comparative ileal efflux profiles for 200 mg ridinirazole tetrahydrate capsules and 200 mg ridinirazole tetrahydrate tablets [equivalent to 169 mg anhydrous ridinirazole, respectively] in the TIM-1 intestinal model. The plots show the amount of ridinirazole measured in the ileal efflux at each 60-minute time point throughout the experimental period. Ileal efflux is equal to the amount of material delivered to the colon. [Figure 14] This shows the dissolution profile of tablets containing the active pharmaceutical ingredient at the limits of the particle size specification. [Figure 15] This chart shows the Bristol Stool stool characteristics and various types of fecal morphology. [Figure 16-1] This shows an exemplary manufacturing process for ridinirazole tetrahydrate 200 mg tablets. [Figure 16-2] This shows an exemplary manufacturing process for ridinirazole tetrahydrate 200 mg tablets. [Figure 17] This shows the dissolution profiles of ridinirazole tetrahydrate tablets in micronized and non-micronized tablet and caplet forms. [Figure 18] The dissolution profiles of lysinirazole tetrahydrate tablets in non-micronized tablets with incomplete granulation, non-micronized tablets with complete granulation, and micronized tablets are shown. [Figure 19] This shows an exemplary manufacturing process for the tablets of the present invention. [Figure 20] This shows dissolution at four different hardness targets. [Figure 21] This shows dissolution at three different hardness targets. [Modes for carrying out the invention]

[0137] Detailed explanation All publications, patents, patent applications, and other references referenced herein are incorporated herein by reference in whole for all purposes as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference, and as if their contents were fully described.

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

[0139] Unless otherwise specified by the context, the use of the singular form in this specification should be interpreted as including the plural form, and vice versa. The term "a" or "an" used in reference to a single entity should be interpreted as meaning one or more such entities. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably in this specification.

[0140] The term “about” as used herein with respect to a number or range of numbers should be interpreted as being as precise as the method used to measure it. This term may also be used synonymously with the term “or its vicinity” in this context, and therefore, a reference to “about” with respect to a particular number or range of numbers may be interpreted as specifying that particular number or range of numbers, or its vicinity. Thus, a reference to “about x” may be interpreted as “x, or about x,” while a reference to “about x ~ y” may be interpreted as “x ~ y, or about x ~ about y, or about x ~ y.” This term may also be interpreted as specifying a ±10% error limit for the number or range being referred to. In certain embodiments, when referring to a single value, the term “about” includes ±10% of that stated value. For example, about 50% includes the range of 45% to 55%, while about 20 molar equivalents includes the range of 18 to 22 molar equivalents. Therefore, when referring to a range, "approximately" means ±10% of each listed value at each end of that range.

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

[0142] The term "aggregate" refers to 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 separated into smaller particles except at very high energy applications. In any sample, they typically constitute only a fraction of a percent. Aggregation is the fusion of particles by processes other than heat / pressure, i.e., the deposition of ionic salts on the surface during manufacturing. Aggregates are usually formed when powder is heated, compressed, or dried from a suspension. Aggregates have a large interfacial contact area between each particle, and the force required to break these bonds is considerable. For all practical purposes, aggregates constitute the largest single part with any particle size distribution (PSD) that can be desired to be achieved in a formulation.

[0143] The term "aggregate" refers to a collection of particles loosely held together by weak electromagnetic forces, van der Waals forces, mechanical friction, and coupling at two points of contact. Aggregates form when particles are handled undisturbed in one location, or when they are shaken, rotated, or stored. They are readily decomposed by appropriate dispersion techniques.

[0144] The term bioisoster (or simply isoster) is a term used in the art to describe drug analogs in which one or more atoms (or groups of atoms) are substituted with alternative atoms (or groups of alternative atoms) that have similar steric and / or electronic characteristics to the original atom. Substitution of a hydrogen atom or hydroxyl group with a fluorine atom is a commonly used bioisosteric substitution. Sila substitution (C / Si exchange) is a relatively recent technique for producing isosters. This approach involves replacing one or more specific carbon atoms in a compound with silicon (see the paper by Tacke and Zilch in Endeavour, New Series, 1986, 10, 191-197 for an overview). Sila-substituted isosters (silicon isosters) may exhibit improved pharmacological properties, such as improved tolerability, extended half-life, or increased potency (see, for example, the paper by Englebienne in Med. Chem., 2005, 1(3), 215-226). Similarly, replacing one atom with one of its isotopes, for example, replacing hydrogen with deuterium, can improve pharmacological properties, such as extending the half-life (see, for example, Kushner et al (1999) Can J Physiol Pharmacol. 77(2):79-88). In its broadest embodiment, the present invention envisions all bioisosteres (specifically all silicon bioisosteres) of the compounds of the present invention.

[0145] As used herein, the term “composition” is intended to encompass formulations that include, for example, a specified active pharmaceutical ingredient (API) as described herein (e.g., ridinirazole tetrahydrate, preferably form A) and pharmaceutically acceptable excipients, carriers, or diluents, in specified amounts as defined throughout the original disclosure, obtained by combining specific components, for example, the specified components described herein in specified amounts as defined herein.

[0146] The term “comprise,” as used herein, or variations thereof such as “comprises” or “comprising,” should be read to indicate the inclusion of any described integer (e.g., features, elements, characteristics, properties, method / process steps, or limitations) or group of integers (e.g., features, elements, characteristics, properties, method / process steps, or limitations), and not to indicate the exclusion of any other integer or group of integers. Therefore, the term “comprising” as used herein is either inclusive or nonexclusive and does not exclude any additional undescribed integers or method / process steps.

[0147] In this specification, the phrase "essentially consisting of" is used to require a specified integer or step, and an integer or step that does not substantially affect the nature or function of the claimed invention.

[0148] As used herein, the term "consists of" is used to indicate the existence of only the integers described (e.g., features, elements, characteristics, properties, method / process steps, or limitations) or groups of integers (e.g., features, elements, characteristics, properties, method / process steps, or limitations).

[0149] The term "disintegrant" refers to a pharmaceutically acceptable excipient incorporated into a composition to facilitate its disintegration upon contact with a liquid. For example, a disintegrant is a pharmaceutically acceptable agent used in the preparation of tablets to cause the tablet to disintegrate and release its medicinal components upon contact with moisture. Examples of disintegrants include, but are not limited to, cross-linked polymers including cross-linked polyvinylpyrrolidone (crospovidone) and cross-linked sodium carboxymethylcellulose (croscarmellose sodium), modified starch, and sodium starch glycolate.

[0150] The term "D" as used herein # " represents the distributed particle size distribution. For example, the unit D 10 This indicates that 10% of the particles in the powder are smaller than the stated particle size. Typically, the unit is μm (micrometers). A laser particle size analyzer measures particles using a laser at different angles and then acquires a diffraction pattern from an image sensor. Finally, by performing addition, subtraction, or cross-analysis calculations, the instrument determines the statistical proportion of particle sizes. 90 This means that 90% of the total particles are smaller than the particle size in question. For example, D 10 It is 2.557 μm, D 90 The particle size is 46.88 μm. 10 and D 90 This range encompasses the particle size of the sample powder. Particle sizes exceeding this range can be ignored due to their small number. D 50 This means that 50% of the total particles are smaller than the particle size in question, or 50% of the particles are larger than the particle size in question. 50 This is the median of the particle size distribution, and the inventors sometimes refer to this value as the "median."

[0151] As used herein, the term “placed on top of ~” means placing one phase or coating on top of another phase or coating. Such placement may be consistent with the shape of the underlying phase or coating, and therefore the lamination of the phases and coatings does not create any substantial gaps between them.

[0152] As used herein, the term “granular outer phase” refers to the bulk portion of the core structure that exists between the inner phase and the outer coating of a composition. The granular outer phase may be considered a coating in itself, but is generally thicker than a simple coating, thereby imparting significant structure / dimensions to the composition.

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

[0154] As used herein, "D-form" of lysinirazole means the crystalline form of lysinirazole tetrahydrate characterized by a powder X-ray diffractogram that includes characteristic peaks at 2θ angles (12.7±0.2)°, (23.18±0.2)°, and (27.82±0.2)°, and possibly at 2θ angles (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 “N-form” of lysinirazole means the crystalline form of lysinirazole tetrahydrate characterized by a powder X-ray diffractogram that includes characteristic peaks at 2θ angles (10.82±0.2)°, (13.35±0.2)°, and (19.15±0.2)°, and possibly at 2θ angles (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 intensity of XRPD patterns can vary depending on the measurement conditions used. Relative intensity can also vary depending on experimental conditions, and therefore, relative intensity should not be considered 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 angle described. It will be recognized that the various crystal forms described herein are not limited to those that produce X-ray diffraction patterns completely identical to those shown in the accompanying drawings. Rather, any crystal form of ridinirazole that produces an X-ray diffraction pattern substantially identical (as defined above) to that shown in the drawings is within the scope of the present invention.

[0157] The term "flow enhancer" refers to a substance added to a powder to improve its flowability and / or lubricity. Examples of flow enhancers 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 produced by mixing them together and granulating them into a particulate form. This mixture produces a particulate material composed of two or more drugs.

[0159] The term "hydrophilic silica" refers to a pharmaceutical excipient usable as a fluidizer (anti-caking agent), adsorbent, and desiccant in solid formulations. Hydrophilic silica may also be used to increase the mechanical stability and decay rate of a composition. Hydrophilic silica may also be fumed silica, i.e., it may be produced through an exothermic process for generating silica nanoparticles. Fumed silica particles can 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 m². 2 / g or 50-600m 2It may have a specific surface area of ​​approximately 200 m². An example of hydrophilic silica is a silica with a specific surface area of ​​approximately 200 m². 2 Aerosil 200 containing / g is an example.

[0160] The term "granular inner phase" refers to the central part of the composition. In this embodiment, the granular inner phase is the position where the active ingredient lysinirazole tetrahydrate is located.

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

[0162] The terms "crystalline cellulose" or "MCC" refer to pharmaceutical-grade cellulose produced from refined wood pulp. MCC may be unmodified or modified, such as silicified crystalline cellulose (SMCC). MCC can function as a bulking agent and, due to its desirable compressibility, can facilitate tablet formation.

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

[0164] As used herein, the term “medicine pack” refers to a series of one or more lysinirazole tetrahydrate tablets, which may be contained in a typical outer packaging. The tablets may be contained in a blister pack. The medicine pack may further include instructions for use. The lysinirazole tetrahydrate tablet composition of the present invention may be contained in a medicine pack or a patient pack.

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

[0166] The term "pharmaceutically acceptable derivative" as applied to lysinirazole tetrahydrate defines compounds obtained (or obtainable) by the chemical derivatization of lysinirazole tetrahydrate. Therefore, pharmaceutically acceptable derivatives are suitable for administration to or contact with mammalian tissues and are free from excessive toxicity, irritation, or allergic reactions (i.e., corresponding to a reasonable benefit / risk ratio). Preferred derivatives are those obtained (or obtainable) by alkylation, esterification, or acylation of lysinirazole tetrahydrate. Derivatives may be active in themselves or inactive until treated in vivo. In the latter case, the derivatives of the present invention act as prodrugs. Particularly preferred prodrugs are ester derivatives that are esterified at one or more free hydroxyls and activated by hydrolysis in vivo. Other preferred prodrugs are covalent compounds that release the active parent drug of formula (I) after covalent cleavage in vivo.

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

[0168] The term "pharmaceutically acceptable salt" as applied to ridinirazole tetrahydrate defines any non-toxic organic or inorganic acid addition salt of a free base compound that is suitable for use in contact with mammalian tissues, is free from excessive toxicity, irritation, or allergic reactions, and has a reasonable benefit-risk ratio. Suitable pharmaceutically acceptable salts are well known in the art. Examples include salts of 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 to (monobasic or dibasic) salts by reaction with suitable bases, such as alkali metal hydroxides, methoxides, ethoxides, or tert-butoxides, or alkyllithium selected from NaOH, NaOMe, KOH, KOtBu, LiOH, and BuLi, and pharmaceutically acceptable salts of lysinirazole tetrahydrate can also be prepared in this manner.

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

[0170] The term "pharmaceutically acceptable solvate," as applied to ridinirazole tetrahydrate, defines any pharmaceutically acceptable solvated form of the compound that preserves the biological efficacy of the designated compound. Examples of solvates include combinations of the compound of the present invention with water (hydrates), short-chain alcohols (including isopropanol, ethanol, and methanol), dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, acetone, dimethylformamide (DMF), dimethylacetamide (DMAc), pyrrolidone (e.g., N-methyl-2-pyrrolidone (NMP)), tetrahydrofuran (THF), and ethers (e.g., tert-butyl methyl ether (TBME)).

[0171] Miscible formulations of solvated mixtures, such as combinations of the compound of the present invention with an acetone-ethanol mixture, are also included. In preferred embodiments, the solvate includes a combination of the compound of the present invention with about 20% ethanol and about 80% acetone. Therefore, the structural formulas include compounds having the indicated structure, including hydrated and unhydrated forms.

[0172] The term "pharmaceutically acceptable prodrug" as applied to ridinirazole tetrahydrate defines any pharmaceutically acceptable compound that can be converted in vivo to pharmaceutically acceptable salts of ridinirazole tetrahydrate, either under physiological conditions or by solvolysis, or to compounds that share at least some of the antimicrobial activity of the compound (e.g., exhibiting activity against Clostridioides difficile).

[0173] The term pharmaceutically acceptable metabolite, as applied to lysinirazole tetrahydrate, refers to pharmacologically active products produced through the metabolism of lysinirazole tetrahydrate or its salts in the body.

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

[0175] The term "pharmaceutically acceptable complex," as applied to ridinirazole tetrahydrate, defines a compound or composition in which the compound of the present invention forms a component. Therefore, the complexes of the present invention include derivatives in which the compound of the present invention is physically bonded (e.g., by covalent or non-covalent bonds) to one or more other parts. Thus, this term includes the polymeric forms of the compound of the present invention. These polymers can be produced by linking or arranging multiple copies of the compound of the present invention in close proximity to one another (e.g., through scaffold or carrier parts). This term includes cyclodextrin complexes.

[0176] In its most broadest embodiment, the present invention assumes all tautomers, optical isomers, racemic forms, and diastereoisomers of the compounds described herein. Those skilled in the art will recognize that, due to the asymmetric substituted carbon atoms present in the compounds of the present invention, the compounds may be produced in optically active and racemic forms. Where a chiral center or another form of isomeric center is present in the compounds of the present invention, all forms of such one or more isomers, including enantiomers and diastereoisomers, are intended to be encompassed herein. A compound of the present invention containing one (or more) chiral centers may be used as a racemic mixture, an enantiomerically concentrated mixture, or the racemic mixture may be separated using well-known techniques to obtain individual enantiomers individually. Thus, references to the compounds of the present invention encompass the products in the form of a diastereoisomer mixture, individual diastereoisomers, an enantiomer mixture, and individual enantiomers.

[0177] Therefore, the present invention assumes all optical isomers and racemic forms of the compounds of the present invention, and unless otherwise indicated (e.g., by the use of dashed wedge structures), the compounds shown herein are intended to encompass all possible optical isomers of the compounds as described. Where the stereochemical form of a compound is important for its pharmaceutically usefulness, the present invention assumes the use of isolated utemers.

[0178] As used herein, the term “lisinirazole” is used to define the active ingredient in this formulation, which is the compound 2,2'-di(pyridinyl-4-yl)-1H,1'H-5,5'-bibenzo[d]imidazole (2,2'-di-4-pyridinyl-6,6'-bi-1H-benzoimidazole; 5,5'-bis[2-(4-pyridinyl)-1H-benzoimidazole]; 2,2'-bis(4-pyridyl)-3H,3'H-5,5'-bibenzoimidazole; or sometimes known as 2-pyridinyl-4-yl-6-(2-pyridinyl-4-yl-3H-benzoimidazole-5-yl)-1H-benzoimidazole). The term also includes pharmaceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites, or prodrugs of lisinirazole as defined herein. The active ingredient in the drug formulation, lidinirazole tetrahydrate (i.e., form A), has the following structure.

[0179] [ka]

[0180] The abbreviation "XRPD" stands for X-ray powder diffraction (or, if the context allows, X-ray powder diffractogram).

[0181] "Silicified crystalline cellulose" or "SMCC" refers to a particulate aggregate of crystalline cellulose and silicon dioxide processed simultaneously. 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 crystalline 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, silicon dioxide may be present in an amount of about 0.5% to about 10% by weight of silicified crystalline cellulose, or about 1.25% to about 5% by weight relative to the crystalline cellulose. Furthermore, 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 has a surface area of ​​about 10 m². 2 / g~about 500m 2 / g, or approximately 50m 2 / g~about 500m 2 / g, or approximately 175m 2 / g ~ approx. 350m 2 It may have a concentration of / g. Silicified crystalline cellulose is commercially available from several suppliers known to those skilled in the art, for example, 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 position and relative intensity is acceptable. The ability to confirm the substantial identity of X-ray diffraction patterns is within the understanding of those skilled in the art. For example, the typical precision of the 2θ value is in the range of ±0.2°2θ. Therefore, a diffraction peak that normally appears at 14.9°2θ may appear at 14.7° to 15.1°2θ on most X-ray diffractometers under standard conditions. Furthermore, variability can also arise from the specific equipment used, as well as the crystallinity, orientation, sample preparation, and other factors in the sample. Typically, XRPD measurements are performed at room temperature, e.g., 20°C, and preferably at 40% relative humidity.

[0183] As used herein, the term “substantially pure” with respect to a particular crystalline form (polymorph) of lysinirazole is used to define a form that includes any other physical form of lysinirazole in 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.

[0184] As used herein, the term "room temperature" (RT) refers to temperatures between 15°C and 25°C.

[0185] D 90 Particle size is a parameter such that 90% of the particles, in terms of their longest dimension, are smaller than the parameter, as can be measured by any common particle size measurement technique known to those skilled in the art. These techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering (e.g., laser diffraction), and centrifugation with separation plates.

[0186] Composition D 50 Particle size is the parameter such that 50% by volume of particles in a composition are smaller than the parameter in terms of their longest dimension, as can be measured by any common particle size measurement technique known to those skilled in the art (and as described above). Therefore, D 50 Particle size is a measure of the median particle size by volume, but is sometimes also called "average" or "mean" particle size.

[0187] Composition D 10 Particle size is the parameter such that 10 volume percent of the particles in a composition are smaller than the parameter in terms of their longest dimension, as can be measured by any common particle size measurement technique known to those skilled in the art (and as described above).

[0188] As used herein, the term “tableting composition” as used in reference to the compositions of the present invention defines a composition comprising lysinirazole tetrahydrate that is suitable for compression into tablets. Typically, the tableting compositions of the present invention are suitable as feed for tablet presses, such as stamp-type or rotary tablet presses. In a preferred embodiment, the tableting composition of the present invention is suitable for compression into lysinirazole tetrahydrate tablets comprising an inner granular solid phase incorporated into an outer granular solid phase, where (a) the inner granular phase has a particle size D of 4 to 30 μm. 90 (b) comprising lysinirazole tetrahydrate crystalline aggregates dispersed in a first pharmaceutically acceptable excipient system having; (b) the granular outer phase comprising a second pharmaceutically acceptable excipient system, wherein the first and second excipient systems are different.

[0189] "Therapeutic dose" refers to the amount of a compound or pharmaceutical composition that is useful to treat or improve an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. Therapeutic dose also includes, within its scope, a non-toxic but sufficient amount of a particular drug claimed to exhibit the desired therapeutic effect. The exact required dose varies from subject to subject, depending on factors such as the patient's overall health and age. The exact amount is subject to the purpose of treatment and can be determined 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] "To treat," "to treat," and "treatment" mean any evidence of success in treating or restoring an injury, condition, or state, including any objective or subjective parameters such as remission; remission; reduction of symptoms, or increased patient tolerance to the injury, condition, or state; slowing the rate of weakness or decline; reducing the degree of weakness at the final point of weakness; or improving the patient's physical or mental health. Treatment or restoring symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0191] The abbreviation "(w / w)" means "weight versus weight," that is, the proportion of a particular substance in a mixture measured by weight or mass, or the weight ratio of one component of the composition to the total weight ratio of the composition disclosed herein. Therefore, the quantity is unitless and represents the weight ratio of one component 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 present invention as defined herein may also be suitable for other applications. In particular, the tableting compositions of the present invention may also be suitable for use as a basis for dosage forms other than tablets, including liquid suspensions, granule-filled capsules, and granule-filled sachets (or other containers).

[0193] Method for manufacturing ridinirazole tetrahydrate tablets Both small-scale synthesis (approximately 1 kg granulation, 6-liter granulator) and 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 Figure 15.

[0194] Overall, the process development tests demonstrated the importance of a wet agglomeration step, including the use of micronized APIs, as well as the appropriate ratio of the intragranular relative granular outer phase to the final blend that should be compressed into tablets exhibiting suitable hardness and disintegration time.

[0195] In prototype tablet process manufacturing tests, the granulation endpoint was reached within a short wetting rate window, indicating that the wet agglomeration step is critically important for the product. Attempts using relatively low granulation water levels (20% and 15%) to produce relatively low-density granules confirmed that relatively low water levels may 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 exhibiting good hardness and short disintegration times. Furthermore, one product lot evaluated using this process failed to produce good granules, making tablet formation impossible.

[0196] The presence of aggregated particles in the API, and the overwhelming dominance of the API in the granulator blend during wet agglomeration in the prototype tablet process (approximately 65% ​​by weight of the granulation blend), were considered to be contributing factors to the low reproducibility of granulation. Therefore, tests were conducted to attempt to improve the degree of freedom in granulation and the reproducibility of granulation and dissolution in the tablet process.

[0197] To recognize the presence of varying amounts of aggregates in the API, we decided to use pulverized API. This will ensure that the API particle characteristics are more consistent from lot to lot, for example, with respect to particle size distribution, and may also promote the reproducibility of the wet granulation step. To increase the flexibility of the wet granulation step, we transferred a further portion of the excipients (other than magnesium stearate) from the outer phase to the inner phase of the wet granulation step so that the inner phase constitutes 90% by weight of the final blend.

[0198] Small-scale testing (granulation of approximately 200g in a 1L granulation bowl) confirmed improved flexibility in the granulation endpoint. Good-formed granules were produced in a range of 30% to 37% by weight of water added during wet granulation, resulting in tablets exhibiting good hardness (approximately 170N) and a short disintegration time (approximately 5 minutes). The identified tableting process was adapted to 6L (approximately 1kg granulation), 25L (approximately 3kg granulation), and 65L (approximately 9kg granulation) granulation bowls, and this process was then advanced to the production of larger-scale supplies.

[0199] To avoid flow problems observed in initial investigations into dry granulation options such as direct compression and roller compaction, a conventional wet granulation approach was pursued for product manufacturing. The initial research, described here as tablet development, focused on the selection and quantity of excipients, as well as initial wet granulation parameters (e.g., water addition). Subsequently, research was conducted to refine the process for clinical trial formulations in order to improve the performance of the granulation process.

[0200] Following initial development and compatibility testing, a prototype wet-granulated tablet formulation was identified. The compatibility of the lysinirazole tetrahydrate active ingredient with a range of commonly used excipients in tablet formulations was effectively demonstrated. Wet-granulation screening identified a lead formulation that produced granules exhibiting good flowability and acceptable tablet processability at small and low compressive forces. 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, enabling the samples to be subjected to a 6-month stability test. Under long-term conditions (25°C / 60%RH) or accelerated conditions (40°C / 75%RH), no significant changes were observed in appearance, assays, related substances, hardness, moisture content, or disintegration time, thus confirming the stability of the prototype tablet formulation.

[0201] Next, with the aim of identifying a manufacturing process that would enable the production of robust tablets suitable for large-scale, high-speed tablet presses, further development and optimization were pursued using small-scale prototype tablet formulations. The prototype formulations were investigated in tests evaluating variations in lactose:crystalline cellulose ratio, amount of disintegrant, amount of binder, and amount of water. Eleven formulations were manufactured and tested. To understand the compaction behavior, poles and center points were also tested along the compression curve. Key outputs were performed through statistical software packages to identify any trends regarding critically important property attributes. However, the tablets from these tests were found to exhibit longer disintegration times compared to the initial process prototype tablets, thus requiring further investigation.

[0202] Therefore, a second test was conducted employing a "one variable at a time" approach to establish a process for a prototype formulation that could produce tablets that fit the desired target formulation profile in terms of disintegration, solubility, manufacturability, and the ability to produce a robust formulation for scale-up. Further evaluation of the amount of binder, the amount of water, the lactose distribution ratio (in-granule / out-granule), and the disintegrant distribution ratio (in-granule / out-granule) was attempted to determine the final optimized process. However, these tablets exhibited problems with granule endpoint detection, resulting in problems with flowability in the tablet press on the one hand, and problems with tablet crushing strength / disintegration on the other hand. Despite the challenges in the granulation process, it was possible to produce tablets for stability testing.

[0203] Therefore, further development of the granulation process was undertaken to further ensure the acceptability of the tablet manufacturing process for larger-scale production. This was achieved by moving most of the excipients in the tablet to the granular inner phase and optimizing the particle size of the excipients remaining in the granular outer phase, without changing the quantitative and qualitative composition from previously developed processes. Furthermore, by using ridinirazole tetrahydrate API that has been micronized and has a controlled particle size to improve the reproducibility of the API properties during wet granulation, a process was created that exhibits an acceptable degree of freedom regarding the granulation endpoint based on water requirements and shows good flowability in the tablet press.

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

[0205] In the case of the lysinirazole tetrahydrate tablets of the present invention, the first pharmaceutically acceptable excipient system forms part of the granular inner phase together with dispersed lysinirazole tetrahydrate crystal aggregates, while the second pharmaceutically acceptable excipient system constitutes the granular outer phase relative to the granular inner phase, which includes the API and the first excipient system.

[0206] Similarly, in the tablet composition of the present invention, the first pharmaceutically acceptable excipient system is present within the granules together with dispersed lysinirazole tetrahydrate crystal aggregates, and these granules are surrounded by a second pharmaceutically acceptable excipient system (therefore the second excipient system is outside the granules).

[0207] Each excipient system contains at least one pharmaceutically acceptable excipient, but in preferred embodiments, both excipients contain 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. They may differ in particular with respect to (a) the characteristics of one or more excipients present; (b) the number of chemically and / or functionally distinct excipients present; (c) the concentration of the excipients present; (d) the relative concentrations of two or more excipients present; and / or (e) the presence or absence of a distinct functional class of excipients.

[0209] In preferred embodiments, both the first and second pharmaceutically acceptable excipient systems include a diluent. In this specification, the diluent may be referred to as the “first diluent” if present in the first pharmaceutically acceptable excipient system, and as the “second diluent” if present in the second pharmaceutically acceptable excipient system. Preferably, two distinct diluents are used in one or both of the first and second pharmaceutically acceptable excipient systems, which may be referred to here as the first diluent and the second diluent, respectively.

[0210] In preferred embodiments, both the first and second pharmaceutically acceptable excipient systems include a disintegrant. In this specification, the disintegrant may be referred to as the "first disintegrant" if it is present in the first pharmaceutically acceptable excipient system, and as the "second disintegrant" if it is present in the second pharmaceutically acceptable excipient system. Preferably, one disintegrant is used in one or both of the first and second pharmaceutically acceptable excipient systems, which may be referred to here as the first disintegrant and the second disintegrant, respectively. The first and second disintegrants may be the same or different, and in preferred embodiments, the first and second disintegrants are the same.

[0211] In a preferred embodiment, the first pharmaceutically acceptable excipient system includes a binder, while the second pharmaceutically acceptable excipient system does not include a binder.

[0212] In a preferred embodiment, the first pharmaceutically acceptable excipient system does not contain a lubricant, while the second pharmaceutically acceptable excipient system contains a lubricant.

[0213] Therefore, in certain preferred embodiments, the two excipient systems differ in the presence or absence of two specific functional classes of excipients: binders and lubricants. Specifically, particularly preferably, (a) the first pharmaceutically acceptable excipient system includes a binder, and this class of excipients is not present in the second excipient system, while (b) the second pharmaceutically acceptable excipient system includes a lubricant, while this class of excipients is not present 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, long-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 may contain diluents. Any suitable pharmaceutically acceptable diluent or combination thereof may be used. These include diluents containing, consisting of, or essentially comprising lactose monohydrate and / or crystalline cellulose, for example, a combination of lactose monohydrate and crystalline cellulose.

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

[0217] Disintegrant As described above, both the first and second pharmaceutically acceptable excipient systems may contain disintegrants. Any suitable pharmaceutically acceptable disintegrant or combination thereof may be used. These include disintegrants selected from croscarmellose sodium, crospovidone, crystalline cellulose, polariline potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch.

[0218] Croscarmellose sodium, such as Ac Di Sol® or Primellose®, is particularly preferred as the first and second disintegrants. Croscarmellose sodium proved unexpectedly advantageous as a disintegrant in the tablets and tableting compositions of the present invention. While it is undesirable to be constrained by theory, it is thought that the ionic interaction between lysinirazole tetrahydrate and croscarmellose sodium occurs in conjunction with the formation of an anionic hydrogel upon contact with water (see, for example, Huang et al. (2006) Elimination of meformin-croscarmellose sodium interaction by competition Int J Pharm 311(1-2): 33-39). In particular, the inventors unexpectedly found that the disintegration time was improved when croscarmellose sodium was used as a disintegrant compared to tablets that were otherwise identical except for the use of crospovidone as a disintegrant.

[0219] Binder As described above, the first pharmaceutically acceptable excipient system may include a binder (whereas the second pharmaceutically acceptable excipient system preferably does not include a binder). Any suitable pharmaceutically acceptable binder or combination thereof can be used. Preferred binders include, consist of, or are essentially composed of a hydrophilic polymer.

[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 cellulose ethers selected from hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), and sodium carboxymethylcellulose (NaCMC).

[0221] In preferred embodiments, the binder comprises, consists of, or is essentially composed of hydroxypropylcellulose, which is present only in the first pharmaceutically acceptable excipient system (the second pharmaceutically acceptable excipient system does not contain a binder).

[0222] lubricant As explained above, the second pharmaceutically acceptable excipient system may contain a lubricant (whereas the first pharmaceutically acceptable excipient system preferably does not contain a lubricant). Any suitable pharmaceutically acceptable lubricant or combination thereof can be used.

[0223] Preferred lubricants are (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. bipo It can be selected from Rimmer.

[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 preferred; 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. Sugar esters selected from sorbitan monostearate and sucrose monopalmitate are also preferred. The lubricant may also contain, be derived from, or essentially be derived from sodium stearyl fumarate and / or lysine.

[0226] In preferred embodiments, the lubricant comprises, consists of, or is essentially composed of magnesium stearate. More preferably, it is present only in the second pharmaceutically acceptable excipient system (the first pharmaceutically acceptable excipient system does not contain a lubricant).

[0227] Pharmaceutical active ingredients (APIs) The API present in the tablets and tableting compositions of the present invention is lysinirazole tetrahydrate. As used herein, the term lysinirazole is used to define the compound 2,2'-di(pyridinyl-4-yl)-1H,1'H-5,5'-bibenzo[d]imidazole (also known as 2,2'-di-4-pyridinyl-6,6'-bi-1H-benzoimidazole; 5,5'-bis[2-(4-pyridinyl)-1H-benzoimidazole]; 2,2'-bis(4-pyridyl)-3H,3'H-5,5'-bibenzoimidazole; or 2-pyridinyl-4-yl-6-(2-pyridinyl-4-yl-3H-benzoimidazole-5-yl)-1H-benzoimidazole). This term also includes pharmaceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites, or prodrugs of lysinirazole as defined herein, such as lysinirazole tetrahydrate.

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

[0229] Therefore, in the above-mentioned rilginirazole tetrahydrate tablet formulation, the rilginirazole tetrahydrate API is preferably present in the form of rilginirazole tetrahydrate crystal Form A, 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)°.

[0230] Particle size Rilginirazole tetrahydrate exhibits very low water solubility and relatively low wettability. The inventors have unexpectedly found that controlling the API particle size is important in controlling the variability in the processability and performance of the tablets, tablet formulation compositions, and methods of the present invention that directly or indirectly affect the granule structure and thereby the quality of the tablets.

[0231] Particularly, D outside the range of about 10 to about 20 μm 90 having (particularly D less than 4 μm or greater than 30 μm 90 having) crystalline aggregate particles, it has been found that rilginirazole tetrahydrate tablets produced using the drug substance result in tablets having characteristics unsuitable for the manufacture and performance of pharmaceutical formulations (see Example 9 below).

[0232] In multiple embodiments, the crystalline aggregates can have a particle size D of about 5 μm to about 40 μm 90 and preferably a particle size D of about 10 to about 20 μm 90 having. In other embodiments, the crystalline aggregates can have a particle size D 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 having.

[0233] Therefore, the rilginirazole tetrahydrate API is present in the form of rilginirazole tetrahydrate aggregates having a particle size D of about 4 to about 30 μm 90 , preferably D of 7 to 25 μm 90 , more preferably D of 10 to 20 μm 90 in the tablets, tablet formulation compositions, and methods of the present invention.

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

[0235] The API particle size can be determined using any convenient and well-documented analytical technique. These techniques include sedimentation field-flow fractionation, photon correlation spectroscopy, light scattering methods (e.g., laser diffraction), and centrifugal partition chromatography. The dry laser diffraction method described herein is preferred.

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

[0237] The inventors have unexpectedly discovered that the size-reduced API having a desired particle size D of 4 - 30 μm 90 shows a significant tendency to re-aggregate and form secondary "soft aggregates". Specifically, the rilzabrutinib tetrahydrate API that has undergone a size reduction operation (e.g., air jet milling or other micronization methods) is a highly cohesive and low-flowability powder that shows a tendency to recombine due to electrostatic charges and form secondary "soft aggregates".

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

[0239] Soft aggregates of lysinirazole tetrahydrate particles can cause blockage and clogging of sieve and screen openings, as well as seepage across their surfaces, especially for particle sizes D of 4-30 μm. 90 Sieving or screening reduced-particle-size ridinirazole tetrahydrate is an extremely difficult and time-consuming operation, whether performed manually or mechanically (e.g., using a cone mill or oscillator). Ultimately, this results in blockages that inevitably interrupt the cleaning / clearing process, and incomplete and time-consuming movement of the powder through the sieve. Thus, sieving and screening are difficult, time-consuming, and even impossible.

[0240] This problem concerns particle size D of 4-30 μm. 90 This can be overcome by preparing a preliminary blend of lysinirazole tetrahydrate crystalline aggregate particles and a portion of a first pharmaceutically acceptable intragranular excipient system (e.g., a subset of the constituent excipients of the first excipient system as defined herein). For example, it has been found that blending lysinirazole tetrahydrate particles with all of the first excipients except some or all of the first diluent (e.g., crystalline cellulose in a preferred embodiment) to form an initial intermediate blend allows for effective and easy sieving of the intermediate blend, enabling the effective degradation of all soft aggregates of lysinirazole tetrahydrate.

[0241] Next, the sieve can be “washed” or “rinsed” with the reserved excipient (e.g., crystalline cellulose in a preferred embodiment). This has been found to be effective in transferring all of the granular blend of the first excipient and API remaining on the surface of the sieve into the final blend (for example, the crystalline cellulose or other first diluent passing through the sieve can be combined with the remaining ridinirazole tetrahydrate mixture that has already been sieved, 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 the lysinirazole tetrahydrate API within the granular phase of the tablets of the present invention and within the granules of the various compositions of the present invention.

[0243] The above findings apply to methods for producing compositions of the present invention. For example, they apply to a method for producing a granular lysinirazole tetrahydrate composition according to the third aspect of the present invention described above. In these cases, the lysinirazole tetrahydrate aggregate is first mixed with a first portion of a first pharmaceutically acceptable granular excipient system to form an initial pre-granulation mixture, the pre-granulation mixture is then screened or sieved to form a screened initial pre-granulation mixture, and then the second portion of the first pharmaceutically acceptable granular excipient system is passed through the same screen or sieve to form a screened second portion. Next, the screened initial pre-granulation mixture and the screened second excipient portion are 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 aggregates of lysinirazole tetrahydrate can be avoided, and the uniformity of the distribution of lysinirazole tetrahydrate API in the tablet composition (and ultimately the lysinirazole tetrahydrate tablets) is improved.

[0244] Pre-blending and API distribution in other particulate or granular ridinirazole tetrahydrate compositions As described above, the tableting compositions of the present invention may also be suitable for use as a basis for dosage forms other than tablets, including liquid suspensions, granule-filled capsules, and granule-filled sachets (or other containers). Therefore, the recognition of potential problems arising from reaggregation in lysinirazole tetrahydrate particulate compositions with reduced particle size, and the discovery of advantages related to effective means for preventing, removing, or breaking down secondary soft aggregates (e.g., by the preliminary blending step described above), also applies to the production of lysinirazole 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] Therefore, the above findings are broadly applicable to the production of granular or particulate ridinirazole tetrahydrate compositions in which secondary soft aggregates (formed by the above-mentioned re-aggregation of APIs with reduced particle size) are substantially absent. Accordingly, the present invention relates to a particle size D of 4 to 30 μm in which secondary soft aggregates resulting from the re-aggregation of crystalline aggregates are substantially absent. 90 We also envision granular or particulate lysinirazole tetrahydrate compositions containing crystalline aggregates of crystalline lysinirazole tetrahydrate having the characteristic.

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

[0247] Tablet formulation The lysinirazole tetrahydrate tablets of the present invention contain an inner granular solid phase incorporated into an outer granular solid phase, where (a) the inner granular phase has a particle size D of approximately 4 to approximately 30 μm. 90comprising ranitidine tetrahydrate aggregates dispersed within a first pharmaceutically acceptable excipient system; (b) the outer phase of the granules comprises a second pharmaceutically acceptable excipient system, wherein the first excipient system and the second excipient system are different. Preferred ranitidine tetrahydrate tablets of the present invention have the following composition.

[0248] [Table 2]

[0249] More preferred ranitidine tetrahydrate tablets of the present invention have the following composition.

[0250] [Table 3]

[0251] Even more preferred ranitidine tetrahydrate tablets of the present invention have the following composition.

[0252] [Table 4]

[0253] Even more preferred ranitidine tetrahydrate tablets of the present invention have the following composition.

[0254] [Table 5]

[0255] Even more preferred ranitidine tetrahydrate tablets of the present invention have the following composition.

[0256] [Table 6]

[0257] Even more preferred ranitidine tetrahydrate tablets of the present invention have the following composition.

[0258] [Table 7]

[0259] A more preferred lysinirazole tetrahydrate tablet of the present invention has the following composition.

[0260] [Table 8]

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

[0262] In the exemplary tablet formulation described above, each tablet preferably contains about 100 to 400 mg of lysinirazole tetrahydrate, more preferably about 100 to 300 mg of lysinirazole tetrahydrate, even more preferably about 150 to 250 mg of lysinirazole tetrahydrate, and most preferably about 200 mg of lysinirazole tetrahydrate. A person skilled in the art will be able to calculate, for example, that about 200 mg of lysinirazole tetrahydrate is equivalent to 169 mg of lysinirazole on an anhydrous basis.

[0263] Particularly preferred tablet formulations have the following composition.

[0264] [Table 9]

[0265] In the above-mentioned lysinirazole tetrahydrate tablet formulation, the lysinirazole tetrahydrate API preferably exists in the form of lysinirazole tetrahydrate crystal A, characterized by a powder X-ray diffractogram containing characteristic peaks at 2θ angles (11.02±0.2)°, (16.53±0.2)°, and (13.0±0.2)°.

[0266] The most preferred tablet formulation has one of the following compositions:

[0267] [Table 10]

[0268] [Table 11]

[0269] Treatment method The described formulations comprising ridinirazole tetrahydrate (e.g., ridinirazole tetrahydrate form A) can be used to treat or eliminate Clostridium difficile infection (CDI) and / or one or more Clostridioides difficile-related diseases (CDAD). In some embodiments, CDI contains C. difficile (C. difficile) of toxin A and / or toxin B in the feces. In some embodiments, a composition comprising ridinirazole tetrahydrate is administered to the subject in need. In some embodiments, the composition comprises the ridinirazole tetrahydrate tablets described herein. Administration may be effective in reducing or eliminating CDI and / or CDAD in the subject in need.

[0270] In several embodiments, the target subject is treated with a therapeutically effective dose of ridinirazole tetrahydrate (e.g., ridinirazole tetrahydrate form A). In several embodiments, the target subject is treated with a therapeutically effective dose of ridinirazole tetrahydrate, where a therapeutically effective dose is sufficient to reduce or eliminate at least one symptom of CDI and / or CDAD. In several embodiments, a therapeutically effective dose comprises at least about 200 mg, at most about 200 mg, or about 200 mg of ridinirazole tetrahydrate once or multiple times daily. In several embodiments, the therapeutically effective dose contains approximately 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 ridinirazole tetrahydrate (e.g., ridinirazole tetrahydrate form A).

[0271] A person skilled in the art would understand, for example, that approximately 100 mg of ridinirazole tetrahydrate is equivalent to 84.5 mg of anhydrous ridinirazole (and that approximately 200 mg of ridinirazole tetrahydrate is equivalent to 169 mg of anhydrous ridinirazole).

[0272] Therefore, in certain embodiments, administering one amount of lysinirazole tetrahydrate form A is equivalent to administering to a subject with an anhydrous lysinirazole content of approximately 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, or 450 mg.

[0273] In several embodiments, lysinirazole tetrahydrate is administered to the target for any number of days. In several embodiments, lysinirazole tetrahydrate is administered for approximately 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 several embodiments, lysinirazole tetrahydrate is administered for approximately 10 days. In several embodiments, lysinirazole tetrahydrate is administered for approximately 5 to 10 days. In several embodiments, lysinirazole tetrahydrate is administered for approximately 5 to 20 days. In several embodiments, lysinirazole tetrahydrate is administered multiple times a day. For example, lidinirazole tetrahydrate can be administered once, twice, three, four, five, or six times a day, preferably twice a day. In some embodiments, lidinirazole tetrahydrate is administered every 12 hours. In some embodiments, lidinirazole tetrahydrate is administered until CDI and / or CDAD are resolved. In some embodiments, lidinirazole tetrahydrate is administered until the symptoms of lidinirazole tetrahydrate are reduced or eliminated.

[0274] In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing CDI and / or CDAD, as determined by the reduction or elimination of symptoms associated with CDI, including but not limited to diarrhea (e.g., amorphous stools), fever, gastric tenderness, loss of appetite, nausea, and combinations thereof. In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing the symptoms of CDI and / or CDAD for at least about 1 day compared to another equivalent subject without administration. In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing the 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 equivalent subject without administration.

[0275] In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing CDI and / or CDAD, as confirmed by a decrease in the frequency of atypical bowel movements (UBM) in subjects compared to before administration. In multiple embodiments, administration of ridinirazole tetrahydrate is effective in eliminating CDI and / or CDAD in subjects requiring it, as confirmed by the resolution of atypical bowel movements (UBM). In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing the detection of UBM for at least about 1 day compared to subjects with no administration, except for equivalent subjects. In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing the detection of UBM for at least about 1 day, 2 days, 3 days, 4 days, or 5 consecutive days compared to equivalent subjects with no administration. In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing the recurrence of diarrheal episodes (e.g., more than about 3 UBMs) by 1 day. In multiple embodiments, the target subjects exhibit a clinical response after administration of ridinirazole tetrahydrate. In multiple embodiments, the target subjects do not exhibit relapses of CDI and / or CDAD for approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 days after treatment. In multiple embodiments, the target subjects do not exhibit relapses of CDI and / or CDAD for at least approximately 30 or 90 days after treatment.

[0276] In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing CDI and / or CDAD, as determined by a reduction in the frequency of amorphous bowel movements (UBM) in subjects compared to comparable subjects who received vancomycin, except for vancomycin administration. In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing the detection of UBM compared to other comparable subjects who received vancomycin for at least about 1 day. In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing the detection of UBM compared to comparable subjects who received vancomycin for at least about 1 day, 2 days, 3 days, 4 days, or 5 consecutive days. In multiple embodiments, administration of ridinirazole tetrahydrate is effective in reducing the recurrence of diarrheal episodes (e.g., more than about 3 UBMs) compared to comparable subjects who received vancomycin for 1 day.

[0277] UBM can be determined by the Bristol Stool Characteristics Chart. See Figure 16. In several embodiments, UBM includes bowel movements of type 5, 6, or 7 on the Bristol Stool Characteristics Chart. In several embodiments, administration of ridinirazole tetrahydrate is effective in reducing the frequency (temporal frequency) or detection of UBM in subjects of interest. In several embodiments, administration of ridinirazole tetrahydrate is effective in returning the bowel movements of subjects of interest to a type selected from the group consisting of 1, 2, 3, and 4, rather than type 5, 6, or 7. In several embodiments, administration of ridinirazole tetrahydrate is effective in returning the bowel movement type to at least 1, 2, 3, 4, 5, or 6 types compared to equivalent subjects who did not receive the administration based on the Bristol Stool Characteristics Chart.

[0278] In several embodiments, the subject of need has already been administered an antibiotic. In several embodiments, the antibiotic is selected from the group consisting of ampicillin, amoxicillin, cephalosporins, and clindamycin. However, any antibiotic is envisioned. In several embodiments, the subject is simultaneously treated with ridinirazole tetrahydrate and at least one further therapeutic agent. In several embodiments, the one further therapeutic agent includes an antibiotic. In several embodiments, the subject of need has already been administered an antibiotic other than ridinirazole tetrahydrate. In several embodiments, the subject of need has already been administered vancomycin.

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

[0280] In several embodiments, CDI is detected using in vitro assays. Suitable in vitro assays available include, but are not limited to, ELISA, latex agglutination assays, cell cytotoxicity assays, PCR, C. difficile culture, and combinations thereof. [Examples]

[0281] Examples The present invention will be described below with reference to specific examples. These are merely illustrative and for illustrative purposes only, and are not intended in any way to limit the scope of the claimed exclusive rights or the scope of the invention described. These examples constitute the best currently conceivable mode for carrying out the present invention.

[0282] method Water activity (A w ) The water activity coefficient and water activity 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 had a range of 3–40°²θ, a step size of 0.013°, a count time of 99 seconds, and an operating time of approximately 22 minutes. XRPD patterns were sorted using HighScore Plus 2.2c software.

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

[0285] In vitro lysis The solubility is measured by HPLC using 2.5% sodium lauryl sulfate (SLS) in 0.01N HCl, with the solubility parameters shown in the table below.

[0286] Place the degassed dissolution medium (1 liter) into the dissolution container and equilibrate to 37±0.5°C. Drop the tablets for analysis into the dissolution container and allow them to sink to the bottom. Next, start paddle rotation (100 rpm). Using a syringe fitted with a stainless steel cannula and full-flow filter, at 15, 30, 45, and 60 minutes, remove 5 mL of the solution from the area between the surface of the dissolution medium and the top of the paddle, at a position of more than 1 cm from the container wall. After 60 minutes, increase the rotation speed to 250 rpm and rotate for 15 minutes, then remove 5 mL of the solution from the container. Next, filter the solution through an Acrodisc 25 mm syringe filter with a 1 μm glass fiber membrane, discard the first 3 mL of filtrate, and collect the remaining filtrate in an HPLC vial for analysis.

[0287] Ridinirazole Crystal Aggregate Particle Sizing This was performed by laser diffraction using a Malvern 2000 dry dispersion apparatus. The settings used for sizing are described below. Equipment: Malvern Mastersizer dry dispersion equipment Balanced: Minimum 2 sides equipment method Accessory name: Scirocco 2000 Mode: General Purpose Calculation sensitivity: Normal (Select "Fine Power" only for pulverized samples) Sample refractive index: 1.704 Particle absorption: 0.01 Obfuscation limit: 0.1% to 6.0% (if achievable) Vibration supply rate: 45% Mesh size: Large mesh, 1.6mm Sample measurement time: 20 seconds Dispersed air pressure: 2 bar Sample tray: General purpose (<200g) Aliquote: 3 per method Measurement: 1 measurement per aliquot Background time: 3 seconds Measurement snap: 20,000 Background snaps: 3,000

[0288] Sample preparation - trilogy Turn the sample jar or vial upside down 10 times. Weigh approximately 2g of the sample and transfer it to the sample tray. Distribute the sample evenly in the sample tray.

[0289] Example 1: Preparation of lysinirazole type A tetrahydrate crystal aggregates Reaction: 4-cyanopyridine (0.85 kg) and MeOH (5.4 kg) were added to a reaction flask, and NAM-30 (NaOMe as a 30 wt% solution in MeOH; 0.5 equivalents; 0.15 kg) was added. The resulting mixture was heated at 60°C for 10 minutes and then cooled. This solution was added over 1 hour at 60°C to a mixture of 3,3'-diaminobenzidine (DAB) (0.35 kg) and acetic acid (0.25 kg) in MeOH (1 L). The mixture was then heated for 2 hours. The reaction mixture was cooled overnight to ambient temperature. The crystal mass was filtered, washed with MeOH (1.4 L), and drained by dry suction on the filter.

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

[0291] Polymorph formation: Desired polymorphs were 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 nitrogen purging for 6 days.

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

[0293] [Table 12-1]

[0294] [Table 12-2]

[0295] Next, the crystal aggregates are formed to the target particle size (D 90Approximately 4 to approximately 30 μm, preferably D 90 Approximately 7 to approximately 25 μm, more preferably D 90 The particles were ground using an air jet mill to a size of approximately 10-20 μm.

[0296] Example 2: Crystal structure of lysinirazole tetrahydrate form A Single crystals of lysinirazole type A were grown by liquid diffusion at room temperature in an NMP / dioxane solution of lysinirazole using chloroform as a poor solvent. Needle-shaped crystal samples with approximate dimensions of 0.380 mm × 0.015 mm × 0.010 mm were used for X-ray crystal structure analysis at beamline 119 of the Diamond Light Source.

[0297] The atomic numbering scheme for lysinirazole molecules and water molecules is shown in Figure 2 as an ORTEP plot. Packing diagrams of the lysinirazole form A structure are shown in Figures 3 to 5, along each crystal axis. Since only one hydrogen bond can be clearly located between N24-H24…N51, it is not possible to describe the hydrogen bonding between lysinirazole molecules. Other hydrogen bonds occurring in the structure are formed between water molecules, imidazole hydrogens, and pyridine nitrogen atoms. Due to the large disorder of water molecules and their hydrogen atoms, it is not possible to fully resolve the hydrogen bonding network structure.

[0298] Example 3: Preparation of lysinirazole type D Reaction: 4-cyanopyridine (0.85 kg) and MeOH (5.4 kg) were added to a reaction flask, and 0.5 equivalents (0.15 kg) of NaOMe (NAM-30) as a 30 wt% solution in MeOH were added. The resulting mixture was heated at 60°C for 10 minutes 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) over 1 hour at 60°C. The mixture was then heated for 2 hours. The reaction mixture was allowed to cool overnight to ambient temperature. The crystal mass was filtered, washed with MeOH (1.4 L), and drained by dry suction on the filter.

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

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

[0301] [Table 13-1]

[0302] [Table 13-2]

[0303] Example 4: Crystal structure of lysinirazole anhydride form D Single crystals of lysinirazole D-form were grown by vapor diffusion at room temperature in an ethanol solution of lysinirazole using water as a poor solvent, and the single crystal structure was determined. A prism-shaped crystal sample with approximate dimensions of 0.3 mm × 0.2 mm × 0.1 mm was used for X-ray crystal structure analysis.

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

[0305] Example 5: Conversion from lysinirazole D to A Lidinirazole form D was prepared as described in Example 3. Lidinirazole form A was prepared as described in Example 1. Seed crystals were prepared by manual grinding and sieving. The conversion was carried out as follows: 1) Add the 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% by weight of type A (or 2% by weight of type A in a slurry prepared in MeOH / H2O (80 / 20 v / v) and slurred for 2.5 hours before addition). 8) Wait for 1 hour. The slurry is thick and has 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. A 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 for each wash. Wash the wet cake with 3 ml of 1 volume of MeOH / H2O (80 / 20 v / v).

[0306] Example 6: Ridinirazole 200 mg oral tablets Preferred tablet formulations are listed in Tables 3 and 4 below.

[0307] [Table 14]

[0308] [Table 15]

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

[0310] XRPD tracing of the sample compared to form A showed a small peak shift, but additional peaks were present at approximately 12.5°2θ and approximately 19–24°2θ. XRPD analysis of ridinirazole tablets, ridinirazole form A, and placebo blend confirmed that these additional peaks were due to the placebo mixture (Figure 12), i.e., the additional peaks were present in the placebo mixture and therefore due to the excipients.

[0311] The stability of the ridinirazole crystalline form in tablets packaged in the proposed commercial packaging configuration was evaluated using a proven, specialized X-ray powder diffraction (XRPD) method developed as a limiting test for detecting D and N forms in drug formulations. No morphological conversion was detected; therefore, form A is stable in tablets under proposed storage conditions in the proposed commercial packaging configuration.

[0312] Example 7: Comparison of release profiles and colonic delivery profiles of ridinirazole capsule and tablet formulations in the in vitro dynamic GI model TIM-1. Furthermore, the release profiles and colonic delivery profiles of ridinirazole 200 mg capsules and 200 mg tablets were compared in the in vitro dynamic GI model TIM-1. TIM-1 is a dynamic, multi-compartmental, and predictive in vitro system that simulates 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, digestive fluid flow rate and composition, pH, and removal of water and metabolites. TIM-1 consists of four compartments (stomach, duodenum, jejunum, and ileum) and can simulate feeding or fasting conditions.

[0313] Both ridinirazole formulations were tested under simulated fasting conditions, and analysis was performed on samples from each compartment and ileal outflow throughout the entire experimental time course. For compartmental analysis, dialysate samples were taken from each compartment (stomach, jejunum, ileum) at 60-minute intervals.

[0314] Surprisingly, the capsule formulation breaks down more slowly than the tablet formulation, which in turn reduces the T content of measured ridinirazole in the ileal effluent. MAX It was found that the reaction was delayed compared to the tablet formulation (Figure 13). In the tablet formulation, the peak dose of lidinirazole was measured within a period of 60 to 120 minutes, while in the capsule formulation, it was measured within a period of 120 to 180 minutes.

[0315] Example 8: Comparison of in vivo release profiles of lidinirazole capsule and tablet formulations The lidinirazole Phase II liquid capsule formulation and the lidinirazole solid tablet formulation of the present invention were evaluated in dogs using a single-dose pharmacokinetic (PK) study. Three animals were administered a single dose (200 mg) of the test product, and blood samples were collected 8 hours after administration. All bioanalysis results were below the limit of quantification, and no adverse effects were observed in either formulation in the test subjects.

[0316] Example 9: Particle size For materials exhibiting very low water solubility and relatively low wettability, controlling the particle size of the active pharmaceutical ingredient is crucial for controlling process processability and performance variability, thereby enabling control of granule structure and, consequently, tablet quality.

[0317] The particle size of lidinirazole is controlled within the active pharmaceutical ingredient (API), and the reduction in the particle size of lidinirazole crystal aggregates is performed as the final step in API manufacturing (see Example 1). This not only ensures batch-to-batch consistency of the particle size distribution within the API, but also guarantees batch-to-batch consistency in both the manufacturing and quality of the lidinirazole drug formulation.

[0318] Proposed commercial specification range for active pharmaceutical ingredients with reduced particle size (D 90The suitability of drug formulations for manufacturing and performance was evaluated for particle sizes (10-20 μm). Ridinirazole tablets were manufactured using the API batches at the limits of the proposed specification (Table 4). Figure 14 shows that the dissolution profiles from these batches, representing the limits of the proposed API particle size specification, are suitable for the manufacturing and performance of the drug formulation.

[0319] [Table 16]

[0320] D outside the range of 10-20 μm 90 (especially D, which is less than 4 μm or greater than 30 μm) 90 It has D larger than 40 μm in particular. 90 Lidinirazole tablets manufactured using an active pharmaceutical ingredient (API) containing crystalline aggregate particles resulted in tableting materials with properties unsuitable for the manufacture and performance of drug formulations.

[0321] Further tests were completed to evaluate the particle size of the micronized lysinirazole tetrahydrate used in tablet formulations. The data are shown in Table 6 below.

[0322] [Table 17]

[0323] According to one embodiment of the present invention, the lysinirazole tetrahydrate crystal aggregate used to produce 200 mg lysinirazole tetrahydrate tablets is D 90 Approximately 10μm~approximately 20μm, D 50 Approximately 2 μm to approximately 9 μm, and D 10 The particle size is in the range of less than 2 μm. According to other embodiments, the lysinirazole tetrahydrate crystal aggregate is D 90 Approx. 8μm~Approx. 15μm, D 50 Approximately 2 μm to approximately 8 μm, and D 10 The particle size is in the range of less than 2 μm.

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

[0325] Wet granulation After screening in a high-shear granulation bowl, batch quantities of lysinirazole (type A), lactose monohydrate, crystalline cellulose, hydroxypropyl cellulose, and croscarmellose sodium for the granule internal phase are subjected to a short initial premixing at 80 revolutions per minute (rpm) for approximately 1 minute.

[0326] Add purified water while continuing to mix. When the water content reaches 12% by weight and 24% by weight, manually move the wet mass through a 2000 μm screen to improve the water content, and return it to the granulation bowl each time to continue granulation. When the water content reaches approximately 35% by weight, transfer the wet granules to a fluidized bed dryer.

[0327] dry Next, the wet-milled granules are transferred to a fluidized bed dryer at an inlet air temperature of approximately 60°C until the target limit of detection (LOD) is achieved. Upon completion of drying, the dried granules are transferred to a blender bin of appropriate size through a Comil equipped with a 1143 μm screen.

[0328] Final blending The dried, milled granules are combined with lactose monohydrate, crystalline cellulose, and croscarmellose sodium for the granular outer phase.

[0329] Lubrication After adding the calculated batch amount of magnesium stearate to the dry blend, manually transfer it through a 250 μm screen into a 20 L bottle containing the final blend. Lubricate the 20 L bottle in the blender by tumbling it at 30 rpm for 2 minutes.

[0330] compression The tablets are compressed using an oval-shaped tool. Dust removal and metal detection are performed during line post compression.

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

[0332] Example 11 Effect of micronization on tablet properties of lysinirazole API The effect of micronization on the tablet properties of ridinirazole API was investigated twice separately during the development process.

[0333] First, during formulation development testing, tablets produced with micronized APIs were compared to tablets produced with non-micronized APIs. The tablets were compressed using both round and capsule-shaped tools, and their dissolution profiles were compared (Figure 16).

[0334] Tablets produced using non-micronized APIs exhibited relatively slow and incomplete dissolution. Disintegration time was also prolonged.

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

[0336] A difference was observed during compression. Normally, tablets are compressed to a target hardness of 17.5 kp. Achieving this target hardness using the maximum compression pressure of the tabletop machine was impossible. Tablets were manufactured in two sub-lots with hardnesses of 7.7 kp and 12.9 kp.

[0337] The dissolution profile of the non-micronized batch reflected that of previous tests. Compared to batches produced by the same process using micronized API, both the rate and degree of dissolution were significantly lower (Figure 17).

[0338] Example 12 - Development of a Formulation The objective of this study was to develop formulations and processes for a ridinirazole tetrahydrate active pharmaceutical ingredient that can be compressed into tablets with a strength of 200 mg. Table 7 outlines the components for producing tablets that meet the desired specification targets regarding disintegration, solubility, and manufacturability, as well as producing a robust formulation for scale-up.

[0339] [Table 18]

[0340] The batch was manufactured using wet granulation. An exemplary process is shown in Figure 19.

[0341] 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 higher tablet hardness resulting in slower release. However, tablets at all four hardness levels completely release the drug by 50 minutes.

[0342] An extended disintegration time was expected at a hardness of 250N. This is because as the hardness of the tablet increases, its porosity decreases, and therefore the time until moisture penetrates increases. This manufacturing process resulted in tablets exhibiting low shatterability with respect to the hardness target.

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

[0344] The above description details currently preferred embodiments of the present invention. Those skilled in the art will expect, by considering these descriptions, to come up with numerous modifications and variations in its implementation. These modifications and variations are intended to be covered within the claims appended herein. The present invention includes the following embodiments. [1] (i) Lidinirazole crystal aggregates; and (ii) Granule internal solid phase incorporated into granule external solid phase Includes, (a) The granular inner phase comprises particles with a particle size of less than 30 μm, dispersed within a first pharmaceutically acceptable excipient system. 90 It contains lysinirazole crystal aggregates having; (b) The granular outer phase comprises a second pharmaceutically acceptable excipient system. Tablet formulation. [2] The tablet formulation according to [1], wherein the lysinirazole crystal aggregate comprises lysinirazole tetrahydrate. [3] The tablet formulation according to [2], wherein the lysinirazole tetrahydrate comprises lysinirazole tetrahydrate type A. [4] The lysinirazole tetrahydrate has a particle size D of approximately 7 to approximately 25 μm. 90 A tablet formulation according to [1], having the following characteristics: [5] The lysinirazole tetrahydrate has a particle size D of approximately 10 to approximately 20 μm. 90 A tablet formulation according to [1], having the following characteristics: [6] The tablet formulation according to [1], wherein the ridinirazole tetrahydrate is present in the tablet in an amount of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% wt / wt. [7] The tablet formulation according to [1], wherein the ridinirazole tetrahydrate is present in the tablet at a concentration of 40% wt / wt or more. [8] The tablet formulation according to [1], wherein the granular inner phase is present in the tablet at a concentration of approximately 65 to approximately 95% wt / wt. [9] The tablet formulation according to [1], wherein the granular outer phase is present in the tablet at a concentration of about 5 to about 35% wt / wt.

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

[11] The tablet formulation according to

[10] , wherein the first excipient system comprises a first diluent, wherein the first diluent is present in the tablet at a maximum concentration of 35% wt / wt.

[12] The first diluent comprises lactose monohydrate and / or crystalline cellulose, The tablet formulation according to

[11] , 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.

[13] The first excipient system includes a first disintegrant, The tablet formulation according to [1], wherein the first disintegrant is selected from croscarmellose sodium, crospovidone, crystalline cellulose, polaritrin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch.

[14] The tablet formulation according to

[13] , wherein the first disintegrant is present in the tablet at a concentration of up to 2% wt / wt.

[15] The first excipient system includes a binder, The tablet formulation according to [1], wherein the binder is 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 hydroxypropylcellulose (HPC), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), and sodium carboxymethylcellulose (NaCMC).

[16] The tablet formulation according to

[15] , wherein the binder is present in the tablet at a concentration of up to 3% wt / wt.

[17] The tablet formulation according to [1], wherein the second excipient system is present in the tablet at a concentration of up to 10% wt / wt.

[18] The tablet formulation according to [1], wherein the second excipient system comprises a second diluent and / or a second disintegrant and / or lubricant.

[19] The tablet formulation according to

[18] , wherein the second diluent is present in the tablet at a concentration of up to 6% wt / wt.

[20] The second diluent comprises lactose monohydrate and / or crystalline cellulose, The tablet formulation according to

[18] , 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.

[21] The second excipient system includes a second disintegrant, The tablet formulation according to [1], wherein the second disintegrant is selected from croscarmellose sodium, crospovidone, crystalline cellulose, polaritrin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, and starch.

[22] The tablet formulation according to

[21] , wherein the second disintegrant is present in the tablet at a concentration of up to 3% wt / wt.

[23] The second excipient system includes a lubricant, The tablet formulation according to [1], 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.

[24] The tablet formulation according to

[23] , comprising the following lubricant: (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.

[25] The tablet formulation according to

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

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

[27] The tablet formulation according to [1], wherein the tablet contains approximately 100 to 400 mg of ridinirazole tetrahydrate.

[28] The tablet formulation according to [1], wherein the tablet contains approximately 200 mg of lidinirazole tetrahydrate.

[29] A tablet formulation according to [1], having the following composition. Table 19

[30] The tablet formulation according to

[29] , 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.

[31] When measured using the TIM-1 dynamic in vitro gastrointestinal model, the T content of lysinirazole tetrahydrate in ileal effluent was measured. MAX A tablet formulation as described in [1], which shows a duration of less than 3 hours.

[32] When measured using the TIM-1 dynamic in vitro gastrointestinal model, the T content of lysinirazole tetrahydrate in ileal effluent was measured. MAX A tablet formulation as described in

[29] , which shows a duration of less than 2 hours.

[33] A tablet formulation as described in

[29] , containing 169 mg of anhydrous ridinirazole.

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 time 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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