WO2021257466A1 - Combination antibacterial composition and method for antibacterial therapy - Google Patents

Combination antibacterial composition and method for antibacterial therapy Download PDF

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Publication number
WO2021257466A1
WO2021257466A1 PCT/US2021/037252 US2021037252W WO2021257466A1 WO 2021257466 A1 WO2021257466 A1 WO 2021257466A1 US 2021037252 W US2021037252 W US 2021037252W WO 2021257466 A1 WO2021257466 A1 WO 2021257466A1
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WIPO (PCT)
Prior art keywords
granulate
amount
pretomanid
dosage form
pyrazinamide
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PCT/US2021/037252
Other languages
French (fr)
Inventor
Rajneesh Taneja
Pirthi Pal Singh
Veena Vithalapuram
Jagadeesh Nadigoti
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The Global Alliance For Tb Drug Development, Inc.
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Application filed by The Global Alliance For Tb Drug Development, Inc. filed Critical The Global Alliance For Tb Drug Development, Inc.
Priority to EP21825172.6A priority Critical patent/EP4164645A1/en
Publication of WO2021257466A1 publication Critical patent/WO2021257466A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • Combinations of compounds, such as fixed-dose combinations, are described having antibacterial activity for the treatment of tuberculosis.
  • Mycobacterium tuberculosis is the causative agent of tuberculosis ("TB"), a devastating infectious disease. It is estimated that about 2 million TB patients die each year globally. Failure to properly treat tuberculosis has caused global drug resistance in mycobacterium tuberculosis and thus rendering some medications ineffective.
  • the present disclosure describes fixed-dose pharmaceutical dosage forms comprising a therapeutically effective amount of each of pretomanid, moxifloxacin and pyrazinamide and, optionally, at least one other active ingredient, or a pharmaceutically acceptable salt individually thereof, and a pharmaceutically acceptable carrier.
  • the disclosure also describes methods for treating tuberculosis comprising the step of administering said fixed-dose pharmaceutical dosage form to a patient in need thereof.
  • co-granulates comprising a binder; one or more intragranular excipients; and a total of about 60 wt.% to 95 wt.% of active pharmaceutical ingredients (APIs), wherein the APIs comprise a mixture of pretomanid, moxifloxacin, and pyrazinamide, or a pharmaceutically acceptable salt and/or solvate thereof.
  • APIs active pharmaceutical ingredients
  • Tablets, capsules, and oral suspensions, among other dosage forms may be prepared using the granulate herein.
  • a process for preparing a co-granulate comprising, granulating a first mixture comprising pretomanid, moxifloxacin, pyrazinamide, a binder, and one or more intragranular excipients to provide the co-granulate.
  • a process for preparing a tablet comprising combining a co- granulate described herein with one or more extragranular excipients to provide a blend; and compressing a portion of the blend into a tablet.
  • a method for treating tuberculosis comprising administering one or more dosage forms described herein a person in need of such treatment, wherein the dosage form(s) as administered to the person comprises a therapeutically effective amount of pretomanid, moxifloxacin, pyrazinamide, and optionally bedaquiline, or pharmaceutically acceptable salt and/or solvate thereof.
  • Figure 1 shows a flow diagram of the manufacturing process for an exemplary fixed dose combination (FDC) formulation containing a co-granulate of pretomanid, moxifloxacin, and pyrazinamide (PaMZ).
  • FDC fixed dose combination
  • FIG 2 shows a flow diagram of the manufacturing process for an exemplary fixed dose combination (FDC) formulation containing a co-granulate of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ).
  • FDC fixed dose combination
  • Figure 3 is a graph comparing the dissolution of pretomanid as a function of time for three pretomanid-containing formulations; diamonds, PaMZ Formulation A (Table 1); triangles, PaMZ Formulation B (Table 2); and pretomanid tablets, 200 mg (Table 4).
  • the present disclosure generally relates to a fixed-dose combination of pretomanid, moxifloxacin and pyrazinamide as active ingredients and optionally a fourth active ingredient such as, for example, bedaquiline.
  • the fixed-dose combination comprises a granulate comprising pretomanid, moxifloxacin, and pyrazinamide, and optionally, bedaquiline.
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • the combinations herein may conveniently be presented as a pharmaceutical formulation in a unitary dosage form.
  • Active Ingredients The pharmaceutically active compounds and combinations thereof herein may be referred to as “active ingredients”, “API” or “pharmaceutically active agents.”
  • Pretomanid (also known as "Pa” or "PA-824”) is a novel nitroimidazole anti-bacterial agent recently approved by the U.S. FDA as a TB therapy, and having many attractive characteristics - most notably its novel mechanism of action, its activity in vitro against all tested drug-resistant clinical isolates, and its activity as both a potent bactericidal and a sterilizing agent.
  • the compound shows no evidence of mutagenicity in a standard battery of genotoxicity studies, no significant cytochrome P450 interactions, and no significant activity against a broad range of Gram-positive and Gram-negative bacteria.
  • the lUPAC designation for pretomanid is (6S)-2-nitro-6- ⁇ [4-(trifluoromethoxy)benzyl]oxy ⁇ -6,7- dihydro-5H-imidazo[2,l-b][l,3]oxazine.
  • Pretomanid has the following structure:
  • Moxifloxacin (l-cyclopropyl-7-[(lS,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl]-6-fluoro-8-methoxy-4- oxoquinoline-3-carboxylic acid, also referred herein as "M" is a synthetic fluoroquinolone antibacterial agent developed by Bayer AG (initially called BAY 12-8039). It is marketed worldwide (as the hydrochloride salt, often as the monohydrate of the hydrochloride salt) under the brand names AVELOX, AVALOX and AVELON for oral treatment.
  • moxifloxacin refers to the free base as well as a pharmaceutically acceptable salt and/or solvate thereof, such as moxifloxacin hydrochloride and/or moxifloxacin hydrochloride monohydrate.
  • Solvate refers to a complex of variable, but defined, stoichiometry formed by a solute (the referenced compound) and a solvent. Solvates should be understood not to include solid forms of a reference compound containing sub stoichiometric amounts of residual solvents. Solvents, by way of example, include water (such can be referred to as a "hydrate”), methanol, ethanol, isopropyl alcohol, ethyl acetate, ethylene glycol, propylene glycol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and acetic acid, among others.
  • salt and/or solvate refers to each of a salt (e.g., moxifloxacin hydrochloride), a solvate, and a solvate of a salt (e.g., moxifloxacin hydrochloride monohydrate).
  • Pyrazinamide (pyrazine-2-carboxamide, also referred herein as "Z") is the pyrazine analogue of nicotinamide and used as an anti-tuberculous agent. Pyrazinamide is most commonly used for treatment of active tuberculosis (TB) during the initial phase of therapy (generally the first two months of treatment), in combination with other agents. Pyrazinamide demonstrates clinically significant antibacterial activity against Mycobacterium tuberculosis and M. africanum.
  • Bedaquiline ((aS ⁇ R)-6-Bromo-a-[2-(dimethylamino)ethyl]-2-methoxy-a-l-naphthalenyl ⁇ - phenyl-3-quinolineethanol; also known herein as "B") is a diarylquinoline antimycobacterial drug having the formula:
  • Bedaquiline is marketed as SIRTURO” and specifically inhibits mycobacterial ATP (adenosine 5'- triphosphate) synthase, by binding to subunit c of the enzyme that is essential for the generation of energy in Mycobacterium tuberculosis.
  • bedaquiline refers to the free base as well as a pharmaceutically acceptable salt and/or solvate thereof, such as bedaquiline fumarate.
  • Each of the APIs in the present dosage forms may be present in any suitable polymorphic form and/or any suitable solvate thereof.
  • any of the active compounds in the compositions herein also includes any physiologically acceptable salt thereof.
  • physiologically acceptable salts and their physiologically functional derivatives include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4 + (wherein X is Ci-C4alkyl), or an organic acid such as fumaric acid, acetic acid, succinic acid.
  • Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX4 + (wherein X is independently selected from H or a Ci-C4alkyl group).
  • a suitable cation such as Na + and NX4 + (wherein X is independently selected from H or a Ci-C4alkyl group).
  • Alkyl refers to a univalent group derived from a linear or branched alkane by removal of a hydrogen atom from any carbon atom (-C n H2n +i ). Examples of alkyl groups include, but are not limited to, methyl, ethyl, isopropyl, sec-butyl, and n-butyl.
  • each active ingredient that may produce a single dosage form may vary depending upon the host treated and the particular mode of administration.
  • a convenient unitary dosage formulation may contain each of the active ingredients in any amount from 1 mg to 1 g each, for example but not limited to, 10 mg to 500 mg for each active ingredient.
  • Daily dosages of the active ingredients in such an embodiment can be as follows:
  • the daily dosages of the active ingredients can be as follows:
  • FDC Fixed dose combinations
  • Pretomanid is a BCS class ll/IV compound that demonstrates poor solubility but high permeability which can result in solubility-limited absorption.
  • Formulations of BCS class ll/IV can contain a large proportion of inactive ingredients to aid in the dispersion and dissolution of the drug.
  • the total weight of recently approved pretomanid 200 mg tablets is 800 mg. Dissolution is essential for a drug before it can be absorbed systemically and provide the desired therapeutic response.
  • “chemical stability” or “chemically stable” means that a formulation described herein shows no "significant change” upon storage under at least one of the following storage conditions:
  • “Significant change” for a drug product (e.g., formulation) herein means either 5 percent change in a drug substance (API) assay from its initial value or any degradation product exceeding 1 wt.% at the termination of the time period.
  • the FDCs may be formulated in a unit dosage formulation comprising a fixed amount of each active pharmaceutical ingredient for a periodic, e.g. daily, dose or sub-dose of the active ingredients. In certain embodiments, a total daily dose of Pa, M and Z can be included in more than one unit dosage that could be ingested comfortably.
  • the total daily dose of each active agent may be equally divided among two or more unit dosages to facilitate daily dosing.
  • the total daily dose of each active agent is equally divided among two to six unit dosages, or two to five unit dosages, or two to four unit dosages, or two, or three, or four, or five, or six unit dosage.
  • the plurality of unit dosages comprising the total daily dose can be administered together simultaneously or sequentially to provide the total daily dose to the patient in need thereof.
  • a total daily dose of 200 mg Pa, 400 mg M, 1500 mg Z and optionally, 200 mg or 100 mg B may be equally divided among several unit dosages according to any one of the following embodiments:
  • each of the three unit dosages can contain 80.6 mg of bedaquiline fumarate, 152 mg of moxifloxacin hydrochloride monohydrate, 66.7 mg of pretomanid and 500 mg of pyrazinamide as active ingredients.
  • compositions herein comprise a co-granulate of Pa, M, Z, and optionally B, together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredients may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, hard or soft capsules, syrups or elixirs may be prepared (see, for example, Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.)).
  • the FDCs described herein can encompass solid dosage forms such as monolithic tablets, multi-layer tablets, and combinations thereof.
  • a monolithic approach involves an intimate contact between two or more of the different APIs (active pharmaceutical ingredients), such as by blending and/or granulating the different APIs together.
  • a combination approach may include, for example, a bilayer tablet where one layer comprises the co-granulate of Pa, M, and Z while the second layer contains bedaquiline or a pharmaceutically acceptable salt thereof.
  • a combination approach may also include, for example, a monolithic tablet containing the co granulate that includes Pa, M, and Z along with intragranular excipients, as discussed herein, which is blended with an extragranular phase that may include bedaquiline or a pharmaceutically acceptable salt thereof along with extragranular excipients, as discussed herein.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including antioxidants, sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient or auxiliary agents which are suitable for manufacture of tablets are acceptable.
  • the several dosage forms herein may be produced from a co-granulation of at least Pa, M and Z in a single phase (monolithic) granulate (e.g., the co-granulate).
  • a granulate comprising a binder; one or more intragranular excipients; and a total of about 60 wt.% to 95 wt.% of active pharmaceutical ingredients (APIs), wherein the APIs comprise a mixture of pretomanid, moxifloxacin, and pyrazinamide, or a pharmaceutically acceptable salt and/or solvate thereof.
  • APIs active pharmaceutical ingredients
  • the co-granulate comprise about 40 - 90 wt.% of the APIs (i.e., the sum of all APIs present in the co-granulate); or about 60-90 wt.%; about 70 - 90 wt.%; or about 75 - 85 wt.% or about 80-90 wt.% of the co-granulate.
  • the binder may be present in about 0.1 - 10 wt.% or 0.5 -5 wt.% or 1 - 3 wt.% of the co-granulate.
  • the sum of all intragranular excipients may comprise about 10 - 60 wt.% or 10 - 40 wt.% or 10 -30 wt. % or 15- 25 wt. % or 10 -20 wt.% of the co-granulate.
  • the intragranular excipients may comprise one or more independently selected from the group consisting of a surfactant, a diluent, a disintegrant, a glidant, a lubricant, a coloring agent, a sweetener, and a flavoring.
  • the intragranular excipients may comprise a diluent, a disintegrant, and a surfactant.
  • the diluent may be present at about 5 -15 wt. % or about 5 - 10 wt. % of the co-granulate.
  • the disintegrant may be present at about 1 - 10 wt. % or about 3 - 10 wt.
  • the surfactant may be present at about 0.1 - 5 wt.% or about 0.1 - 3 wt.% or about 0.3 - 2 wt.% of the co-granulate.
  • Diluents can include pharmaceutically acceptable inert fillers such as, but are not limited to, inorganic fillers such as calcium carbonate, dibasic calcium phosphate(such as anhydrous or dihydrate forms, e.g., Emcompress ® Calcium Phosphates (JRS PHARMA GmbH & Co.
  • inorganic fillers such as calcium carbonate, dibasic calcium phosphate(such as anhydrous or dihydrate forms, e.g., Emcompress ® Calcium Phosphates (JRS PHARMA GmbH & Co.
  • the diluent may comprise an inorganic filler, a monosaccharide, a disaccharide, a polysaccharides, a sugar alcohol, a cellulose, ora mixture thereof.
  • the diluent may comprise dibasic calcium phosphate, tribasic calcium phosphate, lactose, maltose, sucrose, trehalose, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, microcrystalline cellulose, or a mixture thereof.
  • the diluent may comprise lactose, microcrystalline cellulose, or a mixture thereof.
  • an intragranular excipient that is a diluent can be microcrystalline cellulose.
  • Binders include pharmaceutically acceptable agents that can hold various ingredients together in a cohesive mix, for example, to hold together an active pharmaceutical ingredient and inactive ingredients.
  • suitable binders include, but are not limited to, dry binders such as partially pre gelatinized starch (e.g., UNI-PURE ® DW partially pre-gelatinized maize starch, National Starch & Chemical); anhydrous lactose, and dibasic calcium phosphate dehydrate; and wet binders such as pre gelatinized starch, povidone (e.g.
  • Disintegrants include pharmaceutically acceptable agents that can promote disintegration of a dosage form, including, but not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, powdered cellulose, croscarmellose sodium, crospovidone, guar gum, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, maltose, trehalose, methylcellulose, polacrilin potassium, pullulan, colloidal silicon dioxide, sodium alginate, sodium starch glycolate; a starch such as pregelatinized modified starch, corn starch, hydroxypropyl corn starch, pregelatinized hydroxypropyl corn starch, pea starch, hydroxypropyl pea starch, pregelatinized hydroxypropyl pea starch, potato starch, hydroxypropyl potato starch, pregelatinized hydroxypropyl potato starch, tapioca starch, or wheat starch; and mixtures thereof.
  • alginic acid carboxymethyl
  • the disintegrant may comprise carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, sodium starch glycolate, corn starch, or a mixture thereof.
  • the disintegrant may comprise a starch (e.g., corn starch), sodium starch glycolate, crospovidone, or a mixture thereof.
  • Surfactants may include amphoteric, non-ionic, cationic, and/or anionic surfactants.
  • amphoteric surfactants include, but are not limited to, lecithin, cocamidopropyl betaine, lauryldimethylamine oxide, myristamine oxide, coco amino propionate (SERVO AM 1010 Elementis Specialties, Delden, The Netherlands), sodium lauryl imino dipropionate (SERVO AM 1020), sodium octyl imino dipropionate (SERVO AM 2020), sodium coco imino mono/dipropionate (SERVO AM 1015), oleyldimethylbetaine, and sodium N-cocoamidethyl N-hydroxyethylglycine, and mixtures thereof.
  • non-ionic surfactants include, but are not limited to, alkylphenols, such as 4-(2,4- dimethylheptan-3-yl)phenol; fatty acid glycerides such as glyceryl dibehenate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, and glyceryl tristearate; sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate, sorbitan sesqueoleate, sorbitan trioleate, and sorbitan tristearate; ethoxylated fatty acids such as stearic acid ethoxylate and lauric acid ethoxylate; ethoxylated fatty alcohols such as polyoxyethylene lauryl ethers (Brij); ethoxylated alkylphenols such as nonylphenol ethoxylate and ethoxylated p
  • cationic surfactants include, but are not limited to, quaternary fatty ammonium salts such as cetyl trimethyl ammonium bromide (CTAB), dodecyltrimethylammonium bromide, methylbenzethonium chloride, and hexadecyltrimethylammonium bromide; 2-alkyl-l-hydroxyethyl-2- imidazolines such as lauryl hydroxyethyl imidazoline and stearyl hydroxyethyl imidazoline; polyoxamines, such as Tetronic ® 908 (i.e., poloxamine 908, a tetrafunctional polyethylene oxide (PEO)-polypropylene oxide ethylenediamine block copolymer); N,N,N,N-tetrakis substituted ethylenediamines such as ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol and ethylenediamine tetrakispropi
  • anionic surfactants include, but are not limited to, alkyl sulfates, such as sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium lauryl sulfate; bile salts such as sodium deoxycholate and sodium cholate; sulfosuccinate diesters such as docusate sodium (AEROSEL OT, American Cyanamid), ammonium dinonyl sulfosuccinate, diamyl sulfosuccinate sodium, dicapryl sulfosuccinate sodium, diheptyl sulfosuccinate sodium, dihexyl sulfosuccinate sodium, diisobutyl sulfosuccinate sodium, and ditridecyl sulfosuccinate sodium; alkylbenzene sulfonates such as sodium dodecylbenzenesulfonate; sodium petroleum sulfonates such
  • the surfactant may comprise a fatty acid glyceride, a sorbitan ester, an ethoxylated fatty acid, an ethoxylated hydrogenated vegetable oil, an ethoxylated sorbitan ester, a polyoxamer, a quaternary ammonium salt, an alkyl sulfate, a sulfosuccinate diester, an alkylbenzene sulfonate, a sulfated ethoxylated fatty alcohol, or a mixture thereof.
  • the surfactant may comprise a polyoxamer or sodium lauryl sulfate.
  • Lubricants may comprise one or more, but not limited to fatty acids such as lauric acid, myristic acid, palmitic acid, and stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate or other metallic stearate); talc; polyethylene glycols (such CARBOWAXTM Polyethylene Glycol (PEG) 3350, Dow Chemical, Midland, Michigan); light mineral oil; poloxamers, such as Kolliphor ® P188 and P407 available from BASF, Ludwigshafen, Germany; polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80; sodium lauryl sulfate; sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate and sorbitan trioleate;
  • the lubricant may comprise a fatty acid or salt thereof, a polyethylene glycol, or a glyceride.
  • the lubricant may comprise magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, polyethylene glycol, glyceryl dibehenate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, or glyceryl tristearate.
  • the lubricant may comprise magnesium stearate.
  • Glidants include pharmaceutically acceptable agents that can promote powder flow by reducing interparticle friction and cohesion. Glidants may be added to pharmaceutical compositions immediately prior to tablet compression to facilitate the flow of granular material into the die cavities of tablet presses. Glidants include: colloidal silicon dioxide such as Aerosil ® 200 (a hydrophilic fumed silica with a specific surface area of 200 m 2 /g; Evonik Corp., Piscataway, New Jersey) or CAB-O-SIL, M-5P (a fumed silica with a specific surface area of 200 m 2 /g; Cabot Corp., Billerica, Massachusetts), asbestos free talc, sodium aluminosilicate, calcium silicate, calcium phosphate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, stearowet C (a combination of calcium stearate and sodium la
  • compositions herein may contain glidants to effect and maintain homogeneity of active ingredients during handling prior to tablet compression.
  • the glidant may comprise colloidal silicon dioxide, sodium aluminosilicate, calcium silicate, magnesium silicate, magnesium trisilicate, magnesium aluminosilicate, or a mixture thereof.
  • the glidant may comprise colloidal silicon dioxide.
  • Coloring agent as used herein include, but are not limited to, pharmaceutically acceptable dyes, such as FD&C dyes including Blue No. 1, Blue No. 1 Lake, Blue No. 1--Aluminum Lake, Blue No. 2, Blue No. 2--Aluminum Lake, Green No. 3, Red No. 3, Red No. 40, Red No. 40--Aluminum Lake, Yellow No. 5, Yellow No. 5--Aluminum Lake, Yellow No. 6, and Yellow No. 6-Aluminum Lake; and inorganic colorants, such as alumina, titanium dioxide, ferric oxide brown, ferric oxide orange, ferric oxide red, ferric oxide yellow, ferrosoferric oxide, ferrous oxide; and natural colorants such as caramel and annatto extract.
  • pharmaceutically acceptable dyes such as FD&C dyes including Blue No. 1, Blue No. 1 Lake, Blue No. 1--Aluminum Lake, Blue No. 2, Blue No. 2--Aluminum Lake, Green No. 3, Red No. 3, Red No. 40, Red No. 40--A
  • the co-granulates described above may be prepared according to a process comprising granulating a first mixture comprising pretomanid, moxifloxacin, pyrazinamide, a binder, and one or more intragranular excipients to provide a co-granulate.
  • the granulation may be according to wet or dry granulation process familiar to those skilled in the art. Where a dry granulating process is utilized (e.g., blending and slugging of the dry components), the binder may comprise pre-gelatinized starch, anhydrous lactose, dibasic calcium phosphate, or a mixture thereof.
  • the APIs and intragranular excipients may be granulated together using a solution (e.g., a solution comprising the binder and a surfactant).
  • a solution e.g., a solution comprising the binder and a surfactant.
  • the co-granulate prepared by wet or dry granulation processes may be milled (e.g., via wet or dry milling) to provide a first milled co-granulate.
  • Such first milled co-granulate may be dried to a suitable wt.% residual solvent and/or water to provide a dried co-granulate.
  • the dried co-granulate can be further milled to provide a second milled co-granulate having a desired particle size distribution.
  • a tablet can be prepared comprising the co-granulate and one or more extragranular excipients.
  • the tablet comprises about 75 - 95 wt.% of the co-granulate and about 5 - 25 wt.% of the one or more extragranular excipients; or 80 - 95 wt.% of the co-granulate and about 5 - 20 wt.% of the one or more extragranular excipients; or 85-95 wt.% of the co-granulate and about 5 - 15 wt.% of the one or more extragranular excipients; or 70-90 wt.% of the co-granulate and about 10-30 wt.% of the one or more extragranular excipients; or 80-90 wt.% of the co-granulate and about 10-20 wt.% of the one or more extragranular excipients.
  • the extragranular excipients can be selected from the group consisting of a diluent, a disintegrant, a glidant, a lubricant, a coloring agent, a sweetener, a flavoring, and mixtures thereof. Examples of suitable extragranular excipients are described further above. In one embodiment, the extragranular excipients comprise one or more of a glidant, a disintegrant, and a lubricant.
  • a tablet may be prepared by combining the co-granulate the one or more extragranular excipients to provide a blend; and compressing a portion of the blend into a tablet.
  • Such tablets may optionally contain a coating layer over an outer surface of the tablet.
  • the optional film coating agents may, for example, comprise cellulose derivatives such as methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), methacrylic acid/acrylate copolymers, hydroxypropyl methylcellulose (HPMC), vinyl polymers or natural film formers, such as shellac.
  • cellulose derivatives such as methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), methacrylic acid/acrylate copolymers, hydroxypropyl methylcellulose (HPMC), vinyl polymers or natural film formers, such as shellac.
  • MC methyl cellulose
  • EC ethyl cellulose
  • HEC hydroxyethyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • vinyl polymers such as shellac.
  • film formers such as shellac.
  • commercially available film formers include, but are not limited to, Opadry ® (HPMC), Op
  • Such coatings may be applied as is known by one skilled in the art and controlled to an added weight% to the uncoated tablets.
  • an optional film coating may be applied to add about 1 - 10 wt.% or 1-5 wt.% to the weight of the uncoated tablets.
  • Formulations suitable for oral administration may also be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example pregelatinized starch, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example pregelatinized starch, calcium phosphate, or kaolin
  • an oil medium such as peanut oil, liquid paraffin, or olive oil.
  • the co-granulate as described above can be mixed with an inert solid diluent and filled into a hard gelatin capsule; or mini-tablets comprising the co-granulate above may be filled into a hard gelatin capsule; or the co-granulate as described above can be mixed an oil medium and filled into soft gelatin capsules.
  • Aqueous suspensions may contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent such as sodium carboxymethyl
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, sucralose or saccharin.
  • preservatives such as ethyl or n-propyl p- hydroxybenzoate
  • coloring agents such as a coloring agent
  • flavoring agents such as sucrose, sucralose or saccharin.
  • sweetening agents such as sucrose, sucralose or saccharin.
  • the co-granulate as described above can be mixed with the foregoing excipients suitable for the manufacture of aqueous suspensions.
  • Oil suspensions may be formulated by suspending the active ingredient in a liquid carrier such as a vegetable oil, including arachis oil, olive oil, sesame oil or coconut oil; or in a mineral oil such as liquid paraffin.
  • a liquid carrier such as a vegetable oil, including arachis oil, olive oil, sesame oil or coconut oil; or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain an antioxidant, an antimicrobial preservative agent, and/or a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an antioxidant such as ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, citric acid, sodium ascorbate, ascorbyl palmitate, malic acid, or tocopherol.
  • an antioxidant such as ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, citric acid, sodium ascorbate, ascorbyl palmitate, malic acid, or tocopherol.
  • additional antimicrobial agents such as benzyl alcohol, benzalkonium chloride, benzoic acid, boric acid, methylparaben, methylparaben sodium, ethylparaben, ethylparaben sodium, propylparaben, propylparaben sodium, propylene glycol, potassium benzoate, potassium sorbate, sodium benzoate, sodium sulfite, sorbic acid, thymol, or mixtures thereof may be added.
  • the co-granulate as described above can be mixed with a vegetable oil ora mineral oil for the manufacture of an oral suspensions.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water, can provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent e.g., a suspending agent
  • a preservative e.g., a preservative for suspending aqueous suspension
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the co-granulate as described above can be mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • Fixed-dose combinations may offer patients greater freedom from multiple dosage medication regimens and ease the needed diligence required in remembering and complying with complex daily dosing times and schedules.
  • the desired daily regimen may be presented in a single dose or as two or more sub-doses per day.
  • Segregation of active ingredients in pharmaceutical powders and granulations is a widely recognized problem that can result in inconsistent dispersions of the active ingredients in final dosage forms.
  • Some of the main factors contributing to segregation are particle size, shape and density. Segregation is particularly troublesome when attempting to formulate a single homogenous tablet containing multiple active ingredients having different densities and different particle sizes.
  • compositions may be administered to a human or other mammal in a safe and therapeutically effective amount as described herein.
  • safe and therapeutically effective amounts will vary according to the type and size of mammal being treated and the desired results of the treatment.
  • a “therapeutically effective amount” is an amount effective for treating a recited disease or condition, such as, tuberculosis.
  • treating refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder.
  • the number of unit dosages of the compositions (e.g., tablets or capsules or amount of oral suspension) administered to the person typically comprises a therapeutically effective amount of pretomanid, moxifloxacin, pyrazinamide, and optionally bedaquiline, or pharmaceutically acceptable salt and/or solvate thereof.
  • a therapeutically effective amount of pretomanid, moxifloxacin, pyrazinamide, and optionally bedaquiline, or pharmaceutically acceptable salt and/or solvate thereof for example, when treating tuberculosis, sputum samples or chest x-rays may be monitored to show improvement and/or amelioration of the disease.
  • the tuberculosis is drug-sensitive tuberculosis (DS-TB), multidrug- resistant tuberculosis (MDR-TB), or extensively drug-resistant tuberculosis (XDR-TB).
  • DS-TB drug-sensitive tuberculosis
  • MDR-TB multidrug- resistant tuberculosis
  • XDR-TB extensively drug-resistant tuberculosis
  • the tuberculosis is drug-sensitive tuberculosis (DS-TB).
  • DS-TB refers to TB which is not resistant to any of the TB drugs; in certain embodiments, the DS-TB is tuberculosis that is caused by a bacteria that is sensitive to rifampicin (RIF) and isoniazid (INH), as identified, for example, by rapid molecular sputum-based test.
  • RAF rifampicin
  • IH isoniazid
  • the pharmaceutical composition of the present disclosure can be used for the treatment of multi-drug resistant tuberculosis (MDR-TB).
  • MDR-TB refers to TB caused by a bacteria resistant to isoniazid (INH) and rifampin (RIF).
  • the pharmaceutical composition of the present disclosure can be used for the treatment of extensively-drug resistant tuberculosis (XDR-TB).
  • XDR-TB refers to a rare type of MDR- TB that is caused by a bacteria that is resistant to INH and RIF, and is additionally resistant to any fluoroquinolone, such as ciprofloxacin, levofloxacin, ofloxacin, or sparfloxacin, and at least one of three injectable second-line drugs, such as amikacin, kanamycin, or capreomycin.
  • a person in need of treatment herein refers to a patient diagnosed with tuberculosis according to methods familiar to those skilled in the art, including patients having a sputum positive for Mycobacterium tuberculosis (M.tb) bacilli (at least 1+ on the International Union against Tuberculosis and Lung Disease [IUATLD]/WHO scale on smear microscopy), or having diagnosed pulmonary TB based on a chest x-ray.
  • M.tb Mycobacterium tuberculosis
  • IUATLD International Union against Tuberculosis and Lung Disease
  • any of the various methods known by persons skilled in the art for packaging tablets, caplets, or other solid dosage forms suitable for oral administration, that will not degrade the components of the present formulations, are suitable for use in packaging.
  • the combinations may be packaged in glass and plastic bottles.
  • Tablets, caplets, or other solid dosage forms suitable for oral administration may be packaged and contained in various packaging materials optionally including a desiccant e.g. silica gel.
  • Packaging may be in the form of unit dose blister packaging.
  • the package may contain a blister tray of the co-formulated combination of pretomanid, pyrazinamide, and moxifloxacin (and optionally, bedaquiline) in a single pill, tablet, caplet or capsule.
  • the packaging material may also have labeling and information related to the pharmaceutical composition printed thereon.
  • an article of manufacture may contain a brochure, report, notice, pamphlet, or leaflet containing product information. This form of pharmaceutical information is referred to in the pharmaceutical industry as a "package insert.”
  • a package insert may be attached to or included with a pharmaceutical article of manufacture.
  • the package insert and any article of manufacture labeling provides information relating to the pharmaceutical composition.
  • the information and labeling provides various forms of information utilized by health-care professionals and patients, describing the composition, its dosage and various other parameters required by regulatory agencies such as the United States Food and Drug Agency.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, cellulose ether derivatives (e.g., hydroxypropyl methylcellulose) or methacrylate derivatives in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • cellulose ether derivatives e.g., hydroxypropyl methylcellulose
  • methacrylate derivatives in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • the manufacturing of the PaMZ FDC inter-granules is far less stringent and thus allows for a wider range of %water uptake for the manufacturing of the inter-granules.
  • Tablet compression can be carried out on a rotary tablet press fitted with suitable tooling, for example, 19.0 mm x 9.0 mm capsule shaped, normal biconcave tooling. The usual in process controls of tablet weight, thickness, hardness, friability and disintegration time are monitored during the compression process.
  • the dosage forms herein may optionally be coated with one or more materials suitable for the regulation of release, for the protection of the formulation or for aesthetic purposes.
  • the tablets are aqueous film coated using a commercially supplied coating material, OPADRY from Colorcon, in a perforated drum type of coating pan, such as the Neocota from Neo Machines.
  • coatings are provided to permit either pH-dependent or pH- independent release.
  • a pH-dependent coating serves to release the active in desired areas of the gastro intestinal (Gl) tract, e.g., the stomach or small intestine, such that an absorption profile is provided which is capable of providing, for example, at least about eight hours and preferably about twelve hours to up to about twenty-four hours of drug release to a patient.
  • Formulations that utilize pH-dependent coatings may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract.
  • Coatings which are pH-dependent may be used, including shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.
  • Example 1 PaMZ Manufacturing Process A flow diagram of the manufacturing process for the PaMZ FDCs is shown in Figure 1. Given the absence of incompatibility between any of the components, a simple mixing and wet granulation process was employed to prepare the compression mix. Batch size and equipment availability necessitated the wet granulation step to be conducted in two sub-lots which were subsequently blended together after the dry milling step. All subsequent steps were carried out as a single batch process.
  • the materials for the intragranular dry powder mix were first screened through an appropriate size mesh into the bowl of a mixer-granulator where they are dry mixed using both mixer and impeller blades.
  • the flow chart of Figure 1 shows the alternative disintegrants and surfactants used to prepare FDC Formulations A and B: sodium starch glycolate and poloxamer 188 for FDC Formulation A and crospovidone and sodium lauryl sulfate for FDC Formulation B.
  • the granulating solution was prepared using povidone as the binder with the surfactant appropriate to the formulation being made, as indicated above. After dry mixing, the binder solution was added to the moving powder bed in the mixergranulator.
  • the granules were dried to a moisture content of not more than 2% w/w and then dry milled (again using a Co-Mil or similar) prior to blending with extragranular excipients.
  • the two sub-lots from the granulation process were combined at this point into a single lot for all the subsequent processing steps.
  • the appropriate disintegrant and colloidal silicon dioxide were added to the granules and blended in a double cone blender, or similar equipment, and then the lubricant, magnesium stearate, was blended to create the final compression blend.
  • Example 3 PaMZ Dissolution Comparison Examination of the dissolution rate for pretomanid API from pretomanid 200-mg tablets versus FDC Formulations A and B was performed. Comparison Table 3 provides the full dissolution profile for the pretomanid tablets (see, Table 4), PaMZ Formulation A, and PaMZ Formulation B. Dissolution of pretomanid from each of the preceding were measured with a USP-II (paddle) apparatus at 75 rpm and 37 °C+/-0.5 °c in 1000 mL of 0.1N HCI containing 0.5% hexadecyltrimethylammonium bromide (HDTMA).
  • USP-II paddle
  • the recently approved pretomanid 200 mg tablet formulation includes 25.0% active [200 mg] and 75.0% inactive inert excipients [600 mg].
  • Marketed moxifloxacin 400 mg tablets have formulations that consist of 64.9% active (400 mg) and 35.1% inactive inert excipients (216.5 mg).
  • marketed pyrazinamide 500 mg tablets tend to have a high active to inactive ratio (88.3% active [500.0 mg] and 11.7% inactive [66.0 mg]).
  • the amount of inert excipients required to dose one pretomanid tablet, one moxifloxacin tablet, and three pyrazinamide tablets is high and may be reduced when in a FDC tablet formulation.
  • the qualitative and quantitative composition for the PaMZ FDC formulations A and B are detailed in Tables 1 and 2.
  • the percentile ratio of actives to inactive excipients in the FDCs are 73.2% (700.0 mg) to 26.8% (256.0 mg) for Formulation A and 68.3% (700.0 mg) to 31.7% (324.3 mg).
  • Table 5 has been prepared to more easily discern and cross-compare the amount of inactive excipients PaMZ FDCs vs the 5 tablets (1 pretomanid tablet, 1 moxifloxacin tablet, and 3 pyrazinamide tablets).
  • the Formulation A and B have a 24.3% and 4.1% reduction of overall inactive components.
  • the PaMZ FDCs could be reduced in size to allow patients to comfortably ingest, for example, a 3-pill daily dose. Moreover, with the reduction of excipients, this will allow patients with other aliments requiring large daily dosing (e.g. HIV) to ingest their other medications with decreased unneeded excipients.
  • FDC Formulations A and B were measured under long-term (25 °C ⁇ 2 °C/60 % RH ⁇ 5 % RH) and accelerated (40 °C ⁇ 2 °C/75 % RH ⁇ 5%) conditions as detailed in Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products, in lots of 30 tablets sealed in HDPE bottles with a child-resistant closure.
  • API assay results for Pa, M, and Z, individually, are described in Tables 6 and 7. Total impurities measured during the course of the testing are provided in Table 8. Total impurities are reported as the sum of the impurities identified with each API assay.
  • A Dissolve 1.36 g potassium dihydrogen phosphate in 1000 mL HPLC grade water. Add 2.0 mL triethylamine and adjust pH of solution to 3.0 with orthophosphoric acid. Filter through 0.45 micron filter.
  • Bedaquiline is used in a milled form with a controlled particle size. It is non-hygroscopic and is relatively insoluble in aqueous media, not dissimilar to pretomanid. In the solid state it shows good stability, with no significant changes detected after storage for up to 6 months at 40 9 C and 75% relative humidity. It is, however, prone to degradation upon exposure to light.
  • FIG. 2 A flow diagram of the manufacturing process for the BPaMZ FDCs is shown Figure 2. As shown therein, all active materials are blended together to produce a "single" active material. Excipients are added and a uniform co-granulate is made analogous to the process. A film coat from aqueous solution using appropriate OPADRY coating can also be applied.
  • Example 9 BPaMZ Formulation C Using the procedure outlined in Example 6, the following formulation can be made:
  • a fixed-dose pharmaceutical dosage form comprising a therapeutically effective amount of each of pretomanid, moxifloxacin and pyrazinamide and, optionally, at least one other antibacterial agent, or a pharmaceutically acceptable salt individually thereof, and a pharmaceutically acceptable carrier.
  • a method for the treatment of tuberculosis comprising the step of administering to a patient in need thereof the fixed-dose pharmaceutical dosage form according to any one of paragraphs 1-7.
  • bedaquiline is in an amount of 10 to 400 mg
  • pretomanid is in an amount of 10 to 400 mg
  • moxifloxacin is in an amount of 10 to 800 mg
  • pyrazinamide is in an amount of 50 to 2000 mg.
  • a fixed-dose pharmaceutical dosage form comprising a therapeutically effective amount of each of bedaquiline, pretomanid, moxifloxacin and pyrazinamide, or a pharmaceutically acceptable salt individually thereof, and a 30 pharmaceutically acceptable carrier.
  • bedaquiline is in an amount of 10 to 400 mg
  • pretomanid is in an amount of 10 to 400 mg
  • moxifloxacin is in an amount of 10 to 800 mg
  • pyrazinamide is in an amount of 50 to 2000 mg.
  • bedaquiline or salt thereof is in an amount equivalent to about 50 mg or 100 mg bedaquiline free base
  • pretomanid is in an amount of about 100 mg
  • moxifloxacin or salt thereof is in an amount equivalent to about 200 mg moxifloxacin free base
  • pyrazinamide is in an amount of about 750 mg.
  • bedaquiline or salt thereof is in an amount equivalent to about 33.3 mg or 66.7 mg bedaquiline free base
  • pretomanid is in an amount of about 66.7 mg
  • moxifloxacin or salt thereof is in an amount equivalent to about 133.3 mg moxifloxacin free base
  • pyrazinamide is in an amount about 500 mg.
  • bedaquiline or salt thereof is in an amount equivalent to about 25 mg or 50 mg bedaquiline free base
  • pretomanid is in an amount of about 50 mg
  • moxifloxacin or salt thereof is in an amount equivalent to about 100 mg moxifloxacin free base
  • pyrazinamide is in an amount about 375 mg.
  • a co-granulate comprising a binder; one or more intragranular excipients; and a total of about 40 wt.% to 90 wt.% of active pharmaceutical ingredients (APIs), wherein the APIs comprise a mixture of pretomanid, moxifloxacin, and pyrazinamide, or a pharmaceutically acceptable salt and/or solvate thereof.
  • APIs active pharmaceutical ingredients
  • the co-granulate of claim 17, comprising about 0.1 to 10 wt.% of the binder.
  • the co-granulate of claim 17, comprising about 0.5 to 5 wt.% of the binder.
  • the co-granulate of claim 17, comprising about 1 to 3 wt.% of the binder.
  • 21. The co-granulate of any one of claims 17-20, wherein the binder comprises pre-gelatinized starch, povidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose or a mixture thereof.
  • the co-granulate of claim 23, comprising about 10 wt.% to about 30 wt.% of intragranular excipients.
  • the co-granulate of claim 23, comprising about 15 wt.% to about 25 wt.% of intragranular excipients.
  • any one of claims 23-25, wherein the intragranular excipients are one or more independently selected from the group consisting of a surfactant, a diluent, a disintegrant, a glidant, a lubricant, a coloring agent, a sweetener, and a flavoring.
  • the co-granulate of claim 27, comprising about 5 - 10 wt. % of the diluent.
  • the diluent comprises an inorganic filler, a monosaccharide, a disaccharide, a polysaccharides, a sugar alcohol, a cellulose, or a mixture thereof.
  • the diluent comprises dibasic calcium phosphate, tribasic calcium phosphate, lactose, maltose, sucrose, trehalose, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, microcrystalline cellulose, or a mixture thereof.
  • the co-granulate of claim 27, comprising about 1 - 10 wt. % of the disintegrant.
  • the co-granulate of claim 33 comprising about 3 - 10 wt. % of the disintegrant.
  • the co-granulate of claim 34 comprising about 4 - 8 wt. % of the disintegrant.
  • the disintegrant comprises carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, sodium starch glycolate, corn starch, or a mixture thereof.
  • the disintegrant comprises a starch, sodium starch glycolate, crospovidone, or a mixture thereof.
  • the co-granulate of claim 27, comprising about 0.1 - 5 wt.% of the surfactant.
  • the co-granulate of claim 38 comprising about 0.1 - 3 wt.% of the surfactant.
  • the co-granulate of claim 38 comprising about 0.3 - 2 wt.% of the surfactant.
  • the surfactant comprises a fatty acid glyceride, a sorbitan ester, an ethoxylated fatty acid, an ethoxylated hydrogenated vegetable oil, an ethoxylated sorbitan ester, a polyoxamer, a quaternary ammonium salt, an alkyl sulfate, a sulfosuccinate diester, an alkylbenzene sulfonate, a sulfated ethoxylated fatty alcohol, or a mixture thereof.
  • the co-granulate of claim 43 comprising about a total of about 75 wt.% to 85 wt.% of the
  • a tablet comprising the co-granulate of any one of claims 17-47.
  • the tablet of claim 48 further comprising one or more extragranular excipients.
  • the tablet of claim 49 comprising about 70 - 90 wt.% of the cogranulate and about 10 -30 wt.% of the one or more extragranular excipients.
  • the tablet of any one of claims 48 - 51 further comprising a coating layer over an outer surface of the tablet.
  • a capsule comprising the co-granulate of any one of claims 17-47.
  • the oral suspension of claims 54 comprising a pharmaceutically acceptable liquid carrier.
  • the oral suspension of claim 55 further comprising one or more of an antioxidant, an antimicrobial preservative agent, a thickening agent, a sweetener, and a flavoring.
  • a process for preparing a co-granulate comprising, granulating a first mixture comprising pretomanid, moxifloxacin, pyrazinamide, a binder, and one or more intragranular excipients to provide the co-granulate.
  • the binder comprises pre-gelatinized starch, anhydrous lactose, dibasic calcium phosphate, or a mixture thereof.
  • a process for preparing a tablet comprising combining a co-granulate according to any one of claims 17-47 with one or more extragranular excipients to provide a blend; and compressing a portion of the blend into a tablet.
  • a method for treating tuberculosis comprising administering one or more tablets of any one of claims 48-52 or one or more capsules according to claim 53 or an oral suspension of any one of claims 54 - 56 to a person in need of such treatment, wherein the number or tablets or capsules or amount of oral suspension administered to the person comprises a therapeutically effective amount of pretomanid, moxifloxacin, pyrazinamide, and optionally bedaquiline, or pharmaceutically acceptable salt and/or solvate thereof.

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Abstract

Fixed-dose pharmaceutical dosage form are described that may be useful in methods for the treatment of tuberculosis.

Description

COMBINATION ANTIBACTERIAL COMPOSITION AND METHOD FOR ANTIBACTERIAL THERAPY
CROSS REFERENCE TO RELATED APPLICATION(S)
The present application claims priority to Indian Patent Application No. 202041025104, filed on June 15, 2020, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
Combinations of compounds, such as fixed-dose combinations, are described having antibacterial activity for the treatment of tuberculosis.
BACKGROUND OF THE INVENTION
Mycobacterium tuberculosis is the causative agent of tuberculosis ("TB"), a devastating infectious disease. It is estimated that about 2 million TB patients die each year globally. Failure to properly treat tuberculosis has caused global drug resistance in mycobacterium tuberculosis and thus rendering some medications ineffective.
Current TB treatments include multi-tablet, monotherapeutic administration of chemically diverse antibacterial agents. Such administration, however, involves a plurality of tablets a day which can be costly and raise patient non-compliance issues. A need exists in the art for pharmaceutical compositions of active antibacterial agents in combination, such as a fixed-dose tableted form, that provides advantages over the individual monotherapies currently used in the art.
SUMMARY OF THE INVENTION
The present disclosure describes fixed-dose pharmaceutical dosage forms comprising a therapeutically effective amount of each of pretomanid, moxifloxacin and pyrazinamide and, optionally, at least one other active ingredient, or a pharmaceutically acceptable salt individually thereof, and a pharmaceutically acceptable carrier. The disclosure also describes methods for treating tuberculosis comprising the step of administering said fixed-dose pharmaceutical dosage form to a patient in need thereof.
In another aspect, co-granulates are described comprising a binder; one or more intragranular excipients; and a total of about 60 wt.% to 95 wt.% of active pharmaceutical ingredients (APIs), wherein the APIs comprise a mixture of pretomanid, moxifloxacin, and pyrazinamide, or a pharmaceutically acceptable salt and/or solvate thereof. Tablets, capsules, and oral suspensions, among other dosage forms may be prepared using the granulate herein. In another aspect, a process for preparing a co-granulate is provided comprising, granulating a first mixture comprising pretomanid, moxifloxacin, pyrazinamide, a binder, and one or more intragranular excipients to provide the co-granulate.
In another aspect, a process for preparing a tablet is provided comprising combining a co- granulate described herein with one or more extragranular excipients to provide a blend; and compressing a portion of the blend into a tablet.
In yet another aspect, a method for treating tuberculosis is provided comprising administering one or more dosage forms described herein a person in need of such treatment, wherein the dosage form(s) as administered to the person comprises a therapeutically effective amount of pretomanid, moxifloxacin, pyrazinamide, and optionally bedaquiline, or pharmaceutically acceptable salt and/or solvate thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows a flow diagram of the manufacturing process for an exemplary fixed dose combination (FDC) formulation containing a co-granulate of pretomanid, moxifloxacin, and pyrazinamide (PaMZ).
Figure 2 shows a flow diagram of the manufacturing process for an exemplary fixed dose combination (FDC) formulation containing a co-granulate of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ).
Figure 3 is a graph comparing the dissolution of pretomanid as a function of time for three pretomanid-containing formulations; diamonds, PaMZ Formulation A (Table 1); triangles, PaMZ Formulation B (Table 2); and pretomanid tablets, 200 mg (Table 4).
DETAILED DESCRIPTION OF THE INVENTION
The present disclosure generally relates to a fixed-dose combination of pretomanid, moxifloxacin and pyrazinamide as active ingredients and optionally a fourth active ingredient such as, for example, bedaquiline. In certain embodiments, the fixed-dose combination comprises a granulate comprising pretomanid, moxifloxacin, and pyrazinamide, and optionally, bedaquiline.
The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. The combinations herein may conveniently be presented as a pharmaceutical formulation in a unitary dosage form.
Active Ingredients The pharmaceutically active compounds and combinations thereof herein may be referred to as "active ingredients", "API" or "pharmaceutically active agents."
Pretomanid (also known as "Pa" or "PA-824") is a novel nitroimidazole anti-bacterial agent recently approved by the U.S. FDA as a TB therapy, and having many attractive characteristics - most notably its novel mechanism of action, its activity in vitro against all tested drug-resistant clinical isolates, and its activity as both a potent bactericidal and a sterilizing agent. In addition, the compound shows no evidence of mutagenicity in a standard battery of genotoxicity studies, no significant cytochrome P450 interactions, and no significant activity against a broad range of Gram-positive and Gram-negative bacteria. The lUPAC designation for pretomanid is (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7- dihydro-5H-imidazo[2,l-b][l,3]oxazine. Pretomanid has the following structure:
Figure imgf000005_0001
Moxifloxacin (l-cyclopropyl-7-[(lS,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl]-6-fluoro-8-methoxy-4- oxoquinoline-3-carboxylic acid, also referred herein as "M") is a synthetic fluoroquinolone antibacterial agent developed by Bayer AG (initially called BAY 12-8039). It is marketed worldwide (as the hydrochloride salt, often as the monohydrate of the hydrochloride salt) under the brand names AVELOX, AVALOX and AVELON for oral treatment. Herein, unless otherwise noted, "moxifloxacin" refers to the free base as well as a pharmaceutically acceptable salt and/or solvate thereof, such as moxifloxacin hydrochloride and/or moxifloxacin hydrochloride monohydrate.
"Solvate" as used herein refers to a complex of variable, but defined, stoichiometry formed by a solute (the referenced compound) and a solvent. Solvates should be understood not to include solid forms of a reference compound containing sub stoichiometric amounts of residual solvents. Solvents, by way of example, include water (such can be referred to as a "hydrate"), methanol, ethanol, isopropyl alcohol, ethyl acetate, ethylene glycol, propylene glycol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and acetic acid, among others. The phrase "salt and/or solvate" refers to each of a salt (e.g., moxifloxacin hydrochloride), a solvate, and a solvate of a salt (e.g., moxifloxacin hydrochloride monohydrate).
Pyrazinamide (pyrazine-2-carboxamide, also referred herein as "Z") is the pyrazine analogue of nicotinamide and used as an anti-tuberculous agent. Pyrazinamide is most commonly used for treatment of active tuberculosis (TB) during the initial phase of therapy (generally the first two months of treatment), in combination with other agents. Pyrazinamide demonstrates clinically significant antibacterial activity against Mycobacterium tuberculosis and M. africanum.
Bedaquiline ((aS^R)-6-Bromo-a-[2-(dimethylamino)ethyl]-2-methoxy-a-l-naphthalenyl^- phenyl-3-quinolineethanol; also known herein as "B") is a diarylquinoline antimycobacterial drug having the formula:
Figure imgf000006_0001
Bedaquiline is marketed as SIRTURO” and specifically inhibits mycobacterial ATP (adenosine 5'- triphosphate) synthase, by binding to subunit c of the enzyme that is essential for the generation of energy in Mycobacterium tuberculosis. Herein, unless otherwise noted, "bedaquiline" refers to the free base as well as a pharmaceutically acceptable salt and/or solvate thereof, such as bedaquiline fumarate.
Each of the APIs in the present dosage forms may be present in any suitable polymorphic form and/or any suitable solvate thereof.
As noted, reference any of the active compounds in the compositions herein also includes any physiologically acceptable salt thereof. Examples of physiologically acceptable salts and their physiologically functional derivatives include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4 + (wherein X is Ci-C4alkyl), or an organic acid such as fumaric acid, acetic acid, succinic acid. Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NX4 + (wherein X is independently selected from H or a Ci-C4alkyl group). "Alkyl" as used herein refers to a univalent group derived from a linear or branched alkane by removal of a hydrogen atom from any carbon atom (-CnH2n+i). Examples of alkyl groups include, but are not limited to, methyl, ethyl, isopropyl, sec-butyl, and n-butyl.
The amount of each active ingredient that may produce a single dosage form may vary depending upon the host treated and the particular mode of administration. A convenient unitary dosage formulation may contain each of the active ingredients in any amount from 1 mg to 1 g each, for example but not limited to, 10 mg to 500 mg for each active ingredient. Daily dosages of the active ingredients in such an embodiment can be as follows:
Figure imgf000007_0001
In certain embodiments, the daily dosages of the active ingredients can be as follows:
Figure imgf000007_0002
Fixed Dose Combinations
Fixed dose combinations (FDC) offer several advantages over monotherapy used in the art. Some advantages of FDC administration include:
• enhancing patient compliance that ultimately improves treatment outcomes;
• reducing inadvertent medication errors and total tablet burden upon administration;
• preventing and/or slowing antimicrobial resistance by eliminating potentially ineffective monotherapy administration;
• reducing drug shortages by not having to obtain multiple drug products from separate organizations;
• simplifying expiry date compliance (single products tend to have different expiry dates);
• simplifying procurement, management, and handling of drugs; and
• lowering production, packing, and shipping costs.
Pretomanid is a BCS class ll/IV compound that demonstrates poor solubility but high permeability which can result in solubility-limited absorption. Formulations of BCS class ll/IV can contain a large proportion of inactive ingredients to aid in the dispersion and dissolution of the drug. For example, the total weight of recently approved pretomanid 200 mg tablets is 800 mg. Dissolution is essential for a drug before it can be absorbed systemically and provide the desired therapeutic response.
An excipient drug compatibility study was conducted to select an appropriate formulation (e.g., tablet) type. It was surprisingly discovered that the Pa, M and Z could be blended together without affecting the chemical stability of each other. It was even more surprisingly discovered that pyrazinamide and moxifloxacin aided the dissolution of Pa. Therefore, the amount of inert excipients required was greatly reduced without negatively affecting dissolution. It is contemplated that the addition of bedaquiline to Pa, M and Z would have a comparable compatibility. The term "chemical stability" or "chemically stable" means that the three antibacterial agents in combination are substantially stable to chemical degradation. In one embodiment, "chemical stability" or "chemically stable" means that a formulation described herein shows no "significant change" upon storage under at least one of the following storage conditions:
Figure imgf000008_0001
"Significant change" for a drug product (e.g., formulation) herein, means either 5 percent change in a drug substance (API) assay from its initial value or any degradation product exceeding 1 wt.% at the termination of the time period. The FDCs may be formulated in a unit dosage formulation comprising a fixed amount of each active pharmaceutical ingredient for a periodic, e.g. daily, dose or sub-dose of the active ingredients. In certain embodiments, a total daily dose of Pa, M and Z can be included in more than one unit dosage that could be ingested comfortably. For example, the total daily dose of each active agent may be equally divided among two or more unit dosages to facilitate daily dosing. In another embodiment, the total daily dose of each active agent is equally divided among two to six unit dosages, or two to five unit dosages, or two to four unit dosages, or two, or three, or four, or five, or six unit dosage. In each instance, the plurality of unit dosages comprising the total daily dose can be administered together simultaneously or sequentially to provide the total daily dose to the patient in need thereof.
In several examples, a total daily dose of 200 mg Pa, 400 mg M, 1500 mg Z and optionally, 200 mg or 100 mg B, may be equally divided among several unit dosages according to any one of the following embodiments:
Figure imgf000008_0002
Figure imgf000009_0001
The several unit doses noted above may be administered together to a person in need thereof to provide the total daily dose. In one embodiment, each of the three unit dosages can contain 80.6 mg of bedaquiline fumarate, 152 mg of moxifloxacin hydrochloride monohydrate, 66.7 mg of pretomanid and 500 mg of pyrazinamide as active ingredients.
Pharmaceutical formulations herein comprise a co-granulate of Pa, M, Z, and optionally B, together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredients may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, hard or soft capsules, syrups or elixirs may be prepared (see, for example, Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.)).
In certain embodiments, the FDCs described herein can encompass solid dosage forms such as monolithic tablets, multi-layer tablets, and combinations thereof. A monolithic approach involves an intimate contact between two or more of the different APIs (active pharmaceutical ingredients), such as by blending and/or granulating the different APIs together.
A combination approach may include, for example, a bilayer tablet where one layer comprises the co-granulate of Pa, M, and Z while the second layer contains bedaquiline or a pharmaceutically acceptable salt thereof.
A combination approach may also include, for example, a monolithic tablet containing the co granulate that includes Pa, M, and Z along with intragranular excipients, as discussed herein, which is blended with an extragranular phase that may include bedaquiline or a pharmaceutically acceptable salt thereof along with extragranular excipients, as discussed herein.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including antioxidants, sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient or auxiliary agents which are suitable for manufacture of tablets are acceptable.
In certain embodiments, the several dosage forms herein may be produced from a co-granulation of at least Pa, M and Z in a single phase (monolithic) granulate (e.g., the co-granulate). In one embodiment, a granulate is provided comprising a binder; one or more intragranular excipients; and a total of about 60 wt.% to 95 wt.% of active pharmaceutical ingredients (APIs), wherein the APIs comprise a mixture of pretomanid, moxifloxacin, and pyrazinamide, or a pharmaceutically acceptable salt and/or solvate thereof.
In various embodiments, the co-granulate comprise about 40 - 90 wt.% of the APIs (i.e., the sum of all APIs present in the co-granulate); or about 60-90 wt.%; about 70 - 90 wt.%; or about 75 - 85 wt.% or about 80-90 wt.% of the co-granulate.
The binder may be present in about 0.1 - 10 wt.% or 0.5 -5 wt.% or 1 - 3 wt.% of the co-granulate. The sum of all intragranular excipients may comprise about 10 - 60 wt.% or 10 - 40 wt.% or 10 -30 wt. % or 15- 25 wt. % or 10 -20 wt.% of the co-granulate. In any of the preceding embodiments, the intragranular excipients may comprise one or more independently selected from the group consisting of a surfactant, a diluent, a disintegrant, a glidant, a lubricant, a coloring agent, a sweetener, and a flavoring. In particular, the intragranular excipients may comprise a diluent, a disintegrant, and a surfactant. The diluent may be present at about 5 -15 wt. % or about 5 - 10 wt. % of the co-granulate. The disintegrant may be present at about 1 - 10 wt. % or about 3 - 10 wt. % or about 4 - 8 wt. % of the co-granulate. The surfactant may be present at about 0.1 - 5 wt.% or about 0.1 - 3 wt.% or about 0.3 - 2 wt.% of the co-granulate.
Diluents can include pharmaceutically acceptable inert fillers such as, but are not limited to, inorganic fillers such as calcium carbonate, dibasic calcium phosphate(such as anhydrous or dihydrate forms, e.g., Emcompress® Calcium Phosphates (JRS PHARMA GmbH & Co. KG, Rosenberg, Germany), tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium chloride, talc, and clays (such as kaolin and bentonite); monosaccharides, disaccharides, and polysaccharides such corn syrup, corn syrup solids, dextrin, maltodextrin, polydextrose, dextrose, fructose, invert sugar, isomalt, lactose, (e.g., anhydrous, monohydrate, and/or spray-dried forms such as PHARMATOSE DCL21 (Universal Preserv-A-Chem Inc., Somerset NJ)), maltose, pullulan, sucrose, trehalose, and combinations thereof, such as dextrates (e.g., EMDEX® from JRS Pharma LP, USA, Patterson, NY; a combination of glucose monohydrate and polysaccharides derived from starch); sugar alcohols such as erythritol, lactitol, maltitol, mannitol (e.g., Pearlitol® SD 200 (Roquette Freres SA, Lestrem, France)), sorbitol, and xylitol; celluloses and modified celluloses such as, microcrystalline cellulose (e.g., Avicel® PH 101, Avicel® PH 102, Avicel® PH 112, Avicel® PH 200, Avicel® PH 301, and Avicel® PH 302; CEOLUS KG-1000, CEOLUS KG-802, CELOLUS UF-702 (Asahi Kasei, Tokyo, Japan)), silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, and cellaburate; and mixtures of the foregoing.
In one embodiment, the diluent may comprise an inorganic filler, a monosaccharide, a disaccharide, a polysaccharides, a sugar alcohol, a cellulose, ora mixture thereof. For example, the diluent may comprise dibasic calcium phosphate, tribasic calcium phosphate, lactose, maltose, sucrose, trehalose, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, microcrystalline cellulose, or a mixture thereof. In another embodiment, the diluent may comprise lactose, microcrystalline cellulose, or a mixture thereof. In certain embodiments, an intragranular excipient that is a diluent can be microcrystalline cellulose. Binders include pharmaceutically acceptable agents that can hold various ingredients together in a cohesive mix, for example, to hold together an active pharmaceutical ingredient and inactive ingredients. Examples of suitable binders include, but are not limited to, dry binders such as partially pre gelatinized starch (e.g., UNI-PURE® DW partially pre-gelatinized maize starch, National Starch & Chemical); anhydrous lactose, and dibasic calcium phosphate dehydrate; and wet binders such as pre gelatinized starch, povidone (e.g. Povidone K-30 USP/Kollidon® 30, BASF, Ludwigshafen, Germany); methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose; and mixtures thereof.
Disintegrants include pharmaceutically acceptable agents that can promote disintegration of a dosage form, including, but not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, powdered cellulose, croscarmellose sodium, crospovidone, guar gum, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, maltose, trehalose, methylcellulose, polacrilin potassium, pullulan, colloidal silicon dioxide, sodium alginate, sodium starch glycolate; a starch such as pregelatinized modified starch, corn starch, hydroxypropyl corn starch, pregelatinized hydroxypropyl corn starch, pea starch, hydroxypropyl pea starch, pregelatinized hydroxypropyl pea starch, potato starch, hydroxypropyl potato starch, pregelatinized hydroxypropyl potato starch, tapioca starch, or wheat starch; and mixtures thereof.
In one embodiment, the disintegrant may comprise carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, sodium starch glycolate, corn starch, or a mixture thereof. In another embodiment, the disintegrant may comprise a starch (e.g., corn starch), sodium starch glycolate, crospovidone, or a mixture thereof.
Surfactants may include amphoteric, non-ionic, cationic, and/or anionic surfactants. Examples of amphoteric surfactants include, but are not limited to, lecithin, cocamidopropyl betaine, lauryldimethylamine oxide, myristamine oxide, coco amino propionate (SERVO AM 1010 Elementis Specialties, Delden, The Netherlands), sodium lauryl imino dipropionate (SERVO AM 1020), sodium octyl imino dipropionate (SERVO AM 2020), sodium coco imino mono/dipropionate (SERVO AM 1015), oleyldimethylbetaine, and sodium N-cocoamidethyl N-hydroxyethylglycine, and mixtures thereof.
Examples of non-ionic surfactants include, but are not limited to, alkylphenols, such as 4-(2,4- dimethylheptan-3-yl)phenol; fatty acid glycerides such as glyceryl dibehenate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, and glyceryl tristearate; sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate, sorbitan sesqueoleate, sorbitan trioleate, and sorbitan tristearate; ethoxylated fatty acids such as stearic acid ethoxylate and lauric acid ethoxylate; ethoxylated fatty alcohols such as polyoxyethylene lauryl ethers (Brij); ethoxylated alkylphenols such as nonylphenol ethoxylate and ethoxylated p-tert-octylphenol; ethoxylated hydrogenated vegetable oils such as polyoxyl 35 castor oil (Cremophor EL) and hydrogenated polyoxyl 40 castor oil (Cremophor RH 40); ethoxylated sorbitan esters such as polyoxyethylene sorbitan monolaurate (polysorbate 20), polyoxyethylene sorbitan monopalmitate (polysorbate 40), polyoxyethylene sorbitan monostearate (polysorbate 60), polyoxyethylene sorbitan monooleate (polysorbate 80); ethoxylated fatty acid amides such as cocoamide monoethanolamine and cocamide diethanolamine; and block copolymers of polyoxypropylene (polypropylene oxide)) and polyoxyethylene (poly(ethylene oxide), including polyoxamers (nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene polypthylene oxide)), such as polyoxamer 188/Kolliphor® P188, polyoxamer 407/Kolliphor® P407, BASF); maltosides such as n- dodecyl^-D-maltoside; glucamides such as octanoyl-N-methylglucamide, decanoyl-N-methylglucamide and heptanoyl-N-methylglucamide; pyranosides such as n-hexyl^-D-glucopyranoside, n-decyl-b-O- glucopyranoside, n-octyl^-D-glucopyranoside; thioglucosides such as n-heptyl^-D-thioglucoside; p- isononylphenoxypoly(glycidol), also known as Olin 10-G or 10-GR surfactant (Olin Chemicals, Stamford, Conn.); and mixtures thereof (such as CRODESTAS F-110, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.)).
Examples of cationic surfactants include, but are not limited to, quaternary fatty ammonium salts such as cetyl trimethyl ammonium bromide (CTAB), dodecyltrimethylammonium bromide, methylbenzethonium chloride, and hexadecyltrimethylammonium bromide; 2-alkyl-l-hydroxyethyl-2- imidazolines such as lauryl hydroxyethyl imidazoline and stearyl hydroxyethyl imidazoline; polyoxamines, such as Tetronic®908 (i.e., poloxamine 908, a tetrafunctional polyethylene oxide (PEO)-polypropylene oxide ethylenediamine block copolymer); N,N,N,N-tetrakis substituted ethylenediamines such as ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol and ethylenediamine tetrakispropoxylate- block-ethoxylate)tetrol; fatty amine ethoxylates such as stearyl amine ethoxylate, oleyl amine ethoxylate, tallow amine ethoxylate and coco amine ethoxylate; and mixtures thereof.
Examples of anionic surfactants include, but are not limited to, alkyl sulfates, such as sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium lauryl sulfate; bile salts such as sodium deoxycholate and sodium cholate; sulfosuccinate diesters such as docusate sodium (AEROSEL OT, American Cyanamid), ammonium dinonyl sulfosuccinate, diamyl sulfosuccinate sodium, dicapryl sulfosuccinate sodium, diheptyl sulfosuccinate sodium, dihexyl sulfosuccinate sodium, diisobutyl sulfosuccinate sodium, and ditridecyl sulfosuccinate sodium; alkylbenzene sulfonates such as sodium dodecylbenzenesulfonate; sodium petroleum sulfonates such as those available under the tradename PETRONATE from Sonneborn, LLC Petrolia, Pennsylvania; sodium alkyl naphthalene sulfonate such as those available under the tradename NAXAN from Nease Performance Chemicals, West Chester Township, Ohio; sulfated natural oils and glycerides such as lauryl monoglyceryl sulfate and sulfated castor oil; sulfated ethoxylated fatty alcohols such as sodium laureth sulfate and sodium myreth sulfate; charged phospholipids such as dimyristoylphosphatidylglycerin; and mixtures thereof.
In one embodiment, the surfactant may comprise a fatty acid glyceride, a sorbitan ester, an ethoxylated fatty acid, an ethoxylated hydrogenated vegetable oil, an ethoxylated sorbitan ester, a polyoxamer, a quaternary ammonium salt, an alkyl sulfate, a sulfosuccinate diester, an alkylbenzene sulfonate, a sulfated ethoxylated fatty alcohol, or a mixture thereof. In another embodiment, the surfactant may comprise a polyoxamer or sodium lauryl sulfate.
Lubricants may comprise one or more, but not limited to fatty acids such as lauric acid, myristic acid, palmitic acid, and stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate or other metallic stearate); talc; polyethylene glycols (such CARBOWAX™ Polyethylene Glycol (PEG) 3350, Dow Chemical, Midland, Michigan); light mineral oil; poloxamers, such as Kolliphor® P188 and P407 available from BASF, Ludwigshafen, Germany; polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80; sodium lauryl sulfate; sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate and sorbitan trioleate; ethoxylated fatty acids such as polyoxyl 40 stearate and polyoxyl 15 hydroxystearate; ethoxylated alkanols such as polyoxyl 20 cetostearyl ether and polyoxyl 10 oleyl ether; ethoxylated vegetable oils and ethoxylated hydrogenated vegetable oils such as polyoxyl 35 castor oil (Cremophor EL/Kolliphor® EL, BASF) and hydrogenated polyoxyl 40 castor oil (Cremophor RH40/ Kolliphor® RH40, BASF); waxes (for example, microcrystalline waxes); glycerides, such as glyceryl dibehenate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, and glyceryl tristearate; sucrose ester of fatty acids such as sucrose stearate; hydrogenated vegetable oils (for example, hydrogenated castor oil and hydrogenated palm oil); and mixtures thereof. In certain embodiments, the lubricant may comprise a fatty acid or salt thereof, a polyethylene glycol, or a glyceride. In certain other embodiments, the lubricant may comprise magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, polyethylene glycol, glyceryl dibehenate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, or glyceryl tristearate. In certain other embodiments, the lubricant may comprise magnesium stearate.
Glidants include pharmaceutically acceptable agents that can promote powder flow by reducing interparticle friction and cohesion. Glidants may be added to pharmaceutical compositions immediately prior to tablet compression to facilitate the flow of granular material into the die cavities of tablet presses. Glidants include: colloidal silicon dioxide such as Aerosil® 200 (a hydrophilic fumed silica with a specific surface area of 200 m2/g; Evonik Corp., Piscataway, New Jersey) or CAB-O-SIL, M-5P (a fumed silica with a specific surface area of 200 m2/g; Cabot Corp., Billerica, Massachusetts), asbestos free talc, sodium aluminosilicate, calcium silicate, calcium phosphate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, stearowet C (a combination of calcium stearate and sodium lauryl sulfate), starch, starch 1500, magnesium lauryl sulfate, magnesium silicate, magnesium trisilicate, magnesium aluminosilicate, magnesium oxide and mixtures thereof. The compositions herein may contain glidants to effect and maintain homogeneity of active ingredients during handling prior to tablet compression. In certain embodiments, the glidant may comprise colloidal silicon dioxide, sodium aluminosilicate, calcium silicate, magnesium silicate, magnesium trisilicate, magnesium aluminosilicate, or a mixture thereof. In certain other embodiments, the glidant may comprise colloidal silicon dioxide.
Coloring agent as used herein include, but are not limited to, pharmaceutically acceptable dyes, such as FD&C dyes including Blue No. 1, Blue No. 1 Lake, Blue No. 1--Aluminum Lake, Blue No. 2, Blue No. 2--Aluminum Lake, Green No. 3, Red No. 3, Red No. 40, Red No. 40--Aluminum Lake, Yellow No. 5, Yellow No. 5--Aluminum Lake, Yellow No. 6, and Yellow No. 6-Aluminum Lake; and inorganic colorants, such as alumina, titanium dioxide, ferric oxide brown, ferric oxide orange, ferric oxide red, ferric oxide yellow, ferrosoferric oxide, ferrous oxide; and natural colorants such as caramel and annatto extract.
The co-granulates described above may be prepared according to a process comprising granulating a first mixture comprising pretomanid, moxifloxacin, pyrazinamide, a binder, and one or more intragranular excipients to provide a co-granulate. The granulation may be according to wet or dry granulation process familiar to those skilled in the art. Where a dry granulating process is utilized (e.g., blending and slugging of the dry components), the binder may comprise pre-gelatinized starch, anhydrous lactose, dibasic calcium phosphate, or a mixture thereof. When a wet granulation process is utilized, the APIs and intragranular excipients may be granulated together using a solution (e.g., a solution comprising the binder and a surfactant). In either case, the co-granulate prepared by wet or dry granulation processes may be milled (e.g., via wet or dry milling) to provide a first milled co-granulate. Such first milled co-granulate may be dried to a suitable wt.% residual solvent and/or water to provide a dried co-granulate. As necessary, the dried co-granulate can be further milled to provide a second milled co-granulate having a desired particle size distribution.
Such co-granulates may be used to prepare a variety of oral unit dosage forms. In one example, a tablet can be prepared comprising the co-granulate and one or more extragranular excipients. In certain embodiments, the tablet comprises about 75 - 95 wt.% of the co-granulate and about 5 - 25 wt.% of the one or more extragranular excipients; or 80 - 95 wt.% of the co-granulate and about 5 - 20 wt.% of the one or more extragranular excipients; or 85-95 wt.% of the co-granulate and about 5 - 15 wt.% of the one or more extragranular excipients; or 70-90 wt.% of the co-granulate and about 10-30 wt.% of the one or more extragranular excipients; or 80-90 wt.% of the co-granulate and about 10-20 wt.% of the one or more extragranular excipients.
The extragranular excipients can be selected from the group consisting of a diluent, a disintegrant, a glidant, a lubricant, a coloring agent, a sweetener, a flavoring, and mixtures thereof. Examples of suitable extragranular excipients are described further above. In one embodiment, the extragranular excipients comprise one or more of a glidant, a disintegrant, and a lubricant.
A tablet may be prepared by combining the co-granulate the one or more extragranular excipients to provide a blend; and compressing a portion of the blend into a tablet. Such tablets may optionally contain a coating layer over an outer surface of the tablet.
The optional film coating agents may, for example, comprise cellulose derivatives such as methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), methacrylic acid/acrylate copolymers, hydroxypropyl methylcellulose (HPMC), vinyl polymers or natural film formers, such as shellac. Examples of commercially available film formers include, but are not limited to, Opadry® (HPMC), Opadry® II (poly(vinyl alcohol)), and Surelease® (Ethylcellulose Dispersion Type B NF) Film Coating Systems (each available from Colorcon, Inc., North Wales, Pennsylvania), and mixtures thereof. Such coatings may be applied as is known by one skilled in the art and controlled to an added weight% to the uncoated tablets. For example, an optional film coating may be applied to add about 1 - 10 wt.% or 1-5 wt.% to the weight of the uncoated tablets. Further Oral Dosage Forms
Formulations suitable for oral administration may also be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example pregelatinized starch, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. In certain embodiments, the co-granulate as described above can be mixed with an inert solid diluent and filled into a hard gelatin capsule; or mini-tablets comprising the co-granulate above may be filled into a hard gelatin capsule; or the co-granulate as described above can be mixed an oil medium and filled into soft gelatin capsules.
Aqueous suspensions may contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, sucralose or saccharin. In certain embodiments, the co-granulate as described above can be mixed with the foregoing excipients suitable for the manufacture of aqueous suspensions.
Oil suspensions may be formulated by suspending the active ingredient in a liquid carrier such as a vegetable oil, including arachis oil, olive oil, sesame oil or coconut oil; or in a mineral oil such as liquid paraffin. The oral suspensions may contain an antioxidant, an antimicrobial preservative agent, and/or a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, citric acid, sodium ascorbate, ascorbyl palmitate, malic acid, or tocopherol. Further, additional antimicrobial agents, such as benzyl alcohol, benzalkonium chloride, benzoic acid, boric acid, methylparaben, methylparaben sodium, ethylparaben, ethylparaben sodium, propylparaben, propylparaben sodium, propylene glycol, potassium benzoate, potassium sorbate, sodium benzoate, sodium sulfite, sorbic acid, thymol, or mixtures thereof may be added. In certain embodiments, the co-granulate as described above can be mixed with a vegetable oil ora mineral oil for the manufacture of an oral suspensions.
Dispersible powders and granules, suitable for preparation of an aqueous suspension by the addition of water, can provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. In certain embodiments, the co-granulate as described above can be mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
Fixed-dose combinations may offer patients greater freedom from multiple dosage medication regimens and ease the needed diligence required in remembering and complying with complex daily dosing times and schedules. By combining pretomanid, moxifloxacin and pyrazinamide into a single dosage form, the desired daily regimen may be presented in a single dose or as two or more sub-doses per day.
Segregation of active ingredients in pharmaceutical powders and granulations is a widely recognized problem that can result in inconsistent dispersions of the active ingredients in final dosage forms. Some of the main factors contributing to segregation are particle size, shape and density. Segregation is particularly troublesome when attempting to formulate a single homogenous tablet containing multiple active ingredients having different densities and different particle sizes.
Any of the preceding compositions may be administered to a human or other mammal in a safe and therapeutically effective amount as described herein. These safe and therapeutically effective amounts will vary according to the type and size of mammal being treated and the desired results of the treatment. A "therapeutically effective amount" is an amount effective for treating a recited disease or condition, such as, tuberculosis. The term "treating", with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder. The number of unit dosages of the compositions (e.g., tablets or capsules or amount of oral suspension) administered to the person typically comprises a therapeutically effective amount of pretomanid, moxifloxacin, pyrazinamide, and optionally bedaquiline, or pharmaceutically acceptable salt and/or solvate thereof. For example, when treating tuberculosis, sputum samples or chest x-rays may be monitored to show improvement and/or amelioration of the disease.
In certain embodiments, the tuberculosis is drug-sensitive tuberculosis (DS-TB), multidrug- resistant tuberculosis (MDR-TB), or extensively drug-resistant tuberculosis (XDR-TB).
In one embodiment, the tuberculosis is drug-sensitive tuberculosis (DS-TB). DS-TB refers to TB which is not resistant to any of the TB drugs; in certain embodiments, the DS-TB is tuberculosis that is caused by a bacteria that is sensitive to rifampicin (RIF) and isoniazid (INH), as identified, for example, by rapid molecular sputum-based test.
In some embodiments, the pharmaceutical composition of the present disclosure can be used for the treatment of multi-drug resistant tuberculosis (MDR-TB). MDR-TB refers to TB caused by a bacteria resistant to isoniazid (INH) and rifampin (RIF).
In some embodiments, the pharmaceutical composition of the present disclosure can be used for the treatment of extensively-drug resistant tuberculosis (XDR-TB). XDR-TB refers to a rare type of MDR- TB that is caused by a bacteria that is resistant to INH and RIF, and is additionally resistant to any fluoroquinolone, such as ciprofloxacin, levofloxacin, ofloxacin, or sparfloxacin, and at least one of three injectable second-line drugs, such as amikacin, kanamycin, or capreomycin.
"A person in need of treatment" herein refers to a patient diagnosed with tuberculosis according to methods familiar to those skilled in the art, including patients having a sputum positive for Mycobacterium tuberculosis (M.tb) bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease [IUATLD]/WHO scale on smear microscopy), or having diagnosed pulmonary TB based on a chest x-ray.
Any of the various methods known by persons skilled in the art for packaging tablets, caplets, or other solid dosage forms suitable for oral administration, that will not degrade the components of the present formulations, are suitable for use in packaging. The combinations may be packaged in glass and plastic bottles. Tablets, caplets, or other solid dosage forms suitable for oral administration may be packaged and contained in various packaging materials optionally including a desiccant e.g. silica gel. Packaging may be in the form of unit dose blister packaging. For example, the package may contain a blister tray of the co-formulated combination of pretomanid, pyrazinamide, and moxifloxacin (and optionally, bedaquiline) in a single pill, tablet, caplet or capsule.
The packaging material may also have labeling and information related to the pharmaceutical composition printed thereon. Additionally, an article of manufacture may contain a brochure, report, notice, pamphlet, or leaflet containing product information. This form of pharmaceutical information is referred to in the pharmaceutical industry as a "package insert." A package insert may be attached to or included with a pharmaceutical article of manufacture. The package insert and any article of manufacture labeling provides information relating to the pharmaceutical composition. The information and labeling provides various forms of information utilized by health-care professionals and patients, describing the composition, its dosage and various other parameters required by regulatory agencies such as the United States Food and Drug Agency.
General Procedure for Preparation of Certain Embodiments
In one embodiment, a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, cellulose ether derivatives (e.g., hydroxypropyl methylcellulose) or methacrylate derivatives in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
One added benefit to a fixed-dose combination PaMZ formulation or BPaMZ formulation is the simplicity of manufacturing a single tablet rather than manufacturing three separate products. Moreover, the inter-granules are dramatically more easily reproducible in the FDC formulations over the inter granules in the mono-API pretomanid tablets. It was noted that more % water uptake in the manufacturing of the inter-granules creates granules that can be too dense. The tablets with dense granules yield a dramatic decreased dissolution rate— in fact, the dissolution rate with the dense granules would not meet the USP dissolution criteria for the tablet formulation. Therefore, during the manufacturing process, it is an important parameter that the % water uptake is heavily controlled. On the other hand, the manufacturing of the PaMZ FDC inter-granules is far less stringent and thus allows for a wider range of %water uptake for the manufacturing of the inter-granules. Tablet compression can be carried out on a rotary tablet press fitted with suitable tooling, for example, 19.0 mm x 9.0 mm capsule shaped, normal biconcave tooling. The usual in process controls of tablet weight, thickness, hardness, friability and disintegration time are monitored during the compression process.
As noted above, the dosage forms herein may optionally be coated with one or more materials suitable for the regulation of release, for the protection of the formulation or for aesthetic purposes. In one embodiment, the tablets are aqueous film coated using a commercially supplied coating material, OPADRY from Colorcon, in a perforated drum type of coating pan, such as the Neocota from Neo Machines. In another embodiment, coatings are provided to permit either pH-dependent or pH- independent release. A pH-dependent coating serves to release the active in desired areas of the gastro intestinal (Gl) tract, e.g., the stomach or small intestine, such that an absorption profile is provided which is capable of providing, for example, at least about eight hours and preferably about twelve hours to up to about twenty-four hours of drug release to a patient.
Formulations that utilize pH-dependent coatings may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract. Coatings which are pH-dependent may be used, including shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.
EXAMPLES
The following examples further describe and demonstrate particular embodiments within the scope of the present disclosure. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.
Example 1 PaMZ Manufacturing Process A flow diagram of the manufacturing process for the PaMZ FDCs is shown in Figure 1. Given the absence of incompatibility between any of the components, a simple mixing and wet granulation process was employed to prepare the compression mix. Batch size and equipment availability necessitated the wet granulation step to be conducted in two sub-lots which were subsequently blended together after the dry milling step. All subsequent steps were carried out as a single batch process.
The materials for the intragranular dry powder mix (granules) were first screened through an appropriate size mesh into the bowl of a mixer-granulator where they are dry mixed using both mixer and impeller blades. The flow chart of Figure 1 shows the alternative disintegrants and surfactants used to prepare FDC Formulations A and B: sodium starch glycolate and poloxamer 188 for FDC Formulation A and crospovidone and sodium lauryl sulfate for FDC Formulation B. The granulating solution was prepared using povidone as the binder with the surfactant appropriate to the formulation being made, as indicated above. After dry mixing, the binder solution was added to the moving powder bed in the mixergranulator. During this kneading process, additional purified water was added when required to effect complete granulation. Once a suitable wet granule was prepared in the mixer granulator bowl it was passed through a wet milling process, usually a Co-Mil or similar equipment, to the bowl of a fluid bed drier.
The granules were dried to a moisture content of not more than 2% w/w and then dry milled (again using a Co-Mil or similar) prior to blending with extragranular excipients. The two sub-lots from the granulation process were combined at this point into a single lot for all the subsequent processing steps. The appropriate disintegrant and colloidal silicon dioxide were added to the granules and blended in a double cone blender, or similar equipment, and then the lubricant, magnesium stearate, was blended to create the final compression blend.
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000024_0001
Example 2 PaMZ Stability and Dissolution Analyses
Various ratios of excipients were granulated with the three APIs (pretomanid, moxifloxacin, and pyrazinamide followed by extra-granular excipients and then compacted into prototype tablets. In order to confirm the stability of the three APIs and the potential performance of the FDC, the prototype tablet batches were put on stability at both 25 °C/60% relative humidity (RH) and 40 °C/ 75% RH. The three APIs were found to be stable throughout the prototype stability studies, up to 18 months at 25 °C/60% RH and 6 months at 40 °C/ 75% RH.
Surprisingly, however, it was discovered that pyrazinamide and/or moxifloxacin aided in the dissolution performance of pretomanid. This allowed for a reduction in the use of excipients and thus allowed for the development of a relatively small sized PaMZ FDC tablet with a similar dissolution rate to that of the mono-API.
Moreover, it was discovered that the dissolution rates were actually improved for pretomanid, moxifloxacin, and pyrazinamide in their separate dissolution assays. Ultimately, two monolithic PaMZ FDC formulations (Formulations A and B above) were discovered with the superior dissolution rates for the 3 APIs.
Example 3 PaMZ Dissolution Comparison Examination of the dissolution rate for pretomanid API from pretomanid 200-mg tablets versus FDC Formulations A and B was performed. Comparison Table 3 provides the full dissolution profile for the pretomanid tablets (see, Table 4), PaMZ Formulation A, and PaMZ Formulation B. Dissolution of pretomanid from each of the preceding were measured with a USP-II (paddle) apparatus at 75 rpm and 37 °C+/-0.5 °c in 1000 mL of 0.1N HCI containing 0.5% hexadecyltrimethylammonium bromide (HDTMA).
In brief, an improved dissolution rate of pretomanid from the FDCs was found over the mono tablet formulation, as illustrated in Figure 3. At 20 minutes, pretomanid from both formulations of the FDCs are 100% dissolved whereas that from the mono-tablet is 81% dissolved. For a successful PaMZ FDC, it was critical to have an FDC formulation with at least a comparable profile, however, likely due to the effects of pyrazinamide and moxifloxacin, the FDCs had an improved dissolution profile.
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0001
Example 4 PaMZ Excipient Ratio Analysis between Pretomanid 200 mg tablet vs FDCs
As noted in Table 4 below, the recently approved pretomanid 200 mg tablet formulation includes 25.0% active [200 mg] and 75.0% inactive inert excipients [600 mg]. Marketed moxifloxacin 400 mg tablets have formulations that consist of 64.9% active (400 mg) and 35.1% inactive inert excipients (216.5 mg). Similarly, marketed pyrazinamide 500 mg tablets tend to have a high active to inactive ratio (88.3% active [500.0 mg] and 11.7% inactive [66.0 mg]). The amount of inert excipients required to dose one pretomanid tablet, one moxifloxacin tablet, and three pyrazinamide tablets is high and may be reduced when in a FDC tablet formulation.
The qualitative and quantitative composition for the PaMZ FDC formulations A and B are detailed in Tables 1 and 2. The percentile ratio of actives to inactive excipients in the FDCs are 73.2% (700.0 mg) to 26.8% (256.0 mg) for Formulation A and 68.3% (700.0 mg) to 31.7% (324.3 mg). Table 5 has been prepared to more easily discern and cross-compare the amount of inactive excipients PaMZ FDCs vs the 5 tablets (1 pretomanid tablet, 1 moxifloxacin tablet, and 3 pyrazinamide tablets). Overall, in comparison to the use of the individual 5 mono-API tablets vs the 3-pill FDC daily dose, the Formulation A and B have a 24.3% and 4.1% reduction of overall inactive components.
Figure imgf000027_0001
Thus, as shown above, with the decreased amount of required inactive excipients, the PaMZ FDCs could be reduced in size to allow patients to comfortably ingest, for example, a 3-pill daily dose. Moreover, with the reduction of excipients, this will allow patients with other aliments requiring large daily dosing (e.g. HIV) to ingest their other medications with decreased unneeded excipients.
Example 5. FDC Stability
Stability of FDC Formulations A and B were measured under long-term (25 °C ± 2 °C/60 % RH ± 5 % RH) and accelerated (40 °C ± 2 °C/75 % RH ± 5%) conditions as detailed in Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products, in lots of 30 tablets sealed in HDPE bottles with a child-resistant closure. API assay results for Pa, M, and Z, individually, are described in Tables 6 and 7. Total impurities measured during the course of the testing are provided in Table 8. Total impurities are reported as the sum of the impurities identified with each API assay. At all time points noted in Tables 6-8, and for both FDC Formulations A & B, each individual impurity was found at less than 0.1 wt.%, including each individual unidentified impurity. HPLC assay conditions for each API and related impurities are provided in Table 9.
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000028_0003
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000030_0001
Mobile phases:
A: Dissolve 1.36 g potassium dihydrogen phosphate in 1000 mL HPLC grade water. Add 2.0 mL triethylamine and adjust pH of solution to 3.0 with orthophosphoric acid. Filter through 0.45 micron filter.
B, D, F, H: 100% Acetonitrile.
C: Dissolve 1.36 g potassium dihydrogen phosphate in 1000 mL HPLC grade water. Add 4.0 mL triethylamine and adjust pH of solution to 3.0 with orthophosphoric acid. Filter through 0.45 micron filter.
E: Dissolve 0.5 g tetrabutylammonium hydrogen sulfate and 1 g potassium dihydrogen phosphate in 1000 mL HPLC grade water. Adjust pH of solution to 2.0 with orthophosphoric acid. Filter through 0.45 micron filter.
G: Dissolve 6.8 g potassium dihydrogen phosphate and 1.84 g sodium hydroxide in 1000 mL HPLC grade water. Adjust pH of solution to 3.0 with orthophosphoric acid. Add 30 mL acetonitrile and 1 mL tetrahydrofuran. Filter through 0.45 micron filter.
Example 6. BPaMZ Manufacturing Process
Examples 1-5 above show that Pa, M and Z are chemically compatible with each other. It is expected that the addition of bedaquiline would also be compatible with Pa, M and Z in combination.
Bedaquiline is used in a milled form with a controlled particle size. It is non-hygroscopic and is relatively insoluble in aqueous media, not dissimilar to pretomanid. In the solid state it shows good stability, with no significant changes detected after storage for up to 6 months at 409C and 75% relative humidity. It is, however, prone to degradation upon exposure to light.
A flow diagram of the manufacturing process for the BPaMZ FDCs is shown Figure 2. As shown therein, all active materials are blended together to produce a "single" active material. Excipients are added and a uniform co-granulate is made analogous to the process. A film coat from aqueous solution using appropriate OPADRY coating can also be applied.
Example 7. BPaMZ Formulation A
Using the procedure outlined in Example 6, the following formulation can be made:
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000032_0003
Example 8. BPaMZ Formulation B
Using the procedure outlined in Example 6, the following formulation can be made:
Figure imgf000032_0002
Figure imgf000033_0001
Figure imgf000033_0003
Example 9. BPaMZ Formulation C Using the procedure outlined in Example 6, the following formulation can be made:
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000034_0002
The disclosure can be further described, without limitation, by the embodiments in following numbered paragraphs:
1. A fixed-dose pharmaceutical dosage form, comprising a therapeutically effective amount of each of pretomanid, moxifloxacin and pyrazinamide and, optionally, at least one other antibacterial agent, or a pharmaceutically acceptable salt individually thereof, and a pharmaceutically acceptable carrier.
2. The fixed-dose pharmaceutical dosage form according to paragraph 1, wherein the dosage form is oral.
3. The fixed-dose pharmaceutical dosage form according to paragraph 1 or 2, provided in the form of a tablet.
4. The fixed-dose pharmaceutical dosage form according to paragraph 1 or 2 provided in the form of a capsule.
5. The fixed-dose pharmaceutical dosage form according to any one of paragraphs 1-4, wherein said composition is chemically stable.
6. The fixed-dose pharmaceutical dosage form according to any one of paragraphs 1-5, wherein pretomanid is in an amount of 10 to 400 mg, moxifloxacin is in an amount of 10 to 800 mg and pyrazinamide is in an amount of 50 to 2000 mg.
7. The fixed-dose pharmaceutical dosage form according to any one of paragraphs 1-6, wherein pretomanid is in an amount of 66.7 mg, moxifloxacin is in an amount of 152 mg and pyrazinamide is in an amount of 500 mg.
8 A method for the treatment of tuberculosis, comprising the step of administering to a patient in need thereof the fixed-dose pharmaceutical dosage form according to any one of paragraphs 1-7.
9. The fixed-dose pharmaceutical dosage form according to any one of paragraphs 1-7, wherein said one other antibacterial agent is bedaquiline or a pharmaceutically acceptable salt thereof (e.g., fumarate). 10. The fixed-dose pharmaceutical dosage form according to paragraph 9, wherein bedaquiline is in an amount of from 10 to 400 mg.
11. The fixed-dose pharmaceutical dosage form according to any one of paragraphs 1-5, wherein bedaquiline is in an amount of 10 to 400 mg, pretomanid is in an amount of 10 to 400 mg, moxifloxacin is in an amount of 10 to 800 mg and pyrazinamide is in an amount of 50 to 2000 mg.
12. A fixed-dose pharmaceutical dosage form, comprising a therapeutically effective amount of each of bedaquiline, pretomanid, moxifloxacin and pyrazinamide, or a pharmaceutically acceptable salt individually thereof, and a 30 pharmaceutically acceptable carrier.
13. The fixed-dose pharmaceutical dosage form according to paragraph 12, wherein bedaquiline is in an amount of 10 to 400 mg, pretomanid is in an amount of 10 to 400 mg, moxifloxacin is in an amount of 10 to 800 mg and pyrazinamide is in an amount of 50 to 2000 mg.
14. The fixed-dose pharmaceutical dosage form according to paragraph 12, wherein bedaquiline or salt thereof is in an amount equivalent to about 50 mg or 100 mg bedaquiline free base, pretomanid is in an amount of about 100 mg, moxifloxacin or salt thereof is in an amount equivalent to about 200 mg moxifloxacin free base, and pyrazinamide is in an amount of about 750 mg.
15. The fixed-dose pharmaceutical dosage form according to paragraph 12, wherein bedaquiline or salt thereof is in an amount equivalent to about 33.3 mg or 66.7 mg bedaquiline free base, pretomanid is in an amount of about 66.7 mg, moxifloxacin or salt thereof is in an amount equivalent to about 133.3 mg moxifloxacin free base, and pyrazinamide is in an amount about 500 mg.
16. The fixed-dose pharmaceutical dosage form according to paragraph 12, wherein bedaquiline or salt thereof is in an amount equivalent to about 25 mg or 50 mg bedaquiline free base, pretomanid is in an amount of about 50 mg, moxifloxacin or salt thereof is in an amount equivalent to about 100 mg moxifloxacin free base, and pyrazinamide is in an amount about 375 mg.
17. A co-granulate comprising a binder; one or more intragranular excipients; and a total of about 40 wt.% to 90 wt.% of active pharmaceutical ingredients (APIs), wherein the APIs comprise a mixture of pretomanid, moxifloxacin, and pyrazinamide, or a pharmaceutically acceptable salt and/or solvate thereof.
18. The co-granulate of claim 17, comprising about 0.1 to 10 wt.% of the binder.
19. The co-granulate of claim 17, comprising about 0.5 to 5 wt.% of the binder.
20. The co-granulate of claim 17, comprising about 1 to 3 wt.% of the binder. 21. The co-granulate of any one of claims 17-20, wherein the binder comprises pre-gelatinized starch, povidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose or a mixture thereof.
22. The co-granulate of any one of claims 17-20, wherein the binder comprises pre-gelatinized starch, anhydrous lactose, dibasic calcium phosphate, or a mixture thereof.
23. The co-granulate of any one of claims 17-22, comprising about 5 wt.% to about 40 wt.% of intragranular excipients.
24. The co-granulate of claim 23, comprising about 10 wt.% to about 30 wt.% of intragranular excipients.
25. The co-granulate of claim 23, comprising about 15 wt.% to about 25 wt.% of intragranular excipients.
26. The co-granulate of any one of claims 23-25, wherein the intragranular excipients are one or more independently selected from the group consisting of a surfactant, a diluent, a disintegrant, a glidant, a lubricant, a coloring agent, a sweetener, and a flavoring.
27. The co-granulate of claim 26, wherein the intragranular excipients comprise a diluent, a disintegrant, and a surfactant.
28. The co-granulate of claim 27, comprising about 5 - 15 wt. % of the diluent.
29. The co-granulate of claim 27, comprising about 5 - 10 wt. % of the diluent.
30. The co-granulate of claim 27, wherein the diluent comprises an inorganic filler, a monosaccharide, a disaccharide, a polysaccharides, a sugar alcohol, a cellulose, or a mixture thereof.
31. The co-granulate of claim 27, wherein the diluent comprises dibasic calcium phosphate, tribasic calcium phosphate, lactose, maltose, sucrose, trehalose, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, microcrystalline cellulose, or a mixture thereof.
32. The co-granulate of claim 27, wherein the diluent comprises lactose, microcrystalline cellulose, or a mixture thereof.
33. The co-granulate of claim 27, comprising about 1 - 10 wt. % of the disintegrant.
34. The co-granulate of claim 33, comprising about 3 - 10 wt. % of the disintegrant.
35. The co-granulate of claim 34, comprising about 4 - 8 wt. % of the disintegrant.
36. The co-granulate of claim 33, wherein the disintegrant comprises carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, sodium starch glycolate, corn starch, or a mixture thereof. 37. The co-granulate of claim 33, wherein the disintegrant comprises a starch, sodium starch glycolate, crospovidone, or a mixture thereof.
38. The co-granulate of claim 27, comprising about 0.1 - 5 wt.% of the surfactant.
39. The co-granulate of claim 38, comprising about 0.1 - 3 wt.% of the surfactant.
40. The co-granulate of claim 38, comprising about 0.3 - 2 wt.% of the surfactant.
41. The co-granulate of claim 38, wherein the surfactant comprises a fatty acid glyceride, a sorbitan ester, an ethoxylated fatty acid, an ethoxylated hydrogenated vegetable oil, an ethoxylated sorbitan ester, a polyoxamer, a quaternary ammonium salt, an alkyl sulfate, a sulfosuccinate diester, an alkylbenzene sulfonate, a sulfated ethoxylated fatty alcohol, or a mixture thereof.
42. The co-granulate of claim 38, wherein the surfactant comprises a polyoxamer or sodium lauryl sulfate.
43. The co-granulate of any one of claims 17-42, comprising about a total of about 70 wt.% to 90 wt.% of the APIs.
44. The co-granulate of claim 43, comprising about a total of about 75 wt.% to 85 wt.% of the
APIs.
45. The co-granulate of any one of claims 17-44, wherein the APIs comprise of pretomanid, moxifloxacin hydrochloride, and pyrazinamide.
46. The co-granulate of any one of claims 17-45, wherein the APIs further comprise bedaquiline or a pharmaceutically acceptable salt.
47. The co-granulate of claim 46, wherein the APIs further comprise bedaquiline fumarate.
48. A tablet comprising the co-granulate of any one of claims 17-47.
49. The tablet of claim 48, further comprising one or more extragranular excipients.
50. The tablet of claim 49, comprising about 70 - 90 wt.% of the cogranulate and about 10 -30 wt.% of the one or more extragranular excipients.
51. The tablet of claim 49 or 50, wherein the one or more extragranular excipients are independently a lubricant, a glidant, a disintegrant, a flavoring, a sweetener, a coloring agent, or a diluent.
52. The tablet of any one of claims 48 - 51 further comprising a coating layer over an outer surface of the tablet.
53. A capsule comprising the co-granulate of any one of claims 17-47.
54. An oral suspension comprising the co-granulate of any one of claims 17-47.
55. The oral suspension of claims 54, comprising a pharmaceutically acceptable liquid carrier. 56. The oral suspension of claim 55, further comprising one or more of an antioxidant, an antimicrobial preservative agent, a thickening agent, a sweetener, and a flavoring.
57. A process for preparing a co-granulate comprising, granulating a first mixture comprising pretomanid, moxifloxacin, pyrazinamide, a binder, and one or more intragranular excipients to provide the co-granulate.
58. The process of claim 57, further comprising milling the co-granulate to provide a first milled co-granulate.
59. The process of claim 57 or 58, wherein the granulating is dry granulating.
60. The process of claim 59, wherein the binder comprises pre-gelatinized starch, anhydrous lactose, dibasic calcium phosphate, or a mixture thereof.
61. The process of claim 57, wherein the granulating is wet granulating (e.g., with a solution comprising the binder and a surfactant).
62. The process of claim 61, wherein the milling is wet milling.
63. The process of claim 61 or 62, further comprising drying the cogranulate or first milled co- granulate to provide a dried co-granulate.
64. The process of claim 63, further comprising milling the dried cogranulate to provide a second milled co-granulate.
65. A process for preparing a tablet comprising combining a co-granulate according to any one of claims 17-47 with one or more extragranular excipients to provide a blend; and compressing a portion of the blend into a tablet.
66. A method for treating tuberculosis comprising administering one or more tablets of any one of claims 48-52 or one or more capsules according to claim 53 or an oral suspension of any one of claims 54 - 56 to a person in need of such treatment, wherein the number or tablets or capsules or amount of oral suspension administered to the person comprises a therapeutically effective amount of pretomanid, moxifloxacin, pyrazinamide, and optionally bedaquiline, or pharmaceutically acceptable salt and/or solvate thereof.
Where trade names are used herein, applicants intend to independently include the trade name product and the active pharmaceutical ingredient(s) of the trade name product. It is to be understood that the disclosure is not limited to the particular embodiments described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims.
It is to be understood that the descriptions have been simplified to illustrate elements that are relevant for a clear understanding, while eliminating, for the purpose of clarity, many other elements found in typical pharmaceutical compositions. Those of ordinary skill in the art will recognize that other elements and/or steps are desirable and/or required in implementing the present disclosure. However, because such elements and steps are well known in the art, and because they do not facilitate a better understanding, a discussion of such elements and steps is not provided herein. The disclosure herein is directed to all such variations and modifications to such elements and methods known to those skilled in the art. Furthermore, the embodiments identified and illustrated herein are for exemplary purposes only, and are not meant to be exclusive or limited in their description of the present disclosure.

Claims

We Claim:
1. A fixed-dose pharmaceutical dosage form, comprising a therapeutically effective amount of each of pretomanid, moxifloxacin and pyrazinamide and, optionally, at least one other antibacterial agent, or a pharmaceutically acceptable salt individually thereof, and a pharmaceutically acceptable carrier.
2. The fixed-dose pharmaceutical dosage form according to claim 1, wherein the dosage form is oral.
3. The fixed-dose pharmaceutical dosage form according to claim 1, provided in the form of a tablet.
4. The fixed-dose pharmaceutical dosage form according to claim 1 provided in the form of a capsule.
5. The fixed-dose pharmaceutical dosage form according to claim 1, wherein said composition is chemically stable.
6. The fixed-dose pharmaceutical dosage form according to claim 1, wherein pretomanid is in an amount of 10 to 400 mg, moxifloxacin is in an amount of 10 to 800 mg and pyrazinamide is in an amount of 50 to 2000 mg.
7. The fixed-dose pharmaceutical dosage form according to claim 1, wherein pretomanid is in an amount of 66.7 mg, moxifloxacin hydrochloride is in an amount of 152 mg and pyrazinamide is in an amount of 500 mg.
8. A method for the treatment of tuberculosis, comprising the step of administering to a patient in need thereof the fixed-dose pharmaceutical dosage form according to claim 1.
9. The fixed-dose pharmaceutical dosage form according to claim 1, wherein said one other antibacterial agent is bedaquiline or a pharmaceutically acceptable salt thereof.
10. The fixed-dose pharmaceutical dosage form according to claim 9, wherein bedaquiline or a pharmaceutically acceptable salt thereof is in an amount of from 10 to 400 mg
11. The fixed-dose pharmaceutical dosage form according to claim 1, wherein bedaquiline is in an amount of 10 to 400 mg, pretomanid is in an amount of 10 to 400 mg, moxifloxacin hydrochloride is in an amount of 10 to 800 mg and pyrazinamide is in an amount of 50 to 2000 mg.
12. A fixed-dose pharmaceutical dosage form, comprising a therapeutically effective amount of each of bedaquiline, pretomanid, moxifloxacin and pyrazinamide, or a pharmaceutically acceptable salt individually thereof, and a pharmaceutically acceptable carrier.
13. The fixed-dose pharmaceutical dosage form according to claim 12, wherein bedaquiline is in an amount of 10 to 400 mg, pretomanid is in an amount of 10 to 400 mg, moxifloxacin hydrochloride is in an amount of 10 to 800 mg and pyrazinamide is in an amount of 50 to 2000 mg.
14. A co-granulate comprising a binder; one or more intragranular excipients; and a total of about 40 wt.% to 90 wt.% of active pharmaceutical ingredients (APIs), wherein the APIs comprise a mixture of pretomanid, moxifloxacin, and pyrazinamide, or a pharmaceutically acceptable salt and/or solvate thereof.
15. The co-granulate of claim 14, comprising about 0.1 to 10 wt.% of the binder.
16. The co-granulate of claim 14, comprising about 0.5 to 5 wt.% of the binder.
17. The co-granulate of claim 14, comprising about 1 to 3 wt.% of the binder.
18. The co-granulate of any one of claims 14-17, wherein the binder comprises pre-gelatinized starch, povidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose or a mixture thereof.
19. The co-granulate of any one of claims 14-17, wherein the binder comprises pre-gelatinized starch, anhydrous lactose, dibasic calcium phosphate, or a mixture thereof.
20. The co-granulate of any one of claims 14-19, comprising about 5 wt.% to about 40 wt.% of intragranular excipients.
21. The co-granulate of claim 20, comprising about 10 wt.% to about 30 wt.% of intragranular excipients.
22. The co-granulate of claim 20, comprising about 15 wt.% to about 25 wt.% of intragranular excipients.
23. The co-granulate of any one of claims 20-22, wherein the intragranular excipients are one or more independently selected from the group consisting of a surfactant, a diluent, a disintegrant, a glidant, a lubricant, a coloring agent, a sweetener, and a flavoring.
24. The co-granulate of claim 23, wherein the intragranular excipients comprise a diluent, a disintegrant, and a surfactant.
25. The co-granulate of claim 24, comprising about 5 - 15 wt. % of the diluent.
26. The co-granulate of claim 24, comprising about 5 - 10 wt. % of the diluent.
27. The co-granulate of any one of claims 24-26, wherein the diluent comprises an inorganic filler, a monosaccharide, a disaccharide, a polysaccharides, a sugar alcohol, a cellulose, or a mixture thereof.
28. The co-granulate of claim 27, wherein the diluent comprises dibasic calcium phosphate, tribasic calcium phosphate, lactose, maltose, sucrose, trehalose, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, microcrystalline cellulose, or a mixture thereof.
29. The co-granulate of claim 27, wherein the diluent comprises lactose, microcrystalline cellulose, or a mixture thereof.
30. The co-granulate of any one of claims 23-29, comprising about 1 - 10 wt. % of the disintegrant.
31. The co-granulate of claim 30, comprising about 3 - 10 wt. % of the disintegrant.
32. The co-granulate of claim 31, comprising about 4 - 8 wt. % of the disintegrant.
33. The co-granulate of claim any one of claims 30 - 32, wherein the disintegrant comprises carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, sodium starch glycolate, corn starch, or a mixture thereof.
34. The co-granulate of claim 33, wherein the disintegrant comprises a starch, sodium starch glycolate, crospovidone, or a mixture thereof.
35. The co-granulate any one of claims 23 - 33, comprising about 0.1 - 5 wt.% of the surfactant.
36. The co-granulate of claim 35, comprising about 0.1 - 3 wt.% of the surfactant.
37. The co-granulate of claim 35, comprising about 0.3 - 2 wt.% of the surfactant.
38. The co-granulate of any one of claims 35-37, wherein the surfactant comprises a fatty acid glyceride, a sorbitan ester, an ethoxylated fatty acid, an ethoxylated hydrogenated vegetable oil, an ethoxylated sorbitan ester, a polyoxamer, a quaternary ammonium salt, an alkyl sulfate, a sulfosuccinate diester, an alkylbenzene sulfonate, a sulfated ethoxylated fatty alcohol, or a mixture thereof.
39. The co-granulate of claim 38, wherein the surfactant comprises a polyoxamer or sodium lauryl sulfate.
40. The co-granulate of any one of claims 14-39, comprising about a total of about 70 wt.% to 90 wt.% of the APIs.
41. The co-granulate of claim 40, comprising about a total of about 75 wt.% to 85 wt.% of the
APIs.
42. The co-granulate of any one of claims 14-41, wherein the APIs comprise of pretomanid, moxifloxacin hydrochloride, and pyrazinamide.
43. The co-granulate of any one of claims 14-42, wherein the APIs further comprise bedaquiline or a pharmaceutically acceptable salt.
44. The co- granulate of claim 43, wherein the APIs further comprise bedaquiline fumarate.
45. A tablet comprising the co-granulate of any one of claims 14-44.
46. The tablet of claim 45, further comprising one or more extragranular excipients.
47. The tablet of claim 46, comprising about 70 - 90 wt.% of the co-granulate and about 10 -30 wt.% of the one or more extragranular excipients.
48. The tablet of claim 46 or 47, wherein the one or more extragranular excipients are independently a lubricant, a glidant, a disintegrant, a flavoring, a sweetener, a coloring agent, or a diluent.
49. The tablet of any one of claims 45-48, further comprising a coating layer over the outer surface of the tablet.
50. A capsule comprising the co-granulate of any one of claims 14-44.
51. An oral suspension comprising the co-granulate of any one of claims 14-44.
52. The oral suspension of claim 51, comprising a pharmaceutically acceptable liquid carrier.
53. The oral suspension of claim 52, further comprising one or more of an antioxidant, an antimicrobial preservative agent, a thickening agent, a sweetener, and a flavoring.
54. A process for preparing a co-granulate comprising, granulating a first mixture comprising pretomanid, moxifloxacin, pyrazinamide, a binder, and one or more intragranular excipients to provide the co-granulate.
55. The process of claim 54, further comprising milling the co-granulate to provide a first milled co-granulate.
56. The process of claim 54 or 55, wherein the granulating is dry granulating.
57. The process of claim 54 or 55, wherein the granulating is wet granulating (e.g., with a solution comprising the binder and a surfactant).
58. The process of any one of claims 55 - 57, wherein the milling is wet milling.
59. The process of any one of claims 55 - 58, further comprising drying the co-granulate or first milled co-granulate to provide a dried co-granulate.
60. The process of claim 59, further comprising milling the dried co-granulate to provide a second milled co-granulate.
61. A process for preparing a tablet comprising combining a co-granulate according to any one of claims 14-44 with one or more extragranular excipients to provide a blend; and compressing a portion of the blend into a tablet.
62. A method for treating tuberculosis comprising administering one or more tablets of any one of claims 45-49 or one or more capsules according to claim 50 or an oral suspension of any one of claims 51-53 to a person in need of such treatment, wherein the number or tablets or capsules or amount of oral suspension administered to the person comprises a therapeutically effective amount of pretomanid, moxifloxacin, pyrazinamide, and optionally bedaquiline, or pharmaceutically acceptable salt and/or solvate thereof.
PCT/US2021/037252 2020-06-15 2021-06-14 Combination antibacterial composition and method for antibacterial therapy WO2021257466A1 (en)

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