WO2021257466A1 - Composition antibactérienne combinée et procédé de thérapie antibactérienne - Google Patents

Composition antibactérienne combinée et procédé de thérapie antibactérienne Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
granulate
amount
pretomanid
dosage form
pyrazinamide
Prior art date
Application number
PCT/US2021/037252
Other languages
English (en)
Inventor
Rajneesh Taneja
Pirthi Pal Singh
Veena Vithalapuram
Jagadeesh Nadigoti
Original Assignee
The Global Alliance For Tb Drug Development, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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/fr
Publication of WO2021257466A1 publication Critical patent/WO2021257466A1/fr

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme posologique pharmaceutique en dose fixe qui peut être utile dans des procédés de traitement de la tuberculose.
PCT/US2021/037252 2020-06-15 2021-06-14 Composition antibactérienne combinée et procédé de thérapie antibactérienne WO2021257466A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP21825172.6A EP4164645A1 (fr) 2020-06-15 2021-06-14 Composition antibactérienne combinée et procédé de thérapie antibactérienne

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202041025104 2020-06-15
IN202041025104 2020-06-15

Publications (1)

Publication Number Publication Date
WO2021257466A1 true WO2021257466A1 (fr) 2021-12-23

Family

ID=79268322

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/037252 WO2021257466A1 (fr) 2020-06-15 2021-06-14 Composition antibactérienne combinée et procédé de thérapie antibactérienne

Country Status (2)

Country Link
EP (1) EP4164645A1 (fr)
WO (1) WO2021257466A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110190199A1 (en) * 2008-09-03 2011-08-04 Pfizer Inc. Combination Therapy for Tuberculosis
US20160251380A1 (en) * 2013-08-09 2016-09-01 Glaxosmithkline Intellectual Property (No.2) Limited Tricyclic benzoxaborole compounds and uses thereof
WO2018158280A1 (fr) * 2017-03-01 2018-09-07 Janssen Sciences Ireland Uc Polythérapie
US20190030026A1 (en) * 2014-11-03 2019-01-31 The Regents Of The University Of California Multi-drug therapies for tuberculosis treatment

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110190199A1 (en) * 2008-09-03 2011-08-04 Pfizer Inc. Combination Therapy for Tuberculosis
US20160251380A1 (en) * 2013-08-09 2016-09-01 Glaxosmithkline Intellectual Property (No.2) Limited Tricyclic benzoxaborole compounds and uses thereof
US20190030026A1 (en) * 2014-11-03 2019-01-31 The Regents Of The University Of California Multi-drug therapies for tuberculosis treatment
WO2018158280A1 (fr) * 2017-03-01 2018-09-07 Janssen Sciences Ireland Uc Polythérapie

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Bedaquiline ", WIKIPEDIA, 21 August 2021 (2021-08-21), XP055888303, Retrieved from the Internet <URL:https://en.wikipedia.org/w/index.php?title=Bedaquiline&oldid=1039941461> [retrieved on 20220207] *
ANONYMOUS: "Pretomanid ", WIKIPEDIA, 30 October 2021 (2021-10-30), XP055888302, Retrieved from the Internet <URL:https://en.wikipedia.org/wiki/Pretomanid> [retrieved on 20220207] *

Also Published As

Publication number Publication date
EP4164645A1 (fr) 2023-04-19

Similar Documents

Publication Publication Date Title
JP4868695B2 (ja) 崩壊性が良好な経口製剤
US9937153B2 (en) Oral pharmaceutical formulation of omarigliptin
EP2026787B1 (fr) Formulation de comprime comprenant du repaglinide et de la metformine
AU2011260614B2 (en) Oral dosage forms of bendamustine and therapeutic use thereof
US20150157618A1 (en) Stabilized pharmaceutical compositions of dabigatran and process for preparation thereof
US10603282B2 (en) Pharmaceutical compositions containing doravirine, tenofovir disoproxil fumarate and lamivudine
CA2942877A1 (fr) Forme pharmaceutique unitaire comprenant de l&#39;emtricitabine, du tenofovir, du darunavir et du ritonavir
WO2014030051A1 (fr) Compositions pharmaceutiques stables comprenant de la saxagliptine
JP7455189B2 (ja) プレトマニド組成物
US20120141586A1 (en) Thrombin receptor antagonist and clopidogrel fixed dose tablet
US20080193527A1 (en) Pharmaceutical compositions containing quetiapine fumarate
WO2010046932A2 (fr) Composition pharmaceutique de minocycline à libération prolongée et son procédé
WO2015028875A2 (fr) Forme pharmaceutique unitaire comprenant de l&#39;emtricitabine, du ténofovir, du darunavir et du ritonavir et un comprimé monolithique comprenant du darunavir et du ritonavir
KR20160060764A (ko) 아타자나비르 및 코비시스타트의 ｈｉｖ 치료 제제
WO2009084036A2 (fr) Composition utilisée pour traiter les infections virales
US20160199396A1 (en) Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavir
US20150141376A1 (en) Pharmaceutical compositions of anti-viral compounds and process for preparation thereof
CN101405004A (zh) 新型薄膜衣片剂
EP4164645A1 (fr) Composition antibactérienne combinée et procédé de thérapie antibactérienne
US20240024307A1 (en) Pharmaceutical combination of a corticosteroid and an antihistamine for the treatment and control of the inflammatory component of allergic processes
WO2021257461A1 (fr) Composition antibactérienne polythérapeutique et méthode de thérapie antibactérienne
EP2303233B1 (fr) Forme galénique orale solide contenant l agent anti-plaquettaire clopidogrel et son procédé de préparation
US20130259935A1 (en) Pharmaceutical compositions comprising glimepiride and polyethylene glycol castor oil
KR20210096162A (ko) 의약 조성물
EP3079672B1 (fr) Composition pharmaceutique comprenant un sel pharmaceutiquement acceptable de rasagiline

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21825172

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021825172

Country of ref document: EP

Effective date: 20230116