WO2024079245A1 - Ridinilazole pour traitement de clostridium difficile - Google Patents

Ridinilazole pour traitement de clostridium difficile Download PDF

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Publication number
WO2024079245A1
WO2024079245A1 PCT/EP2023/078299 EP2023078299W WO2024079245A1 WO 2024079245 A1 WO2024079245 A1 WO 2024079245A1 EP 2023078299 W EP2023078299 W EP 2023078299W WO 2024079245 A1 WO2024079245 A1 WO 2024079245A1
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WIPO (PCT)
Prior art keywords
ridinilazole
tetrahydrate
vancomycin
tablet
treatment
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PCT/EP2023/078299
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English (en)
Inventor
Esther DUPERCHY
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Summit (Oxford) Limited
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Publication of WO2024079245A1 publication Critical patent/WO2024079245A1/fr

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    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents

Definitions

  • the present invention relates to methods of treating clostridium difficile by administering ridinilazole, and pharmaceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites or prodrugs thereof.
  • Clostridioides difficile (previously named Clostridium difficile) (CDI) causes Clostridioides difficile-associated diseases (CD AD).
  • CDI Clostridium difficile
  • CD AD Clostridioides difficile-associated diseases
  • C. difficile is an anaerobic Gram-positive spore-forming species of bacteria which is responsible for epidemics and individual cases of CDI, with symptoms ranging from mild, self-limiting diarrhea to more severe and potentially life-threatening manifestations such as pseudomembranous colitis and toxic megacolon.
  • Over 450,000 cases of CDI occur in the US annually, with over 80,000 first recurrences and approximately 29,000 deaths.
  • C. difficile can often be a harmless resident of the gastrointestinal (GI) tract with levels typically kept in check by the complex community of microorganisms that make up the indigenous gut microbiota.
  • GI gastrointestinal
  • disruption to the healthy ecological balance of the gut microbiota typically by prior antibiotic use, diminishes the ability of the host to resist colonization by C. difficile spores that can undergo germination, leading to toxin production and disease symptoms.
  • 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. Of concern is recurrent infection with up to 30% of patients experiencing a subsequent episode following initial infection with rates increasing to 65% after a third episode.
  • Each episode of recurrent disease is associated with an increased risk of further recurrent episodes placing a significant burden on patients through increased morbidity and diminished quality of life.
  • the risk of subsequent episodes was 45%.
  • Recurrence rates may be > 65% following a 3rd episode of CDI.
  • Treatment of recurrent CDI is challenging, and there is no uniformly effective therapeutic approach.
  • Both microbiota biomass and composition at the intestinal-bacterial interface likely influence the C. difficile colonization niche. Although colonization resistance has been associated with specific taxa, it is likely that different, yet diverse, microbiota community structures can confer protection.
  • CDI Faecal microbiota transplantation
  • Ridinilazole also known as SMT19969, and which may be variously referenced as 2,2'-di(pyridin-4-yl)-1H,1'H-5,5'-bibenzo[d]imidazole or 5,5’-bis[2-(4-pyridinyl)-1H- benzimidazole], 2,2'-bis(4-pyridyl)-3H,3'H-5,5'-bibenzimidazole or 2-pyridin-4-yl-6-(2- pyridin-4-yl-3H-benzimidazol-5-yl)-1H-benzimidazole in the literature), is a narrow- spectrum, poorly-absorbable, potent C. difficile-targeting antimicrobial. Ridinilazole may be represented by the following formula:
  • 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.
  • risks arising from lack of uniformity are acute in relation to suspension formulations).
  • 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.
  • even ready to use suspensions are inconvenient, as the entire course of treatment needs is contained within a bottle of liquid that must be properly handled and stored by the patient.
  • 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 manufacturability and processability.
  • the formulation of ridinilazole as appropriately sized solid oral tablets therefore presents acute problems.
  • Ridinilazole has several different distinct crystalline polymorphic forms that exhibit suitable properties for pharmaceutical applications.
  • the present inventors have now discovered that problems arising from these characteristics can be overcome by selection of a specific particle size of 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 micro structure) 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 25pm.
  • 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, [0036] wherein the first disintegrant is selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate and starch.
  • 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 (HPC), 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 (HPC), 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;
  • a glyceride ester selected from glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate;
  • a sugar ester selected from sorbitan monostearate and sucrose monopalmitate; and/or
  • 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:
  • 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 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 mm 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 D90 that is less than 40 pm.
  • 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 PH101®.
  • 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 (P VP-poly vinyl 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).
  • HPC hydroxypropyl cellulose
  • MC methyl cellulose
  • HPMC hydroxypropylmethyl cellulose
  • EC ethylcellulose
  • NaCMC sodium carboxymethyl cellulose
  • 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 PH101, 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 PH102®.
  • 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; (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 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 100M, Avicel PH102® and magnesium stearate.
  • 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.
  • 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.
  • composition comprising granules containing ridinilazole tetrahydrate, optionally in the form of agglomerates, having a particle size D90 of about 4 to about 30pm 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%, 9%, 8.5%, 8%, 7.5%, 7%, 5%, 4%, 3%, 2% or 1% by weight.
  • the crystal agglomerates may have a particle size D90 of about 5mm 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 mm, 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.
  • 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 non-oral 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 D90 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:
  • step (bl) mixing the agglomerates of step (a) with an initial fraction of a first pharmaceutically acceptable intragranular excipient system to form an initial pre-granulation 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 re- agglomerated 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.
  • a process for making a ridinilazole tetrahydrate tablet comprising the steps of: a. providing a granular ridinilazole composition by a process of the third aspect of the invention; and then b. compressing the granular composition to produce the ridinilazole tablet.
  • 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.
  • a method for the treatment, therapy or prophylaxis of CDI or CDAD in a patient in need thereof comprising orally administering to the patient a tablet of the invention.
  • intragranular solid phase incorporated in an extragranular solid phase
  • 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
  • the crystal agglomerates may have a particle size D90 of about 5mm 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 mm, 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 (HPC), 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 (HPC), 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 PH102® 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. 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 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
  • 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 (middle trace) and Form A (lower trace) between about 10 0 2 Theta and about 25 0 2 Theta.
  • 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).
  • Figure 25 illustrates the reduction in recurrence rate after administration of ridinilazole compared to vancomycin in key subgroups.
  • Figures 26A and 26B illustrate that administration of ridinilazole minimally impacted baseline microbiota community structure compared to vancomycin at the end of treatment as illustrated by Jaccard Distance analysis (FIG. 26A) and Bray-Curtis Dissimilarity analysis (FIG. 26B).
  • Figure 27 illustrates preservation of the levels of protective secondary bile acids (SBA) at the end of treatment (EOT) with ridinilazole compared to vancomycin, which treatment resulted in a substantial decrease in SBA.
  • SBA protective secondary bile acids
  • Figure 28 illustrates higher levels of SBA at EOT are associated with higher rates of sustained clinical response (SCR) in all patients in combined treatment arms.
  • SCR sustained clinical response
  • FIG. 29A Carbapenem-Resistant Genes
  • FIG. 29B Cephalosporin-Resistant Genes
  • Figure 30A and 30B illustrates that ridinilazole resulted in a numerically higher SCR (FIG. 30A) and a 60% reduction in recurrence rate compared to vancomycin, in this pre- specified sub-population (70% of patients in the study) (FIG. 30B).
  • Figure 31 illustrates alpha microbiome taxonomic diversity calculated as richness (number of metagenomic species (MGSs) observed in a sample).
  • Figure 32 illustrates alpha microbiome taxonomic diversity calculated as Shannon index (number of MGSs observed in a sample in addition accounts for the abundance evenness of the MGSs).
  • Figure 33 illustrates microbiome percentage change in baseline in richness (mITT population).
  • Figure 34 illustrates microbiome percentage change from baseline in Shannon Index (mITT population).
  • Figure 35 illustrates treatment induced differences in microbial community composition by calculating same-subject Jaccard distances between baseline and later visits.
  • Principal coordinates analysis PCoA
  • BSL baseline
  • EOT end of treatment
  • D40 Day 40
  • D70 Day 70
  • D100 Day 100
  • N number of subjects with paired samples at the indicated time- points
  • REC recurrence.
  • Each small symbol represents a sample from a patient. Samples near each other have similar microbiome compositions, whereas samples far from each other have distinct microbiome compositions.
  • the larger solid symbols represent centroids (solid circle for BSL and solid triangle for post-BSL samples), which are the arithmetic mean position of all the points within each sample group.
  • the ellipse represents 95%confidence interval for each sample group.
  • the percentage of variation explained by the principal coordinates (PCol and PCo2) is indicated on the axes.
  • Figure 36 illustrates treatment induced differences in microbial community composition by calculating same-subject Bray-Curtis dissimilarity between baseline and later visits.
  • Principal coordinates analysis PCoA
  • BSL baseline
  • EOT end of treatment
  • D40 Day 40
  • D70 Day 70
  • D100 Day 100
  • N number of subjects with paired samples at the indicated time-points
  • REC recurrence.
  • Each small symbol represents a sample from a patient. Samples near each other have similar microbiome compositions, whereas samples far from each other have distinct microbiome compositions.
  • FIG. 37 illustrates treatment induced differences in microbial community composition by calculating same-subject Jaccard distances between baseline and later visits.
  • the Jaccard distance measures the degree of microbiome dissimilarity based on the number of metagenomic species shared by two (group of) samples and the number of metagenomic species unique to each of them.
  • EOT end of treatment
  • D40 Day 40
  • D70 Day 70
  • D100 Day 100
  • REC recurrence.
  • Circles indicate means and horizontal bars indicate medians for all samples in each treatment at each visit. Numbers below the boxplots indicate the numbers of paired samples with baseline at the indicated visit for ridinilazole and vancomycin treatment groups. P-value from Wilcoxon rank-sum test to compare ridinilazole and vancomycin treatments are indicated.
  • Figure 38 illustrates treatment induced differences in microbial community composition by calculating same-subject Bray-Curtis dissimilarity between baseline and later visits.
  • the Bray-Curtis dissimilarity measures the degree of microbiome dissimilarity based on the number of metagenomic species shared by two group of samples, the number of metagenomic species unique to each of them and the metagenomic species relative abundance.
  • Figure 39 illustrates Log2-fold changes from baseline to end of treatment and day 40 in relative abundance of bacterial families (mITT population).
  • Figure 40 illustrates Log2-Fold Changes From Baseline to End of Treatment and to Day 40 in Relative Abundance of Bacterial Species (mITT Population).
  • Figure 41 illustrates relative abundance of bacterial genera with potential to produce primary bile acids (mITT Population).
  • Figure 42 illustrates relative abundance of bacterial bsh genes required to produce primary bile acids (mITT Population).
  • Figure 43 illustrates relative abundance of bacterial species with potential to produce secondary bile acids (mITT Population).
  • Figure 44 illustrates total relative abundance of all the bai operon genes considered in the analysis and detected in the study samples.
  • Figure 45 illustrates relative abundance of bacterial 7-alpha-hsdh and 7-beta-hsdh genes required to produce secondary bile acids (mITT Population).
  • Figure 46 illustrates relative abundance of individual bacterial genes required to produce secondary bile acids (mITT Population).
  • FIG 47 illustrates the relative abundance of antibacterial resistance genes (ARGs) (mITT Population).
  • FIG 48 illustrates relative abundance of antibacterial resistance genes (ARGs) per antibiotic class (mITT Population).
  • FIG 49 illustrate relative abundance of antibacterial resistance genes (ARGs) conferring resistance to carbapenems (mITT Population).
  • Figure 50 illustrates relative abundance of antibacterial resistance genes (args) conferring resistance to third generation cephalosporins (mITT Population).
  • Figure 51 illustrates the relative abundance of microbiome-derived secondary bile acids - mITT Population.
  • Figure 52 illustrates the difference between a sub-population of patients not receiving other antibiotics at baseline (greater secondary bile acids and microbiome diversity) versus patients receiving other antibiotics at baseline.
  • the invention generally encompasses compositions and methods comprising ridinilazole, an antibiotic for use in the treatment of C. difficile infection (CDI) and reducing the recurrence of CDI.
  • ridinilazole has been shown to demonstrate potent growth inhibition with a narrow minimum inhibitory concentration (MIC) range against a broad range of C. difficile ribotypes collected. In certain embodiments, this range includes hyper-virulent ribotypes such as 027 and isolates showing reduced susceptibility to vancomycin and metronidazole.
  • ridinilazole demonstrates a narrow spectrum of activity with typically >1,000 fold selectivity for C. difficile over Gram-positive and Gram-negative anaerobic and facultative members of the gut microbiota. The inventors have determined that this feature of ridinilazole results in minimal collateral damage to the gut microbiota compared with vancomycin, throughout the course of treatment of CDI and ultimately led to a marked reduction in rates of recurrent CDI.
  • the invention further encompasses methods and composition comprising ridinilazole and the positive effect on reducing CDI recurrence of infection.
  • SCR provides a measure of efficacy for comparison to vancomycin since it captures both cure of the initial infection and any onset of CDI recurrence.
  • administration of ridinilazole a single dose of 200 mg twice per day for 10 days provides for effective gut concentrations of drug from animal models and from fecal concentrations.
  • the dose was shown to be safe and well-tolerated and demonstrated superiority in sustained clinical response over vancomycin at the 10% level of significance (2-sided test).
  • SD mean
  • ng/mL ng/mL at nominal 4 hours post-dose on Days 1, 5, and 10, respectively.
  • compositions and methods are useful for the treatment of CDI and the risk of recurrent CDI after resolution of the initial signs and symptoms.
  • dysbiosis leads to at least 1 recurrent CDI episode following initial therapy in a substantial proportion of cases.
  • No treatment eliminates all C. difficile spores; thus, the risk of recurrent CDI is associated with inability to suppress regrowth of C. difficile because of inadequate reconstitution of the microbiome and/or host immune factors.
  • Patient risk factors include advanced age, ongoing use of antibiotics for other infections, impaired immune function, and prior episodes of CDI.
  • Episodes of recurrent CDI are associated with decreased patient quality of life, increased morbidity and mortality, and increased healthcare costs.
  • the compositions can be used to mitigate the risk of recurrence in combination with experimental fecal microbiota transplant (FMT) to help increase the diversity of the host microbiome.
  • FMT experimental fecal microbiota transplant
  • C difficile toxin binding therapy can also be employed.
  • Intravenous infusions of bezlotuxumab, an anti-CDI toxin antibody, in combination with CDI treatment can also mitigate the risk of recurrent CDI in select populations.
  • ridinilazole in the mITT population, ridinilazole showed targeted activity against C. difficile and sparing of the gut microbiome compared to vancomycin, which resulted in further gut dysbiosis associated with activity against C. difficile in CDI patients.
  • ridinilazole preserved gut microbiome diversity and community structure compared to vancomycin with higher alpha-diversity measures (richness and Shannon Index, p ⁇ 0.0001) and lower beta-diversity (dissimilarity) measures which indicate lower same-subject microbiome compositional changes from baseline (Jaccard distance and Bray-Curtis dissimilarities, p ⁇ 0.0001).
  • ridinilazole did not decrease the median relative abundance of any bacterial phylum while vancomycin led to reduction in Bacteroidetes (-7.10-median log2FC, FDR-adjusted p ⁇ 0.0001) and Actinobacteria (FDR-adjusted p ⁇ 0.0001), 2 major phyla of the healthy gut, and a concomitant expansion of Proteobacteria (FDR-adjusted p ⁇ 0.0001).
  • Proteobacteria are minor constituents of the healthy microbiome which often increase in relative abundance in the dysbiotic gut.
  • ridinilazole resulted in a 4.60-median log2 fold decrease in relative abundance of C.
  • Vancomycin resulted in a 10.43 -median log2 fold decrease in relative abundance of C. difficile compared to baseline (FDR-adjusted p ⁇ 0.0001) but also in changes in relative abundance of 19 other bacterial species including an increase in Enterobacterales pathogens such as Klebsiella oxytoca and Citrobacter freundii.
  • ridinilazole preserved the gut microbiome diversity and community structure at end of treatment compared to vancomycin and prevented an expansion of the gut resistome
  • treatment with ridinilazole resulted in a numerically higher sustained clinical response rate vs vancomycin.
  • treatment with ridinilazole resulted in about 53% reduction in recurrence compared to vancomycin which was consistent across subgroups.
  • the inventors have shown that compared to vancomycin, ridinilazole had (1) minimal impact on gut microbiome diversity, (2) preserved the relative abundance of protective secondary bile acids; (3) was supportive of an earlier recovery of gut microbiome health and enhanced the ability of the microbiome to resist CDI; and (4) was well tolerated with a low rate of treatment discontinuation for adverse events.
  • the observed reduction of CDI recurrence is supportive for the mechanism of action of ridinilazole, as a highly selective antibiotic for C. difficile which minimally impacts the gut microbiome and thereby reduces the chances for recurrence compared with vancomycin.
  • the alpha diversity was assessed by richness and Shannon index. Richness (as number of metagenomic species detected, an operational definition corresponding to microbial species and sometimes subspecies) and Shannon index (that takes into account richness and abundance evenness) decreased 38.96% and 21.76%, respectively, at end of vancomycin treatment (EOT). In contrast, richness and Shannon index increased 3.51% and 2.76%, respectively, at ridinilazole EOT. Post- treatment samples (D40, D70 and D100) from both ridinilazole and vancomycin groups showed increased richness and Shannon index when compared to baseline but at D40 significant higher richness and Shannon index was observed in ridinilazole group compared to vancomycin group. Both richness and Shannon index dropped to BSL levels in case of recurrences.
  • beta diversity was assessed by Jaccard distances (taking into account only metagenomic species detection) and Bray-Curtis dissimilarities (taking into account both metagenomic species detection and abundance evenness). No compositional differences (measured as beta diversity) were observed between treatments at BSL. At end of treatment a significantly lower microbiome compositional change was observed in the ridinilazole group compared to the vancomycin group. At D40, D70 and DI 00, both treatment groups exhibited compositional differences compared to BSL samples, reflecting a diversity increase and some microbiome recovery after treatment. The microbiome composition in patients with recurrence (REC) became closer to BSL composition again (measured as beta diversity).
  • REC recurrence
  • the diversity differences between treatment groups at EOT were mainly explained by vancomycin resulting in a significant expansion of Proteobacteria, particularly Enterobacteriaceae species such as opportunistic pathogens Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Klebsiella oxytoca, and a decrease of common gut commensals, including species from known short chain fatty acid-producers (generally considered beneficial for host health) such as Bacteroidetes (some are butyrate producers), Lachnospiraceae (some are butyrate producers), Oscillospiraceae (some are butyrate producers) and Bifidobacteriaceae (some are acetate and lactate producers), as well as secondary bile acid producers, such as Eggerthellaceae species.
  • Enterobacteriaceae species such as opportunistic pathogens Escherichia coli, Citrobacter freundii, Klebs
  • gut bacteria carrying genes involved in bile acid metabolism can produce protective secondary bile acids that inhibit C. difficile vegetative growth.
  • bile salt hydrolase (bsh) genes were significantly depleted after vancomycin treatment (56.11% reduction) as well as of 28 genera reported in the literature to carry a bsh gene (including the 10 genera from the representative panel whose bsh genes were detected in this study: Alistipes, Bacteroides, Bifidobacterium, Blautia, Clostridium, Enterococcus, Parabacteroides, Phocaeicola, Roseburia, and Ruminococcus).
  • bile acid- induced (bai) operon genes was significantly depleted after vancomycin treatment (99.60% reduction), as well as 18 species reported in the literature to carry bai, 7-alpha- or 7-beta-HSDH genes (including 7 species from the representative panel whose bai and/or HSDH genes were detected in this study: Clostridium scindens, Clostridium symbiosum, Ruminococcus gnavus, Bacteroides fragilis, Eggerthella lenta, Eubacterium sp. c-25, and Holdemania filiformis).
  • ridinilazole reduced C. difficile relative abundance (median relative abundance 0% at EOT) while preserving the gut microbiota alpha diversity (richness and Shannon index) and with minimal impact on microbial composition (betadiversity) at EOT compared to vancomycin treatment. Microbial potential to produce protective secondary bile acids was also preserved at end of ridinilazole treatment. Furthermore, in contrast to vancomycin, ridinilazole treatment did not increase the antibiotic resistance potential of the gut microbiome.
  • the term "about” is used in relation to a numerical value or range is to be interpreted as being as accurate as the method used to measure it.
  • the term may also be used in this context synonymously with the term “or thereabout”, so that references to “about” in relation to a particular numerical value or range may also be interpreted to define that particular numerical value or range or thereabout.
  • a reference to “about x” may be interpreted as “x, or about x”
  • 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.
  • about 50% includes a range of from 45% to 55%
  • 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.
  • 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.
  • the term “consisting” is used to indicate the presence of the 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) alone.
  • disintegranf 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 mm, 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.
  • 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, 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.
  • a “more intact microbiome” as used herein refers to the microbiome of a subject who was not treated with non-CDI antibiotics within 3 days prior to treatment with ridinilazole or vancomycin over a treatment period of 10 days.
  • 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
  • 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, hydroxy maleic, 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
  • salts and the free base compounds can exist in either a solvated, hydrated or a substantially anhydrous form. Crystalline forms of the compounds of the invention are also contemplated and in general the acid addition salts of the compounds of the invention are crystalline materials.
  • 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 A-Methy 1-2 -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 A-Methy 1-2 -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.
  • compositions [00267]
  • 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.
  • the compounds shown herein are intended to encompass all possible optical isomers of the compounds so depicted.
  • the invention contemplates use of an isolated eutomer.
  • ribotype or “ribotyping” on Clostridium difficile isolates from patients with Clostridium difficile infection allows for the identification of certain strains such as 027 that can be difficult to control when causing outbreaks and/or may be associated with poor clinical outcome.
  • the increase in the number and severity of CDI in the United States is largely attributed to the emergence of the epidemic C. difficile clinical isolates, e.g. BI/NAP 1/027 (type 027) and ribotype 078.
  • Ribotype 027 is common among healthcare- associated CDI cases, while the type 078 is more commonly associated with community- acquired CDI.
  • Ribotype 027 is responsible for 19 to 22.5% of hospital acquired CDI cases, and most of these cases are significantly associated with increased disease severity, recurrence, and mortality. It was recently suggested that one possibility why ribotypes 027 and 078 have become epidemic strains was due to their ability to utilize low concentrations of the sugar trehalose..
  • ridinilazole is used to define the active ingredient in the instant formulations, which is 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-lH- benzimidazole; 5,5’-bis[2-(4-pyridinyl)-17/-benzimidazole]; 2,2'-bis(4-pyridyl)-37/,3'77-5,5'- bibenzimidazole; or 2-pyridin-4-yl-6-(2-pyridin-4-yl-37/-benzimidazol-5-yl)-177- benzimidazole).
  • Ridinilazole tetrahydrate which is the active ingredient (i.e., Form A) in the drug product has the following structure:
  • 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 ( ⁇ m), 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 ⁇ m, or from about 5 nm to about 50 ⁇ m.
  • 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.
  • the term "substantially in accordance" with reference to 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.
  • a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta.
  • 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 D 10 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 4-30pm 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.
  • “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. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • 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. For example, 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. In particular, 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. Specifically, it is particularly preferred that: (a) the first pharmaceutically acceptable excipient system contains a binder and that this class of excipient is absent from the second excipient system, while (b) the second pharmaceutically acceptable excipient system contains a lubricant and that this class of excipient is absent from the first excipient system. [00308] In various embodiments, depending on the first and second excipient systems use 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 PH101®.
  • the second diluent comprises, consists of, or consists essentially of, a combination of lactose monohydrate 100M and Avicel PH102®.
  • 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 metformin- 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).
  • 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)- 1/7, 177-5, 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 5mm 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 mm, 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 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 7-25pm, 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 4-30pm have a marked tendency to re-agglomorate 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”.
  • This problem can be overcome by making a preliminary blend of the ridinilazole tetrahydrate crystal agglomerate particles having a particle size D90 of 4-30pm with a fraction of a first pharmaceutically acceptable intragranular excipient system (e.g. a subset of the constituent excipients of a first excipient system as herein defined).
  • a first pharmaceutically acceptable intragranular excipient system e.g. a subset of the constituent excipients of a first excipient system as herein defined.
  • 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
  • Such processes ensure good, uniform distribution of ridinilazole tetrahydrate API within the intragranular phase of the tablet of the invention and within granules of the various compositions of the invention.
  • 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.
  • the invention encompasses a method of reducing the recurrence of 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 an increase in the concentration of secondary bile acids (SBA) as compared to subjects administered vancomycin.
  • SBA secondary bile acids
  • the increase in SBA concentration is at least 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, 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 up to at least about 70%.
  • the increase in SBA concentration is at least about 1-3%, at least about 2 to about 10%, at least about 5 to about 15%, at least about 10 to about 30%, at least about 20 to about 40%, at least about 30 to about 60%, or at least about 40 to about 70%.
  • the invention encompasses a method wherein a subject was administered ridinilazole or a pharmaceutically acceptable salt thereof which resulted in an increase in the concentration of SBA compared to subjects administered vancomycin. In various embodiments, the invention encompasses a method wherein a subject was administered ridinilazole or a pharmaceutically acceptable salt thereof which resulted in an increase in the concentration of SBA compared to subjects administered vancomycin, and the increase in SBA lasted through the end of treatment.
  • the invention encompasses a method wherein a subject was administered ridinilazole or a pharmaceutically acceptable salt thereof which resulted in an increase in the concentration of SBA compared to subjects administered vancomycin, and the relative increase in SBA for the subject administered ridinilazole persisted after the final administration.
  • the invention encompasses a method wherein a subject was administered ridinilazole or a pharmaceutically acceptable salt thereof which resulted in an increase in the concentration of SBA compared to subjects administered vancomycin, and the relative increase in SBA for the subject administered ridinilazole persisted for at least about 1 day, 2 days, 3 days, 4 days, 5, days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or at least about 5 years, or up to the lifetime of the patient, after the final administration.
  • the invention encompasses a method wherein a subject was administered ridinilazole or a pharmaceutically acceptable salt thereof which resulted in an increase in the concentration of SBA compared to subjects administered vancomycin, and the relative increase in SBA for the subject administered ridinilazole persisted for at least about 1 day, 2 days, 3 days, 4 days, 5, days, 6 days, or at least about 7 days.
  • the invention encompasses a method wherein a subject was administered ridinilazole or a pharmaceutically acceptable salt thereof which resulted in an increase in the concentration of SBA compared to subjects administered vancomycin, and the relative increase in SBA for the subject administered ridinilazole persisted for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or at least about 12 weeks.
  • the invention encompasses a method wherein a subject was administered ridinilazole or a pharmaceutically acceptable salt thereof which resulted in an increase in the concentration of SBA compared to subjects administered vancomycin, and the relative increase in SBA for the subject administered ridinilazole persisted for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or at least about 12 months.
  • the invention encompasses a method wherein a subject was administered ridinilazole or a pharmaceutically acceptable salt thereof which resulted in an increase in the concentration of SBA compared to subjects administered vancomycin, and the relative increase in SBA for the subject administered ridinilazole persisted for at least about 1 year, 2 years, or at least about 5 years, or up to the lifetime of the patient, after the final administration.
  • the invention encompasses a method wherein a subject was administered ridinilazole or a pharmaceutically acceptable salt thereof which resulted in an increase in the concentration of SBA compared to subjects administered vancomycin, and the relative increase in SBA for the subject administered ridinilazole persisted for at least about 40 days after the final administration.
  • the relative abundance of microbiome-derived secondary bile acids at baseline were similar in both ridinilazole and vancomycin treatment groups with median values of 17.36% and 13.00%, respectively.
  • treatment with ridinilazole resulted in slightly higher levels of secondary bile acids while vancomycin treatment lowered the SBA levels substantially, resulting in higher relative abundance of secondary bile acids in the ridinilazole group compared to the vancomycin group of 18.99% versus 0.49%, respectively.
  • Post treatment increases in the secondary bile acids were observed in both treatment groups, but at Day 40, the SBA were still higher in the ridinilazole group (92.35%) versus the vancomycin group (79.69%).
  • 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:
  • More preferred ridinilazole tetrahydrate tablets of the invention have the following composition:
  • Yet more preferred ridinilazole tetrahydrate tablets of the invention have the following composition: 1 It is to be understood that selections may be selected within the ranges specified provided that the % Formula w/w values total 100.
  • Yet more preferred 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.
  • Yet more preferred ridinilazole tetrahydrate tablets of the invention have the following composition:
  • % values may each be independently varied by ⁇ 5%, ⁇ 2% or ⁇ 1%, provided that the % Formula w/w values total 100.
  • Yet more preferred 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 CDAD 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 CDAD 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 CDAD 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 CDAD 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.
  • Example 1 Production of ridinilazole Form A tetrah vdrate crystal agglomerates
  • 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 3-40°29, step size 0.013°, counting time 99sec, ⁇ 22min run time. XRPD patterns were sorted using HighScore Plus 2.2c software.
  • 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 25pm, more preferably a D90 of about 10 to about 20pm).
  • Example 2 Crystal structure of ridinilazole tetrah vdrate 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
  • Single crystals of ridinilazole Form D were grown via vapour diffusion at RT of a solution of ridinilazole in ethanol using water as antisolvent and were submitted for single crystal structure determination.
  • Example 5 Conversion of ridinilazole Form D to Form A
  • Ridinilazole Form D is prepared as described in Example 3.
  • Ridinilazole Form A is prepared as described in Example 1. Seed crystals were prepared by hand grinding and sifting. The conversion was carried out as follows:
  • XRPD analysis was carried out on the ridinilazole tablet to confirm no form change occurred after tableting.
  • One tablet was crushed with a pestle and mortar and analysed by transmission XRPD. Small amounts of the sample coating could not be isolated completely from the crushed sample.
  • 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
  • the release and colonic delivery profiles of the ridinilazole 200mg capsule and 200mg tablets formulation were also compared in the in vitro dynamic GI model TIM-1.
  • TIM- 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. et al. (eds) The Impact of Food Bioactives on Health. Springer, Cham.
  • Simulated conditions include gastric and small intestinal transit, flow rates and composition of digestive fluids, pH, and removal of water and metabolites.
  • TIM-1 consists of four compartments (stomach, duodenum, jejunum and ileum) and can 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.
  • Ridinilazole tablets manufactured using drug substance with crystal agglomerate particles having a D90 outside of the 10 -20 pm range yielded material for tableting having properties which were unsuitable for drug product manufacture and performance.
  • 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 pm, D 50 between about 2pm to about 9 pm , and D 10 below 2pm.
  • the ridinilazole tetrahydrate crystal agglomerates have particle sizes within the ranges: D 90 between 8 pm and 15 pm, D 50 between 2pm and 8 pm, and D 10 below 2pm.
  • 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.
  • Tablets are compressed using oval shaped tooling. Dedusting and metal checking are performed in line post compression. [00439] Coating
  • 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.
  • 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.
  • 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 ridinilazole 200mg twice daily (BID) vs vancomycin 125 mg four times a day (QID) for CDI.
  • the primary endpoint was sustained clinical response (SCR) defined as clinical response (CR) and no recurrent CDI through 30 days post-end of treatment (EOT).
  • Other endpoints included CR, recurrent CDI, the relative abundance of microbiome-derived 2° BAs, and microbiome diversity and composition.
  • Recurrent CDI 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).
  • Ridinilazole was effective and safe for the treatment of patients with CDI. Ridinilazole patients had faster recovery of fecal 2° BA, consistent with the preservation of microbiome diversity, resulting in a significantly lower rate of recurrent CDI. A prespecified sub-population not receiving other antibiotics experienced optimal benefit from ridinilazole.
  • Example 14 Microbiome Taxonomic Diversity And Composition
  • the p-values obtained for these tests were corrected for multiple testing using the Benjamini-Hochberg (BH) method to control the false discovery rate (FDR) at a level of 10% (threshold often used in microbiome research, see for instance a pioneering key publication in the field: Nature, 2013, Aug. 29; 500, (7464):541-6, incorporate herein by reference).
  • the correction of the p-values was done per comparison, i.e. when comparing between treatments p-values were corrected per visit; when comparing between visits (e.g. BSL to EOT) within a treatment (e.g ridinilazole treatment) correction was done for each treatment.
  • FDR-adjustment of p values was performed when comparing taxa relative abundance, new detection of pathogens, relative abundance of bsh-carrying genera, relative abundance of bai/HSDH carrying species, relative abundance of bai/HSDH genes and relative abundance of antibiotic class resistance genes. Summary statistics were calculated for all features as mean, standard deviation (SD), median, 25% quantile (QI) - 75% quantile (Q3), minimum, and maximum.
  • Fold change and log2 fold change from BSL were also calculated for taxa and antibiotic class resistance relative abundances and summarized likewise.
  • Log2 fold change from BSL Log2 (post-BSL value/BSL value).
  • a pseudocount to the relative abundance table was added to avoid log(0) or infinity values. This pseudo count was the lowest relative abundance from the relative abundance table divided by two, resulting in 4.32 x 10-5 for taxa relative abundance and 1.44 x 10-8 for gene relative abundance, and it can be interpreted as the limit of abundance detection of the method for taxa and genes.
  • Alpha diversity microbial diversity within samples was calculated as richness (number of MGSs observed in a sample), and as Shannon index which in addition accounts for the abundance evenness of the MGSs. Both measures were calculated from downsized relative abundances. No significant differences in alpha diversity between ridinilazole and vancomycin treatments were observed at BSL.
  • Example 15 Changes in Taxonomic Composition from Baseline at the Family Level
  • Example 16 Changes In Taxonomic Composition From Baseline At The Species Level
  • Example 17 Potential of the Microbiome to Metabolize Bile Acids
  • Conjugated primary bile acids secreted through biliary system into small intestine such as taurocholic acid promotes the germination of C. difficile spores, while secondary bile acids (deoxy cholic acid and lithocholic acid) inhibit the growth of C. difficile and may bind to and limit activity of C. difficile toxins.
  • bile salt hydrolases (bsh gene product - once bile acids enter the distal gut, responsible of deconjugation of glycine or taurine group from conjugated primary bile acids [such as taurocholic acid and glycolic acid] into unconjugated primary bile acids [cholic acid and chenodeoxy cholic acid]) and 7-alpha-dehydroxylases (bai operon gene products - responsible for the multi-step process of 7-alpha-dehydroxylation of unconjugated primary bile acids into secondary bile acids such as deoxycholic acid and lithocholic acid), likely contributes significantly to C. difficile infection progression (Therap Adv Gastroenterol.
  • microbial enzymes are also able to perform transformations on unconjugated primary bile acids, for instance, 7-alpha/beta- epimerisation (by 7-alpha/beta-HSDH genes) to form the secondary bile acid ursodeoxycholic acid, which may mitigate C. difficile infection host inflammation through farnesoid X receptor signalling
  • Facultative anaerobes Escherichia and Streptococcus were among the genera with the lowest relative abundances in ridinilazole treatment, whereas usual gut microbiota commensals such as Bacteroides, Phocaeicola, Mediterraneibacter, and Bifidobacterium were among the genera with the highest relative abundances in ridinilazole treatment compared to vancomycin at EOT.
  • the relative abundance of a representative panel of 10 bacterial genera whose bsh gene was detected in this study is summarized in Figure 41 for each treatment at each visit.
  • the vancomycin group exhibited a significant reduction of 56.11% in total relative abundance of bsh genes compared to BSL samples, while an increase of 9.85% was observed in the ridinilazole group (Wilcoxon signed-rank test; p ⁇ 0.0001, Table 5.8), this resulted in significantly higher bsh relative abundance in the ridinilazole group compared to vancomycin group (Wilcoxon rank-sum test; p ⁇ 0.0001).
  • Species were selected based on their mean relative abundance across all samples, number of distinct bai genes (baiA, baiB, baiCDH, baiEI, baiF, baiG, baiN, 7- alpha-HSDH and 7-beta-HSDH), and total number of bai operon or 7- alpha/beta-HSDH genes detected within each species. From the representative panel of bai and HSDH gene carriers, the 7-alpha-HSDH carriers, [Clostridium] symbiosum, Eubacterium sp.
  • Bacterial genes (bai, 7-alpha-HSDH and 7-beta-HSDH)
  • the ridinilazole group showed higher relative abundance for all 7 individual bai genes when compared to the vancomycin group (Wilcoxon rank-sum test, FDR p ⁇ 0.0001, Figure 46), and two genes baiB and baiG showed significantly higher relative abundance at REC in the ridinilazole treatment compared to the vancomycin treatment (Wilcoxon rank-sum test, FDR p ⁇ 0.0744, Table 5.10, Figure 46). No significant differences in total bai gene relative abundance were observed for the rest of the visits (Wilcoxon rank-sum test; p 3 0.3080).
  • ARG class relative abundance To study the impact of the antibiotic treatments at the level of antibiotic class resistance gene abundance (referred as ARG class relative abundance), the relative abundance of all resistance genes conferring resistance to a given antibiotic class for the 21 most common antibiotics classes (enumerated in Methods section) was aggregated. Isoniazide and fusidic acids resistance genes were not detected in this dataset and therefore not included on the statistics. None of the remaining 19 ARG class relative abundance exhibited significant differences between treatments at BSL (Wilcoxon rank-sum test; FDR p 3 0.9790). Relative abundance of 18 ARG classes was different between treatments at least in one of the visits (Figure 48).
  • Relative abundance of 14 ARG classes including aminocyclitol, aminoglycoside, betalactam, diaminopyrimidine, fluoroquinolone, fosfomycin, iminophenazine, macrolide, phenicol, polymyxin, rifamycin, sulfonamide, tetracycline and multidrug efflux pumps (MEPs) was significantly higher in vancomycin by EOT ( Figure 48).
  • the relative abundance of 4 of them were still significantly higher in vancomycin treatment at D40 although glycopetide resistance genes relative abundance was significantly lower in the vancomycin treatment right after treatment (EOT).

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Abstract

L'invention concerne des méthodes de traitement de Clostridium difficile par administration de ridinilazole, et de ses dérivés, sels, hydrates, solvates, complexes, bioisostères, métabolites ou promédicaments pharmaceutiquement acceptables.<i />
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