EP4164626A1 - Antibakterielle kombinationszusammensetzung und antibakterielles therapieverfahren - Google Patents
Antibakterielle kombinationszusammensetzung und antibakterielles therapieverfahrenInfo
- Publication number
- EP4164626A1 EP4164626A1 EP21825333.4A EP21825333A EP4164626A1 EP 4164626 A1 EP4164626 A1 EP 4164626A1 EP 21825333 A EP21825333 A EP 21825333A EP 4164626 A1 EP4164626 A1 EP 4164626A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- granulate
- pretomanid
- solvate
- formulation
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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- 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
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- 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
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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 and/or solvate individually thereof, and a pharmaceutically acceptable excipient.
- the disclosure also describes methods for preparing the same and for treating tuberculosis comprising the step of administering said fixed-dose pharmaceutical dosage form to a patient in need thereof.
- a formulation comprising extragranular excipients; and a plurality of granulates, each granulate independently comprising intragranular excipients and one or two APIs; wherein the APIs are each independently pretomanid, moxifloxacin, or pyrazinamide; each API, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof; and the plurality of granulates, taken in combination, contain each of pretomanid, moxifloxacin, or pyrazinamide, or the salt and/or solvates thereof.
- a process for preparing a formulation comprising either compressing a portion of a blend to provide a tablet or filling capsules or sachets with a blend, wherein the blend comprises a mixture of: extragranular excipients; and a plurality of granulates, each granulate comprising intragranular excipients and one or two APIs, wherein the APIs are each independently pretomanid, moxifloxacin, or pyrazinamide; each API, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof; and the plurality of granulates, taken in combination, contain each of pretomanid, moxifloxacin, or pyrazinamide, or the salt and/or solvates thereof.
- a process for preparing a formulation comprising either compressing a portion of a first blend and a portion of a second blend to provide a bilayer tablet, or filling capsules or sachets with a first and second blend, wherein the bilayer comprises a first layer and a second layer in cohesive contact with the first layer; the first layer comprises the first blend and the second layer comprises the second blend, the first and second blend each, independently, comprise extragranular excipients and one or more granulates of a plurality of granulates, each of the plurality of granulates comprising intragranular excipients and one or two APIs, the APIs are each independently pretomanid, moxifloxacin, or pyrazinamide, each API, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof, and the plurality of granulates, taken in combination, contain each of pretomanid, moxifloxacin, or pyra
- a method of treating tuberculosis comprising administering a therapeutically effective amount of a formulation according to or prepared according to any of the preceding aspects.
- Figure 1 is a flow chart illustrating an exemplary process for preparing API granulates as described herein; elements shown with dashed outlines are optional.
- Figure 2a is a flow chart illustrating an exemplary process for preparing a monolayer tablet as described herein; elements shown with dashed outlines are optional.
- Figure 2b is a flow chart illustrating an exemplary process for preparing a monolayer tablet as described herein; elements shown with dashed outlines are optional.
- Figure 3a is a flow chart illustrating an exemplary process for preparing a bilayer tablet as described herein; elements shown with dashed outlines are optional.
- Figure 3b is a flow chart illustrating an exemplary process for preparing a bilayer tablet as described herein; elements shown with dashed outlines are optional.
- Figure 3c is a flow chart illustrating an exemplary process for preparing a bilayer tablet as described herein; elements shown with dashed outlines are optional.
- 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, 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.
- FDC Fixed dose combinations
- a desired daily regimen may be presented in a single dose or as two or more sub-doses per day.
- the pharmaceutically active compounds and combinations thereof herein may be referred to as "active ingredients", “API” or “pharmaceutically active agents.”
- APIs described herein include pretomanid, bedaquiline, moxifloxacin, and pyrazinamide, and the pharmaceutically acceptable salts and/or solvates thereof.
- Each of the APIs in the dosage forms may be present in any suitable polymorphic form, any pharmaceutically acceptable salt, and/or any suitable solvate thereof.
- pharmaceutically acceptable salts 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, hydrobromic, 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 or carboxylic 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 C1-C4 alkyl group).
- a suitable cation such as Na + and NX4 + (wherein X is independently selected from H or a C1-C4 alkyl group).
- Alkyl refers to a univalent group derived from a linear or branched alkane by removal of a hydrogen atom from any carbon atom (-CnFhn +i ). Examples of alkyl groups include, but are not limited to, methyl, ethyl, isopropyl, sec-butyl, and n-butyl.
- 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).
- Pretomanid 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 is a BCS class ll/IV compound that demonstrates poor solubility but high permeability which can result in solubility-limited absorption.
- 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 currently 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.
- Pyrazinamide (pyrazine-2-carboxamide, also referred herein as "Z") is the pyrazine analogue of nicotinamide and is 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”).
- 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 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, for example 50-2000 mg pyrazinamide, 10 - 800 mg moxifloxacin, 10 - 400 mg pretomanid, and 10 - 400 mg bedaquiline.
- the daily dosages of the active ingredients can be 1500 mg pyrazinamide, 400 mg moxifloxacin, 200 mg pretomanid, and 100 or 200 mg bedaquiline, when present.
- Each of the preceding amounts of APIs can be understood to refer to the amount of the API free base, where an equivalent amount of a pharmaceutically acceptable salt and/or solvate may be used in place of a free base form.
- 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:
- the several unit doses noted above may be administered together to a person in need thereof to provide the total daily dose.
- 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 to provide the total daily dose.
- compositions containing the active ingredients may be in any form suitable for the intended method of administration.
- tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules for oral suspension, sachets, emulsions, 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 may involve 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; or may involve blending of two or more granulates, each prepared to contain one or more APIs.
- a formulation may be in the form of a monolithic tablet that contains Pa, M, Z, and optionally B.
- each of the preceding APIs may be separately granulated, and the granulates of the individual APIs may be blended together with optional extragranular excipients to provide the monolithic tablet.
- a formulation may be in the form of a bilayer tablet, for example, that contains a first layer that contains M and Z and a second layer that contains Pa and optionally B.
- each of the preceding APIs may be separately granulated, and the granulates of the individual APIs may be blended together with optional extragranular excipients to provide the layers of a bilayer tablet.
- "Bilayer” as used herein means two chemically distinct domains that are in physical contact to form a unitary dosage form.
- bilayer includes two domains that are either vertically or horizontally arranged stacked or in a core-shell arrangement.
- each API granulate comprises the respective API and one or more intragranular excipients.
- Suitable intragranular excipients include, but are not limited to, one or more diluents, binders, surfactants, disintegrants, and mixtures thereof. Examples of intragranular excipients are described further below.
- each layer may independently contain extragranular excipients, i.e., a first layer can contain first extragranular excipients, and a second layer can contain second extragranular excipients.
- Each extragranular excipient can be selected, independently, from the group consisting of a diluent, a disintegrant, a glidant, a lubricant, a coloring agent, a sweetener, a flavoring, an antioxidant, a preservative, and mixtures thereof. Examples of extragranular excipients are described further below.
- extragranular excipients may be include, one or more diluents (fillers), sweeteners, binders, suspending (thickening) agents, buffers, glidants, flavorings, or coloring agents.
- Suitable suspending agents include, for example, hydrocolloid gums such as xanthan gum, guar gum, locust bean gum, gum tragacanth, veegum, sodium alginate, and the like.
- synthetic suspending agents may be used such as sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and the like.
- the amount of the suspending agent used in the powder for oral suspension compositions may be in the range of from about 0.1% to about 10% w/w based on the total weight of the powder for oral suspension.
- 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.
- diluents may be selected from the group consisting of dibasic calcium phosphate, tribasic calcium phosphate, talc, dextrose, fructose, isomalt, lactose, maltose, sucrose, trehalose, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, and mixtures thereof.
- diluents may be selected from the group consisting of dextrose, fructose, lactose, maltose, sucrose, trehalose, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof.
- diluents may be selected from the group consisting of dextrose, lactose, sucrose, trehalose, mannitol, sorbitol, xylitol, microcrystalline cellulose, and mixtures thereof.
- diluents may be selected from the group consisting of lactose, microcrystalline cellulose, and mixtures thereof.
- 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.
- binders may be selected from the group consisting of pre-gelatinized starch, povidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose; and mixtures thereof. In certain embodiments, binders may be selected from the group consisting of pre-gelatinized starch, povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose; and mixtures thereof.
- binders may be selected from the group consisting of pre-gelatinized starch, povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose; and mixtures thereof. In certain embodiments, binders may be selected from the group consisting of povidone, hydroxypropyl methylcellulose (HPMC), 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.
- alginic acid carboxymethyl
- disintegrants may be selected from the group consisting of carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium alginate, sodium starch glycolate, corn starch, and mixtures thereof. In certain embodiments, disintegrants may be selected from the group consisting of carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, corn starch, and mixtures thereof. In certain embodiments, disintegrants may be selected from the group consisting of corn starch, sodium starch glycolate, croscarmellose sodium, and mixtures 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 tetrakis(
- 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
- surfactants may be one or more non-ionic surfactants.
- one or more non-ionic surfactants may be selected from the group consisting of glyceryl dibehenate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, glyceryl tristearate; sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate, sorbitan trioleate, and sorbitan tristearate; stearic acid ethoxylate, lauric acid ethoxylate, polyoxyethylene lauryl ethers (Brij), polyoxyl 35 castor oil (Cremophor EL), hydrogenated polyoxyl 40 castor oil (Cremophor RH 40), polyoxyethylene sorbitan monolaurate (polysorbate 20), polyoxyethylene sorbitan monopalmitate (polysorbate 40), polyoxyethylene sorbitan monostea
- one or more non-ionic surfactants may be selected from the group consisting of polyoxyethylene sorbitan monolaurate (polysorbate 20), polyoxyethylene sorbitan monopalmitate (polysorbate 40), polyoxyethylene sorbitan monostearate (polysorbate 60), polyoxyethylene sorbitan monooleate (polysorbate 80), and mixtures thereof.
- surfactants may be one or more anionic surfactants.
- one or more anionic surfactants may be selected from the group consisting of sodium dodecyl sulfate (sodium lauryl sulfate), ammonium lauryl sulfate, sodium deoxycholate, docusate sodium , sodium dodecylbenzenesulfonate, ammonium dinonyl sulfosuccinate, diamyl sulfosuccinate sodium, dicapryl sulfosuccinate sodium, diheptyl sulfosuccinate sodium, dihexyl sulfosuccinate sodium, diisobutyl sulfosuccinate sodium, and ditridecyl sulfosuccinate sodium, lauryl monoglyceryl sulfate, and mixtures thereof.
- sodium dodecyl sulfate sodium lauryl sulfate
- ammonium lauryl sulfate sodium deoxycholate
- docusate sodium sodium
- surfactants may be selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, ammonium lauryl sulfate, sodium deoxycholate, docusate sodium, sodium dodecylbenzenesulfonate, and mixtures thereof. In certain embodiments, surfactants may be selected from the group consisting of sodium lauryl sulfate, polysorbate 20, and mixtures thereof.
- Lubricants may be added to pharmaceutical compositions immediately prior to tablet compression to reduce the frictional forces between particles and between particles and metal-contact surfaces of manufacturing equipment such as tablet punches and dies used in the manufacture of solid dosage forms.
- 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
- lubricants may be selected from the group consisting of 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.
- lubricants may be selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate and mixtures thereof.
- a lubricant may be 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.
- the glidant may comprise colloidal silicon dioxide, microcrystalline cellulose, sodium aluminosilicate, calcium silicate, magnesium silicate, magnesium trisilicate, magnesium aluminosilicate, or a mixture thereof.
- the glidant may comprise colloidal silicon dioxide.
- glidants may be selected from the group consisting of microcrystalline cellulose, colloidal silicon dioxide, and mixtures thereof.
- 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.
- 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
- each of the APIs may be separately granulated with intragranular excipients, or two of the APIs may be granulated together with intragranular excipients to provide a plurality of granulates. That is, a pretomanid granulate (“Pa granulate”), a bedaquiline granulate (“B granulate”), a moxifloxacin granulate (“M granulate”), and/or a pyrazinamide granulate (“Z granulate”) may be prepared.
- a pretomanid granulate (“Pa granulate")
- B granulate bedaquiline granulate
- M granulate moxifloxacin granulate
- Z granulate a pyrazinamide granulate
- combination granulates include a pretomanid and bedaquiline granulate ("B+Pa granulate”) and a moxifloxacin and pyrazinamide granulate (“M+Z granulate”).
- B+Pa granulate pretomanid and bedaquiline granulate
- M+Z granulate moxifloxacin and pyrazinamide granulate
- a Pa granulate and a M+Z granulate are prepared.
- a B granulate, a Pa granulate, and a M+Z granulate are prepared.
- a B+Pa granulate and a M+Z granulate are prepared.
- the following sets of granulates may be prepared, where individual granulates are separated by commas and combination granulates are joined by "+":
- Each granulation may be according to a wet or dry granulation process in the presence of a suitable binder, as is familiar to those skilled in the art.
- a dry granulating process e.g., blending and slugging of the dry components
- the binder may comprise a dry binder such as 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 a wet binder and, optionally, a surfactant).
- wet binders include, pre-gelatinized starch, povidone (e.g. Povidone K30), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC), and mixtures thereof.
- povidone e.g. Povidone K30
- HPMC hydroxypropyl methylcellulose
- a mixture thereof may be used as a wet binder.
- the prepared API granulate may be sized and/or dried to a suitable wt.% residual solvent and/or water and particle size distribution.
- Sizing may be through one or more reduction processes, such as sieving and/or milling to provide a sized API granulate having a desired particle size distribution. Drying and sizing can be in any suitable order depending on the properties of the granulate. For example, a granulate prepared by wet granulation may be wet milled prior to drying. In another example, a wet granulate may be dried followed by dry milling and/or sieving.
- each API granulate independently comprises one or more intragranular excipients.
- intragranular excipients may be one or excipient selected from the group consisting of binders, diluents, surfactants, disintegrants, and mixtures thereof.
- each API granulate independently comprises one or more intragranular excipients selected from the group consisting of binders, diluents, disintegrants, optional surfactants, and mixtures thereof.
- a B granulate may comprise bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and one or more intragranular excipients.
- the B granulate comprises one or more intragranular excipients selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, and mixtures thereof.
- the B granulate comprises one or more intragranular excipients that are lactose, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose (E15), and polysorbate 20.
- a B granulate may comprise 10 - 50 w/w% bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof (e.g., bedaquiline fumarate), 30 - 70 w/w% diluent; 5 - 35 w/w% disintegrant, 1-10 w/w% binder, and 0 - 5 w/w% surfactant.
- a Pa granulate may comprise pretomanid or a pharmaceutically acceptable salt and/or solvate thereof and one or more intragranular excipients.
- the Pa granulate comprises one or more intragranular excipients selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, and mixtures thereof.
- the Pa granulate comprises one or more intragranular excipients that are lactose, sodium starch glycolate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.
- a Pa granulate may comprise 10 - 50 w/w% pretomanid or a pharmaceutically acceptable salt and/or solvate thereof (e.g., pretomanid free base), 40 - 85 w/w% diluent; 0 - 5 w/w% disintegrant, 1-10 w/w% binder, and 0 - 5 w/w% surfactant.
- a B+Pa granulate may comprise bedaquiline, pretomanid or a pharmaceutically acceptable salt and/or solvate of either thereof and one or more intragranular excipients.
- the B+Pa granulate comprises one or more intragranular excipients selected from the group consisting of a diluent, a disintegrant, a binder, and mixtures thereof.
- the M+Z granulate comprises one or more intragranular excipients that are lactose, sodium starch glycolate, microcrystalline cellulose, povidone, sodium lauryl sulfate, corn starch, hydroxypropyl methylcellulose (E15), and polysorbate 20.
- a B+Pa granulate may comprise 50 - 95 w/w% of the sum of moxifloxacin and pyrazinamide or a pharmaceutically acceptable salt and/or solvate of either thereof (e.g., moxifloxacin free base or moxifloxacin hydrochloride and pyrazinamide), 1 - 15 w/w% diluent; 0 - 10 w/w% disintegrant, 1-5 w/w% binder, and 0-5 w/w% surfactant.
- the B+Pa granulate comprises pretomanid free base and bedaquiline free base.
- the B+Pa granulate comprises pretomanid and bedaquiline fumarate.
- a M granulate may comprise moxifloxacin or a pharmaceutically acceptable salt and/or solvate of thereof and one or more intragranular excipients.
- the M granulate comprises one or more intragranular excipients selected from the group consisting of a diluent, a disintegrant, a binder, and mixtures thereof.
- the M granulate comprises moxifloxacin free base and pyrazinamide free base.
- the M granulate comprises moxifloxacin hydrochloride.
- the M granulate comprises moxifloxacin hydrochloride monohydrate.
- a M granulate may comprise 10 - 50 w/w% moxifloxacin or a pharmaceutically acceptable salt and/or solvate thereof (e.g., moxifloxacin hydrochloride), 40 85 w/w% diluent; 0 5 w/w% disintegrant, 1-10 w/w% binder, and 0 5 w/w% surfactant.
- a pharmaceutically acceptable salt and/or solvate thereof e.g., moxifloxacin hydrochloride
- a Z granulate may comprise pyrazinamide or a pharmaceutically acceptable salt and/or solvate of thereof and one or more intragranular excipients.
- the Z granulate comprises one or more intragranular excipients selected from the group consisting of a diluent, a disintegrant, a binder, and mixtures thereof.
- the Z granulate comprises pyrazinamide free base.
- a Z granulate may comprise 10 50 w/w% pyrazinamide or a pharmaceutically acceptable salt and/or solvate thereof (e.g., pyrazinamide free base), 40 85 w/w% diluent; 0 5 w/w% disintegrant, 1-10 w/w% binder, and 0 - 5 w/w% surfactant.
- a M+Z granulate may comprise moxifloxacin, pyrazinamide or a pharmaceutically acceptable salt and/or solvate of either thereof and one or more intragranular excipients.
- the M+Z granulate comprises one or more intragranular excipients selected from the group consisting of a diluent, a disintegrant, a binder, and mixtures thereof.
- the M+Z granulate comprises one or more intragranular excipients that are microcrystalline cellulose, croscarmellose sodium, and povidone.
- a M+Z granulate may comprise 60 95 w/w% of the sum of moxifloxacin and pyrazinamide or a pharmaceutically acceptable salt and/or solvate of either thereof (e.g., moxifloxacin free base or moxifloxacin hydrochloride and pyrazinamide), 1 - 15 w/w% diluent; 0 10 w/w% disintegrant, 1-5 w/w% binder, and 0 5 w/w% surfactant.
- the M+Z granulate comprises moxifloxacin free base and pyrazinamide free base.
- the M+Z granulate comprises moxifloxacin hydrochloride and pyrazinamide free base. In another example, the M+Z granulate comprises moxifloxacin hydrochloride monohydrate and pyrazinamide free base.
- a process is exemplified for the preparation of the API granulates.
- a selected API (100) or combination of APIs and intragranular excipients (101) are sifted through a suitable sized screen (e.g., through 20 or 30 ASTM).
- a granulation solution (121) comprising a wet binder and an optional surfactant in a solvent (e.g., water) is prepared.
- the sifted materials are wet granulated (120) with the granulation solution (121), for example, by a top spray granulation process or in a rapid mixer granulator.
- API granulates are processed (130) to provide the API granulate (140) having a desired residual solvent content and/or particle size distribution.
- examples of API granulates that may be prepared include B granulates, Pa granulates, and M+Z granulates.
- Processing (130) may include one or more drying and/or particle size reduction processes in a suitable order, as discussed above.
- the granules may be dried to a desired residual solvent content, and the particle size of the dried granules may be reduced by sifting through a suitable screen (e.g., through #25 ASTM screen) followed by milling the retention through a second suitable screen (e.g., a 40G screen via a co-mill).
- a suitable screen e.g., through #25 ASTM screen
- a second suitable screen e.g., a 40G screen via a co-mill
- the granules may be wet milled (e.g., in a Quadro Co mil fitted with 250 Q screen), the milled granules dried (e.g., in a fluidized bed dryer at an inlet air temperature of 50°C until loss on drying (LOD) of no more than (NMT) 2.0% w/w is achieved), and the dried granules sifted through a suitable screen (e.g., through a Quadro Co mil fitted with an 50G screen).
- LOD loss on drying
- Such API granulates may be used to prepare a variety of oral unit dosage forms, including, but not limited to, monolayer tablets, bilayer tablets, filled hard capsules, and sachets containing powders for oral suspension.
- Oral unit dosage forms may be prepared by combining one or more API granulates with one or more extragranular excipients to provide a blend. In the preparation of tablets, a portion of the blend may be compressed into a tablet. Such tablets may optionally contain a coating layer over an outer surface of the tablet.
- Oral unit dosage forms herein may comprise about 60 - 99 w/w % API granulates (i.e., the sum of all API granulates present) and about 1 - 40 w/w % extragranular excipients; or 70 - 99 w/w % API granulates (i.e., the sum of all API granulates present) and about 1 - 30 w/w % extragranular excipients; 80 - 99 w/w % API granulates (i.e., the sum of all API granulates present) and about 1 - 20 w/w % extragranular excipients.
- the tablets herein may comprise about 85 - 95 w/w % API granulates and about 5 - 15 w/w % extragranular excipients; or about 90 - 95 w/w % API granulates and about 5 - 10 w/w % extragranular excipients.
- extragranular excipients (201) are sifted (210) through a suitable sized screen (e.g., through 30 # ASTM) and blended (220) with one or more additional API granulates (221, 223, 224 and/or 225).
- an optional lubricant (231) such as magnesium stearate that has been sifted through #60 ASTM, may be added and blending (230) continued to yield a blend.
- a desired portion of the blend may be compressed (240) to provide tablets that may be optionally coated (250) with a coating layer (e.g., an OPADRY coating) to provide the monolayer tablets (260).
- extragranular excipients (201) are sifted (210) through a suitable sized screen (e.g., through 30 # ASTM) and blended (220) with one or more additional API granulates (221, 222, and/or 225).
- an optional lubricant (231) such as magnesium stearate that has been sifted through #60 ASTM, may be added and blending (230) continued to yield a blend.
- a desired portion of the blend may be compressed (240) to provide tablets that may be optionally coated (250) with a coating layer (e.g., an OPADRY coating) to provide the monolayer tablets (260).
- the process of Figures 2a and 2b may be modified for the preparation of other oral dosage forms described herein.
- the blend may be directly filled into capsules or sachets to provide such alternative dosage forms (not illustrated).
- the blend may filled directly into capsules or be formed into minitablets or pellets for filling into capsules.
- minitablets and pellets may have a diameter suitable for inserting into a capsule for oral administration.
- minitablets may have a diameter of about 2 - 5 mm (e.g., about 2.25 mm), and pellets may have a diameter of about 0.5 - 2 mm (e.g., about 0.6 - 1.2 mm).
- the minitablets or pellets may be optionally coating with a film coating agent as noted below.
- the preceding formulations may comprise 10 - 30 w/w% of a B granulate, 10 - 30 w/w% of a Pa granulate, 35 - 75 w/w% of a M+Z granulate, and 0 - 20 w/w% of the extragranular excipients.
- the extragranular excipient portion may comprise 30-70 w/w% glidants. 5 - 45 w/w% disintegrants, and 5 -25 w/w% lubricants.
- extragranular excipients for the preparation of the preceding formulations when present, may be selected from the group consisting of glidants, disintegrants, lubricants, coloring agents, antioxidants, preservatives, and flavorings.
- extragranular excipients for the preparation of monolayer tablets when present, may be selected from the group consisting of one or more glidant, disintegrant, lubricant, and mixtures thereof.
- extragranular excipients for the preparation of the preceding formulations when present, are microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and optionally, magnesium stearate.
- extragranular excipients for the preparation of the preceding formulations e.g., monolayer tablets, capsules, or sachets
- extragranular excipients for the preparation of the preceding formulations are microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
- all extragranular excipients are provided at (210) except for an optional lubricant (231) which, when present, is provided at blending (230).
- 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.
- 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.
- the film coating agents
- 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.
- FIG. 3a a process is exemplified for the preparation of bilayer tablets from the preceding API granulates.
- two blends (380, 385) are prepared via similar processes to that of Figure 2, wherein, when present, first extragranular excipients (300) and second extragranular excipients (305) are separately sifted (310, 315) through a suitable sized screen (e.g., through 30 # ASTM) and blended (320, 325) with one or more additional API granulates (322, 323, 326, and/or 327).
- first extragranular excipients 300
- second extragranular excipients (305) are separately sifted (310, 315) through a suitable sized screen (e.g., through 30 # ASTM) and blended (320, 325) with one or more additional API granulates (322, 323, 326, and/or 327).
- first extragranular excipients (300) are blended (320) with an M granulate (322) and a Z granulate (323), and second extragranular excipients (305) are blended (325) with a Pa granulate (326) and optionally, a B granulate (327).
- an optional lubricant (331, 332) such as magnesium stearate that has been sifted through #60 ASTM, may be added to the respective blend and blending (330, 335) continued to yield blend A (380) and blend B (385).
- a desired portion of each of blend A (380) and blend B (385) may be compressed (340) to provide bilayer tablets, where one layer consists of blend A (380) and the other layer consists of blend B (385).
- the bilayer tablet may be optionally coated (350) with a coating layer (e.g., an OPADRY coating or a film coating agent noted above) to provide the bilayer tablets (360).
- a coating layer e.g., an OPADRY coating or a film coating agent noted above
- first extragranular excipients (300) are blended (320) with an M+Z granulate (321) and second extragranular excipients (305) are blended (325) with a Pa granulate (326) and optionally, a B granulate (327).
- an optional lubricant (331, 332) such as magnesium stearate that has been sifted through #60 ASTM, may be added to the respective blend and blending (330, 335) continued to yield blend A (380) and blend B (385).
- a desired portion of each of blend A (380) and blend B (385) may be compressed (340) to provide bilayer tablets, where one layer consists of blend A (380) and the other layer consists of blend B (385).
- the bilayer tablet may be optionally coated (350) with a coating layer (e.g., an OPADRY coating or a film coating agent noted above) to provide the bilayer tablets (360).
- a coating layer e.g., an OPADRY coating or a film coating agent noted above
- all extragranular excipients (300, 305) are added at (310, 315) except for lubricants (331,332) that are added at blending (330) and (335).
- FIG. 3c a process is exemplified for the preparation of bilayer tablets from the preceding API granulates.
- two blends (380, 385) are prepared via similar processes to that of Figure 2, wherein, when present, first extragranular excipients (300) and second extragranular excipients (305) are separately sifted (310, 315) through a suitable sized screen (e.g., through 30 # ASTM) and blended (320, 325) with one or more additional API granulates (321 and 328).
- first extragranular excipients (300) and second extragranular excipients (305) are separately sifted (310, 315) through a suitable sized screen (e.g., through 30 # ASTM) and blended (320, 325) with one or more additional API granulates (321 and 328).
- first extragranular excipients (300) are blended (320) with an M+Z granulate (321) and second extragranular excipients (305) are blended (325) with a B+Pa granulate (328).
- an optional lubricant (331, 332) such as magnesium stearate that has been sifted through #60 ASTM, may be added to the respective blend and blending (330, 335) continued to yield blend A (380) and blend B (385).
- a desired portion of each of blend A (380) and blend B (385) may be compressed (340) to provide bilayer tablets, where one layer consists of blend A (380) and the other layer consists of blend B (385).
- the bilayer tablet may be optionally coated (350) with a coating layer (e.g., an OPADRY coating or a film coating agent noted above) to provide the bilayer tablets (360).
- a coating layer e.g., an OPADRY coating or a film coating agent noted above
- all extragranular excipients (300, 305) are added at (310, 315) except for lubricants (331,332) that are added at blending (330) and (335).
- Blends (A) and (B) may be filled into capsules or sachets to provide such alternative dosage forms (not illustrated).
- Such oral dosage forms of Figures 3a - 3c e.g., bilayer tablets, capsules, or sachets
- Such oral dosage forms of Figures 3a - 3c may comprise 50 - 70 w/w% of blend A (380) and 30 - 50 w/w% of blend B (385); or 55-65 w/w% of blend A (380) and 35 - 45 w/w% of blend B (385).
- Blend (A) may comprise, for example, 75 - 100 w/w% of the M+Z granulate and 0-25 w/w% of first extragranular excipients. Or, Blend (A) may comprise, for example 85 - 95 w/w% of the M+Z granulate and 5 - 15 w/w% of first extragranular excipients. Blend (B) may comprise, for example, 35 - 65 w/w% of the B granulate, 35-65 w/w% of the Pa granulate, and 0 -10 w/w% of the second extragranular excipients. Or, blend (B) may comprise, for example, 43 - 53 w/w% of the B granulate, 43 - 53 w/w% of the Pa granulate, and 1-5 w/w% of the second extragranular excipients.
- the formulations of Figures 3a - 3c may comprise 10 - 30 w/w% of the B granulate, 10 - 30 w/w% of the Pa granulate, 35 - 75 w/w% of the M+Z granulate, and 0 - 20 w/w% of the sum of the first and second extragranular excipients.
- the bilayer tablets may comprise 15 - 25 w/w% of the B granulate, 15 - 25 w/w% of the Pa granulate, 45 - 65 w/w% of the M+Z granulate, and 5-15 w/w% of the sum of the first and second extragranular excipients.
- the formulations of Figures 3a - 3c may comprise 20 - 60 w/w% of the B+Pa granulate, 35 - 75 w/w% of the M+Z granulate, and 0 - 20 w/w% of the sum of the first and second extragranular excipients.
- the bilayer tablets may comprise 30 - 50 w/w% of the B+Pa granulate, 45 - 65 w/w% of the M+Z granulate, and 5-15 w/w% of the sum of the first and second extragranular excipients.
- first extragranular excipients (300) and second extragranular excipients (305) in the formulations of Figures 3a - 3c are as described above for monolayer tablets.
- each of the first extragranular excipients and second extragranular excipients independently comprise one or more excipients selected from the group consisting of glidants, disintegrants, lubricants, coloring agents, antioxidants, preservatives, and flavorings.
- each of the first extragranular excipients and second extragranular excipients independently comprise one or more glidant, disintegrant, and/or lubricant.
- each of the first extragranular excipients and the second extragranular excipients may comprise, for example 30 - 70 w/w% of glidants, 5 -45 w/w% disintegrants, and 5-25 w/w% lubricants based on the total mass of all first extragranular excipients or the second extragranular excipients, respectfully.
- the first extragranular excipients (300) comprise one or more glidant, disintegrant, and/or lubricant.
- the first extragranular excipients comprise microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.
- blend (B)(380) comprises a Pa granulate and optionally a B granulate
- the second extragranular excipients (305) comprise one or more glidant, disintegrant, and/or lubricant.
- blend (B) comprises a Pa granulate and optionally a B granulate
- the second extragranular excipients croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.
- blend (B) comprises the B granulate.
- blend (B)(380) comprises a B+Pa granulate then the second extragranular excipients (305) comprise one or more glidant, disintegrant, and/or lubricant.
- the second extragranular excipients croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.
- Monolayer and bilayer 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.
- suitable tooling for example, 19.0 mm x 9.0 mm capsule shaped, normal biconcave tooling.
- 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 tablets may optionally be scored.
- Core-shell tablets may be prepared, for example, by preparing a core from one of Blend (A) or (B) and coating the core with the other of Blend (A) and (B).
- a monolayer tablet, capsule, or sachet can comprise extragranular excipients; a first granulate comprising moxifloxacin and first intragranular excipients; a second granulate comprising pyrazinamide and second intragranular excipients; and a third granulate comprising pretomanid and third intragranular excipients; wherein each of the pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- a monolayer tablet, capsule, or sachet can comprise extragranular excipients; a first granulate comprising moxifloxacin and first intragranular excipients; a second granulate comprising pyrazinamide and second intragranular excipients; a third granulate comprising pretomanid and third intragranular excipients; and a fourth granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and fourth intragranular excipients, wherein each of the bedaquiline, pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- a monolayer tablet, capsule, or sachet can comprise extragranular excipients and one of the following sets of granulates, where granulates are separated by commas and combination granulates are joined by wherein each of the bedaquiline (when present), pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- a monolayer tablet, capsule, or sachet can comprise an extragranular excipient; a first granulate comprising moxifloxacin, pyrazinamide, and first intragranular excipient; and a second granulate comprising pretomanid and second intragranular excipients; wherein the first and second intragranular excipients, independently, comprise one or more diluent, disintegrant, binder, and/or optional surfactant; the extragranular excipient comprises one or more glidant, disintegrant, and lubricant; and each of the pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- a monolayer tablet, capsule, or sachet can comprise an extragranular excipient; a first granulate comprising moxifloxacin, pyrazinamide, and first intragranular excipient; a second granulate comprising pretomanid and second intragranular excipients; and a B granulate comprising bedaquiline and third intragranular excipients, wherein the first, second, and third intragranular excipients, independently, comprise one or more diluent, disintegrant, binder, and/or optional surfactant; the extragranular excipient comprises one or more glidant, disintegrant, and/or lubricant; and each of the pretomanid, bedaquiline, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- a monolayer tablet, capsule, or sachet can comprise a second granulate comprising pretomanid or a pharmaceutically acceptable salt and/or solvate thereof and one or more diluent, disintegrant, binder, and/or surfactant; a first granulate comprising moxifloxacin, pyrazinamide, or a pharmaceutically acceptable salt and/or solvate of either thereof and one or more diluent, disintegrant, and/or binder; and extragranular excipients comprising one or more glidant, disintegrant and/or lubricant.
- a monolayer tablet, capsule, or sachet can comprise a B granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and one or more diluent, disintegrant, binder, and/or surfactant; a second granulate comprising pretomanid or a pharmaceutically acceptable salt and/or solvate thereof and one or more diluent, disintegrant, binder, and/or surfactant; a first granulate comprising moxifloxacin, pyrazinamide, or a pharmaceutically acceptable salt and/or solvate of either thereof and one or more diluent, disintegrant, and/or binder; and extragranular excipients comprising one or more glidant, disintegrant and/or lubricant.
- a monolayer tablet, capsule, or sachet can comprise a second granulate comprising pretomanid or a pharmaceutically acceptable salt and/or solvate thereof, lactose, sodium starch glycolate, microcrystalline cellulose, povidone, and sodium lauryl sulfate; a first granulate comprising moxifloxacin, pyrazinamide, or a pharmaceutically acceptable salt and/or solvate of either thereof, microcrystalline cellulose, croscarmellose sodium, and povidone; extragranular excipients comprising, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
- a monolayer tablet, capsule, or sachet can comprise a B granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof, lactose, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose (E15), and polysorbate 20; a second granulate comprising pretomanid or a pharmaceutically acceptable salt and/or solvate thereof, lactose, sodium starch glycolate, microcrystalline cellulose, povidone, and sodium lauryl sulfate; a first granulate comprising moxifloxacin, pyrazinamide, or a pharmaceutically acceptable salt and/or solvate of either thereof, microcrystalline cellulose, croscarmellose sodium, and povidone; and extragranular excipients comprising microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
- a bilayer tablet comprises extragranular excipients and first, second, and third granulates, wherein the first layer comprises one or two of the first, second, and third granulates, and the second layer, in contact with the first layer, comprises the remaining granulates of the first, second, and third granulates, wherein the first granulate comprises moxifloxacin and first intragranular excipients; a second granulate comprises pyrazinamide and second intragranular excipients; a third granulate comprises pretomanid and third intragranular excipients; wherein each of the pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- a bilayer tablet comprises extragranular excipients and first, second, third, and fourth granulates, wherein the first layer comprises one, two, or three of the first, second, third, and fourth granulates, and the second layer, in contact with the first layer, comprises the remaining granulates of the first, second, third, and fourth granulates, wherein the first granulate comprises moxifloxacin and first intragranular excipients; a second granulate comprises pyrazinamide and second intragranular excipients; a third granulate comprises pretomanid and third intragranular excipients; and a fourth granulate comprises bedaquiline and fourth intragranular excipients, wherein each of the bedaquiline pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- a bilayer tablet comprises a first layer comprising a first granulate and first extragranular excipients, wherein the first granulate comprises moxifloxacin, pyrazinamide, or a pharmaceutically acceptable salt and/or solvate of either thereof and one or more diluent, disintegrant, and/or binder; and the first extragranular excipients comprise one or more glidant, disintegrant, and/or lubricant; and a second layer comprising a second granulate and second extragranular excipients, wherein the second granulate comprises pretomanid or a pharmaceutically acceptable salt and/or solvate thereof and one or more diluent, disintegrant, binder, and/or surfactant; and the second extragranular excipients comprise one or more glidant, disintegrant, and/or lubricant.
- a bilayer tablet comprises a first layer comprising a first granulate and first extragranular excipients, wherein the first granulate comprises moxifloxacin, pyrazinamide, or a pharmaceutically acceptable salt and/or solvate of either thereof and one or more diluent, disintegrant, and/or binder; and the first extragranular excipients comprise one or more glidant, disintegrant, and/or lubricant; and a second layer comprising a B granulate, a Pa granulate, and second extragranular excipients, wherein the B granulate comprises bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and one or more diluent, disintegrant, binder, and/or surfactant; the Pa granulate comprises pretomanid or a pharmaceutically acceptable salt and/or solvate thereof and one or more diluent, disintegrant, binder, and/or surfactant; and the second extragranulate
- a bilayer tablet comprises a first layer comprising a first granulate and first extragranular excipients, wherein the first granulate comprises moxifloxacin, pyrazinamide, or a pharmaceutically acceptable salt and/or solvate of either thereof, microcrystalline cellulose, croscarmellose sodium, and povidone; and the first extragranular excipients comprise microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate; and a second layer comprising a Pa granulate and second extragranular excipients, wherein the Pa granulate comprises pretomanid or a pharmaceutically acceptable salt and/or solvate thereof, lactose, sodium starch glycolate, microcrystalline cellulose, povidone, and sodium lauryl sulfate; and the second extragranular excipients comprise croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
- a bilayer tablet comprises a first layer comprising a first granulate and first extragranular excipients, wherein the first granulate comprises moxifloxacin, pyrazinamide, or a pharmaceutically acceptable salt and/or solvate of either thereof, microcrystalline cellulose, croscarmellose sodium, and povidone; and the first extragranular excipients comprise microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate; and a second layer comprising a B granulate, a Pa granulate, and second extragranular excipients, wherein the B granulate comprises bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof, lactose, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose (E15), and polysorbate 20; the Pa granulate comprises pretomanid or a pharmaceutically acceptable salt and/or solvate thereof, lactose, sodium starch glycolate, microcrystalline cellulose
- a bilayer tablet comprises a first layer and a second layer in cohesive contact with the first layer, wherein the first layer comprises a first blend and the second layer comprises a second blend, or a capsule or sachet comprises a first blend and a second blend, wherein the first and second blends contain first and second extragranular excipients, respectively, and one of the following sets of granulates (where granulates are separated by commas and combination granulates are joined by wherein each of the bedaquiline (when present), pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- the formulations e.g., monolayer and bilayer tablets, as described herein are chemically stable.
- the term “chemical stability” or “chemically stable” means that the antibacterial agents therein combination are substantially stable to chemical degradation.
- 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 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.
- the pretomanid is pretomanid free base or a solvate thereof;
- the bedaquiline when present, is bedaquiline fumarate or a solvate thereof,
- the moxifloxacin is moxifloxacin free base or a solvate thereof, and
- the pyrazinamide is pyrazinamide free base or a solvate thereof.
- the pretomanid is pretomanid free base or a solvate thereof;
- the bedaquiline when present, is bedaquiline fumarate or a solvate thereof,
- the moxifloxacin is moxifloxacin hydrochloride or a solvate thereof, and
- the pyrazinamide is pyrazinamide free base or a solvate thereof.
- the pretomanid is pretomanid free base or a solvate thereof;
- the bedaquiline when present, is bedaquiline fumarate or a solvate thereof,
- the moxifloxacin is moxifloxacin hydrochloride monohydrate, and
- the pyrazinamide is pyrazinamide free base or a solvate thereof.
- 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.
- 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 [IUATLDJ/WHO scale on smear microscopy), or having diagnosed pulmonary TB based on a chest x-ray.
- M.tb Mycobacterium tuberculosis
- bacilli at least 1+ on the International Union against Tuberculosis and Lung Disease [IUATLDJ/WHO scale on smear microscopy
- 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 formulation comprising: extragranular excipients; and a plurality of granulates, each granulate independently comprising intragranular excipients and one or two APIs; wherein the APIs are each independently pretomanid, moxifloxacin, or pyrazinamide; each API, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof; and the plurality of granulates, taken in combination, contain each of pretomanid, moxifloxacin, or pyrazinamide, or the salt and/or solvates thereof.
- a first granulate comprises one or two APIs and first intragranular excipients; and a second granulate comprises one or two APIs and second intragranular excipients.
- the first granulate comprises moxifloxacin and pyrazinamide, each as a free base, a pharmaceutically acceptable salt, and/or a solvate of either thereof.
- the second granulate is a B+Pa granulate comprising pretomanid, bedaquiline, and the second intragranular excipients, wherein bedaquiline and pretomanid are independently present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- bilayer tablet is a core-shell tablet, wherein the core comprises one of a first and second granulates and the shell comprises the other of the first and second granulates.
- paragraph 13 The formulation of paragraph 1, comprising a first granulate comprising moxifloxacin and first intragranular excipients; a second granulate comprising pyrazinamide and second intragranular excipients; and a third granulate comprising pretomanid and third intragranular excipients; wherein each of the pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- paragraph 14 The formulation of paragraph 13, further comprising a fourth granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and fourth intragranular excipients.
- a fourth granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and fourth intragranular excipients.
- the formulation is a bilayer tablet, wherein the first layer comprises one or two of the first, second, and third granulates, and the second layer comprises the remaining granulates of the first, second, and third granulates.
- the bilayer tablet is a core-shell tablet, wherein the core comprises one or two of the first, second, and third granulates and the shell comprises the remaining of the first, second, and third granulate.
- a process for preparing a formulation comprising either compressing a portion of a blend to provide a tablet or filling capsules or sachets with a blend, wherein the blend comprises a mixture of: extragranular excipients; and a plurality of granulates, each granulate comprising intragranular excipients and one or two APIs, wherein the APIs are each independently pretomanid, moxifloxacin, or pyrazinamide; each API, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof; and the plurality of granulates, taken in combination, contain each of pretomanid, moxifloxacin, or pyrazinamide, or the salt and/or solvates thereof.
- a first granulate comprises moxifloxacin and pyrazinamide, each as a free base, a pharmaceutically acceptable salt, and/or a solvate of either thereof.
- a second granulate comprises pretomanid as a free base, a pharmaceutically acceptable salt, and/or a solvate of thereof.
- a second granulate is a B+Pa granulate comprising pretomanid, bedaquiline, and second intragranular excipients, wherein bedaquiline and pretomanid are independently present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- the blend comprises a first granulate comprising moxifloxacin and first intragranular excipients; a second granulate comprising pyrazinamide and second intragranular excipients; and a third granulate comprising pretomanid and third intragranular excipients; wherein each of the pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- the bilayer comprises a first layer and a second layer in cohesive contact with the first layer
- the first layer comprises the first blend and the second layer comprises the second blend
- the first and second blend each, independently, comprise extragranular excipients and one or more granulates of a plurality of granulates, each of the plurality of granulates comprising intragranular excipients and one or two APIs,
- the APIs are each independently pretomanid, moxifloxacin, or pyrazinamide,
- each API independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof, and
- the plurality of granulates, taken in combination contain each of pretomanid, moxifloxacin, or pyrazinamide, or the salt and/or solvates thereof.
- a first granulate comprises first intragranular excipients, and moxifloxacin and pyrazinamide, each as a free base, a pharmaceutically acceptable salt, and/or a solvate of either thereof.
- a second granulate comprises second intragranular excipients and pretomanid as a free base, a pharmaceutically acceptable salt, and/or a solvate of thereof.
- the second granulate is a B+Pa granulate comprising pretomanid, bedaquiline, and second intragranular excipients, wherein bedaquiline and pretomanid are independently present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- first blend comprises first extragranular excipients and one or two of a first, second, and third granulate; and the second blend comprises second extragranular excipients and the remaining of the first, second, and third granulates, wherein the first granulate comprises moxifloxacin and first intragranular excipients; the second granulate comprising pyrazinamide and second intragranular excipients; the third granulate comprising pretomanid and third intragranular excipients; wherein each of the pretomanid, moxifloxacin, and pyrazinamide, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof.
- first or second blend further comprises a fourth granulate comprising bedaquiline or a pharmaceutically acceptable salt thereof and fourth intragranular excipients.
- a method of treating tuberculosis comprising administering a therapeutically effective amount of a formulation according to any one of paragraphs 1-20 or prepared according to any one of paragraphs 21 - 34, to a patient in need thereof.
- tuberculosis is drug-sensitive tuberculosis (DS-TB).
- tuberculosis is multidrug-resistant tuberculosis (MDR- TB).
- Bedaquiline Part 1 Bedaquiline fumarate, lactose monohydrate, microcrystalline cellulose, and corn starch, were sifted through 30# ASTM.
- Step 1 material in GPCG using top spray granulation.
- Step 5 Load and mix the material of Step 5 in Rapid mixer granulator and mixed for 10 min.
- Step 5 material Granulate the Step 5 material by using Step 6 binder solution in Rapid mixer granulator.
- Step 8 Pass the wet mass of Step 8 through Quadro Co mil fitted with 250 Q screen.
- Step 9 Dry the milled wet mass of Step 9 using fluidized bed dryer at an inlet air temperature of 50°C until LOD of NMT 2.0% w/w is achieved (IR Moisture Balance at 105°C).
- step 11 Sift the dried mass of step 10 through Quadro Co mil fitted with an 50G screen.
- Step 13 Load and mix the material of Step 12 in Rapid mixer granulator and mixed for 10 min. Disperse Povidone in purified water under stirring to form a clear solution.
- Step 13 material by using Step povidone binder solution in Rapid mixer granulator.
- Step 15 Dry the wet mass of Step 14 using fluidized bed dryer at an inlet air temperature of 50°C until LOD of NMT 2.0% w/w is achieved (IR Moisture Balance at 105°C).
- the bedaquiline, pretomanid, and moxifloxacin + pyrazinamide granulate portions were prepared as described in Example 1.
- a bilayer tablet was prepared by: Blending for Moxifloxacin + Pyrazinamide Layer
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- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IN202041025097 | 2020-06-15 | ||
PCT/US2021/037245 WO2021257461A1 (en) | 2020-06-15 | 2021-06-14 | Combination antibacterial composition and method for antibacterial therapy |
Publications (2)
Publication Number | Publication Date |
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EP4164626A1 true EP4164626A1 (de) | 2023-04-19 |
EP4164626A4 EP4164626A4 (de) | 2024-07-03 |
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EP21825333.4A Pending EP4164626A4 (de) | 2020-06-15 | 2021-06-14 | Antibakterielle kombinationszusammensetzung und antibakterielles therapieverfahren |
Country Status (2)
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EP (1) | EP4164626A4 (de) |
WO (1) | WO2021257461A1 (de) |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
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DE3906365A1 (de) * | 1988-07-15 | 1990-01-18 | Bayer Ag | 7-(1-pyrrolidinyl)-3-chinolon- und -naphthyridoncarbonsaeure-derivate, verfahren sowie substituierte (oxa)diazabicyclooctane und -nonane als zwischenprodukte zu ihrer herstellung, und sie enthaltende antibakterielle mittel und futterzusatzstoffe |
WO2005020998A1 (en) * | 2003-09-03 | 2005-03-10 | Ranbaxy Laboratories Limited | Pharmaceutical compositions of moxifloxacin and processes for their preparation |
AU2009288820A1 (en) * | 2008-09-03 | 2010-03-11 | Pfizer Inc. | Combination therapy for tuberculosis |
WO2014016850A1 (en) * | 2012-07-24 | 2014-01-30 | Mylan Laboratories Limited | Stable pharmaceutical composition of fluindione |
WO2016116892A1 (en) * | 2015-01-24 | 2016-07-28 | Wockhardt Limited | Antibacterial compositions |
MX2017009681A (es) * | 2015-01-27 | 2017-10-18 | Janssen Pharmaceutica Nv | Composiciones dispersables. |
ES2972618T3 (es) * | 2015-10-14 | 2024-06-13 | The Global Alliance For Tb Drug Dev Inc | Composición antibacteriana de combinación y régimen antibacteriano de corta duración que comprende linezolid, bedaquilina y pretomanida |
BR112022000899A2 (pt) * | 2019-07-19 | 2022-03-29 | The Global Alliance For Tb Drug Dev Inc | Composições de pretomanida |
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2021
- 2021-06-14 EP EP21825333.4A patent/EP4164626A4/de active Pending
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Publication number | Publication date |
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EP4164626A4 (de) | 2024-07-03 |
WO2021257461A1 (en) | 2021-12-23 |
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