WO2023213878A1 - Forme galénique comprimé solide de ridinilazole - Google Patents

Forme galénique comprimé solide de ridinilazole Download PDF

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Publication number
WO2023213878A1
WO2023213878A1 PCT/EP2023/061667 EP2023061667W WO2023213878A1 WO 2023213878 A1 WO2023213878 A1 WO 2023213878A1 EP 2023061667 W EP2023061667 W EP 2023061667W WO 2023213878 A1 WO2023213878 A1 WO 2023213878A1
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WO
WIPO (PCT)
Prior art keywords
ridinilazole
tablet
tetrahydrate
pharmaceutically acceptable
present
Prior art date
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PCT/EP2023/061667
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English (en)
Inventor
Richard Vickers
Original Assignee
Summit (Oxford) Limited
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Publication date
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Publication of WO2023213878A1 publication Critical patent/WO2023213878A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to solid tablet oral dosage forms of 2,2'-di(pyridin-4-yl)- l/f,l'/f-5,5'-bibenzo[d]imidazole (which may also be known as 2,2’-di-4-pyridinyl-6,6’-bi- 1/f-benzimidazole, 5,5’-bis[2-(4-pyridinyl)-lH-benzimidazole], 2,2'-bis(4-pyridyl)-3/f,37T- 5,5'-bibenzimidazole or 2-pyridin-4-yl-6-(2-pyridin-4-yl-3/f-benzimidazol-5-yl)-l/f- benzimidazole), referenced herein by the INN name ridinilazole, and pharmaceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites or prodrugs thereof.
  • CDI Clostridium difficile
  • CD AD Clostridium difficile-associaXeA diseases
  • Ridinilazole also known as SMT19969, and which may be variously referenced as 2,2'- di(pyridin-4-yl)-17/,r/f-5,5'-bibenzo[d]imidazole or 5,5’-bis[2-(4-pyridinyl)-17F- benzimidazole] in the literature
  • Ridinilazole may be represented by the following formula: [007], In a recent Phase 2 randomized, controlled, double-blinded clinical trial comparing its efficacy to vancomycin (Vickers etal.
  • ridinilazole was associated with marked reduction in rates of recurrent disease (14.3% vs. 34.8%). Ridinilazole exhibits enhanced preservation of the human intestinal microbiota compared to vancomycin (which may contribute to the reduced CDI recurrence observed in the Phase 2 study).
  • Ridinilazole is a BCS class IV, orally administered and locally acting (lower intestines) GI antibiotic with minimal systemic exposure and very low solubility across physiologically relevant pH.
  • BCS class IV drugs are known to present particular formulation challenges, especially in the case of oral formulations (see e.g. Ghadi and Dand (2017) BCS class IV drugs: Highly notorious candidates for formulation development Journal of Controlled Release, 248: 71-95).
  • Existing clinical ridinilazole formulations include an aqueous suspension used in a Phase 1 study. Individual doses (2mg - 2000mg) were manufactured at site and dosed within a 24- hour period. The drug substance (2mg - 2000mg) was suspended in 30ml water for injection (WFI) with additional WFI provided as rinse. Ahead of preparation of the unit doses the drug substance was de-aggregated in a pestle and mortar for organoleptic reasons. This formulation successfully delivered the powdered drug substance through the gastrointestinal tract to the colon.
  • WFI water for injection
  • ridinilazole was formulated as an immediate release liquid-filled hard- gelatin capsule at a strength of 200mg. This dosage form was also capable of readily dispersing within the stomach and delivering the powdered drug substance through the gastrointestinal tract to the colon.
  • the ridinilazole capsules were manufactured by liquid filling of a semi-solid blend of ridinilazole and Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS). Ahead of filling ridinilazole was evenly dispersed within 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 compatible with the drug loading, unit dose and capsule size, its compatibility with the manufacturing process, and its compatibility with the active ingredient and capsule shell.
  • suspension and liquid-filled capsule ridinilazole formulations have severe disadvantages.
  • Suspension formulations are inconvenient, as they may need to be extemporaneously prepared immediately prior to use, or if ready prepared may have to be physically processed (e.g. by thorough shaking) before dosing, otherwise there is risk that a non-uniform product is employed when measuring the actual dose to be administered. Indeed, risks arising from lack of uniformity are acute in relation to suspension formulations). For example, the dose must be measured out with a spoon or an oral syringe for administration from the bottle of liquid, which typically leads to inaccuracy of dosing from dose to dose.
  • Liquid-filled capsule formulations also suffer from risks associated with non-uniform doses, since the fluid suspension may suffer sedimentation unless elaborate (and costly) precautions are taken with temperature control and agitation during capsule filling. Capsule filling also requires great care to assure the exact dose of fluid is metered into each capsule, requiring specialist equipment for commercial manufacturing which is not widely available.
  • a solid tablet oral dosage form of ridinilazole is therefore highly desirable.
  • the therapeutic dose of ridinilazole is 200 mg twice a day (BID), with a daily dose of 400 mg.
  • BID twice a day
  • a relatively high drug load is therefore required in any oral tablet appropriately sized for safe and convenient administration with good patient compliance. Consequently, the bulk and surface properties of ridinilazole significantly impact on manufacturability and processability.
  • the formulation of ridinilazole as appropriately sized solid oral tablets therefore presents acute problems.
  • ridinilazole tetrahydrate crystal agglomerates in the context of an intragranular solid phase, which permits, via wet or dry granulation processes, the production of ridinilazole granules with physical attributes (including size, density, morphology and microstructure) which render them unexpectedly useful in the context of solid tablet oral dosage forms.
  • the invention generally encompasses tablet formulations including
  • the intragranular phase comprises ridinilazole crystal agglomerates having a particle size D 90 of less than 30pm dispersed within a first pharmaceutically acceptable excipient system;
  • the extragranular phase comprises a second pharmaceutically acceptable excipient system.
  • the intragranular phase and the extragranular phase are different.
  • the ridinilazole crystal agglomerates comprise ridinilazole tetrahydrate, preferably ridinilazole tetrahydrate crystal agglomerates.
  • the ridinilazole crystal agglomerates has a particle size D 90 of about 7 to about 25 pm.
  • the ridinilazole crystal agglomerates has a particle size D 90 of about 10 to about 20pm.
  • the ridinilazole crystal agglomerates comprises ridinilazole tetrahydrate Form A.
  • the ridinilazole tetrahydrate is present in the tablet in an amount of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% wt/wt.
  • the ridinilazole tetrahydrate is present in the tablet at a concentration greater than or equal to about 40% wt/wt.
  • the intragranular phase is present in the tablet at a concentration of about 65 to about 95% wt/wt.
  • the extragranular phase is present in the tablet at a concentration of about 5 to about 35% wt/wt.
  • the first excipient system is present in the tablet at a concentration of up to about 40% wt/wt.
  • the first excipient system comprises a first diluent, and wherein the first diluent is present in the tablet at a concentration of up to 35% wt/wt.
  • the first diluent comprises lactose monohydrate and/or microcrystalline cellulose
  • lactose monohydrate is present in the tablet at a concentration of up to 30% wt/wt
  • microcrystalline cellulose is present in the tablet at a concentration of up to 10% wt/wt.
  • the first excipient system comprises a first disintegrant
  • the first disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch.
  • the first disintegrant is present in the tablet at a concentration of up to 2% wt/wt.
  • the first excipient system comprises a binder
  • the binder is selected from the group consisting of polyvinyl pyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ethers, wherein the cellulose ethers are selected from hydroxypropyl cellulose (UPC), methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC), ethylcellulose (EC) and sodium carboxymethyl cellulose (NaCMC).
  • PVP polyvinyl pyrrolidone
  • PVP-polyvinyl acetate copolymer partially gelatinized starch
  • cellulose ethers wherein the cellulose ethers are selected from hydroxypropyl cellulose (UPC), methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC), ethylcellulose (EC) and sodium carboxymethyl cellulose (NaCMC).
  • the binder is present in the tablet at a concentration of up to 3% wt/wt.
  • the second excipient system is present in the tablet at a concentration of up to 10% wt/wt.
  • the second excipient system comprises a second diluent and/or a second disintegrant and/or a lubricant.
  • the second diluent is present in the tablet at a concentration of up to 6% wt/wt.
  • the second diluent comprises lactose monohydrate and/or microcrystalline cellulose, wherein
  • the lactose monohydrate is present in the tablet at a concentration of up to 5% wt/wt
  • the microcrystalline cellulose is present in the tablet at a concentration of up to 2% wt/wt.
  • the second excipient system comprises a second disintegrant
  • the second disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch.
  • the second disintegrant is present in the tablet at a concentration of up to 3% wt/wt.
  • the second excipient system comprises a lubricant
  • the lubricant is selected from: (a) fatty acids; (b) metallic salts of fatty acids; (c) combinations of fatty acids and metallic salts thereof; (d) fatty acid esters; (e) metallic salts of fatty acid esters; and (f) inorganic materials and polymers.
  • the lubricant comprises:
  • a fatty acid selected from the group consisting of stearic acid, palmitic acid and myristic acid; [0053], (ii) a metallic salt of a fatty acid selected from magnesium stearate, calcium stearate and zinc 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;
  • the lubricant is present in the tablet at a concentration of up to 1% wt/wt.
  • the second excipient system comprises lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate, and magnesium stearate.
  • the formulation is substantially anhydrous.
  • the tablet contains about 100 about 400 mg of ridinilazole tetrahydrate.
  • the tablet contains about 200 mg of ridinilazole tetrahydrate (which is equivalent to 169 mg of ridinilazole on an anhydrous basis).
  • the tablet formulation comprises or consists of:
  • the intragranular phase takes the form of inclusions embedded within a matrix formed by the extragranular phase.
  • the tablet formulation exhibits a TMAX of less than 3 hours for ridinilazole tetrahydrate in ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model.
  • the tablet formulation exhibits a TMAX of less than 2 hours for ridinilazole tetrahydrate in ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model.
  • a ridinilazole tetrahydrate tablet comprising an intragranular solid phase incorporated in an extragranular solid phase, wherein: (a) the intragranular phase comprises ridinilazole tetrahydrate agglomerates having a particle size D90 of about 4 pm to about 30 pm dispersed within a first pharmaceutically acceptable excipient system; and (b) the extragranular phase comprises a second pharmaceutically acceptable excipient system, wherein the first and second excipient systems are different.
  • the ridinilazole is in the form of ridinilazole tetrahydrate, preferably in the form of ridinilazole tetrahydrate crystal agglomerates, more preferably ridinilazole tetrahydrate Form A (as herein defined).
  • the ridinilazole tetrahydrate crystal agglomerates may have a particle size D90 of about 7 to about 25 pm, and preferably have a particle size D90 of about 10 to about 20pm.
  • the crystal agglomerates may have a particle size D90 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 pm.
  • the crystal agglomerates have a particle size
  • the ridinilazole 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.
  • the ridinilazole is present in the tablet at a concentration of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% wt/wt. More preferably, the ridinilazole tetrahydrate is present in the tablet at a concentration greater than or equal to 40% wt/wt, for example at about 50% wt/wt.
  • the intragranular phase is preferably present in the tablet at a concentration of about 65 to about 95% wt/wt, for example about 90% wt/wt.
  • the extragranular phase is preferably present in the tablet at a concentration of about 5 to about 35% wt/wt, for example about 10% wt/wt.
  • 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 embodiments, the first excipient system preferably does not comprise a lubricant. In embodiments, the first excipient system may comprise a first diluent and/or a first disintegrant and/or a binder.
  • the first excipient system comprises a first diluent or combination of first diluents. Any pharmaceutically acceptable diluent, or combination of diluent, may be used.
  • the first diluent may be present in the tablet at a concentration of up to 35% wt/wt, for example about 35% wt/wt. It may comprise, consist of, or consist essentially of, lactose monohydrate and/or microcrystalline cellulose. Preferably, it consists, or consists essentially, of lactose monohydrate and microcrystalline cellulose, for example lactose monohydrate 200M and Avicel PHI 01®.
  • lactose monohydrate is present in the tablet at a concentration of up to 30% wt/wt, for example about 25% wt/wt
  • the microcrystalline cellulose is present in the tablet at a concentration of up to 10% wt/wt, for example about 9% wt/wt.
  • the first excipient system may comprise a first disintegrant or combination of first disintegrants.
  • Any pharmaceutically acceptable disintegrant, or combination of disintegrants may be used. Suitable disintegrants may be selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch.
  • the first disintegrant comprises, consists of, or consists essentially of, croscarmellose sodium, for example Ac Di Sol® or Primellose®.
  • the first disintegrant may be present in the tablet at a concentration of up to 2% wt/wt, for example about 2% wt/wt.
  • the first excipient system may comprise a binder.
  • a binder Any pharmaceutically acceptable binder, or combination of binders, may be used.
  • Suitable binders may comprise, consist of, or consist essentially of, a hydrophilic polymer.
  • the binder may be selected from polyvinyl pyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ethers.
  • the binder may therefore comprise a cellulose ether selected from hydroxypropyl cellulose (HPC), methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC), ethylcellulose (EC) and sodium carboxymethyl cellulose (NaCMC).
  • the binder comprises, consists of, or consists essentially of, hydroxypropylcellulose.
  • the binder is preferably present in the tablet at a concentration of up to 3% wt/wt, for example about 3% wt/wt.
  • the first excipient system consists, or consists essentially, of the first diluent, the first disintegrant and the binder.
  • the first excipient system preferably consists, or consists essentially, of lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose and croscarmellose sodium, for example lactose monohydrate 200M, Avicel PHI 01, hydroxypropylcellulose and croscarmellose sodium.
  • 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.
  • the second excipient system preferably does not comprise a binder.
  • the second excipient system may comprise a second diluent and/or a second disintegrant and/or a lubricant.
  • the second excipient system comprises a second diluent or combination of second diluents.
  • Any pharmaceutically acceptable diluent, or combination of diluents may be used.
  • the second diluent may be present in the tablet at a concentration of up to 6% wt/wt, for example about 6% wt/wt.
  • the second diluent preferably comprises, consists of, or consists essentially of, lactose monohydrate and/or microcrystalline cellulose, and more preferably may consist, or consist essentially of, lactose monohydrate 100M and Avicel PHI 02®.
  • 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
  • the microcrystalline cellulose is present in the tablet at a concentration of up to 2% wt/wt, for example about 1.5% wt/wt.
  • the second excipient system may comprise a second disintegrant.
  • Any pharmaceutically acceptable disintegrant, or combination of disintegrants, may be used as the second disintegrant.
  • the second disintegrant may be selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch. It may comprise, consist of, or consist essentially of, croscarmellose sodium, for example 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.
  • the second excipient system may comprise a lubricant.
  • a lubricant Any pharmaceutically acceptable lubricant, or combination of lubricants, may be used.
  • the lubricant may be selected from: (a) fatty acids; (b) metallic salts of fatty acids;
  • the lubricant may comprise a fatty acid selected from: stearic acid, palmitic acid and myristic acid.
  • the lubricant may comprise a metallic salt of a fatty acid selected from magnesium stearate, calcium stearate and zinc stearate.
  • Other suitable lubricants comprise combinations of stearic acid and magnesium stearate.
  • the lubricant may also comprise a fatty acid ester selected from glyceride esters and sugar esters.
  • the lubricant may comprise a glyceride ester selected from glyceryl monostearate, glyceryl tribehenate and glyceryl dibehenate.
  • Other suitable lubricants comprise sugar esters selected from sorbitan monostearate and sucrose monopalmitate.
  • the lubricant may also comprise sodium stearyl fumarate or lysine.
  • the lubricant comprises, consists of, or consists essentially of, magnesium stearate.
  • the lubricant is preferably present at a concentration of up to 1% wt/wt, for example about 1% wt/wt.
  • the second excipient system consists, or consists essentially, of the second diluent, the second disintegrant and the lubricant.
  • the second excipient system preferably consists, or consists essentially, of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate, for example lactose monohydrate
  • the tablet of the invention is preferably dried or substantially anhydrous, for example having a water content of less than 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 5%, 4%, 3%, 2% or 1% by weight.
  • the tablets of the invention contain ridinilazole tetrahydrate in a quantity sufficient to provide a therapeutic effect in a human subject.
  • intragranular phase may take the form of inclusions embedded within a matrix formed by the extragranular phase.
  • the tablet of the invention preferably exhibits a TMAX of less than 3 hours for ridinilazole in ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model as described herein (and known to those skilled in the art). More preferably, the tablet of the invention exhibits a TMAX of less than 2 hours for ridinilazole in ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model. Most preferably, the tablet of the invention exhibits a TMAX of about 1 about 2 hours for ridinilazole in ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model.
  • the tablet of the invention preferably further comprises a coating.
  • Any suitable coating may be employed, preferred coatings providing protection from contamination, improved stability, organoleptic properties and swallowability.
  • Preferred coatings include pharmaceutically acceptable water-soluble polymer films.
  • a composition comprising granules containing ridinilazole tetrahydrate, optionally in the form of agglomerates, having a particle size D90 of about 4 to about 30 pm dispersed within a first pharmaceutically acceptable excipient system, and an extragranular second pharmaceutically acceptable excipient system, wherein the first and second excipient systems are different.
  • the granules may be dispersed, preferably homogeneously, within the second pharmaceutically acceptable excipient system.
  • composition of this embodiment is preferably a tableting composition suitable for compression into tablets.
  • composition of this aspect of the invention may be suitable for other uses.
  • Such uses include processes for the formulation of oral and non-oral ridinilazole pharmaceutical compositions of any kind.
  • the compositions of the second aspect of the invention may take the form of, or find application in the preparation of, pharmaceutical formulations other than tablets, including liquid suspensions, granule- filled capsules and granule-filled sachets (or other containers).
  • the ridinilazole tetrahydrate agglomerates are preferably in the form of ridinilazole tetrahydrate crystal agglomerates, more preferably ridinilazole tetrahydrate Form A (as herein defined).
  • the granules may be dispersed within the second pharmaceutically acceptable excipient system.
  • the granules are homogeneously dispersed within the second pharmaceutically acceptable excipient system.
  • the granules are dried, for example having a water content of less than 10%, 5%, 2% or 1% by weight.
  • the second pharmaceutically acceptable excipient system may be particulate, and may also be dried, for example having a water content of less than 10%, 9.5%,
  • the crystal agglomerates may have a particle size D90 of about 5pm to about 40pm, and preferably have a particle size D90 of about 10 to about 20pm. In other embodiments, the crystal agglomerates may have a particle size D90 of less than 40 pm, less than 35 pm, less than 30 pm, less than 25 pm, less than 20 pm, less than 15 pm, less than 10 pm, or less than 5 pm.
  • the ridinilazole tetrahydrate may be present in the composition at a concentration of at least 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65% or 70% wt/wt, preferably at a concentration of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% wt/wt, more preferably at a concentration > 40% wt/wt, for example at about 50% wt/wt.
  • the granules may be present in the composition at a concentration of 65- 95% wt/wt, preferably at about 90% wt/wt.
  • the second excipient system may be present in the composition at a concentration of about 5 to about 35% wt/wt, preferably at about 10% wt/wt.
  • the first and second excipient systems are preferably as defined above in relation to the tablets of the invention.
  • the tableting composition is preferably dried, for example having a water content of less than 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 5%, 4%, 3%, 2% or 1% by weight.
  • a process for producing a granular ridinilazole tetrahydrate composition comprising the steps of (a) providing ridinilazole tetrahydrate agglomerates having a particle size D90 of about 4 to about 30pm;
  • step (b) mixing the agglomerates of step (a) with a first pharmaceutically acceptable intragranular excipient system to form a pre-granulation mix;
  • step (d) blending the granules of step (c) with a second pharmaceutically acceptable extragranular excipient system to form a granular ridinilazole composition, optionally suitable for compression into a tablet.
  • the process is preferably suitable for producing a granular ridinilazole composition as defined according to the second aspect of the invention above.
  • the granular ridinilazole tetrahydrate composition of step (d) is preferably suitable for compression into a tablet as defined according to the first aspect of the invention above.
  • the granular ridinilazole tetrahydrate composition of step (d) may also be suitable for other uses, including processes for the formulation of oral and nonoral ridinilazole tetrahydrate pharmaceutical compositions of any kind.
  • the ridinilazole tetrahydrate composition of step (d) may take the form of, or find application in the preparation of, pharmaceutical formulations other than tablets, including liquid suspensions, granule-filled capsules and granule-filled sachets (or other containers).
  • the ridinilazole tetrahydrate agglomerates are preferably in the form of ridinilazole tetrahydrate crystal agglomerates, more preferably ridinilazole tetrahydrate Form A (as herein defined).
  • the crystal agglomerates may have a particle size D9O of about 7 to about 25 pm, and preferably have a particle size D90 of about 10 to about 20 pm.
  • the ridinilazole tetrahydrate may be present in the granules at a concentration of at least 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65% or 70% wt/wt, for example at a concentration of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% wt/wt.
  • the ridinilazole tetrahydrate is present in the granules at a concentration > 40% wt/wt, for example at about 50% wt/wt.
  • the granules are preferably present in the granular ridinilazole tetrahydrate composition of step (d) at a concentration of about 65 to about 95% wt/wt, for example about 90% wt/wt.
  • the second excipient system may be present in the granular ridinilazole composition of step (d) at a concentration of about 5 to about 35% wt/wt, for example about 10% wt/wt.
  • the first and second excipient systems are preferably as defined above in relation to the tablets and tableting compositions of the invention.
  • the providing step (a) preferably comprises reducing the particle size of crystalline ridinilazole, for example by micronization and/or by a process comprising the steps of milling, grinding, sieving and/or screening, e.g. by air jet milling.
  • the mixing step (b) may further comprise the step of screening or sieving the first excipient system prior to mixing with the agglomerates.
  • the mixing step (b) comprises the steps of (bl) mixing the agglomerates of step (a) with an initial fraction of a first pharmaceutically acceptable intragranular excipient system to form an initial pregranulation mix;
  • step (b2) passing the pre-granulation mix of step (bl) through a screen or sieve to form a screened initial pre-granulation mix
  • step (b3) passing a second fraction of a first pharmaceutically acceptable intragranular excipient system through the screen or sieve of step (b2) to form a screened second fraction; and then
  • step (b4) mixing the screened initial pre-granulation mix of step (b2) with the screened second excipient fraction of step (b3) to form a final pre-granulation mix for granulation according to step (c).
  • the initial fraction of a first pharmaceutically acceptable intragranular excipient system may be a subset of the constituent excipients of a first excipient system as herein described.
  • the initial fraction may constitute all of the constituent excipients of a first excipient system as herein described except for some or all of the first diluent (for example, the microcrystalline cellulose first diluent of the preferred embodiments described above).
  • the agglomerates of step (a) may comprise reagglomerated ridinilazole tetrahydrate particles.
  • steps (bl) and (b2) break down and remove the re-agglomerated ridinilazole particles such that the screened initial pre- granulation mix of step (b2) contains uniformly distributed ridinilazole tetrahydrate crystal agglomerates.
  • the particle size of the API can be analysed by any convenient method, including sedimentation field flow fractionation, photon correlation spectroscopy, light scattering (e.g. laser diffraction) and disk centrifugation.
  • Preferred is dry laser diffraction as described herein.
  • the mixing step (b) preferably comprises high shear dry blending.
  • the granulation step (c) may comprise dry granulation. However, the granulation step (c) preferably comprises wet granulation, more preferably high-shear wet granulation.
  • the tableting process may further comprise the step of coating said ridinilazole tablet to form a coated ridinilazole tetrahydrate tablet. It may also further comprise the step of packaging a plurality of the ridinilazole tablets to form a ridinilazole patient pack, or a bottle or other container containing sufficient tablets for a single course of treatment (e.g., about 20 tablets).
  • a granular ridinilazole tetrahydrate composition suitable for compression into tablets obtainable by the process of the third aspect of the invention.
  • a ridinilazole tetrahydrate tablet, patient pack or container obtainable by the process of the fourth aspect of the invention.
  • a tablet of the invention for use in the treatment, therapy or prophylaxis of CDI or CD AD.
  • the tablet of the invention for the manufacture of a medicament for use in the treatment, therapy or prophylaxis of CDI or CD AD.
  • a method for the treatment, therapy or prophylaxis of CDI or CD AD in a patient in need thereof comprising orally administering to the patient a tablet of the invention.
  • the intragranular phase comprises ridinilazole crystal agglomerates having a particle size D90 of about 4 to about 30pm dispersed within a first pharmaceutically acceptable excipient system;
  • the extragranular phase comprises a second pharmaceutically acceptable excipient system, [00129], wherein the first and second excipient systems are different, and wherein the ridinilazole tetrahydrate crystal agglomerates have a particle size D90 of about 7 to about 25pm.
  • the crystal agglomerates may have a particle size D90 of about 5pm to about 40pm, and preferably have a particle size D90 of about 10 to about 20pm. In other embodiments, the crystal agglomerates may have a particle size D90 of less than 40 pm, less than 35 pm, less than 30 pm, less than 25 pm, less than 20 pm, less than 15 pm, less than 10 pm, or less than 5 pm.
  • the ridinilazole crystal agglomerates comprise ridinilazole tetrahydrate.
  • the ridinilazole tetrahydrate crystal agglomerates comprise ridinilazole tetrahydrate Form A.
  • the ridinilazole is present in the tablet at an amount of up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% wt/wt.
  • the ridinilazole is present in the tablet at a concentration > 40% wt/wt, for example at about 50% wt/wt.
  • the intragranular phase is present in the tablet at a concentration of about 65 to about 95% wt/wt, for example about 90% wt/wt.
  • the extragranular phase is present in the tablet at a concentration of about 5 to about 35% wt/wt, for example about 10% wt/wt.
  • the first excipient system is present in the tablet at a concentration of up to 40% wt/wt, for example about 40% wt/wt.
  • the first excipient system comprises a first diluent, and wherein the first diluent is present in the tablet at a concentration of up to 35% wt/wt.
  • the first diluent comprises, consists of, or consists essentially of, lactose monohydrate and/or microcrystalline cellulose, and wherein the lactose monohydrate is present in the tablet at a concentration of up to 30% wt/wt, and the microcrystalline cellulose is present in the tablet at a concentration of up to 10% wt/wt.
  • the first excipient system comprises a first disintegrant, wherein the first disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch.
  • the first disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch.
  • the first disintegrant is present in the tablet at a concentration of up to 2% wt/wt, for example about 2% wt/wt.
  • the first excipient system comprises a binder, wherein the binder is selected from polyvinyl pyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ethers, wherein the cellulose ethers are selected from hydroxypropyl cellulose (UPC), methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC), ethylcellulose (EC) and sodium carboxymethyl cellulose (NaCMC).
  • PVP polyvinyl pyrrolidone
  • PVP-polyvinyl acetate copolymer copovidone
  • PPS partially gelatinized starch
  • cellulose ethers wherein the cellulose ethers are selected from hydroxypropyl cellulose (UPC), methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC), ethylcellulose (EC) and sodium carboxymethyl cellulose (NaCMC).
  • the binder is present in the tablet at a concentration of up to 3% wt/wt, for example about 3% wt/wt.
  • the second excipient system is present in the tablet at a concentration of up to 10% wt/wt, for example about 10% wt/wt.
  • the second excipient system comprises a second diluent and/or a second disintegrant and/or a lubricant.
  • the second diluent is present in the tablet at a concentration of up to 6% wt/wt.
  • the second diluent comprises lactose monohydrate and/or microcrystalline cellulose, wherein the lactose monohydrate is present in the tablet at a concentration of up to 5% wt/wt, and the microcrystalline cellulose is present in the tablet at a concentration of up to 2% wt/wt.
  • the second excipient system comprises a second disintegrant, optionally wherein the second disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch.
  • the second disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch.
  • the second disintegrant is present in the tablet at a concentration of up to 3% wt/wt, for example about 3% wt/wt.
  • the second excipient system comprises a lubricant, wherein the lubricant is selected from: (a) fatty acids; (b) metallic salts of fatty acids; (c) combinations of fatty acids and metallic salts thereof; (d) fatty acid esters; (e) metallic salts of fatty acid esters; and (f) inorganic materials and polymers.
  • the lubricant is selected from: (a) fatty acids; (b) metallic salts of fatty acids; (c) combinations of fatty acids and metallic salts thereof; (d) fatty acid esters; (e) metallic salts of fatty acid esters; and (f) inorganic materials and polymers.
  • the lubricant comprises a fatty acid selected from: stearic acid, palmitic acid and myristic acid; a metallic 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; sodium stearyl fumarate or lysine.
  • a fatty acid selected from: stearic acid, palmitic acid and myristic acid
  • a metallic 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 este
  • the lubricant is present in the tablet at a concentration of up to 1% wt/wt.
  • the second excipient system comprises lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate, for example lactose monohydrate 100M, Avicel PHI 02® and magnesium stearate.
  • the tablet contains about 100 about 400 mg of ridinilazole tetrahydrate.
  • the tablet contains about 200 mg of ridinilazole tetrahydrate.
  • some or all of the intragranular phase takes the form of inclusions embedded within a matrix formed by the extragranular phase.
  • the tablet formulation exhibits a TMAX of less than 3 hours for ridinilazole in ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model.
  • the tablet formulation exhibits a TMAX of less than 2 hours for ridinilazole in ileal effluent as measured using the TIM-1 dynamic in vitro gastrointestinal model.
  • the invention encompasses a method of treating C.
  • the invention encompasses a method of reducing the recurrence of C. Difficile infection (CDI) in a subject with CDI comprising administering to said subject ridinilazole or a pharmaceutically acceptable salt thereof, wherein administration of ridinilazole or a pharmaceutically acceptable salt thereof resulted in greater concentrations of secondary bile acids at end of treatment compared to subjects administered vancomycin.
  • Figure 1 shows a representative x-ray powder diffraction pattern for ridinilazole tetrahydrate Form A.
  • Figure 2 shows an ORTEP plot for the ridinilazole and water molecules of the Form A structure.
  • Figures 3-5 show packing diagrams for the ridinilazole tetrahydrate Form A structure along each crystallographic axis.
  • Figure 6 shows a representative x-ray powder diffraction pattern for ridinilazole anhydrate Form D.
  • Figure 7 shows an ORTEP plot for the ridinilazole molecule of the Form D structure.
  • Figures 8-10 show packing diagrams for the ridinilazole Form D structure along each crystallographic axis.
  • Figure 11 shows hydrogen bonding between ridinilazole Form D molecules generating a two dimensional network along the ab plane (i.e. as viewed along the c axis).
  • Figure 12 shows an XRPD overlay of ridinilazole tablet (upper trace), placebo
  • Figure 13 shows comparative ileum effluent profiles for the ridinilazole tetrahydrate 200mg capsule and ridinilazole tetrahydrate 200mg tablet [each equivalent to 169 mg of anhydrous ridinilazole in the TIM-1 model gut system.
  • the plot depicts the quantity of ridinilazole measured within the ileum effluent at each 60-minute timepoint over the duration of the experiment. The ileum effluent equates to amount of material delivered to the colon.
  • Figure 14 shows the dissolution profiles for tablets with drug substance at limits of particle size specification.
  • Figure 15 shows the Bristol Stool Chart and various types of fecal morphology.
  • Figure 16 shows an exemplary manufacturing process for ridinilazole tetrahydrate
  • Figure 17 illustrates dissolution profiles of ridinilazole tetrahydrate tablets for micronized and unmicronized tablets and caplets.
  • Figure 18 illustrates dissolution profiles of ridinilazole tetrahydrate tablets for unmicronized tablets - incomplete granulation, unmicronized tablets - complete granulation, and micronized tablets.
  • Figure 19 illustrates an exemplary manufacturing process for the tablets of the invention.
  • Figure 20 illustrates dissolution at four different hardness targets.
  • Figure 21 illustrates dissolution at three different hardness targets.
  • Figure 23 illustrates the relative abundance of microbiome-derived secondary bile acids and alpha diversity measures, which were significantly higher in ridinilazole compared to vancomycin both at end of treatment (EOT) and 30 days after EOT.
  • Figure 24 illustrates vancomycin showing a significant decrease in secondary bile acids and microbiome diversity at EOT (higher concentration of secondary bile acids and greater microbiome diversity at EOT were associated with both lower C. Difficile infection recurrence and higher sustained clinical response rates).
  • a reference to “about x” may be interpreted as “x, or about x”, while a reference to “about x to y” may be interpreted as "x to y, or about x to about y, or about x to y".
  • the term may also be interpreted to define an error margin of ⁇ 10% in relation to the referenced numerical value or to the upper and lower limits of the referenced range.
  • the term “about” when referring to a value includes the stated value ⁇ /- 10% of the stated value. For example, about 50% includes a range of from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values ⁇ /- 10% of the stated value of each end of the range.
  • administering refers to administration of the composition of the present invention to a subject.
  • the term “aggregates” refers to two or more primary particles tightly bound together by rigid chemical bonding resulting from sintering or cementation.
  • Primary particles are inorganic or organic structures held together by atomic or molecular bonding. They are the “fundamental” particles. Primary particles cannot be separated into smaller particles except by the application of ultrahigh energy. In any sample they are usually present at only a fraction of a percent.
  • Aggregation is the coalescence of particles by processes other than heat/pressure, i.e., precipitation of ionic salts onto surfaces during manufacture. Aggregates are typically formed when powders are heated, compressed, or dried from a suspension. They have a large interfacial area of contact between each particle and the force necessary to rupture these bonds is considerable. Aggregates constitute, for all practical purposes, the largest single fraction of any particle size distribution (PSD) that one can hope to achieve in a formulation.
  • PSD particle size distribution
  • agglomerates refers to collections of aggregates, loosely held together at point-to-point contact by weak electromagnetic forces, van der Waals forces, mechanical friction, and interlocking. Agglomerates are formed when fine particles are handled, shaken, rolled or stored undisturbed in a single position. They can readily be broken apart with proper dispersion techniques.
  • bioisostere (or simply isostere) is a term of art used to define drug analogues in which one or more atoms (or groups of atoms) have been substituted with replacement atoms (or groups of atoms) having similar steric and/or electronic features to those atoms which they replace.
  • the substitution of a hydrogen atom or a hydroxyl group with a fluorine atom is a commonly employed bioisosteric replacement.
  • Sila-substitution (C/Si-exchange) is a relatively recent technique for producing isosteres.
  • sila-substituted isosteres may exhibit improved pharmacological properties, and may for example be better tolerated, have a longer half-life or exhibit increased potency (see for example article by Englebienne in Med. Chem., 2005, 1(3), 215- 226).
  • the present invention contemplates all bioisosteres (and specifically, all silicon bioisosteres) of the compounds of the invention.
  • composition as used herein is intended to encompass a product that includes the specified active product ingredient (API) (e.g., ridinilazole tetrahydrate, preferably in Form A) and pharmaceutically acceptable excipients, carriers or diluents as described herein, such as in specified amounts defined throughout the originally filed disclosure, which results from combination of specific components, such as specified ingredients in the specified amounts as described herein.
  • API active product ingredient
  • the term “comprise,” or variations thereof such as “comprises” or “comprising,” are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers.
  • the term “comprising” is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps.
  • disintegrant refers to a pharmaceutical excipient that is incorporated into a composition to promote their disintegration when they come into contact with a liquid.
  • a disintegrant is a pharmaceutically acceptable agent, used in preparation of tablets, which causes tablets to disintegrate and release medicinal substances on contact with moisture.
  • disintegrants include, without limitation, crosslinked polymers, including crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), and modified starch sodium starch glycolate and the like.
  • D # means distribution particle size distribution.
  • D 10 represents the 10% of particles in the powders are smaller than this size.
  • the unit is pm.
  • a laser particle size analyzer measures the particle using laser with different angles, and then retrieves the diffraction patterns from the image sensors. And finally, by performing addition, subtraction, or cross analysis calculations, the instrument determines the statistical proportion of the sizes of particles.
  • D 90 means that 90% of the total particles are smaller than this size. For example, D 10 is 2.557 pm, and D 90 is 46.88 pm.
  • the two sizes, D 10 and D 90 enclose the range of particle sizes of the sample powders. The particle size exceeding this range can be ignored, because of the small number of particles.
  • D 50 means that 50% of the total particles are smaller than this size, or 50% of the particles are larger than this size.
  • D 50 is the median particle size distribution, we can call this value, Median.
  • the term “disposed over” refers to the placement of one phase or coating on top of another phase or coating. Such placement can conform to the shape of the underlying phase or coating such that the layering of phases and coatings do not leave substantial gaps there between.
  • extragranular phase refers to the bulk portion of a core structure that resides between the internal phase and the outer layer coatings of a composition. While the extragranular phase could itself be considered a coating, it can be generally thicker than a mere coating, thereby imparting significant structure/dimensions to the composition.
  • Form A of ridinilazole refers to the crystalline form of ridinilazole tetrahydrate characterized by a powder X-ray diffractogram comprising characteristic peaks at 2-Theta angles of (11.02 ⁇ 0.2)°, (16.53 ⁇ 0.2)° and (13.0 ⁇ 0.2)°.
  • Form D of ridinilazole refers to the crystalline form of ridinilazole anhydrate characterized by a powder X-ray diffractogram comprising characteristic peaks at 2-Theta angles of (12.7 ⁇ 0.2)°, (23.18 ⁇ 0.2)° and (27.82 ⁇ 0.2)°, optionally comprising characteristic peaks at 2-Theta angles of (12.7 ⁇ 0.2)°, (23.18 ⁇ 0.2)°, (27.82 ⁇ 0.2)°, (19.5 ⁇ 0.2)° and (22.22 ⁇ 0.2)°
  • Form N of ridinilazole refers to the crystalline form of ridinilazole tetrahydrate characterized by a powder X-ray diffractogram comprising characteristic peaks at 2-Theta angles of (10.82 ⁇ 0.2)°, (13.35 ⁇ 0.2)° and (19.15 ⁇ 0.2)°, optionally comprising characteristic peaks at 2-Theta angles of (10.82 ⁇ 0.2)°, (13.35 ⁇ 0.2)°, (19.15 ⁇ 0.2)°, (8.15 ⁇ 0.2)° and (21.74 ⁇ 0.2)°
  • an XRPD pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
  • intensities in an XRPD pattern may fluctuate depending upon measurement conditions employed. Relative intensities may also vary depending upon experimental conditions and so relative intensities should not be considered to be definitive.
  • a measurement error of diffraction angle for a conventional XRPD pattern is typically about 5% or less, and such degree of measurement error should be taken into account when considering stated diffraction angles.
  • the various crystalline forms described herein are not limited to the crystalline forms that yield X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures. Rather, crystalline forms of ridinilazole that provide X-ray diffraction patterns substantially in accordance (as hereinbefore defined) with those shown in the Figures fall within the scope of the present invention.
  • glidant refers to a substance that is added to a powder to improve its flowability and/or lubricity.
  • examples of glidants may include, but is not limited to, magnesium stearate, fumed silica, starch and talc and the like.
  • granulated mixture refers to a mixture of two or more agents made by mixing the two or more agents and granulating them together in a particulate form. Such a mixture provides particulate material that is composed of two or more agents.
  • hydrophilic silica refers to a pharmaceutical excipient that can be employed as flow agent (anti-caking), adsorbent and desiccant in solid product forms. It can also be used to increase the mechanical stability and the disintegration rate of the compositions.
  • the hydrophilic silica can be fumed, i.e., referring to its production through a pyrogenic process to generate fine particles of silica. Particles of fumed silica can vary in size such as from 5 nm to 100 nm, or from 5 to 50 nm. The particles can be non-porous and have a surface area from 50-1,000 m 2 /g or from 50-600 m 2 /g. Examples of hydrophilic silicas include Aerosil 200, having a specific surface area of about 200 m 2 /g.
  • intragranular phase refers to the central-most portion of a composition.
  • the intragranular phase is the location where the active ingredient, ridinilazole tetrahydrate, resides.
  • lubricant refers to a substance added to a formulation to reduce friction. Compounds that serve as lubricants can also have properties as glidants. Examples of lubricants may include, but is not limited to, talc, silica, and fats such as vegetable stearin, magnesium stearate or stearic acid and the like.
  • microcrystalline cellulose refers to a pharmaceutical grade of cellulose manufactured from a refined wood pulp.
  • the MCC can be unmodified or chemically modified, such as silicified microcrystalline cellulose (SMCC). MCC can serve the function of a bulking agent and aid in tablet formation due to its favorable compressibility characteristics.
  • SMCC silicified microcrystalline cellulose
  • the term “patient” or “subject” are used interchangeably refers to a living organism, which includes, but is not limited to a human subject suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Further non-limiting examples may include, but is not limited to humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, horse, and other mammalian animals and the like. In some aspects, the patient is human.
  • the term “pharmaceutical pack” defines an array of one or more ridinilazole tetrahydrate tablets, optionally contained within common outer packaging.
  • the tablets may be contained within a blister pack.
  • the pharmaceutical pack may optionally further comprise instructions for use.
  • the compositions of ridinilazole tetrahydrate tablets of the invention may be comprised in a pharmaceutical pack or patient pack.
  • the term “patient pack” defines a package, prescribed to a patient, which contains pharmaceutical compositions for the whole course of treatment.
  • Patient packs usually contain one or more blister pack(s), but may also take the form of a conveniently small bottle or other container containing sufficient tablets for one or more courses of treatment.
  • the container may contain about 20-60 tablets, e.g. about 20 or about 60 tablets (the former being 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, where a pharmacist divides a patient’s supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician’s instructions.
  • the term pharmaceutically acceptable derivative as applied to ridinilazole tetrahydrate define compounds which are obtained (or obtainable) by chemical derivatization of ridinilazole tetrahydrate.
  • the pharmaceutically acceptable derivatives are therefore suitable for administration to or use in contact with mammalian tissues without undue toxicity, irritation or allergic response (i.e. commensurate with a reasonable benefit/risk ratio).
  • Preferred derivatives are those obtained (or obtainable) by alkylation, esterification or acylation of ridinilazole tetrahydrate.
  • the derivatives may be active per se, or may be inactive until processed in vivo. In the latter case, the derivatives of the invention act as prodrugs.
  • Particularly preferred prodrugs are ester derivatives which are esterified at one or more of the free hydroxyls and which are activated by hydrolysis in vivo.
  • Other preferred prodrugs are covalently bonded compounds which release the active parent drug according to formula (I) after cleavage of the covalent bond(s) in vivo.
  • the pharmaceutically acceptable derivatives of the invention retain some or all of the activity of the parent compound. In some cases, the activity is increased by derivatization. Derivatization may also augment other biological activities of the compound, for example bioavailability.
  • compositions as applied to ridinilazole tetrahydrate define any non-toxic organic or inorganic acid addition salt of the free base compound which is suitable for use in contact with mammalian tissues without undue toxicity, irritation, allergic response and which are commensurate with a reasonable benefit/risk ratio.
  • Suitable pharmaceutically acceptable salts are well known in the art.
  • Examples are the salts with inorganic acids (for example hydrochloric, hydrobromic, sulphuric and phosphoric acids), organic carboxylic acids (for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 2- phenoxybenzoic, 2-acetoxybenzoic and mandelic acid) and organic sulfonic acids (for example methanesulfonic acid and p-toluenesulfonic acid).
  • inorganic acids for example hydrochloric, hydrobromic, sulphuric and phosphoric acids
  • organic carboxylic acids for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succin
  • the compounds of the invention may be converted into (mono- or di-) salts by reaction with a suitable base, for example an alkali metal hydroxide, methoxide, ethoxide or tert-butoxide, or an alkyl lithium, for example selected from NaOH, NaOMe, KOH, KOtBu, LiOH and BuLi, and pharmaceutically acceptable salts of ridinilazole tetrahydrate may also be prepared in this way.
  • a suitable base for example an alkali metal hydroxide, methoxide, ethoxide or tert-butoxide, or an alkyl lithium, for example selected from NaOH, NaOMe, KOH, KOtBu, LiOH and BuLi
  • a suitable base for example an alkali metal hydroxide, methoxide, ethoxide or tert-butoxide, or an alkyl lithium, for example selected from NaOH, NaOMe, KOH, KOtBu, LiOH and BuLi
  • solvates include compounds of the invention in combination with water (hydrates), short-chain alcohols (including isopropanol, ethanol and methanol), dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, acetone, dimethylformamide (DMF), dimethylacetamide (DMAc), pyrrolidones (such as JV-Methyl-2-pyrrolidone (NMP)), tetrahydrofuran (THF), and ethers (such as tertiarybutylmethylether (TBME)).
  • water hydrates
  • short-chain alcohols including isopropanol, ethanol and methanol
  • dimethyl sulfoxide ethyl acetate
  • acetic acid ethanolamine
  • DMAc dimethylacetamide
  • DMF dimethylacetamide
  • pyrrolidones such as JV-Methyl-2-pyrrolidone (NMP)
  • THF
  • miscible formulations of solvate mixtures such as a compound of the invention in combination with an acetone and ethanol mixture.
  • the solvate includes a compound of the invention in combination with about 20% ethanol and about 80% acetone.
  • the structural formulae include compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • the term pharmaceutically acceptable prodrug as applied to ridinilazole tetrahydrate defines any pharmaceutically acceptable compound that may be converted under physiological conditions or by solvolysis to ridinilazole tetrahydrate in vivo, to a pharmaceutically acceptable salt of such compound or to a compound that shares at least some of the antibacterial activity of the specified compound (e.g. exhibiting activity against Clostridioides difficile).
  • pharmaceutically acceptable metabolite as applied to ridinilazole tetrahydrate defines a pharmacologically active product produced through metabolism in the body of ridinilazole tetrahydrate or salt thereof
  • Prodrugs and active metabolites of the compounds of the invention may be identified using routine techniques known in the art (see for example, Bertolini et al., J. Med. Chem., 1997, 40, 2011-2016).
  • the term pharmaceutically acceptable complex as applied to ridinilazole tetrahydrate defines compounds or compositions in which the compound of the invention forms a component part.
  • the complexes of the invention include derivatives in which the compound of the invention is physically associated (e.g. by covalent or non-covalent bonding) to another moiety or moieties.
  • the term therefore includes multimeric forms of the compounds of the invention. Such multimers may be generated by linking or placing multiple copies of a compound of the invention in close proximity to each other (e.g. via a scaffolding or carrier moiety).
  • the term also includes cyclodextrin complexes.
  • the present invention contemplates all tautomeric forms, optical isomers, racemic forms and diastereoisomers of the compounds described herein.
  • the compounds may be produced in optically active and racemic forms. If a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • references to the compounds of the present invention encompass the products as a mixture of diastereoisomers, as individual diastereoisomers, as a mixture of enantiomers as well as in the form of individual enantiomers.
  • the present invention contemplates all optical isomers and racemic forms thereof of the compounds of the invention, and unless indicated otherwise (e.g. by use of dash-wedge structural formulae) the compounds shown herein are intended to encompass all possible optical isomers of the compounds so depicted. In cases where the stereochemical form of the compound is important for pharmaceutical utility, the invention contemplates use of an isolated eutomer.
  • the term “ridinilazole” is used to define the active ingredient in the instant formulations, which is the compound 2,2'-di(pyridin-4-yl)-17T, VH-5, 5'- bibenzo[d]imidazole (which may also be known as 2,2’-di-4-pyridinyl-6,6’-bi-lH- benzimidazole; 5,5’-bis[2-(4-pyridinyl)-17/-benzimidazole]; 2,2'-bis(4-pyridyl)-37/,3'7/-5,5'- bibenzimidazole; or 2-pyridin-4-yl-6-(2-pyridin-4-yl-37/-benzimidazol-5-yl)-17T- benzimidazole).
  • Ridinilazole tetrahydrate which is the active ingredient (i.e., Form A) in the drug product has the following structure:
  • XRPD X-ray powder diffraction (or when context permits, an X-ray powder diffractogram).
  • SMCC Siliconified microcrystalline cellulose
  • SMCC refers to a particulate agglomerate of coprocessed microcrystalline cellulose and silicon dioxide. Suitable for use in the present invention, SMCC may include amounts from about 0.1% to about 20% silicon dioxide, by weight of the microcrystalline cellulose, where the silicon dioxide can have a particle size from about 1 nanometer (nm) to about 100 microns (pm), based on average primary particle size.
  • the silicon dioxide can contain from about 0.5% to about 10% of the silicified microcrystalline cellulose, or from about 1.25% to about 5% by weight relative to the microcrystalline cellulose.
  • the silicon dioxide can have a particle size from about 5 nm to about 40 pm, or from about 5 nm to about 50 pm.
  • the silicon dioxide can have a surface area from about 10 m 2 /g to about 500 m 2 /g, or from about 50 m 2 /g to about 500 m 2 /g, or from about 175 m 2 /g to about 350 m 2 /g.
  • Silicified microcrystalline cellulose is commercially available from a number of suppliers known to one of skill in the art, including Penwest Pharmaceuticals, Inc., under the trademark PROSOLV®.
  • PROSOLV® is available in a number of grades, including, for example, PROSOLV® SMCC 50, PROSOLV® SMCC 90, and PROSOLV® HD. Other products include, without limitation, SMCC 50LD, SMCC HD90 and SMCC 90LM and the like.
  • XRPD diffraction patterns means that allowance is made for variability in peak positions and relative intensities of the peaks.
  • the ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art. For example, a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta. Thus, a diffraction peak that usually appears at 14.9° 2-Theta can appear between 14.7° and 15.1° 2-Theta on most X-ray diffractometers under standard conditions.
  • variability may also arise from the particular apparatus employed, as well as the degree of crystallinity in the sample, orientation, sample preparation and other factors.
  • XRPD measurements are typically performed at RT, for example at a temperature of 20°C, and preferably also at a relative humidity of 40%.
  • the term "substantially pure” with reference to a particular crystalline (polymorphic) form of ridinilazole is used to define one which includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1% by weight of any other physical form of ridinilazole.
  • room temperature RT
  • RT room temperature
  • the D90 particle size is a parameter such that 90% by volume of particles are smaller in their longest dimension than that parameter, as measured by any conventional particle size measuring technique known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering (e.g. laser diffraction) and disk centrifugation.
  • the D50 particle size of a composition is a parameter such that 50% by volume of particles in the composition are smaller in their longest dimension than that parameter, as measured by any conventional particle size measuring technique known to those skilled in the art (and as described above). D50 particle size is therefore a measure of volume median particle size but is sometimes referred to as "average" or "mean” particle size.
  • the Dio particle size of a composition is a parameter such that 10% by volume of particles in the composition are smaller in their longest dimension than that parameter, as measured by any conventional particle size measuring technique known to those skilled in the art (and as described above).
  • tablette used in relation to compositions of the invention defines a composition comprising ridinilazole tetrahydrate which is suitable for compression into a tablet.
  • Tableting compositions of the invention are typically suitable as a feed for a tablet press, for example a stamping or rotary tablet press.
  • tableting compositions of the invention are suitable for compression into a ridinilazole tetrahydrate tablet comprising an intragranular solid phase incorporated in an extragranular solid phase, wherein: (a) the intragranular phase comprises ridinilazole tetrahydrate crystal agglomerates having a particle size D90 of 4-30 pm dispersed within a first pharmaceutically acceptable excipient system; and (b) the extragranular phase comprises a second pharmaceutically acceptable excipient system, wherein the first and second excipient systems are different.
  • “Therapeutically effective amount” refers to an amount of a compound or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount” further includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the patient's general health, the patient's age, etc. The exact amounts will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.
  • Treat,” “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • (w/w) refers to the phrase “weight for weight”, i.e., the proportion of a particular substance within a mixture, as measured by weight or mass or a weight amount of a component of the composition disclosed herein relative to the total weight amount of the composition. Accordingly, the quantity is unit less and represents a weight percentage amount of a component relative to the total weight of the composition.
  • a 2% (w/w) solution means 2 grams of solute is dissolved in 100 grams of solution.
  • the tableting compositions of the invention as defined herein may also be suitable for other uses.
  • the tableting compositions of the invention may also be suitable for use as the basis of dosage forms other than tablets, including liquid suspensions, granule-filled capsules and granule-filled sachets (or other containers).
  • the prototype wet granulation tablet formulation was identified after initial development and compatibility studies had been undertaken. Compatibility of ridinilazole tetrahydrate active substance with a range of excipients routinely utilized in tablet formulations was effectively demonstrated.
  • the wet granulation formulation screening identified a lead formulation that produced granules which showed good flow and acceptable tablet processability at small scale at low compression force.
  • the prototype tablet formulation demonstrated rapid disintegration and complete dispersion in less than 4 minutes. This was scaled up in order to progress a 1,000 tablets pilot run to enable samples to be placed onto a 6 months stability study. No significant changes to appearance, assay, related substances, hardness, moisture content or disintegration time were noted at either the long-term (25°C/60%RH) or accelerated (40°C/75%RH) condition, thus confirming stability of the prototype tablet formulation.
  • the tablets and tableting compositions of the invention comprise two distinct pharmaceutically acceptable excipient systems, referenced herein as the first and second pharmaceutically acceptable excipient systems.
  • the first pharmaceutically acceptable excipient system forms part of an intragranular phase along with dispersed ridinilazole tetrahydrate crystal agglomerates, while the second pharmaceutically acceptable excipient system constitutes an extragranular phase in relation to the intragranular phase containing the API and first excipient system.
  • the first pharmaceutically acceptable excipient system is present within granules together with dispersed ridinilazole tetrahydrate crystal agglomerates, and these granules are surrounded by the second pharmaceutically acceptable excipient system (which is therefore extragranular).
  • Each excipient system comprises at least one pharmaceutically acceptable excipient, though in preferred embodiments both excipient systems comprise two or more chemically and/or functionally distinct excipients.
  • the two excipient systems of the tablets and tableting compositions of the invention are distinct, or different. They may differ inter alia: (a) in relation to the identity of one or more of the excipient(s) present; (b) in relation to the number of chemically and/or functionally distinct excipients present; (c) in relation to the concentration of an excipient present; (d) in relation to the relative concentrations of two or more of the excipients present; and/or (e) in relation to the presence, or absence, of a distinct functional class of excipient.
  • both first and second pharmaceutically acceptable excipient systems comprise a diluent.
  • This diluent may be referenced herein as the "first diluent" when present in the first second pharmaceutically acceptable excipient system, and as the “second diluent” when present in the second pharmaceutically acceptable excipient system.
  • two distinct diluents are employed in one or both of the first and second excipient systems, and these may be referenced herein as first and second diluents, respectively.
  • both first and second pharmaceutically acceptable excipient systems comprise a disintegrant.
  • This disintegrant may be referenced herein as the "first disintegrant" when present in the first second pharmaceutically acceptable excipient system, and as the “second disintegrant” when present in the second pharmaceutically acceptable excipient system.
  • a single disintegrant is employed in one or both of the first and second excipient systems, and these may be referenced herein as first and second disintegrant, respectively.
  • the first and second disintegrant may be the same or different, and in preferred embodiments the first and second disintegrant is the same.
  • the first pharmaceutically acceptable excipient system contains a binder, while the second pharmaceutically acceptable excipient system does not contain a binder.
  • the first pharmaceutically acceptable excipient system does not contain a lubricant, while the second pharmaceutically acceptable excipient system contains a lubricant.
  • the two excipient systems differ in relation to the presence/absence of two particular functional classes of excipient, these being binder and lubricant.
  • these being binder and lubricant.
  • the first pharmaceutically acceptable excipient system contains a binder and that this class of excipient is absent from the second excipient system
  • the second pharmaceutically acceptable excipient system contains a lubricant and that this class of excipient is absent from the first excipient system.
  • the tablet formulations can be delivered as immediate release, sustained released, extended release, delayed release, or a combination thereof.
  • first and second pharmaceutically acceptable excipient systems may comprise a diluent.
  • Any suitable pharmaceutically acceptable diluent or combinations thereof may be used. These include diluents which comprise, consist of, or consist essentially of, lactose monohydrate and/or microcrystalline cellulose, for example lactose monohydrate and microcrystalline cellulose in combination.
  • the first diluent comprises, consists of, or consists essentially of, a combination of lactose monohydrate 200M and Avicel PHI 01®.
  • the second diluent comprises, consists of, or consists essentially of, a combination of lactose monohydrate 100M and Avicel PHI 02®.
  • both first and second pharmaceutically acceptable excipient systems may comprise a dsintegrant.
  • Any suitable pharmaceutically acceptable disintegrant, or combinations thereof, may be used. These include disintegrants selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch.
  • first and second disintegrants is croscarmellose sodium, for example Ac Di Sol® or Primellose®.
  • Croscarmellose sodium has been found to be unexpectedly advantageous as a disintegrant in the tablets and tableting compositions of the invention. Without wishing to be bound by any theory, it is believed that ionic interaction between ridinilazole tetrahydrate and croscarmellose sodium attendant on the formation of anionic hydrogels in contact with water (see e.g. Huang et al. (2006) Elimination of meformin-croscarmellose sodium interaction by competition Int J Pharm 311(1-2): 33-39). In particular, the inventors have unexpectedly noted improved disintegration times when using croscarmellose sodium as disintegrant when compared to otherwise identical tablets using crospovidone as disintegrant.
  • the first pharmaceutically acceptable excipient system may contain a binder (while the second pharmaceutically acceptable excipient system preferably does not contain a binder). Any suitable pharmaceutically acceptable binder, or combinations thereof, may be used.
  • Preferred binders comprise, consist of, or consist essentially of, a hydrophilic polymer.
  • Suitable binders may be selected from polyvinyl pyrrolidone (PVP), copovidone (PVP-polyvinyl acetate copolymer), partially gelatinized starch (PGS), and cellulose ethers.
  • the binder may comprise a cellulose ether selected from hydroxypropyl cellulose (HPC), methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC), ethylcellulose (EC) and sodium carboxymethyl cellulose (NaCMC).
  • the binder comprises, consists of, or consists essentially of, hydroxypropylcellulose, this being present only in the first pharmaceutically acceptable excipient system (the second pharmaceutically acceptable excipient system being free of any binders).
  • the second pharmaceutically acceptable excipient system may contain a lubricant (while the first pharmaceutically acceptable excipient system preferably does not contain a lubricant). Any suitable pharmaceutically acceptable lubricant, or combinations thereof, may be used.
  • Preferred lubricants may be selected from: (a) fatty acids; (b) metallic salts of fatty acids; (c) combinations of fatty acids and metallic salts thereof; (d) fatty acid esters; (e) metallic salts of fatty acid esters; and (f) inorganic materials and polymers.
  • Suitable fatty acid lubricants may be selected from: stearic acid, palmitic acid and myristic acid.
  • Suitable metallic salts of fatty acids may be selected from magnesium stearate, calcium stearate and zinc stearate. Combinations of the foregoing are also suitable: for example, the lubricant may comprise a combination of stearic acid and magnesium stearate.
  • the lubricant comprises a fatty acid ester selected from glyceride esters and sugar esters.
  • the lubricant comprises a glyceride ester selected from glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate.
  • a sugar ester selected from sorbitan monostearate and sucrose monopalmitate.
  • the lubricant may also comprise, consist of, or consist essentially of, sodium stearyl fumarate and/or lysine.
  • the lubricant comprises, consists of, or consists essentially of, magnesium stearate. This is more preferably present only in the second pharmaceutically acceptable excipient system (the first pharmaceutically acceptable excipient system being free of any lubricants).
  • ridinilazole tetrahydrate The API present in the tablets and tableting compositions of the invention is ridinilazole tetrahydrate.
  • ridinilazole is used to define the compound 2,2'-di(pyridin-4-yl)- 177, 1'77-5, 5'-bibenzo[d]imidazole (which may also be known as 2,2’-di- 4-pyridinyl-6,6’-bi-177-benzimidazole; 5,5’-bis[2-(4-pyridinyl)-177-benzimidazole]; 2,2'- bis(4-pyridyl)-377, 3'77-5, 5'-bibenzimidazole; or 2-pyridin-4-yl-6-(2-pyridin-4-yl-377- benzimidazol-5-yl)-177-benzimidazole).
  • the term also includes pharmaceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites or prodrugs of ridinilazole, as herein defined, for example, ridinilazole tetrahydrate.
  • the ridinilazole tetrahydrate present in the tablets and tableting compositions of the invention preferably takes the form of ridinilazole tetrahydrate crystal agglomerates. Particularly preferred is ridinilazole tetrahydrate Form A (as herein defined).
  • the ridinilazole tetrahydrate API is preferably present in the form of ridinilazole tetrahydrate crystals Form A characterized by a powder X-ray diffractogram comprising characteristic peaks at 2-Theta angles of (11.02 ⁇ 0.2)°, (16.53 ⁇ 0.2)° and (13.0 ⁇ 0.2)°.
  • Ridinilazole tetrahydrate exhibits very low aqueous solubility and relatively poor wettability, and the present inventors have unexpectedly discovered that control of API particle size is important in controlling variability in the processability and performance of the tablet, tableting composition and processes of the invention, directly or indirectly impacting granule structure and thereby tablet quality.
  • the crystal agglomerates may have a particle size D90 of about 5pm to about 40pm, and preferably have a particle size D90 of about 10 to about 20pm. In other embodiments, the crystal agglomerates may have a particle size D90 of less than 40 pm, less than 35 pm, less than 30 pm, less than 25 pm, less than 20 pm, less than 15 pm, less than
  • the ridinilazole tetrahydrate API is present in the tablets, tableting compositions and processes of the invention in the form of ridinilazole tetrahydrate agglomerates having a particle size D90 of about 4 to about 30pm, preferably a D90 of 7- 25 pm, more preferably a D90 of 10-20pm).
  • Size reduction of the ridinilazole tetrahydrate API can be achieved by any convenient method, including milling, grinding, sieving and/or screening. Preferred is size reduction by air jet milling.
  • 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 (e.g. laser diffraction) and disk centrifugation. Preferred is dry laser diffraction as described herein.
  • Stationary bulk solids such as dry powder or granules (i.e. aggregates) tend to form agglomerates driven by more or less strong attractive forces.
  • the strength of these forces depend on material properties, surface conditions, residual moisture and particle size, and may involve Van der Waals forces, capillary forces, and/or electrostatic and magnetic forces of attraction. In general, the smaller the particles, the greater the tendency to bind.
  • size-reduced API having the desired particle size D90 of 4-30 pm have a marked tendency to re-agglomerate to form secondary, "soft agglomerates”.
  • ridinilazole tetrahydrate API that has undergone a particle size reduction operation is a very cohesive, poorly flowing powder that exhibits a static charge and a tendency to re-associate to form secondary "soft agglomerates”.
  • blending the ridinilazole tetrahydrate particles with all of the first excipients except for some or all of the first diluent (for example, the microcrystalline cellulose of the preferred embodiments) to form an initial, intermediate, blend allows effective and easy sieving of that intermediate blend, permitting effective break-up of any soft agglomerates of ridinilazole tetrahydrate.
  • the first diluent for example, the microcrystalline cellulose of the preferred embodiments
  • the sieve can then be “washed” or “flushed through” with the reserved diluent (e.g. the microcrystalline cellulose of the preferred embodiments), which has been found to be effective to transfer of any granule blend of first excipients and API remaining on the sieve surface into the final blend (e.g. microcrystalline cellulose, or other first diluent, passing through the sieve can be combined with the rest of the ridinilazole tetrahydrate mixture already sieved and the whole material then finally mixed to yield a final blend for granulation).
  • the reserved diluent e.g. the microcrystalline cellulose of the preferred embodiments
  • the discovery described above finds application in processes for producing the compositions of the invention. For example, it finds application in a process for producing a granular ridinilazole tetrahydrate composition according to the third aspect of the invention described above.
  • the ridinilazole tetrahydrate agglomerates are first mixed with an initial fraction of a first pharmaceutically acceptable intragranular excipient system to form an initial pre-granulation mix, which pre-granulation mix is then screened or sieved to form a screened initial pre-granulation mix, before a second fraction of the first pharmaceutically acceptable intragranular excipient system, is passed through the same screen or sieve to form a screened second fraction.
  • the screened initial pre-granulation mix can then be mixed with the screened second excipient fraction to form a final pre-granulation mix for granulation according to step (c) of the third aspect of the invention.
  • step (c) of the third aspect of the invention In this way, "hot spots" arising from soft agglomerates of ridinilazole tetrahydrate may be avoided, and a more uniform distribution of ridinilazole tetrahydrate API in the tableting composition (and ultimately, the ridinilazole tetrahydrate tablet) is achieved.
  • the tableting compositions of the invention may also be suitable for use as the basis of dosage forms other than tablets, including liquid suspensions, granule-filled capsules and granule-filled sachets (or other containers).
  • dosage forms other than tablets, including liquid suspensions, granule-filled capsules and granule-filled sachets (or other containers).
  • ridinilazole tetrahydrate compositions sharing the composition of the tableting compositions of the invention but which are suitable for uses other than tableting (including other oral dosage forms such as liquid suspensions, granule- filled capsules and granule- filled sachets).
  • the discovery described above therefore find broad application in the production of granular or particulate ridinilazole tetrahydrate compositions in which secondary soft agglomerates (formed by re-agglomeration of size-reduced API as described above) are substantially absent.
  • the invention therefore also contemplates granular or particulate ridinilazole tetrahydrate compositions comprising crystal agglomerates of crystalline ridinilazole tetrahydrate having a particle size D90 of 4-30pm in which soft secondary agglomerate arising from re-agglomeration of said crystal agglomerates are substantially absent.
  • Such granular or particulate ridinilazole tetrahydrate compositions are preferably, but not necessarily, suitable for compression into a tablet. They may, for example, be suitable for uses other than tableting. Such uses include oral and non-oral ridinilazole tetrahydrate pharmaceutical compositions.
  • the granular or particulate ridinilazole tetrahydrate compositions of the invention may take the form of, or find application in the preparation of, pharmaceutical formulations other than tablets, including liquid suspensions, granule-filled capsules and granule-filled sachets (or other containers).
  • compositions of the invention can be used in methods of treating C. Difficile infection (CDI) in a subject in need thereof comprising administering to said subject ridinilazole or a pharmaceutically acceptable salt thereof, wherein administration of ridinilazole or a pharmaceutically acceptable salt thereof resulted in at least a 25% reduction in CDI recurrence rate compared to subjects administered vancomycin.
  • CDI C. Difficile infection
  • the reduction in CDI recurrence is about 10%, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or about 70%.
  • the invention encompasses a method of reducing the recurrence of C. Difficile infection (CDI) in a subject with CDI comprising administering to said subject ridinilazole or a pharmaceutically acceptable salt thereof, wherein administration of ridinilazole or a pharmaceutically acceptable salt thereof resulted in greater concentrations of secondary bile acids at end of treatment compared to subjects administered vancomycin.
  • CDI C. Difficile infection
  • the invention encompasses a method of reducing the recurrence of C. Difficile infection (CDI) in a subject with CDI comprising administering to said subject ridinilazole or a pharmaceutically acceptable salt thereof, wherein administration of ridinilazole or a pharmaceutically acceptable salt thereof resulted in greater concentrations of secondary bile acids at end of treatment compared to subjects administered vancomycin.
  • higher concentration of secondary bile acids and greater microbiome diversity at end of treatment were associated with both lower recurrence of CDI and higher sustained clinical response rates.
  • Ridinilazole tetrahydrate tablets of the invention comprise an intragranular solid phase incorporated in an extragranular solid phase, wherein: (a) the intragranular phase comprises ridinilazole tetrahydrate agglomerates having a particle size D90 of about 4 to about 30pm dispersed within a first pharmaceutically acceptable excipient system; and (b) the extragranular phase comprises a second pharmaceutically acceptable excipient system, wherein the first and second excipient systems are different.
  • Preferred ridinilazole tetrahydrate tablets of the invention have the following composition: [00300]
  • More preferred ridinilazole tetrahydrate tablets of the invention have the following composition:
  • ridinilazole tetrahydrate tablets of the invention have the following composition:
  • % values may each be independently varied by ⁇ 10%, ⁇ 5%, ⁇ 2% or ⁇ 1%, provided that the % Formula w/w values total 100.
  • % values may each be independently varied by ⁇ 5%, ⁇ 2% or ⁇ 1%, provided that the % Formula w/w values total 100.
  • ridinilazole tetrahydrate tablets of the invention have the following composition:
  • ridinilazole tetrahydrate tablets of the invention have the following composition:
  • the tablet preferably further comprises a coating, for example a water-soluble polymer film.
  • the tablet preferably contains about 100 to about 400 mg of ridinilazole tetrahydrate, more preferably about 100 to about 300 mg of ridinilazole tetrahydrate, yet more preferably about 150 to about 250 mg of ridinilazole tetrahydrate, most preferably about 200 mg of ridinilazole tetrahydrate.
  • One of ordinary skill in the art will be able to calculate that, for example, 200 mg of ridinilazole tetrahydrate is equivalent to 169 mg of ridinilazole on an anhydrous basis.
  • a particularly preferred tablet formulation has the following composition:
  • the quantity 200 mg of ridinilazole tetrahydrate is equivalent to 169 mg of ridinilazole on an anhydrous basis.
  • the ridinilazole tetrahydrate API is preferably present in the form of ridinilazole tetrahydrate crystals Form A characterized by a powder X-ray diffractogram comprising characteristic peaks at 2-Theta angles of (11.02 ⁇ 0.2)°, (16.53 ⁇ 0.2)° and (13.0 ⁇ 0.2)°.
  • Most preferred tablet formulations have one of the following compositions:
  • the quantity 200 mg of ridinilazole tetrahydrate Form A is equivalent to 169 mg of ridinilazole on an anhydrous basis.
  • the formulations described comprising ridinilazole tetrahydrate may be utilized for the treatment or elimination of Clostridium difficile infection (CDI) and/or one or more Clostridioides difficile-associated diseases (CDAD).
  • CDI comprises toxin A and/or toxin B C. difficile in the stool.
  • a subject in need thereof is administered a composition comprising ridinilazole tetrahydrate.
  • the composition comprises a ridinilazole tetrahydrate tablet as described herein.
  • the administering may be effective to reduce or eliminate CDI and/or CDAD in a subject in need thereof.
  • a subject in need thereof is treated with a therapeutically effective amount of ridinilazole tetrahydrate (e.g., ridinilazole tetrahydrate Form A).
  • a subject in need thereof is treated with a therapeutically effective amount of ridinilazole, wherein the therapeutically effective amount is sufficient to reduce or eliminate at least one symptom of CDI and/or CDAD.
  • a therapeutically effective amount comprises at least about, at most about, or about 200 mg of ridinilazole tetrahydrate one or more times per day.
  • a therapeutically effective amount comprises about 10, 25, 50, 75, 100, 120, 140, 160, 180, 185, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 275, 300, 350, 400, 450, or 500 mg of ridinilazole tetrahydrate (e.g., ridinilazole tetrahydrate Form A).
  • ridinilazole tetrahydrate e.g., ridinilazole tetrahydrate Form A
  • the administration of an amount of ridinilazole tetrahydrate Form A is equivalent to administering a subject about 8.45, 17, 25.5, 43, 76, 84.5, 93, 101, 110, 118, 126.5, 135, 143.5, 152, 160.5, 169, 178.5, 190, 200, 210, 220, 230, 240, 250, 275, 300, 350, 400, 450 mg of ridinilazole content on an anhydrous basis.
  • a subject in need thereof is administered ridinilazole tetrahydrate for any number of days.
  • ridinilazole tetrahydrate is administered about 1, 2, 3, 4, 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, or up to 30 days.
  • ridinilazole tetrahydrate is administered for about 10 days.
  • ridinilazole tetrahydrate is administered for about 5-10 days.
  • ridinilazole tetrahydrate is administered for about 5-20 days.
  • ridinilazole tetrahydrate is administered multiple times a day.
  • ridinilazole tetrahydrate can be administered once, twice, three times, four times, five times, or six times daily, preferably twice a day. In embodiments, ridinilazole tetrahydrate is administered every 12 hours. In embodiments, ridinilazole tetrahydrate is administered until CDI and/or CD AD is resolved. In embodiments, ridinilazole tetrahydrate is administered until a symptom of ridinilazole tetrahydrate is reduced or eliminated.
  • the administration of ridinilazole tetrahydrate is effective in reducing CDI and/or CD AD as determined by reduced or eliminated symptoms associated with CDI including but not limited to diarrhea (e.g., unformed bowel movement), fever, stomach tenderness, loss of appetite, nausea, and combinations thereof.
  • administration of ridinilazole tetrahydrate is effective in reducing a symptom of CDI and/or CD AD by at least about 1 day as compared to an otherwise comparable subject lacking the administering.
  • administration of ridinilazole tetrahydrate is effective in reducing a symptom of CDI and/or CD AD by at least about 1 day, 2 days, 3 days, 4 days, or 5 consecutive days as compared to an otherwise comparable subject lacking the administering.
  • the administration of ridinilazole tetrahydrate is effective in reducing CDI and/or CD AD as determined by reduced frequency of unformed bowel movements (UBMs) by the subject as compared to before the administration.
  • administration of ridinilazole tetrahydrate is effective in eliminating CDI and/or CD AD in a subject in need thereof as determined by resolution of unformed bowel movement (UBM).
  • administration of ridinilazole tetrahydrate is effective in reducing detection of a UBM by at least about 1 day as compared to an otherwise comparable subject lacking the administering.
  • administration of ridinilazole tetrahydrate is effective in reducing detection of a UBM by at least about 1 day, 2 days, 3 days, 4 days, or 5 consecutive days as compared to an otherwise comparable subject lacking the administering.
  • administration of ridinilazole tetrahydrate is effective in reducing recurrence of an episode of diarrhoea (e.g., over about 3 UBMs) in a 1-day period.
  • a subject in need thereof achieves a clinical response following administration of ridinilazole tetrahydrate.
  • a subject in need thereof achieves no recurrence of CDI and/or CD AD through about 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 160 days, 170 days, 180 days, 190 days, or 200 days post treatment.
  • a subject in need thereof achieves no recurrence of CDI and/or CD AD for at least about 30 days or 90 days post treatment.
  • the administration of ridinilazole tetrahydrate is effective in reducing CDI and/or CD AD as determined by reduced frequency of unformed bowel movements (UBMs) by the subject as compared to an otherwise comparable subject administered vancomycin.
  • administration of ridinilazole tetrahydrate is effective in reducing detection of a UBM by at least about 1 day as compared to an otherwise comparable subject administered vancomycin.
  • administration of ridinilazole tetrahydrate is effective in reducing detection of a UBM by at least about 1 day, 2 days, 3 days, 4 days, or 5 consecutive days as compared to an otherwise comparable subject administered vancomycin.
  • administration of ridinilazole tetrahydrate is effective in reducing recurrence of an episode of diarrhoea (e.g., over about 3 UBMs) in a 1-day period as compared to an otherwise comparable subject administered vancomycin.
  • UBMs can be determined by way of the Bristol Stool Chart, see Figure 16.
  • a UBM comprises a type 5, 6, or 7 bowel movement in the Bristol Stool Chart.
  • administration of ridinilazole tetrahydrate is effective in reducing frequency (in time) or detection of a UBM in a subject in need thereof.
  • administration of ridinilazole tetrahydrate is effective in reverting a subject in need thereof bowel movements from a type 5, 6, or 7 to a type selected from the group consisting of 1, 2, 3, and 4.
  • administration of ridinilazole tetrahydrate is effective in reverting a bowel movement type by at least about 1, 2, 3, 4, 5, or 6 types on the Bristol Stool Chart as compared to an otherwise comparable subject lacking the administration.
  • a subject in need thereof has previously been administered an antibiotic.
  • the antibiotic is selected from the group consisting of ampicillin, amoxicillin, cephalosporins, and clindamycin. However, any antibiotic is contemplated.
  • a subject is co-treated with ridinilazole tetrahydrate and at least one additional therapeutic.
  • the one additional therapeutic comprises an antibiotic.
  • a subject in need thereof has previously been administered an antibiotic that is not ridinilazole tetrahydrate.
  • a subject in need thereof has previously been administered vancomycin.
  • a subject in need thereof has been hospitalized or is hospitalized.
  • a subject in need thereof has antibiotic-resistant C. difficile.
  • a subject in need thereof is immunosuppressed.
  • a subject in need thereof is undergoing a cancer chemotherapy.
  • CDI is detected using an in vitro assay.
  • Suitable in vitro assays include but are not limited to: ELISA, latex agglutination assay, cell cytotoxicity assay, PCR, C. difficile culture, and combinations thereof.
  • XRPD analyses were performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. The isothermal samples were analysed in transmission mode and held between low density polyethylene films. The XRPD program used range 3-4O°20, step size 0.013°, counting time 99sec, ⁇ 22min run time. XRPD patterns were sorted using HighScore Plus 2.2c software.
  • Example 1 Production of ridinilazole Form A tetrahydrate crystal agglomerates [00337], Reaction: The reaction flask was charged with 4-cyano-pyridine (0.85 kg), and MeOH (5.4 kg) and NAM-30 (NaOMe as 30 wt% solution in MeOH; 0.5 eq; 0.15 kg) was dosed in. The resulting mixture was heated at 60°C for lOmin. and then cooled. This solution was added to a mixture of 3,3 ’-diaminobenzidine (DAB) (0.35 kg) and acetic acid (0.25 kg) in MeOH (1 1) at 60°C in Ih. The mixture was then heated for 2h. The reaction mixture was allowed to cool to ambient temperature overnight. The crystalline mass was filtered and washed with MeOH (1.4 L) and sucked dry on the filter.
  • DAB 3,3 ’-diaminobenzidine
  • the crystal agglomerates were then air jet milled to the target particle size (D90 of about 4 to about 30pm, preferably a D90 of about 7 to about 25 pm, more preferably a D90 of about 10 to about 20pm).
  • Example 2 Crystal structure of ridinilazole tetrahydrate Form A
  • FIG. 2 An atom numbering scheme for the ridinilazole and water molecules is displayed in Figure 2 as an ORTEP plot.
  • Packing diagrams for the ridinilazole Form A structure are displayed in Figure 3 to Figure 5 and are shown along each crystallographic axis.
  • Hydrogen bonding between ridinilazole molecules cannot be described as only one hydrogen bond between N24-H24- • -N51 can be clearly located.
  • the other hydrogen bonds occurring in the structure are formed between the water molecules, imidazole hydrogens and pyridine nitrogen atoms.
  • the hydrogen bond network cannot be fully resolved.
  • Example 4 Crystal structure of ridinilazole anhydrate Form D
  • Ridinilazole Form D is prepared as described in Example 3.
  • Ridinilazole Form A is prepared as described in Example 1. Seed crystals were prepared by hand grinding and sifting. The conversion was carried out as follows:
  • Preferred tablet formulations are set forth in Tables 3 and 4, below.
  • Example 7 Comparison of the release and colonic delivery profiles of ridinilazole capsule and tablet formulations in the in vitro dynamic GI model TIM-1
  • UM-1 is a dynamic, multi- compartmental and predictive in vitro system that simulates the digestive conditions in the lumen of the gut (Minekus M. (2015) The TNO Gastro-Intestinal Model (TIM). In: Verhoeckx K. etal. (eds) The Impact of Food Bioactives on Health.
  • TIM-1 consists of four compartments (stomach, duodenum, jejunum and ileum) and can simulate fed or fasted conditions.
  • Example 8 Comparison of the in vivo release profiles of ridinilazole capsule and tablet formulations
  • a single dose pharmacokinetic (PK) study evaluated the ridinilazole Phase 2 liquid capsule formulation and the ridinilazole solid tablet formulation of the invention in dog. Groups of 3 animals were administered test articles as a single dose (200mg) with blood samples taken 8 hours post dose. All bioanalysis results were below the limit of quantification and there were no adverse effects of either formulation in the test subjects.
  • control of drug substance particle size is important in controlling variability in the processability and performance of the process thereby providing control over granule structure and thereby tablet quality.
  • the particle size of ridinilazole is controlled within the drug substance; particle size reduction of ridinilazole crystal agglomerates occurs as the last step in drug substance manufacture (see Example 1). This not only ensures batch-to-batch consistency of particle size distribution within the drug substance but also assures batch-to-batch consistency in both manufacture and quality of the ridinilazole drug product.
  • the ridinilazole tetrahydrate crystal agglomerates used to manufacture ridinilazole tetrahydrate 200mg tablets have particle sizes within the ranges: D 90 between about 10 pm and about 20 pun, D 50 between about 2pun to about 9 pun , and D 10 below 2pim.
  • the ridinilazole tetrahydrate crystal agglomerates have particle sizes within the ranges: D 90 between 8 pun and 15 pun, D 50 between 2pim and 8 pun, and D 10 below 2pim.
  • Ridinilazole tablets (200mg) were prepared as described below:
  • purified water is added. At 12% by weight of added water and at 24% by weight of added water the wet mass is transferred manually through a 2000 pm screen to improve water distribution, each time being returned to the granulator bowl to continue granulation. At approximately 35% by weight added water the wet granules are transferred into a fluid bed dryer.
  • the wet milled granules are then transferred to a fluid bed dryer at an inlet air temperature of approximately 60°C until the target limit of detection (LOD) is achieved. Upon completion of the drying. The dried granules are transferred through a Comil equipped with 1143 pm screen into an appropriately sized blender bin.
  • LOD target limit of detection
  • Dried milled granules are combined with lactose monohydrate, microcrystalline cellulose and croscarmellose sodium for the extra granular phase.
  • the calculated batch quantity of magnesium stearate is added to the dry blend and then transferred manually through a 250 micrometer screen into the 20L bin containing the final blend.
  • Lubrication is performed by tumbling the 20L bin in the blender for 2 minutes at 30 rpm.
  • Tablet cores are coated in a pan coater with Opadry® II Yellow. Target weight gain for coated tablets is 3 to 4%.
  • Tablets produced with micronized and unmicronized API were first compared during a formulation development study. Tablets were compressed with both round and capsule shaped tooling and the dissolution profiles were compared ( Figure 16).
  • a batch (1801A) was compressed to generate two different hardness targets (150 - 170 N, 170 - 190 N, 200 - 220 N, and 250 N).
  • Figure 20 reveals the impact of hardness on drug release at the 5 min time point, where harder tablets are associated with slower release; however, tablets at all four hardness levels release the drug completely by 50 minutes.
  • Clostridium difficile Infection is an infection of the colon that typically develops following prior antibiotic use.
  • the disease is associated with significant morbidity and mortality and primarily affects the hospitalized elderly (>65 years of age) although CDI is becoming increasingly associated with the community setting and younger age groups.
  • CDI Clostridium difficile Infection
  • recurrent infection with up to 30% of patients experiencing a subsequent episode following initial infection with rates increasing to 65% after a third episode.
  • Recurrent disease remains a central unmet medical need in CDI. It is difficult to treat, associated with increased morbidity and poorer clinical outcomes, and further increased risk of mortality.
  • Vancomycin use results in microbiome dysbiosis with a decreased production of the microbiome-derived secondary bile acids (2° BAs) which normally inhibit C. difficile growth and help prevent rCDI.
  • Ridinilazole minimizes the impact on gut microbiome diversity.
  • the primary endpoint was to compare the efficacy of 10 days dosing with ridinilazole (200 mg bid) with vancomycin (125 mg qid) in the treatment of patients with CDI. Sustained clinical response defined as clinical cure at the Assessment Of Cure (AOC) visit and no recurrence of CDI within 30 days post End Of Treatment (EOT).
  • Clinical cure at the AOC visit is defined as the resolution of diarrhea, ⁇ 3 unformed bowel movements (UBMs) or ⁇ 200 mL unformed stool for patients using rectal collection devices, in the 24 h period immediately prior to EOT, that is maintained for 48 h.
  • UBMs unformed bowel movements
  • Recurrence is defined as a new episode of diarrhea (>3 unformed bowel movements (UBMs) or >200 mL unformed stool for patients using rectal collection devices) in a 24 h period with a positive C. difficile free toxin test and the patient requiring antimicrobial treatment active against C. difficile.
  • An UBM is defined as Type 5, 6 or 7 on the Bristol Stool Chart.
  • a global, double-blinded, randomized Phase 3 trial assessed a 10-day treatment with RDZ 200mg twice daily (BID) vs VAN 125 mg four times a day (QID) for CDI.
  • the primary endpoint was sustained clinical response (SCR) defined as clinical response (CR) and no rCDI through 30 days post-end of treatment (EOT).
  • Other endpoints included CR, rCDI, the relative abundance of microbiome-derived 2° BAs, and microbiome diversity and composition.
  • rCDI was defined as a new episode of diarrhea, confirmed by a positive free toxin test (FTT), requiring additional CDI therapy.
  • Each dose of ridinilazole or vancomycin was taken approximately every 6 hours as directed in accordance with the study protocol until the end of the course (40 doses).
  • Exclusion Criteria See therapeutic area libraries for suggested text. Numbering will start again for exclusion criteria or be continued from the inclusion criteria dependent on company practice or requirements of technology solutions.
  • HIV a CD4 ⁇ 200 cells/mm3 within 6 months of randomization.
  • RDZ achieved numerically higher SCR rate than VAN (73.0% vs 70.7%), not statistically significant for superiority.
  • VAN VAN (FIG. 22).
  • VAN pts showed a significant decrease in 2° BAs and microbiome diversity at EOT (FIG. 24).
  • Higher concentration of 2° BAs and greater microbiome diversity at EOT were associated with both lower rCDI and higher SCR rates.
  • RDZ was well tolerated (pts with >1 TEAE: RDZ 36.4% vs VAN 35.5%, TEAE leading to treatment discontinuation: RDZ 0.8% vs. VAN 2.9%).
  • RDZ was effective and safe for the treatment of patients with CDI.
  • RDZ patients had faster recovery of fecal 2° BA, consistent with the preservation of microbiome diversity, resulting in a significantly lower rate of rCDI.
  • a prespecified sub-population not receiving other antibiotics experienced optimal benefit from RDZ.

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Abstract

La présente invention se rapporte à des formes galéniques orales, comprimés solides de 2,2'-di(pyridin-4-yl)- 1H,1'H-5,5'-bibenzo[d]imidazole (qui peut également être connu sous le nom de 2,2'-di-4-pyridinyl-6,6'-bi-1H- benzimidazole, de 5,5'-bis[2-(4-pyridinyl)-1H-benzimidazole], de 2,2'-bis(4-pyridyl)-3H,3'H-5,5'- bibenzimidazole ou de 2-pyridin-4-yl-6-(2-pyridin-4-yl-3H-benzimidazol-5-yl)-1H-benzimidazole), référencés ici par le nom d'INN ridinilazole, et des dérivés, des sels, des hydrates, des solvates, des complexes, des bioisostères, des métabolites ou des promédicaments pharmaceutiquement acceptables correspondants.
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