EP4164626A1

EP4164626A1 - Combination antibacterial composition and method for antibacterial therapy

Info

Publication number: EP4164626A1
Application number: EP21825333.4A
Authority: EP
Inventors: Rajneesh Taneja; Pratik Shivram MAHAJAN; Srinivas Panguluri; Chayapathy Issa; Pradip Ghosh; Santanu Chakraborty; Amit ANTARKAR; Abhijit DESHMUKH
Original assignee: Mylan Laboratories Ltd; Global Alliance for TB Drug Development Inc
Current assignee: Mylan Laboratories Ltd; Global Alliance for TB Drug Development Inc
Priority date: 2020-06-15
Filing date: 2021-06-14
Publication date: 2023-04-19
Also published as: EP4164626A4; WO2021257461A1

Abstract

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

Description

COMBINATION ANTIBACTERIAL COMPOSITION AND METHOD FOR ANTIBACTERIAL THERAPY

CROSS REFERENCE TO RELATED APPLICATION (S)

The present application claims priority to Indian Patent Application No. 202041025097, filed on June 15, 2020, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

Combinations of compounds, such as fixed-dose combinations, are described having antibacterial activity for the treatment of tuberculosis.

BACKGROUND OF THE INVENTION

Mycobacterium tuberculosis is the causative agent of tuberculosis ("TB"), a devastating infectious disease. It is estimated that about 2 million TB patients die each year globally. Failure to properly treat tuberculosis has caused global drug resistance in mycobacterium tuberculosis and thus rendering some medications ineffective.

Current TB treatments include multi-tablet, monotherapeutic administration of chemically diverse antibacterial agents. Such administration, however, involves a plurality of tablets a day which can be costly and raise patient non-compliance issues. A need exists in the art for pharmaceutical compositions of active antibacterial agents in combination, such as a fixed-dose tableted form, that provides advantages over the individual monotherapies currently used in the art.

SUMMARY OF THE INVENTION

The present disclosure describes fixed-dose pharmaceutical dosage forms comprising a therapeutically effective amount of each of pretomanid, moxifloxacin and pyrazinamide and, optionally, at least one other active ingredient, or a pharmaceutically acceptable salt 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.

In one aspect, a formulation is provided 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.

In another aspect, a process for preparing a formulation is provided 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.

In another aspect, a process for preparing a formulation is provided 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 pyrazinamide, or the salt and/or solvates thereof.

In another aspect, a method of treating tuberculosis is provided comprising administering a therapeutically effective amount of a formulation according to or prepared according to any of the preceding aspects.

BRIEF DESCRIPTION OF THE DRAWINGS

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.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure generally relates to a fixed-dose combination of pretomanid, moxifloxacin and pyrazinamide as active ingredients and optionally a fourth active ingredient such as, 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.

Fixed Dose Combinations

Fixed dose combinations (FDC) offer several advantages over monotherapy used in the art. Some advantages of FDC administration include enhancing patient compliance that ultimately improves treatment outcomes; reducing inadvertent medication errors and total tablet burden upon administered; preventing and/or slowing antimicrobial resistance by eliminating potential ineffective monotherapy administration; reducing drug shortages by not having to obtain multiple drug products from separate organizations; simplifying expiry date compliance (single products tend to have different expiry dates); simplifying procurement, management, and handling of drugs; and lowering production, packing, and shipping costs.

By combining pretomanid, moxifloxacin and pyrazinamide into a single dosage form, 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. Examples of 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. 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). "Alkyl" as used herein refers to a univalent group derived from a linear or branched alkane by removal of a hydrogen atom from any carbon atom (-CnFhn_+i). Examples of alkyl groups include, but are not limited to, methyl, ethyl, isopropyl, sec-butyl, and n-butyl.

"Solvate" as used herein refers to a complex of variable, but defined, stoichiometry formed by a solute (the referenced compound) and a solvent. Solvates should be understood not to include solid forms of a reference compound containing sub-stoichiometric amounts of residual solvents. Solvents, by way of example, include water (such can be referred to as a "hydrate"), methanol, ethanol, isopropyl alcohol, ethyl acetate, ethylene glycol, propylene glycol, acetonitrile, dimethyl sulfoxide, N,N- dimethylformamide, and acetic acid, among others. The phrase "salt and/or solvate" refers to each of a salt (e.g., moxifloxacin hydrochloride), a solvate, and a solvate of a salt (e.g., moxifloxacin hydrochloride monohydrate).

Pretomanid (also known as "Pa") is a novel nitroimidazole anti-bacterial agent recently approved by the U.S. FDA as a TB therapy, and having many attractive characteristics - most notably its novel mechanism of action, its activity in vitro against all tested drug-resistant clinical isolates, and its activity as both a potent bactericidal and a sterilizing agent. In addition, the compound shows no evidence of mutagenicity in a standard battery of genotoxicity studies, no significant cytochrome P450 interactions, and no significant activity against a broad range of Gram-positive and Gram-negative bacteria. The lUPAC designation for pretomanid is (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H- imidazo[2,l-b][l,3]oxazine. Pretomanid 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. Herein, unless otherwise noted, "moxifloxacin" refers to the free base as well as a pharmaceutically acceptable salt and/or solvate thereof, such as moxifloxacin hydrochloride and/or moxifloxacin hydrochloride monohydrate.

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. Herein, unless otherwise noted, "bedaquiline" refers to the free base as well as a pharmaceutically acceptable salt and/or solvate thereof, such as bedaquiline fumarate.

The amount of each active ingredient that may produce a single dosage form may vary depending upon the host treated and the particular mode of administration. A convenient unitary dosage formulation may contain each of the active ingredients in any amount from 1 mg to 1 g each, for example but not limited to, 10 mg to 500 mg for each active ingredient. Daily dosages of the active ingredients in such an embodiment can be, for example 50-2000 mg pyrazinamide, 10 - 800 mg moxifloxacin, 10 - 400 mg pretomanid, and 10 - 400 mg bedaquiline. In certain embodiments, 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.

In certain embodiments, a total daily dose of Pa, M and Z can be included in more than one unit dosage that could be ingested comfortably. For example, the total daily dose of each active agent may be equally divided among two or more unit dosages to facilitate daily dosing. In another embodiment, the total daily dose of each active agent is equally divided among two to six unit dosages, or two to five unit dosages, or two to four unit dosages, or two, or three, or four, or five, or six unit dosage. In each instance, the plurality of unit dosages comprising the total daily dose can be administered together simultaneously or sequentially to provide the total daily dose to the patient in need thereof. In several examples, a total daily dose of 200 mg Pa, 400 mg M, 1500 mg Z and optionally, 200 mg or 100 mg B, may be equally divided among several unit dosages according to any one of the following embodiments: The several unit doses noted above may be administered together to a person in need thereof to provide the total daily dose. In one embodiment, each of the three unit dosages can contain 80.6 mg of bedaquiline fumarate, 152 mg of moxifloxacin hydrochloride monohydrate, 66.7 mg of pretomanid and 500 mg of pyrazinamide as active ingredients to provide the total daily dose.

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 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.)).

In certain embodiments, the FDCs described herein can encompass solid dosage forms such as monolithic tablets, multi-layer tablets, and combinations thereof. A monolithic approach 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.

In one embodiment, a formulation may be in the form of a monolithic tablet that contains Pa, M, Z, and optionally B. For example, 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.

In another embodiment, 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. For example, 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. For example, bilayer includes two domains that are either vertically or horizontally arranged stacked or in a core-shell arrangement.

When granulated, 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.

For the preparation of oral solid dosage forms, such as tablets, the API granulates may be combined with suitable extragranular excipients prior to tableting. Where a bilayer tablet is prepared, 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.

In one example, for the preparation of powder for oral suspension, 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. Alternatively, 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. KG, Rosenberg, Germany), tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium chloride, talc, and clays (such as kaolin and bentonite); monosaccharides, disaccharides, and polysaccharides such corn syrup, corn syrup solids, dextrin, maltodextrin, polydextrose, dextrose, fructose, invert sugar, isomalt, lactose, (e.g., anhydrous, monohydrate, and/or spray-dried forms such as PHARMATOSE DCL21 (Universal Preserv-A-Chem Inc., Somerset NJ)), maltose, pullulan, sucrose, trehalose, and combinations thereof, such as dextrates (e.g., EMDEX^® from JRS Pharma LP, USA, Patterson, NY; a combination of glucose monohydrate and polysaccharides derived from starch); sugar alcohols such as erythritol, lactitol, maltitol, mannitol (e.g., Pearlitol^® SD 200 (Roquette Freres SA, Lestrem, France)), sorbitol, and xylitol; celluloses and modified celluloses such as, microcrystalline cellulose (e.g., Avicel^® PH 101, Avicel^® PH 102, Avicel^® PH 112, Avicel^® PH 200, Avicel^® PH 301, and Avicel^® PH 302; CEOLUS KG-1000, CEOLUS KG-802, CELOLUS UF-702 (Asahi Kasei, Tokyo, Japan)), silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, and cellaburate; and mixtures of the foregoing.

In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, diluents may be selected from the group consisting of dextrose, lactose, sucrose, trehalose, mannitol, sorbitol, xylitol, microcrystalline cellulose, and mixtures thereof. In certain embodiments, 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. Examples of suitable binders include, but are not limited to, dry binders such as partially pre gelatinized starch (e.g., UNI-PURE^® DW partially pre-gelatinized maize starch, National Starch & Chemical); anhydrous lactose, and dibasic calcium phosphate dehydrate; and wet binders such as pre gelatinized starch, povidone (e.g. Povidone K-30 USP/Kollidon^® 30, BASF, Ludwigshafen, Germany); methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose; and mixtures thereof.

In certain embodiments, 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. In certain embodiments, 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.

In certain embodiments, 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. Examples of amphoteric surfactants include, but are not limited to, lecithin, cocamidopropyl betaine, lauryldimethylamine oxide, myristamine oxide, coco amino propionate (SERVO AM 1010 Elementis Specialties, Delden, The Netherlands), sodium lauryl imino dipropionate (SERVO AM 1020), sodium octyl imino dipropionate (SERVO AM 2020), sodium coco imino mono/dipropionate (SERVO AM 1015), oleyldimethylbetaine, and sodium N-cocoamidethyl N-hydroxyethylglycine, and mixtures thereof.

Examples of non-ionic surfactants include, but are not limited to, alkylphenols, such as 4-(2,4- dimethylheptan-3-yl)phenol; fatty acid glycerides such as glyceryl dibehenate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, and glyceryl tristearate; sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate, sorbitan sesqueoleate, sorbitan trioleate, and sorbitan tristearate; ethoxylated fatty acids such as stearic acid ethoxylate and lauric acid ethoxylate; ethoxylated fatty alcohols such as polyoxyethylene lauryl ethers (Brij); ethoxylated alkylphenols such as nonylphenol ethoxylate and ethoxylated p-tert-octylphenol; ethoxylated hydrogenated vegetable oils such as polyoxyl 35 castor oil (Cremophor EL) and hydrogenated polyoxyl 40 castor oil (Cremophor RH 40); ethoxylated sorbitan esters such as polyoxyethylene sorbitan monolaurate (polysorbate 20), polyoxyethylene sorbitan monopalmitate (polysorbate 40), polyoxyethylene sorbitan monostearate (polysorbate 60), polyoxyethylene sorbitan monooleate (polysorbate 80); ethoxylated fatty acid amides such as cocoamide monoethanolamine and cocamide diethanolamine; and block copolymers of polyoxypropylene (polypropylene oxide)) and polyoxyethylene (poly(ethylene oxide), including polyoxamers (nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene polypthylene oxide)), such as polyoxamer 188/Kolliphor^® P188, polyoxamer 407/Kolliphor^® P407, BASF); maltosides such as n- dodecyl^-D-maltoside; glucamides such as octanoyl-N-methylglucamide, decanoyl-N-methylglucamide and heptanoyl-N-methylglucamide; pyranosides such as n-hexyl^-D-glucopyranoside, n-decyl-b-O- glucopyranoside, n-octyl^-D-glucopyranoside; thioglucosides such as n-heptyl^-D-thioglucoside; p- isononylphenoxypoly(glycidol), also known as Olin 10-G or 10-GR surfactant (Olin Chemicals, Stamford, Conn.); and mixtures thereof (such as CRODESTAS F-110, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.)).

Examples of cationic surfactants include, but are not limited to, quaternary fatty ammonium salts such as cetyl trimethyl ammonium bromide (CTAB), dodecyltrimethylammonium bromide, methylbenzethonium chloride, and hexadecyltrimethylammonium bromide; 2-alkyl-l-hydroxyethyl-2- imidazolines such as lauryl hydroxyethyl imidazoline and stearyl hydroxyethyl imidazoline; polyoxamines, such as Tetronic^®908 (i.e., poloxamine 908, a tetrafunctional polyethylene oxide (PEO)-polypropylene oxide ethylenediamine block copolymer); N,N,N,N-tetrakis substituted ethylenediamines such as ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol and ethylenediamine tetrakis(propoxylate- block-ethoxylate)tetrol; fatty amine ethoxylates such as stearyl amine ethoxylate, oleyl amine ethoxylate, tallow amine ethoxylate and coco amine ethoxylate; and mixtures thereof.

Examples of anionic surfactants include, but are not limited to, alkyl sulfates, such as sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium lauryl sulfate; bile salts such as sodium deoxycholate and sodium cholate; sulfosuccinate diesters such as docusate sodium (AEROSEL OT, American Cyanamid), ammonium dinonyl sulfosuccinate, diamyl sulfosuccinate sodium, dicapryl sulfosuccinate sodium, diheptyl sulfosuccinate sodium, dihexyl sulfosuccinate sodium, diisobutyl sulfosuccinate sodium, and ditridecyl sulfosuccinate sodium; alkylbenzene sulfonates such as sodium dodecylbenzenesulfonate; sodium petroleum sulfonates such as those available under the tradename PETRONATE from Sonneborn, LLC Petrolia, Pennsylvania; sodium alkyl naphthalene sulfonate such as those available under the tradename NAXAN from Nease Performance Chemicals, West Chester Township, Ohio; sulfated natural oils and glycerides such as lauryl monoglyceryl sulfate and sulfated castor oil; sulfated ethoxylated fatty alcohols such as sodium laureth sulfate and sodium myreth sulfate; charged phospholipids such as dimyristoylphosphatidylglycerin; and mixtures thereof.

In certain embodiments, surfactants may be one or more non-ionic surfactants. In certain embodiments, 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 monostearate (polysorbate 60), polyoxyethylene sorbitan monooleate (polysorbate 80), and mixtures thereof. In certain embodiments, 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. In certain embodiments, surfactants may be one or more anionic surfactants. In certain embodiments, 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.

In certain embodiments, 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 CARBOWAX™ Polyethylene Glycol (PEG) 3350, Dow Chemical, Midland, Michigan); light mineral oil; poloxamers, such as Kolliphor^® P188 and P407 available from BASF, Ludwigshafen, Germany; polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80; sodium lauryl sulfate; sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate and sorbitan trioleate; ethoxylated fatty acids such as polyoxyl 40 stearate and polyoxyl 15 hydroxystearate; ethoxylated alkanols such as polyoxyl 20 cetostearyl ether and polyoxyl 10 oleyl ether; ethoxylated vegetable oils and ethoxylated hydrogenated vegetable oils such as polyoxyl 35 castor oil (Cremophor EL/Kolliphor^® EL, BASF) and hydrogenated polyoxyl 40 castor oil (Cremophor RH40/ Kolliphor^® RH40, BASF); waxes (for example, microcrystalline waxes); glycerides, such as glyceryl dibehenate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, and glyceryl tristearate; sucrose ester of fatty acids such as sucrose stearate; hydrogenated vegetable oils (for example, hydrogenated castor oil and hydrogenated palm oil); and mixtures thereof. In certain embodiments, 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. In certain embodiments, lubricants may be selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate and mixtures thereof. In certain embodiments, 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 m²/g; Evonik Corp., Piscataway, New Jersey) or CAB-O-SIL, M-5P (a fumed silica with a specific surface area of 200 m²/g; Cabot Corp., Billerica, Massachusetts), asbestos free talc, sodium aluminosilicate, calcium silicate, calcium phosphate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, stearowet C (a combination of calcium stearate and sodium lauryl sulfate), starch, starch 1500, magnesium lauryl sulfate, magnesium silicate, magnesium trisilicate, magnesium aluminosilicate, magnesium oxide and mixtures thereof. The compositions herein may contain glidants to effect and maintain homogeneity of active ingredients during handling prior to tablet compression. In certain embodiments, the glidant may comprise colloidal silicon dioxide, sodium aluminosilicate, calcium silicate, magnesium silicate, magnesium trisilicate, magnesium aluminosilicate, or a mixture thereof. In certain other embodiments, the glidant may comprise colloidal silicon dioxide.

In certain embodiments, the glidant may comprise colloidal silicon dioxide, microcrystalline cellulose, sodium aluminosilicate, calcium silicate, magnesium silicate, magnesium trisilicate, magnesium aluminosilicate, or a mixture thereof. In certain other embodiments, the glidant may comprise colloidal silicon dioxide. In certain embodiments, 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. Formulation Process

As noted above, 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. Examples of combination granulates include a pretomanid and bedaquiline granulate ("B+Pa granulate") and a moxifloxacin and pyrazinamide granulate ("M+Z granulate"). In one particular embodiment, a Pa granulate and a M+Z granulate are prepared. In another embodiment, a B granulate, a Pa granulate, and a M+Z granulate are prepared. In another embodiment, a B+Pa granulate and a M+Z granulate are prepared.

In certain embodiments, 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. Where a dry granulating process is utilized (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. When a wet granulation process is utilized, the APIs and intragranular excipients may be granulated together using a solution (e.g., a solution comprising a wet binder and, optionally, a surfactant). Examples of 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. In certain embodiments, povidone (e.g. Povidone K30), hydroxypropyl methylcellulose (HPMC), or a mixture thereof may be used as a wet binder.

In either case, 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.

In one embodiment, each API granulate independently comprises one or more intragranular excipients. For example, such intragranular excipients may be one or excipient selected from the group consisting of binders, diluents, surfactants, disintegrants, and mixtures thereof. In one embodiment, 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. In one embodiment, 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. In another embodiment, the B granulate comprises one or more intragranular excipients that are lactose, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose (E15), and polysorbate 20. In another embodiment, 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. In one embodiment, 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. In another embodiment, the Pa granulate comprises one or more intragranular excipients that are lactose, sodium starch glycolate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. In another embodiment, 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. In one embodiment, 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. In another embodiment, 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. In another embodiment, 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. In one example, the B+Pa granulate comprises pretomanid free base and bedaquiline free base. In another example, 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. In one embodiment, the M granulate comprises one or more intragranular excipients selected from the group consisting of a diluent, a disintegrant, a binder, and mixtures thereof. In one example, the M granulate comprises moxifloxacin free base and pyrazinamide free base. In another example, the M granulate comprises moxifloxacin hydrochloride. In another example, the M granulate comprises moxifloxacin hydrochloride monohydrate. In another embodiment, 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 Z granulate may comprise pyrazinamide or a pharmaceutically acceptable salt and/or solvate of thereof and one or more intragranular excipients. In one embodiment, the Z granulate comprises one or more intragranular excipients selected from the group consisting of a diluent, a disintegrant, a binder, and mixtures thereof. In one example, the Z granulate comprises pyrazinamide free base. In another embodiment, 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. In one embodiment, 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. In another embodiment, the M+Z granulate comprises one or more intragranular excipients that are microcrystalline cellulose, croscarmellose sodium, and povidone. In another embodiment, 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. In one example, the M+Z granulate comprises moxifloxacin free base and pyrazinamide free base. In another example, 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.

Referring to Figure 1, a process is exemplified for the preparation of the API granulates. Therein, 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). Separately, 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. The resulting granules are processed (130) to provide the API granulate (140) having a desired residual solvent content and/or particle size distribution. As shown in Figure 1, 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. For example, 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). In another example, 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).

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. For example, 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.

Referring to Figure 2a, a process is exemplified for the preparation of monolayer tablets from the preceding API granulates. Therein, when present, 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). Following blending, 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).

Referring to Figure 2b, a process is exemplified for the preparation of monolayer tablets from the preceding API granulates. Therein, when present, 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). Following blending, 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).

Alternatively, the process of Figures 2a and 2b may be modified for the preparation of other oral dosage forms described herein. For example, following blending (230), 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. Such minitablets and pellets may have a diameter suitable for inserting into a capsule for oral administration. For example, 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.

In one embodiment, the preceding formulations (e.g., monolayer tablets, capsules, or sachets) 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.

In one embodiment, extragranular excipients for the preparation of the preceding formulations (e.g., monolayer tablets, capsules, or sachets), when present, may be selected from the group consisting of glidants, disintegrants, lubricants, coloring agents, antioxidants, preservatives, and flavorings. In another embodiment, 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. In another embodiment, extragranular excipients for the preparation of the preceding formulations (e.g., monolayer tablets, capsules, or sachets) when present, are microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and optionally, magnesium stearate. In another embodiment, extragranular excipients for the preparation of the preceding formulations (e.g., monolayer tablets, capsules, or sachets) are microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. In referencing Figures 2a and 2b, it can be noted that 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. 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. In one embodiment, the film coating agents is OPADRY (HPMC). Such coatings may be applied as is known by one skilled in the art and controlled to an added weight% to the uncoated tablets. For example, an optional film coating may be applied to add about 1 - 10 wt.% or 1-5 wt.% to the weight of the uncoated tablets.

Referring to Figure 3a, a process is exemplified for the preparation of bilayer tablets from the preceding API granulates. Therein, 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). For example, in Figure 3a, 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). Following blending, 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). As noted for Figure 2, all extragranular excipients (300, 305) are added at (310, 315) except for lubricants (331, 332) that are added at blending (330) and (335).

Referring to Figure 3b, a process is exemplified for the preparation of bilayer tablets from the preceding API granulates. Therein, 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, 326, and/or 327). For example, in Figure 3b, 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). Following blending, 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). As noted for Figures 2a and 2b, all extragranular excipients (300, 305) are added at (310, 315) except for lubricants (331,332) that are added at blending (330) and (335).

Referring to Figure 3c a process is exemplified for the preparation of bilayer tablets from the preceding API granulates. Therein, 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). For example, in Figure 3b, 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). Following blending, 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). As noted for Figures 2a and 2b, all extragranular excipients (300, 305) are added at (310, 315) except for lubricants (331,332) that are added at blending (330) and (335).

Alternatively, the process of Figures 3a - 3c may be modified for the preparation of other oral dosage forms described herein. For example, following blending (330, 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) 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.

Taken together, the formulations of Figures 3a - 3c (e.g., bilayer tablets, capsules, or sachets) 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. For example, 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.

Or, the formulations of Figures 3a - 3c (e.g., bilayer tablets, capsules, or sachets) 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. For example, 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.

Certain embodiments for first extragranular excipients (300) and second extragranular excipients (305) in the formulations of Figures 3a - 3c (e.g., bilayer tablets, capsules, or sachets) are as described above for monolayer tablets. In one embodiment, 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. In another embodiment, each of the first extragranular excipients and second extragranular excipients independently comprise one or more glidant, disintegrant, and/or lubricant. Therein, 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.

In one particular embodiment, when blend (A)(380) comprises a M+Z granulate, then the first extragranular excipients (300) comprise one or more glidant, disintegrant, and/or lubricant. For example, when blend (A) comprises a M+Z granulate, then the first extragranular excipients comprise microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

In another embodiment, when blend (B)(380) comprises a Pa granulate and optionally a B granulate, then the second extragranular excipients (305) comprise one or more glidant, disintegrant, and/or lubricant. For example, when blend (B) comprises a Pa granulate and optionally a B granulate, then the second extragranular excipients croscarmellose sodium, colloidal silicon dioxide, magnesium stearate. In one embodiment of the preceding, blend (B) comprises the B granulate.

In another embodiment, when blend (B)(380) comprises a B+Pa granulate then the second extragranular excipients (305) comprise one or more glidant, disintegrant, and/or lubricant. For example, when blend (B) comprises a B+Pa granulate then 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. 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).

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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 extragranular excipients comprise one or more glidant, disintegrant, and/or lubricant.

In another embodiment, 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.

In another embodiment, 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, povidone, and sodium lauryl sulfate; and the second extragranular excipients comprise croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

In another embodiment, 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.

In certain embodiments, 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. In one embodiment, "chemical stability" or "chemically stable" means that a formulation described herein shows no "significant change" upon storage under at least one of the following storage conditions:

"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 one embodiment of each of the preceding embodiments, 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.

In one embodiment of each of the preceding embodiments, 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.

In one embodiment of each of the preceding embodiments, 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. Treatment of Tuberculosis

Any of the preceding compositions may be administered to a human or other mammal in a safe and therapeutically effective amount as described herein. These safe and therapeutically effective amounts will vary according to the type and size of mammal being treated and the desired results of the treatment. A "therapeutically effective amount" is an amount effective for treating a recited disease or condition, such as, tuberculosis.

The term "treating", with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder. The number of unit dosages of the compositions (e.g., tablets or capsules or amount of oral suspension) administered to the person typically comprises a therapeutically effective amount of pretomanid, moxifloxacin, pyrazinamide, and optionally bedaquiline, or pharmaceutically acceptable salt and/or solvate thereof. For example, when treating tuberculosis, sputum samples or chest x-rays may be monitored to show improvement and/or amelioration of the disease.

In certain embodiments, the tuberculosis is drug-sensitive tuberculosis (DS-TB), multidrug- resistant tuberculosis (MDR-TB), or extensively drug-resistant tuberculosis (XDR-TB).

In one embodiment, the tuberculosis is drug-sensitive tuberculosis (DS-TB). DS-TB refers to TB which is not resistant to any of the TB drugs; in certain embodiments, the DS-TB is tuberculosis that is caused by a bacteria that is sensitive to rifampicin (RIF) and isoniazid (INH), as identified, for example, by rapid molecular sputum-based test.

In some embodiments, the pharmaceutical composition of the present disclosure can be used for the treatment of multi-drug resistant tuberculosis (MDR-TB). MDR-TB refers to TB caused by a bacteria resistant to isoniazid (INH) and rifampin (RIF).

In some embodiments, the pharmaceutical composition of the present disclosure can be used for the treatment of extensively-drug resistant tuberculosis (XDR-TB). XDR-TB refers to a rare type of MDR- TB that is caused by a bacteria that is resistant to INH and RIF, and is additionally resistant to any fluoroquinolone, such as ciprofloxacin, levofloxacin, ofloxacin, or sparfloxacin, and at least one of three injectable second-line drugs, such as amikacin, kanamycin, or capreomycin.

"A person in need of treatment" herein refers to a patient diagnosed with tuberculosis according to methods familiar to those skilled in the art, including patients having a sputum positive for Mycobacterium tuberculosis (M.tb) bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease [IUATLDJ/WHO scale on smear microscopy), or having diagnosed pulmonary TB based on a chest x-ray.

Any of the various methods known by persons skilled in the art for packaging tablets, caplets, or other solid dosage forms suitable for oral administration, that will not degrade the components of the present formulations, are suitable for use in packaging. The combinations may be packaged in glass and plastic bottles. Tablets, caplets, or other solid dosage forms suitable for oral administration may be packaged and contained in various packaging materials optionally including a desiccant e.g. silica gel. Packaging may be in the form of unit dose blister packaging. For example, the package may contain a blister tray of the co-formulated combination of pretomanid, pyrazinamide, and moxifloxacin (and optionally, bedaquiline) in a single pill, tablet, caplet or capsule.

The packaging material may also have labeling and information related to the pharmaceutical composition printed thereon. Additionally, an article of manufacture may contain a brochure, report, notice, pamphlet, or leaflet containing product information. This form of pharmaceutical information is referred to in the pharmaceutical industry as a "package insert." A package insert may be attached to or included with a pharmaceutical article of manufacture. The package insert and any article of manufacture labeling provides information relating to the pharmaceutical composition. The information and labeling provides various forms of information utilized by health-care professionals and patients, describing the composition, its dosage and various other parameters required by regulatory agencies such as the United States Food and Drug Agency.

The disclosure can be further described, without limitation, by the following numbered paragraphs:

1. 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.

2. The formulation of paragraph 1, wherein 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. 3. The formulation of paragraph 2, wherein the first granulate comprises moxifloxacin and pyrazinamide, each as a free base, a pharmaceutically acceptable salt, and/or a solvate of either thereof.

4. The formulation of paragraph 2 or 3, wherein the second granulate comprises pretomanid as a free base, a pharmaceutically acceptable salt, and/or a solvate of thereof.

5. The formulation of any one of paragraphs 1-4, further comprising a B granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and third intragranular excipients.

6. The formulation of any one of paragraphs 2-5, wherein 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.

7. The formulation of any one of paragraphs 1 - 6, wherein the formulation is a monolithic tablet.

8. The formulation of any one of paragraphs 1 - 6, wherein the formulation is a bilayer tablet, wherein the first layer comprises a first granulate; and the second layer comprises a second granulate, and when present, a B granulate.

9. The formulation of paragraph 8, wherein the 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.

10. The formulation of any one of paragraphs 7-9, further comprising a coating layer formed over the surface of the monolithic or bilayer tablet.

11. The formulation of any one of paragraphs 1 - 6, wherein the formulation is a filled capsule, sachet, or powder for oral suspension.

12. The formulation of any one of paragraphs 1-11 comprising about 60-99 w/w% of the sum of the plurality of granulates; and about 1 -40 w/w % the extragranular excipients.

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.

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. 15. The formulation of any one of paragraphs -13-14, wherein the formulation is a monolithic tablet.

16. The formulation of any one of paragraphs 13-14, wherein 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. 17. The formulation of paragraph 16, wherein 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.

18. The formulation of any one of paragraphs 13-14, wherein the formulation is a filled capsule, powder for oral suspension, or sachet. 19. The formulation of any one of paragraphs 1-18, wherein 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.

20. The formulation of any one of paragraphs 1-19, comprising an amount of pretomanid (Pa), moxifloxacin (M), pyrazinamide (Z), and when present, bedaquiline (B), or a pharmaceutically acceptable salt and/or solvate thereof equivalent to one of (1) - (15): where the amounts of B, Pa, M, and Z in (1) - (15) are the amount of the respective free base.

21. 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.

22. The process of paragraph 21, wherein a first granulate comprises moxifloxacin and pyrazinamide, each as a free base, a pharmaceutically acceptable salt, and/or a solvate of either thereof.

23. The process of paragraph 21 or 22, wherein a second granulate comprises pretomanid as a free base, a pharmaceutically acceptable salt, and/or a solvate of thereof.

24. The process of any one of paragraphs 21-13, wherein the blend further comprises a B granulate comprising bedaquiline or a pharmaceutically acceptable salt thereof and third intragranular excipients.

25. The process of any one of paragraphs 21-23, wherein 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.

26. The process of paragraph 21, wherein 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.

27. The process of paragraph 26, wherein the blend further comprising a fourth granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and fourth intragranular excipients. 28. 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

(a) the bilayer comprises a first layer and a second layer in cohesive contact with the first layer;

(b) the first layer comprises the first blend and the second layer comprises the second blend,

(c) 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,

(d) the APIs are each independently pretomanid, moxifloxacin, or pyrazinamide,

(e) each API, independently, may be present as the free base, a pharmaceutically acceptable salt, and/or a solvate thereof, and

(f) the plurality of granulates, taken in combination, contain each of pretomanid, moxifloxacin, or pyrazinamide, or the salt and/or solvates thereof.

29. The process of paragraph 28, wherein 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.

30. The process of paragraph 28 or 29, wherein a second granulate comprises second intragranular excipients and pretomanid as a free base, a pharmaceutically acceptable salt, and/or a solvate of thereof.

31. The process of any one of paragraphs 28-30, wherein the second blend further comprises a B granulate comprising bedaquiline or a pharmaceutically acceptable salt thereof and third intragranular excipients.

32. The process of any one of paragraphs 28-30, wherein 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.

33. The process of paragraph 28, wherein the 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.

34. The process of paragraph 33, wherein the first or second blend further comprises a fourth granulate comprising bedaquiline or a pharmaceutically acceptable salt thereof and fourth intragranular excipients.

35. 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.

36. The method of paragraph 35, wherein the tuberculosis is drug-sensitive tuberculosis (DS-TB).

37. The method of paragraph 35, wherein the tuberculosis is multidrug-resistant tuberculosis (MDR- TB).

38. The method of paragraph 35, wherein the tuberculosis is extensively-drug resistant tuberculosis

(XDR-TB).

EXAMPLES

The following examples further describe and demonstrate particular embodiments within the scope of the present disclosure. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

Example 1. Monolayer BPaMZ tablet

Manufacturing Procedure

Bedaquiline Part 1) Bedaquiline fumarate, lactose monohydrate, microcrystalline cellulose, and corn starch, were sifted through 30# ASTM.

2) Add Hypromellose (HPMC E15) in Purified water under Continuous stirring. To form clear solution 3) Add Tween 20 in step 2 solution under stirring until clear solution obtained.

4) Granulate Step 1 material in GPCG using top spray granulation.

Sift Dried granules through #25 ASTM screen and mill retention through 40G screen by using Co mill Pretomanid Part

5) Sift Pretomanid, Lactose monohydrate, Microcrystalline cellulose and Sodium starch glycolate through 18 # ASTM

6) Disperse Povidone in purified water under stirring to form a clear solution. Add Sodium lauryl sulfate to Povidone solution and stirred until a clear solution formed.

7) Load and mix the material of Step 5 in Rapid mixer granulator and mixed for 10 min.

8) Granulate the Step 5 material by using Step 6 binder solution in Rapid mixer granulator.

9) Pass the wet mass of Step 8 through Quadro Co mil fitted with 250 Q screen.

10) 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).

11) Sift the dried mass of step 10 through Quadro Co mil fitted with an 50G screen.

Moxifloxacin and Pyrazinamide Part

12) Sift moxifloxacin HCI, Pyrazinamide, Microcrystalline cellulose, Croscarmellose Sodium through 20# ASTM

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.

14) Granulate the Step 13 material by using Step povidone binder solution in Rapid mixer granulator.

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).

16) Sift Dried Granules through 25 # ASTM and mill retention through Quadro Co mil fitted with an 40G screen. Blending

17) Transfer Bedaquiline Fumarate sized granules, Pretomanid Sized granules, Moxifloxacin HCI and Pyrazinamide sized granules in a suitable blender

18) Sift Microcrystalline cellulose PH 112, Colloidal Silicon dioxide, Croscarmellose sodium through 30 # ASTM

19) Mixed Step 17 and Step 18 in a suitable blender for 15 minutes

20) Sift Magnesium stearate through #60 ASTM and add to step 19 and mixed in blender for 5 minutes

21) Compressed the Lubricated Blend of Step 20 by using 19.10X 9.30 mm, oval shaped, standard concave punch.

22) Disperse Opadry Brown in purified water under continuous stirring to form smooth, lumps free coating solution.

23) Coat The tablet by using suitable Coating Machine.

Example 2. Bilayer BPaMZ tablet

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

1) Transfer Moxifloxacin and Pyrazinamide sized granules, in a suitable blender

2) Sift Colloidal Silicon dioxide, Croscarmellose sodium through 30 # ASTM

3) Mixed Step 17 and Step 18 in a suitable blender for 15 minutes 4) Sift Magnesium stearate through #60 ASTM and add to step 19 and mixed in blender for 5 minutes.

Blending for Bedaquiline + Pretomanid Layer

5) Transfer Bedaquiline Fumarate sized granules, Pretomanid Sized granules, in a suitable blender

6) Sift Microcrystalline cellulose PH 112, Colloidal Silicon dioxide, Croscarmellose sodium through 30 # ASTM

7) Mixed Step 21 and Step 22 in a suitable blender for 15 minutes

8) Sift Magnesium stearate through #60 ASTM and add to step 23 and mixed in blender for 5 minutes.

Tableting

9) Compressed the Lubricated Blend as a bilayer tablet of Step 4 and Step 8 by using 19.10X 9.30 mm, oval shaped, standard concave punch.

10) Disperse Opadry Brown in purified water under continuous stirring to form smooth, lumps free coating solution.

11) Coat The tablet by using suitable Coating Machine.

Where trade names are used herein, applicants intend to independently include the trade name product and the active pharmaceutical ingredient(s) of the trade name product.

It is to be understood that the disclosure is not limited to the particular embodiments described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims.

It is to be understood that the descriptions have been simplified to illustrate elements that are relevant for a clear understanding, while eliminating, for the purpose of clarity, many other elements found in typical pharmaceutical compositions. Those of ordinary skill in the art will recognize that other elements and/or steps are desirable and/or required in implementing the present disclosure. However, because such elements and steps are well known in the art, and because they do not facilitate a better understanding, a discussion of such elements and steps is not provided herein. The disclosure herein is directed to all such variations and modifications to such elements and methods known to those skilled in the art. Furthermore, the embodiments identified and illustrated herein are for exemplary purposes only, and are not meant to be exclusive or limited in their description of the present disclosure.

Claims

We Claim:

2. The formulation of claim 1, wherein 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.

3. The formulation of claim 2, wherein the first granulate comprises moxifloxacin and pyrazinamide, each as a free base, a pharmaceutically acceptable salt, and/or a solvate of either thereof.

4. The formulation of claim 2 or 3, wherein the second granulate comprises pretomanid as a free base, a pharmaceutically acceptable salt, and/or a solvate of thereof.

5. The formulation of any one of claims 1-4, further comprising a B granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and third intragranular excipients.

6. The formulation of any one of claims 2-5, wherein 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.

7. The formulation of any one of claims 1 - 6, wherein the formulation is a monolithic tablet.

8. The formulation of any one of claims 1 - 6, wherein the formulation is a bilayer tablet, wherein the first layer comprises a first granulate; and the second layer comprises a second granulate, and when present, a B granulate.

9. The formulation of claim 8, wherein the 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.

10. The formulation of any one of claims 7-9, further comprising a coating layer formed over the surface of the monolithic or bilayer tablet.

11. The formulation of any one of claims 1 - 6, wherein the formulation is a filled capsule , sachet, or powder for oral suspension.

12. The formulation of any one of claims 1-11 comprising about 60 - 99 w/w % of the sum of the plurality of granulates ; and about 1 -40 w/w % the extragranular excipients.

13. The formulation of claim 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.

14. The formulation of claim 13, further comprising a fourth granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and fourth intragranular excipients.

15. The formulation of any one of claims 13-14, wherein the formulation is a monolithic tablet.

16. The formulation of any one of claims 13-14, wherein 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.

17. The formulation of claim 16, wherein 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.

18. The formulation of any one of claims 13-14, wherein the formulation is a filled capsule, powder for oral suspension, or sachet.

19. The formulation of any one of claims 1-18, wherein 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.

20. The formulation of any one of claims 1-19, comprising an amount of pretomanid (Pa), moxifloxacin (M), pyrazinamide (Z), and when present, bedaquiline (B), or a pharmaceutically acceptable salt and/or solvate thereof equivalent to one of (1) - (15): where the amounts of B, Pa, M, and Z in (1) - (15) are the amount of the respective free base.

22. The process of claim 21, wherein a first granulate comprises moxifloxacin and pyrazinamide, each as a free base, a pharmaceutically acceptable salt, and/or a solvate of either thereof.

23. The process of claim 21 or 22, wherein a second granulate comprises pretomanid as a free base, a pharmaceutically acceptable salt, and/or a solvate of thereof.

24. The process of any one of claims 21-13, wherein the blend further comprises a B granulate comprising bedaquiline or a pharmaceutically acceptable salt thereof and third intragranular excipients.

25. The process of any one of claims 21-23, wherein 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.

26. The process of claim 21, wherein 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.

27. The process of claim 26, wherein the blend further comprising a fourth granulate comprising bedaquiline or a pharmaceutically acceptable salt and/or solvate thereof and fourth intragranular excipients.

28. 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

(d) the APIs are each independently pretomanid, moxifloxacin, or pyrazinamide,

29. The process of claim 28, wherein 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.

30. The process of claim 28 or 29, wherein a second granulate comprises second intragranular excipients and pretomanid as a free base, a pharmaceutically acceptable salt, and/or a solvate of thereof.

31. The process of any one of claims 28-30, wherein the second blend further comprises a B granulate comprising bedaquiline or a pharmaceutically acceptable salt thereof and third intragranular excipients.

32. The process of any one of claims 28-30, wherein 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.

33. The process of claim 28, wherein the 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.

34. The process of claim 33, wherein the first or second blend further comprises a fourth granulate comprising bedaquiline or a pharmaceutically acceptable salt thereof and fourth intragranular excipients.

35. A method of treating tuberculosis comprising administering a therapeutically effective amount of a formulation according to any one of claims 1-20 or prepared according to any one of claims 21 - 34, to a patient in need thereof.

36. The method of claim 35, wherein the tuberculosis is drug-sensitive tuberculosis (DS-TB).

37. The method of claim 35, wherein the tuberculosis is multidrug-resistant tuberculosis (MDR-TB).

38. The method of claim 35, wherein the tuberculosis is extensively-drug resistant tuberculosis (XDR-

TB).