Combination antibacterial compositions and short-term antibacterial regimens

Abstract

To provide therapeutic combinations of antibacterial agents linezolid, bedaquiline and pretomanid, and optionally pyrazinamide, in a short-course oral dosage regimen for treating tuberculosis.SOLUTION: Provided is a method for treating tuberculosis, which comprises a step of administering, to a patient in need thereof, a therapeutically effective amount of each linezolid, bedaquiline and pretomanid, and optionally pyrazinamide, or a pharmaceutically acceptable salt each thereof and a pharmaceutically acceptable carrier. In an embodiment, linezolid is removed from the treatment regimen after one to two months. In another embodiment, linezolid may be re-administered after a 1-2 week drug holiday.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Field of Invention The present invention generally relates to combinations of compounds having antibacterial activity, and more specifically, antituberculous properties. In particular, the present invention relates to chemically stable combinations of the antibacterial agents linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide, in short-term oral administration regimens for the treatment of tuberculosis.

[0002] All references cited or relied upon below are expressly incorporated herein by reference. [Background technology]

[0003] Background of the Invention Mycobacterium tuberculosis is the causative agent of tuberculosis ("TB"), a highly devastating infectious disease. It is estimated that approximately 2 million people worldwide die from TB each year. Due to mishandling of tuberculosis, drug resistance has developed globally in mycobacterium tuberculosis, rendering some drug therapies ineffective.

[0004] Approximately 5 million new cases of multidrug-resistant (MDR) tuberculosis are reported annually (1). Current recommendations necessitate treatment for up to two years with second-line drugs that are poorly tolerable, toxic, more difficult to administer, and less effective than the six-month short-term regimens for so-called drug-susceptible TB. Regimens containing at least six drugs, including newer high-dose fluoroquinolones, the injectable drugs clofazimine (CFZ), pyrazinamide (PZA), and high-dose isoniazid (INH), have shown potential as effective nine-month regimens in MDR-TB cases with minimal bacillary resistance to second-line drugs (2-4). However, these regimens remain extremely difficult to administer and are not expected to be effective in establishing resistance to fluoroquinolones and / or injectable drugs (3).

[0005] Two novel classes of drugs have recently received conditional regulatory approval for use in MDR-TB: the diarylquinoline bedaquiline (BDQ) and the nitroimidazole derivative delamanid. Aside from several known mutations that confer cross-resistance between BDQ and CFZ (5, 6), these drugs are not known to exhibit cross-resistance with other TB drugs. A three-drug regimen of BDQ, adding the second nitroimidazole pretomanid (PMD; formerly known as PA-824) and the oxazolidinone stezolid (SZD; formerly known as PNU-100480), which are entering Phase 3 clinical trials, has recently been reported to have greater bactericidal activity in a mouse model of TB than the first-line regimen of rifampin (RIF), INH, and PZA (7-10). This three-drug combination was more active than either of its two drug components, indicating that SZD provides significant activity. However, SZD has only completed one Phase 2a clinical trial of its initial bactericidal activity (8), and further progress cannot be guaranteed.

[0006] Until recently, linezolid (LZD) was the only oxazolidinone antibiotic available on the market. While efficacy has been demonstrated in salvage therapy for refractory cases of MDR-TB, its use has been reduced due to dose-dependent and duration-dependent toxicity. Novel regimens based on 3 or more oral drugs (one of which is LZD, which has little to no existing resistance) offer simpler and more generally active regimens. Therefore, there is a need in this field for novel regimens that are more effective than current first-line regimens for drug-sensitive TB and thereby shorten and simplify the treatment of pulmonary TB regardless of resistance to existing drugs. [Overview of the project] [Means for solving the problem]

[0007] Summary of the Invention A pharmaceutical composition is provided comprising linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide, or each of each of pharmaceutically acceptable salts thereof in a therapeutically effective amount, and a pharmaceutically acceptable carrier.

[0008] A method for treating tuberculosis is also provided, which comprises administering to patients in need linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide, or each of pharmaceutically acceptable salts thereof, in a therapeutically effective amount, along with a pharmaceutically acceptable carrier. In one embodiment, linezolid is removed from the treatment regimen after 1-2 months. In another embodiment, linezolid may be re-administered after a drug-free period of 1-2 weeks. In embodiments of the present invention, for example, the following items are provided. (Item 1) A pharmaceutical composition comprising linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide, or each of each of pharmaceutically acceptable salts thereof in a therapeutically effective amount, and a pharmaceutically acceptable carrier. (Item 2) Linezolid is the pharmaceutical composition described in item 1, administered at a dose of 100 mg / kg. (Item 3) Linezolid is the pharmaceutical composition described in item 1, administered at a dose of 50 mg / kg. (Item 4) A method for the treatment of tuberculosis, comprising the step of administering to a patient in need a therapeutically effective amount of linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide, or each of each of these pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier. (Item 5) Linezolid is administered for up to 3 months, as described in item 4. (Item 6) Linezolid is administered for up to two months, as described in item 4. (Item 7) Linezolid is administered for up to 1 month by the method described in item 4. (Item 8) Linezolid is administered at 100 mg / kg / day for up to 1 - 2 months by the method described in item 4. (Item 9) Linezolid is administered at 50 mg / kg / day for up to 2 months by the method described in item 4. (Item 10) Linezolid is administered at 100 mg / kg / day for up to 1 month by the method described in item 4. (Item 11) Linezolid is administered at a dose of 600 mg once a day for the first 1 - 2 months by the method described in item 4. (Item 12) Linezolid is readministered after a drug - free period of 1 - 2 weeks by the method described in item 4. (Item 13) Bedaquiline is at a dose of 200 - 400 mg qd in the pharmaceutical composition described in item 1. (Item 14) Bedaquiline is administered at 400 mg qd for 2 weeks, followed by 200 mg tiw by the method described in item 4. (Item 15) Linezolid is at a dose of 600 mg bid or 1200 mg qd in the pharmaceutical composition described in item 1. (Item 16) Pretomanid is at a dose of 100 - 200 mg qd in the pharmaceutical composition described in item 1.

Mode for Carrying Out the Invention

[0009] Detailed Description of the Invention It should be understood that the description of the present invention has been simplified for clarity, excluding many other elements found in typical pharmaceutical compositions, in order to illustrate elements directly relevant to a clear understanding of the invention. Those skilled in the art will recognize that other elements and / or processes are desirable and / or required in carrying out the present invention. However, since such elements and processes are well known in the art and do not facilitate a better understanding of the present invention, no consideration of such elements and processes is provided herein. The disclosure herein relates 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 illustrative purposes only and are not meant to be exclusive or limiting in the description of the present invention.

[0010] Despite the conventional understanding that continuous administration of antibacterial agents over a period of several months is necessary to obtain the desired antibacterial effect, the inventors have surprisingly discovered that LZD in a multi-agent dosage form can be administered for 1-2 months while still retaining its bactericidal activity. More specifically, the inventors have found that LZD adds bactericidal and bactericidal activity to formulations containing BDQ and PMD. This additional bactericidal activity was indistinguishable from that of SZD, as shown in Example 1. In Example 3, where the bacterial load and PMD doses were higher, LZD did not appear to be as effective as SZD, but the difference was not statistically significant. Therefore, the impact of using LZD instead of SZD in relation to the duration required to cure mice is small. These findings form the basis for advancing the evaluation of the BDQ+PMD+LZD regimen to patients with broadly drug-resistant TB (XDR-TB) or treatment-intolerant or unresponsive MDR-TB in the recently initiated NiX-TB clinical trial.

[0011] Given the superior bactericidal activity of BDQ+PMD and oxazolidinone compared to the first-line regimen, it is also reasonable to consider whether a regimen based on this combination can shorten the treatment time for drug-sensitive TB. It has been previously shown that adding PZA to the BDQ+PMD+SZD combination results in even greater bactericidal activity, curing almost all mice after just 6 weeks of treatment (7). However, the contribution of SZD to the four-drug combination was not confirmed. In Example 2, adding LZD to BDQ+PZA+PMD also significantly increased the bactericidal and bactericidal activity of the above regimen, curing all mice after 6 weeks of treatment, while it was confirmed that at least 5 months of treatment with the first-line regimen is typically required to produce this result under the same conditions.

[0012] The 100 mg / kg dose of LZD used in the examples is equivalent to the mean plasma AUC produced by the same dose used to initiate treatment in the NiX-TB clinical trial, which is 600 mg twice daily in humans. 0-24h This resulted in (19, 20). When this dose was administered over a long duration in relief regimens for treating MDR-TB and XDR-TB, it resulted in an unacceptably high rate of myelotoxicity and neuropathy (26). Since these toxicities are dose-dependent and duration-dependent, we determined whether the contribution of LZD to the bactericidal activity of these regimens would be adversely affected by reducing the dose and duration of LZD. The potent bactericidal activity of the four drug regimens including PZA in Example 2 allowed all mice to heal after 1.5 months of treatment. Nevertheless, limiting the duration of LZD 100 mg / kg to the first month did not adversely affect the contribution of LZD to bactericidal activity. In the absence of PZA, the LZD dose had an average AUC comparable to a daily dose of 600 mg in humans. 0-24hReducing the dose to 50 mg / kg resulted in reduced bactericidal activity during the first month of treatment. However, after two months of treatment, only a small number of CFUs were recovered, regardless of whether LZD was administered at 100 mg / kg for one or two months, or at 50 mg / kg for two months. Furthermore, restricting LZD to 100 mg / kg during the first month of treatment did not significantly increase the relapse rate after two or three months of treatment. These results suggest that the use of LZD 600 mg once daily for the first one to two months of treatment, and / or front-loading therapy at higher doses for even shorter periods, may allow LZD to provide significant bactericidal and sterile activity before the onset of potentially irreversible neuropathy occurs (27, 28).

[0013] The inventors have further discovered that linezolid may be readjusted at a lower dose after a 1-2 week interruption (e.g., drug-free or treatment-free days) based on neuropathic findings and subsequent improvement, or similarly, blood findings. The clinical dose for pretomanid may be 200 mg qd or 100 mg qd. For bedaquiline, the clinical dose may be 400 mg qd over two weeks, followed by 200 mg tiw or 200 mg qd. The clinical dose for linezolid is to start with 600 mg bid or 1200 mg qd.

[0014] A specific embodiment of the present invention The present invention generally relates to oral dosage combinations of linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide.

[0015] Linezolid is a synthetic antibacterial agent of the oxazolidinone class. The chemical name of linezolid is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. Its empirical formula is C 16 H 20It is FN3O4. Its molecular weight is 337.35, and its chemical structure is shown below: [ka]

[0016] Bedaquiline is a diarylquinoline antimycobacterial drug marketed as SIRTURO in fumarate form. The chemical name of bedaquiline fumarate is a (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol compound (1:1) with fumarate. Its molecular formula is C 32 H 31 It has the molecular structure BrN2O2·C4H4O4 and a molecular weight of 671.58 (555.50 + 116.07). The molecular structure of bedaquiline fumarate is as follows: [ka]

[0017] Pretomanid is a novel nitroimidazole antibacterial agent currently under development by the Global TB Alliance. As a potential treatment for TB, it possesses many attractive properties—most notably its novel mechanism of action, its in vitro activity against all tested drug-resistant clinical isolates, and its activity as both a potent bactericide and sterilizer. Furthermore, this compound shows no evidence of mutagenicity in a standard series of genotoxicity studies, no significant cytochrome P450 interactions, and no significant activity against a wide range of Gram-positive and Gram-negative bacteria. The IUPAC name for pretomanid is (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine. Pretomanid has the following structure: [ka]

[0018] Pyrazinamide (pyrazine-2-carboxamide): [ka] Pyrazinamide is a pyrazine analog of nicotinamide and is used as an anti-tuberculosis drug. Pyrazinamide is most commonly used in combination with other drugs to treat active tuberculosis (TB) during the initial phase of treatment (generally the first two months of treatment). Pyrazinamide exhibits clinically significant antibacterial activity against Mycobacterium tuberculosis and M. africanum.

[0019] Accordingly, one embodiment of the present invention provides a pharmaceutical composition comprising linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide, or each of pharmaceutically acceptable salts thereof in a therapeutically effective amount, and a pharmaceutically acceptable carrier.

[0020] In another embodiment of the present invention, a pharmaceutical composition is provided in which linezolid is administered at a dose of 100 mg / kg.

[0021] In another embodiment of the present invention, a pharmaceutical composition is provided in which linezolid is administered at a dose of 50 mg / kg.

[0022] In a further embodiment of the present invention, a method for treating tuberculosis is provided, comprising the steps of administering to a patient in need a therapeutically effective amount of linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide, or each of each of pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0023] Another embodiment of the present invention provides a method for treating tuberculosis in which linezolid is administered for up to three months.

[0024] Another embodiment of the present invention provides a method for treating tuberculosis in which linezolid is administered for up to two months.

[0025] Another embodiment of the present invention provides a method for treating tuberculosis in which linezolid is administered for up to one month.

[0026] Another embodiment of the present invention provides a method for treating tuberculosis in which linezolid is administered at a dose of 100 mg / kg / day for up to 1 to 2 months.

[0027] Another embodiment of the present invention provides a method for treating tuberculosis in which linezolid is administered at a dose of 50 mg / kg / day for up to two months.

[0028] Another embodiment of the present invention provides a method for treating tuberculosis in which linezolid is administered at a dose of 100 mg / kg / day for up to one month.

[0029] Another embodiment of the present invention provides a method for treating tuberculosis in which linezolid is administered once daily at a dose of 600 mg for the first one to two months.

[0030] In another embodiment, a method is provided for treating tuberculosis in which linezolid is re-administered after a drug-free period of 1-2 weeks.

[0031] In further embodiments, the dose of bedaquiline is 200-400 mg qd.

[0032] In an alternative embodiment, bedaquiline is administered at 400 mg qd over two weeks, followed by 200 mg tiw. In a further embodiment, linezolid is administered at 600 mg The dosage is either bid or 1200 mg qd.

[0033] In another embodiment, the dose of pretomanid is 100-200 mg qd.

[0034] Definition of an invention and certain components Where a trade name is used herein, the applicant intends to include, independently, the product of that trade name and the active pharmaceutically active ingredient(s) of that product.

[0035] The term "chemical stability" means that the three antibacterial agents in a combination are substantially stable against chemical degradation. Preferably, they are physically stable in combination to enable a commercially useful shelf life for the combination product. Typically, "chemically stable" means that the first component of the mixture does not act to degrade the second component when the two are physically combined to form a pharmaceutical dosage form. More typically, "chemically stable" means that the acidity of the first component does not catalyze or otherwise accelerate the acid decomposition reaction of the second or third component.

[0036] The terms "synergy" and "synergistic" mean that the effect achieved by using a compound together is greater than the sum of the effects that would result from using the compound separately, i.e., greater than what would be predicted based on the two active ingredients administered separately. A synergistic effect can be achieved when the compound is: (1) co-formulated and administered or delivered simultaneously in a combination formulation; (2) delivered alternately or in parallel as separate formulations; or (3) in several other regimens. In alternating therapy, a synergistic effect can be achieved when the compound is administered or delivered sequentially, for example, in separate tablets, pills or capsules, or by different injections in separate syringes. Generally, during alternating therapy, the effective dose of each active ingredient is administered sequentially, i.e., in a series, whereas in combination therapy, the effective dose of two or three active ingredients is administered together. A synergistic antibacterial effect represents an antibacterial effect greater than the simply inferred additive effect of the individual compounds in the combination.

[0037] Bioavailability refers to the extent to which a pharmaceutically active drug becomes available to target tissue after its introduction into the body. Enhancing the bioavailability of a pharmaceutically active drug can provide more efficient and effective treatment for patients because, for the dose administered, more of the pharmaceutically active drug is available to the targeted tissue site.

[0038] The compounds in the combination of the present invention may be referred to as "active ingredients" or "pharmaceutically active agents."

[0039] As used herein, the term "prodrug" means any compound that, when administered to a biological system, produces a drug substance, i.e., an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, and / or metabolic chemical reactions.

[0040] The term "prodrug moiety" refers to an unstable functional group that separates from an active inhibitory compound during metabolism, systemically, intracellularly, by hydrolysis, enzymatic cleavage, or through some other process (Textbook of Drug Design and Development (1991)). Edited by P. Krogsgaard-Larsen and H. Bundgaard, Bundgaard, Hans, “Design and Application of Prodrugs,” pp. 113–191, Harwood Academic Publishers. The prodrug portion may act to optimize drug delivery, bioavailability, and potency by increasing solubility, absorption, and lipophilicity. A “prodrug” is therefore an analog of a therapeutically active compound modified by covalent bonding.

[0041] The definitions and conventions of stereochemistry used herein generally follow SP. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms; that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. With respect to a given chemical structure, these compounds are called stereoisomers and are identical except that they are mirror images of each other. Specific stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate. The terms "racemic mixture" and "racemate" refer to equimolar mixtures of two non-optically active enantiomer species.

[0042] The term "chiral" refers to molecules that have the property of not being able to be superimposed on their mirror image partners, while the term "achiral" refers to molecules that can be superimposed on those mirror image partners.

[0043] Any reference to any of the compounds in the composition of the present invention also includes any of its physiologically acceptable salts. Examples of physiologically acceptable salts and their physiologically functional derivatives include salts obtained from suitable bases (e.g., alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium and NX4 + (where X is C1-C4 alkyl)), or organic acids (e.g., fumaric acid, acetic acid, succinic acid). Physiologically acceptable salts of a hydrogen atom or an amino group include organic carboxylic acids (e.g., acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid and succinic acid); organic sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid); and salts of inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid). Physiologically acceptable salts of a compound having a hydroxy group include anions of the compound in combination with suitable cations (e.g., Na + and NX4 + (where X is independently selected from H or a 1-C4 alkyl group)).

[0044] For therapeutic use, salts of the active ingredients in the combinations of the present invention are physiologically acceptable, i.e., they are salts obtained from physiologically acceptable acids or bases. However, salts of acids or bases that are not physiologically acceptable may also find use, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether obtained from physiologically acceptable acids or bases or not, are within the scope of the present invention.

[0045] The above combination can be formulated in unit dosage formulations containing fixed amounts of each active pharmaceutical ingredient for periodic, e.g., once-daily or divided doses of the active ingredients.

[0046] Pharmaceutical formulations according to the present invention include combinations according to the present invention, together with one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared (Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.)). Compositions intended for oral use may be prepared according to any method known in the art with respect to the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents (including antioxidants, sweeteners, flavoring agents, coloring agents and preservatives) to provide a mouth-friendly preparation. Tablets containing the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients or adjuvants suitable for the manufacture of tablets are acceptable.Suitable excipients or adjuvants include, but are not limited to, inert diluents, solubilizers, suspending agents, adjuvants, wetting agents, sweeteners, aromatic or flavoring substances, isotonic substances, colloidal dispersants and surfactants (including, but not limited to, charged phospholipids (e.g., dimyristoyl phosphatidylglycerin)), alginic acid, alginates, acacia resin, gum arabic, 1,3-butylene glycol, benzalkonium chloride, colloidal silicon dioxide, cetosteryl alcohol, cetomacrogol emulsifying wax, casein, calcium stearate, cetylpyridine chloride, cetyl alcohol, cholesterol, calcium carbonate, and CRODESTAS F-110 (which is a mixture of sucrose stearate and sucrose distearate). Inc.)), clay, kaolin and bentonite, derivatives of cellulose and its salts (e.g., hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, carboxymethylcellulose and its salts, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, amorphous cellulose), dicalcium phosphate, dodecyltrimethylammonium bromide, dextran, dialkyl esters of sodium sulfosuccinate (e.g., AEROSEL OT, American). Cyanamid), gelatin, glycerol, glycerol monostearate, glucose, p-isononylphenoxypoly(glycidol) (also known as Olin 10-G or 10-GR surfactant (Olin Chemicals, Stamford, Conn.)); glucamide (e.g., octanoyl-N-methylglucamide, decanoyl-N-methylglucamide and heptanoyl-N-methylglucamide), lactose, lecithin (phosphatide), maltoside (e.g., n-dodecyl-β-D-maltoside), mannitol, magnesium stearate, magnesium aluminum silicate, oils (e.g., cottonseed oil, seed oil, olive oil, castor oil and sesame oil); paraffin, potato starch, polyethylene glycol (e.g., CARBOWAX 3350, CARBOWAX 1450 and CARBOPOL 9340 (Union Carbide), polyoxyethylene alkyl esters (e.g., macrogol ethers such as CETOMACROGOL 1000), polyoxyethylene sorbitol fatty acid esters (e.g., TWEENS, ICI Specialty Chemicals), polyoxyethylene castor oil derivatives, polyoxyethylene stearate, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), phosphate, ethylene oxide, and 4-(1,1,3,3-tetramethylbutyl)phenol polymers with formaldehyde (also known as TYLOXAPOL, SUPERIONE, and TRITON), poloxamer and poloxamine (e.g., BASF Corporation (Mount Olive, NJ)Examples of commercially available products include PLURONICS F68LF, F87, F108, and TETRONIC 908 (from [company name]), pyranosides (e.g., n-hexyl-β-D-glucopyranoside, n-decyl-β-D-glucopyranoside, n-octyl-β-D-glucopyranoside), quaternary ammonium compounds, silica, sodium citrate, starch, sorbitol esters, sodium carbonate, solid polyethylene glycol, sodium dodecyl sulfate, sodium lauryl sulfate (e.g., DUPONAL P, DuPont), stearic acid, sucrose, tapioca starch, talc, thioglucosides (e.g., n-heptyl-β-D-thioglucoside), tragacanth, triethanolamine, and TRITON X-200 (Rohm and Haas).

[0047] Formulations for oral use may also be presented as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as pregelatinized starch, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0048] The aqueous suspension of the present invention comprises an active substance mixed with an excipient suitable for the production of aqueous suspensions. Examples of such excipients include: suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum), and dispersing or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxides and partial esters obtained from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate)). The aqueous suspension may also contain one or more preservatives (e.g., ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more colorants, one or more flavoring agents, and one or more sweeteners (e.g., sucrose, sucralose, or saccharin).

[0049] Oil suspensions can be formulated by suspending their active ingredients in vegetable oils (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (e.g., liquid paraffin). Oral suspensions may contain thickening agents (e.g., beeswax, solid paraffin, or cetyl alcohol). Sweeteners (e.g., those listed above) and flavoring agents may be added to provide an oral preparation that is palatable. These compositions may be preserved by the addition of antioxidants such as ascorbic acid and BHT.

[0050] The dispersible powders and granules of the present invention, suitable for the preparation of aqueous suspensions by the addition of water, provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Further excipients, such as sweeteners, flavoring agents, and colorants, may also be present.

[0051] According to another embodiment of the present invention, a pharmaceutical composition in the form of a dispersible tablet is provided. The dispersible tablet is intended to be dispersed in water before administration to provide a homogeneous dispersion. The dispersible tablet disintegrates within, for example, 3 minutes using water at 15-25°C.

[0052] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions or liposome formulations. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil), a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring gums (e.g., acacia gum and tragacanth gum), naturally occurring phosphatides (e.g., soy lecithin), esters or partial esters obtained from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsions may also contain sweeteners and flavoring agents. The syrups and elixirs may be formulated with sweeteners (e.g., glycerol, sorbitol, or sucrose). Such formulations may also contain lubricants, preservatives, flavoring agents, or colorants.

[0053] The amount of active ingredient that can be combined with a carrier substance to produce a single dosage form varies depending on the host being treated and the specific mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active ingredient combined with a suitable and convenient amount of carrier substance, which may vary in weight from approximately 5 to approximately 95% of the total composition. Pharmaceutical compositions may be prepared to provide readily measurable amounts for administration. As noted above, formulations of the present invention suitable for oral administration may be expressed as discontinuous units (e.g., capsules, cachets, or tablets (each containing a predetermined amount of the active ingredient)); as powders or granules; as liquids or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions.

[0054] The combinations of the present invention can, for convenience, be represented as pharmaceutical formulations in unit dosage forms. A convenient unit dosage formulation contains any amount of the active ingredient, each ranging from 1 mg to 1 g (for example, 10 mg to 500 mg of each active ingredient, but not limited thereto). In certain embodiments, 50 mg to 300 mg of each active ingredient may be used.

[0055] The separation of active ingredients in pharmaceutical powders and granules is a widely recognized problem that can result in unharmonious dispersion of the active ingredients in the final dosage form. Some of the main factors contributing to separation are particle size, shape, and density. Separation is particularly troublesome when attempting to formulate a single homogeneous tablet containing multiple active ingredients with different densities and particle sizes. Lubricants have traditionally been used to improve the flow characteristics of granules and powders by reducing interparticle friction. See Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms: Tablets, Volume 1, pp. 177-178 (1989) (referenced herein). Lubricants are typically added to the pharmaceutical composition immediately before tableting to facilitate the flow of granular material into the cavity of the tableting die. Examples of lubricants include: colloidal silicon dioxide, asbestos-free talc, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metal stearate, calcium stearate, magnesium stearate, zinc stearate, stearowet C, starch, starch 1500, magnesium lauryl sulfate, and magnesium oxide. The novel compositions of the present invention may contain lubricants to provide and maintain homogeneity of the active ingredients during handling before tableting.

[0056] The compositions of the present invention are administered to humans or other animals in safe and therapeutically effective amounts as described herein. These safe and therapeutically effective amounts vary according to the type and size of the mammal being treated, as well as the desired outcome of the treatment. A “therapeutically effective amount” is an amount effective to treat tuberculosis. The term “treating” refers to improving at least one symptom of a disorder in the subject, in relation to the subject. Treating may mean curing, improving, or at least partially improving a disorder.

[0057] Any of the various methods known to those skilled in the art for packaging tablets, caplets, or other solid dosage forms suitable for oral administration that do not degrade the components of the present invention are suitable for use in packaging. The combination may be packaged in glass and plastic bottles. Tablets, caplets, or other solid dosage forms suitable for oral administration may be packaged and contained within a variety of packaging materials, which may optionally contain a desiccant (e.g., silica gel). The packaging may be in the form of unit dose blister packaging. For example, the package may contain one blister tray of tenofovir DF and another blister tray of emtricitabine pills, tablets, caplets, or capsules. The patient takes one dose (e.g., pills) from one tray and one dose from the other tray. Alternatively, the package may contain a blister tray of a co-formulated combination of tenofovir DF and emtricitabine in a single pill, tablet, caplet, or capsule. As with other combinations and their packages, the combination of the present invention comprises physiologically functional derivatives of tenofovir DF and FTC.

[0058] Packaging materials may also contain labels and information about the pharmaceutical composition printed thereon. Furthermore, manufactured articles may include booklets, reports, notices, brochures, or leaflets containing product information. This form of pharmaceutical information is referred to in the pharmaceutical industry as “packaging inserts.” Packaging inserts may be affixed to or included with the pharmaceutical manufactured article. These packaging inserts and any manufactured article labels provide information about the pharmaceutical composition. This information and labels, describing the composition, its dosage, and various other parameters required by regulatory authorities (e.g., the U.S. Food and Drug Administration), provide various forms of information available to healthcare professionals and patients. [Examples]

[0059] The following examples further describe and illustrate specific embodiments within the scope of the present invention. The techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The present disclosure is further illustrated by the following examples. This should not be construed as limiting the present disclosure in scope or spirit to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and that this is not intended to limit the scope of the present disclosure. It should also be understood that there may be means that can be suggested to those skilled in the art to various other embodiments, modifications, and their equivalents themselves without departing from the spirit of the present disclosure and / or the appended claims.

[0060] material and method Mycobacterial strain M. tuberculosis H37Rv was subcultured in mice, divided into aliquots and frozen. Before infection, the mice were subcultured in Middlebrook 7H9 broth containing 10% oleic acid-albumin-dextrose-catalase (OADC) (Fisher, Pittsburgh, PA) and 0.05% Tween 80.

[0061] Antibacterial agents were obtained: INH, RIF, PZA, BDQ, PMD, and LZD, which were formulated for oral administration as previously described (9, 10, 12, 13). SZD (prepared in PEG-200 / 0.5% methylcellulose suspension) and TZD (prepared as a phosphate prodrug dissolved in water) were synthesized by WuXi (Hubei, China). AZD (prepared as a disodium phosphate prodrug dissolved in 0.3% dextrose and 0.9% salt solution) was provided by AstraZeneca. RWJ (prepared in 0.5% methylcellulose) was provided by Johnson and Johnson.

[0062] Pharmacokinetics of oxazolidinones. Uninfected female BALB / c mice (approximately 20g body weight) were administered a single dose of SZD (50mg / kg), LZD (100mg / kg), TZD (10 or 20mg / kg), or AZD (50 or 200mg / kg). Three mice per dose were sampled by cardiac puncture at 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours post-administration (and an additional 16 hours for AZD). Plasma drug concentrations were quantified by validated LC / MS methods performed at AstraZeneca (for AZD only) (14) or Rutgers New Jersey Medical School (for other oxazolidinones). Reference materials for each of the oxazolidinones were provided by sponsors. In the Rutgers study, the analyte of interest was extracted by combining 20 μl of mouse plasma with 20 μl of acetonitrile:water (1:1) and 180 μl of methanol:acetonitrile (1:1) containing 10 ng / ml verapamil (Sigma-Aldrich) as an internal standard. The mixture was vortexed and centrifuged, and 100 μL of the supernatant was collected and combined with 100 μL of water for analysis. LC / MS-MS analysis was performed on an Agilent 1260 LC system coupled with an AB Sciex 4000 Q-trap mass spectrometer (positive mode, electrospray ionization) and an Agilent SB-C8 column, 2.1 × 30 mm, 3.5 μm (column temperature fixed at 24°C). Mobile phase A was 0.1% formic acid in 100% H2O, and mobile phase B was 0.1% formic acid in 100% acetonitrile. The conventional injection volume was 2 μl. The Mass Selective Detector was set to MRM (Multiple Reaction Monitoring) mode using positive polar ionization, and monitoring was performed for the target ions, SZD (m / z 354.12 / 312.04), SZD-M1 (370.13 / 238.12), LZD (338.00 / 235.00), and TZD (371.12 / 343.00), as well as the internal standard (m / z 455.4 / 165.2). The limit of quantification for all oxazolidinones was 5 ng / ml.PK parameters were determined by non-compartmental analysis using WinNonlin 6.4 (Certara, Princeton, NJ).

[0063] Aerosol transmission of M. tuberculosis. All animal procedures are by Johns. Approved by the Hopkins University Animal Experiments Committee. High-dose aerosol infection was performed as previously described (15). Briefly, 5-6 week old female BALB / c mice (Charles River, Wilmington, MA) were exposed to an inhalation exposure system (Glas-Col, Terre Haute, IN) and fresh logarithmic growth phase broth cultures (optical density at 600 nm: 0.8-1.0) to induce 3.5-4.0 log exposure in the lungs of each mouse. 10 Mycobacterium tuberculosis H37Rv was used to infect mice for the purpose of transplanting CFUs. Two to three mice from each aerosol infection run (Examples 1, 2, and 4) or five mice from a single run (Examples 3a and 3b) were manually killed one day after infection and on the day of treatment commencement (D0), and the number of bacteria transplanted into the lungs and the number of bacteria at the start of treatment were determined.

[0064] Chemotherapy. Mice were randomized to an experimental arm by aerosol execution prior to treatment. Treatment was initiated 14–17 days after injection. Treatment was administered once daily for 5 days per week by force-feeding. Except for dose-ranging monotherapy, the drug doses (in mg / kg) were as follows: INH (10), RIF (10), PZA (150), BDQ (25), PMD (50 or 100), SZD (50), LZD (50 or 100), TZD (10), AZD (125), and RWJ (100) (12, 14, 16–18). Each drug was administered once daily for 5 days per week by force-feeding. For all combinations, PMD was administered immediately after the dose of the combined (9, 12)BDQ±PZA. Oxazolidinone was administered at least 4 hours later.

[0065] In Example 1, control mice received RIF+INH+PZA for 2 months, followed by RIF+INH alone for a total of 4 months. To compare the contributions of SZD and LZD, test mice received either a three-drug combination of BDQ and PMD (50 mg / kg) + SZD (50 mg / kg) or LZD (100 mg / kg), or one or two drug components of each of these three-drug regimens. The one-drug and two-drug regimens were limited to 1-month and 2-month treatments, respectively, except that the BDQ+PMD combination was administered along with the three-drug combination for up to 4 months. In Example 2, the contribution of LZD to regimens containing BDQ+PMD and PZA was evaluated. Control mice received BDQ+PZA and PMD at either 50 or 100 mg / kg. The test mice received BDQ+PZA+PMD (100 mg / kg) and LZD (100 mg / kg) for up to two months. One cohort received LZD for the entire two months. Another cohort received LZD only for the first month.

[0066] Evaluation of treatment efficacy. Efficacy was evaluated based on the number of lung CFUs (measure of bactericidal activity) at selected time points during treatment and the percentage of mice with culture-positive recurrence after treatment completion (measure of sterilization activity). Quantitative cultures of lung homogenates were performed in parallel on OADC-enriched 7H11 agar (basic agar) and on basal agar supplemented with 0.4% activated charcoal to reduce the drug carryover effect (12). Plates were incubated at 37°C for up to 42 days before the final CFU count was determined. In each of Example 1 and Example 2, the lung CFU count was assessed in 4-5 mice per treatment group at each time point. The proportion of mice with culture-positive relapse was determined by maintaining a cohort of 15-20 mice for a further 3 months after completion of treatment, then sacrificing them and determining the proportion with positive lung cultures, as defined by M. tuberculosis of ≥1 CFU detected after plating whole lung homogenates on 5 7H11 plates with or without 0.4% activated charcoal.

[0067] Statistical analysis. The number of CFUs (x) was logarithmically transformed as (x+1) before analysis, and group means were compared using one-way ANOVA and Dunnett's post-test to control multiple comparisons. Group recurrence rates were compared using Fisher's exact test, adjusted for multiple comparisons. GraphPad Prism version 5 (GraphPad, San Diego, CA) was used for all analyses. The use of 15 mice / group for recurrence assessment provides a statistical power of over 80% to detect a 40 percent point difference in recurrence rates after adjusting for up to 5 simultaneous two-sided comparisons by setting α to 0.01. Smaller differences may not be very meaningful regarding shortening the duration of treatment.

[0068] Example 1 Contribution of LZD and SZD to novel combinations with BDQ+PMD Example 1 was conducted to evaluate whether commercially available oxazolidinone LZD could replace SZD in this combination without losing potency, and to clarify the contribution of each drug component to the activity of this combination. Lung CFU count during treatment. The mean CFU count (±SD) at the start of treatment was 6.17±0.27. Table 1 shows the lung CFU counts at 1 month, 2 months, and 3 months after treatment: [Table 1]

[0069] As predicted, RIF+INH+PZA increased the mean lung CFU count by 2.70 log after 1 month and 2 months of treatment, respectively. 10 degree and 4.58 log 10 The activity was reduced to a certain extent, leaving fewer than 10 CFU / mouse after 3 months of treatment. Due to the previously described antagonistic effect of PMD on BDQ activity (7, 12), BDQ+PMD had lower activity than BDQ alone during the first month. However, its activity was virtually identical to that of the first-line regimen over 2-3 months. The addition of SZD significantly increased the initial bactericidal activity of BDQ+PMD (p<0.001). This resulted in all mice becoming culture-negative during the 1-2 month treatment period. The activity of BDQ+PMD+SZD was significantly greater than that of RIF+INH+PZA after 1-month and 2-month treatment (p<0.001). The addition of LZD also significantly increased the activity of BDQ+PMD (p<0.01), resulting in superior activity compared to RIF+INH+PZA after 2-month and 3-month treatment (p<0.001). All two-drug combinations exhibited inferior activity at 2 months compared to three-drug combinations of BDQ+PMD and SZD or LZD (p<0.01). This confirms that each component of the drug contributes to the efficacy of the three-drug combination. However, these three-drug LZD-containing regimens were only superior to BDQ+LZD after 2 months of treatment. The LZD-containing regimens produced higher CFU numbers compared to their SZD-containing comparative regimens.

[0070] Recurrence after treatment completion. Recurrence results are shown in Table 1. Treatment with the first-line regimen for 3 months and 4 months resulted in recurrence in 13 out of 15 mice (87%) and 1 out of 20 mice (5%), respectively. The higher cure rate compared to previous examples is attributed to the lower than the normal bacterial load at the start of treatment. Consistent with the CFU count results, treatment with BDQ+PMD produced similar recurrence results to the first-line regimen at 3 and 4 months, but did not prevent recurrence after just 2 months of treatment. However, unlike the more abrupt decrease in CFU count with the three-drug regimen including SZD compared to LZD, the two BDQ+PMD+oxazolidinone regimens had similar bactericidal activity. While the difference between the SZD-containing regimen and BDQ+PMD alone was only statistically significant after 2 months of treatment, both oxazolidinone-containing regimens resulted in significantly fewer recurrences after 3 months of treatment compared to both BDQ+PMD and the first-line regimen.

[0071] Example 2 LZD's contribution to BDQ+PZA+PMD The potent bactericidal activity of BDQ+PZA+SZD and the additive bactericidal activity of PMD in mice have been previously reported (7, 9, 10, 12). Following the observation that LZD exhibited bactericidal activity comparable to SZD in combination with BDQ+PMD in Example 1, LZD was also able to replace SZD in the BDQ+PZA+PMD+SZD combination. The mean CFU count at the start of treatment was 7.92 ± 0.26. The lung CFU count and recurrence results are shown in Table 2: [Table 2]

[0072] As previously observed, BDQ+PZA+PMD exhibited significantly greater bactericidal activity compared to RIF+INH+PZA (p<0.001). Greater activity was observed when PMD was administered at 100 mg / kg instead of 50 mg / kg, although this difference was only noted after 2 months of treatment (p<0.01). Higher PMD doses helped serve all mice, except for one that was culture-negative at this point. The addition of LZD had a dramatic effect on efficacy, significantly reducing CFU counts at 1 month (p<0.001) and serving all mice, except for one that was culture-negative 1 month earlier. Adding LZD to BDQ+PZA+PMD also significantly reduced the relapse rate from 60% to 0% after 1.5 months of treatment, regardless of whether LZD was discontinued after the first month of treatment (p<0.001).

[0073] Example 3 Contribution of oxazolidinone to novel combinations with BDQ+PMD Example 3 was conducted to confirm the additive bactericidal activity of SZD and LZD when added to BDQ+PMD in Example 1, and to evaluate whether reducing the LZD dose by approximately 50% or limiting the duration of LZD administration to the first 1-2 months significantly affects its contribution.

[0074] Lung CFU count during treatment. The mean CFU count at the start of treatment was 7.74 ± 0.20. The lung CFU counts observed after 1 month, 2 months, and 3 months of treatment are shown in Table 3. RIF+INH+PZA remained approximately 6 log over the 2-month treatment period. 10The mean lung CFU count was reduced to a certain extent. Only BDQ+PMD exhibited slightly lower activity over this period. As previously observed, the addition of SZD 50 mg / kg provided superior activity compared to LZD 100 mg / kg, although both oxazolidinones significantly increased the initial bactericidal activity of BDQ+PMD. However, the results with BDQ+PMD+LZD 100 mg / kg were similar regardless of whether LZD was discontinued after one month or continued for two months. Similarly, using LZD 50 mg / kg instead of 100 mg / kg resulted in a higher CFU count at one month but not at two months. This suggests that the total LZD dose was achieved at 100 mg / kg for one month, or that 50 mg / kg for two months sufficiently maximized the contribution of LZD to that regimen. RWJ at 100 mg / kg performed very similarly to LZD at 50 mg / kg, while AZD and TZD were somewhat less effective. Compared to BDQ+PMD alone, all oxazolidinones significantly increased bactericidal activity at 1 and 2 months, except for TZD at 1 month (p<0.05 for AZD and TZD at M2; p<0.001 for other oxazolidinones). Recurrence after treatment completion. The recurrence results are shown in Table 3: [Table 3]

[0075] Treatment with the first-line regimen for three months resulted in relapse in 8 out of 14 mice (57%). Treatment with BDQ+PMD yielded numerically superior results, with only 3 out of 14 mice (21%) relapsing after three months, although this difference was not statistically significant. Adding SZD to BDQ+PMD resulted in only one relapse after just two months of treatment (at least as effective as three months of BDQ+PMD and more effective than the three-month first-line regimen). Adding SZD at 50 mg / kg also resulted in fewer relapses than the two-month treatment with LZD at 100 mg / kg, but this difference was not statistically significant. Using LZD at 100 mg / kg for only the first month was less effective than two months of SZD, but not significantly different from two months of LZD at 100 mg / kg. Similarly, among the regimens administered for 3 months, no relapses were observed regardless of whether LZD 100 mg / kg was continued throughout, discontinued after 1 or 2 months, or replaced with LZD 50 mg / kg after 2 months. In a post-hoc analysis comparing BDQ+PMD with all BDQ+PMD+LZD regimens, the addition of LZD 100 mg / kg for at least 1 month resulted in fewer relapses after 3 months of treatment.

[0076] Summary of Examples 1-3 The pharmacokinetics of oxazolidinone in BALB / c mice are shown in Table 4: [Table 4]

[0077] As previously described (18), oral administration of SZD at 50 mg / kg resulted in rapid and widespread metabolism to the active sulfoxide M1 metabolite (also known as PNU-101603). The mean AUC for this metabolite was also found. 0-24h and C max The AUC of SZD and SZD M1 was approximately 10 times higher than that of the parent SZD. Overall, the AUC of SZD and SZD M1 was higher. 0-24hThe values ​​were similar to the geometric mean observed in TB patients receiving 1,200 mg per day, or, in the case of SZD, slightly lower than that geometric mean (8). LZD had a 244-hour*μg / mL AUC comparable to the mean among TB patients receiving 1,200 mg once daily. 0-24h (19, 20) showed the highest exposure among the compounds tested. TZD exposure was dose-proportional from 10 mg / kg to 20 mg / kg. For the 10 mg / kg dose evaluated in the efficacy study, the total drug TZD AUC of 40 hours* μg / mL was observed. 0-24h The mean AZD AUCs produced by 50 and 200 mg / kg doses were similar to those determined in other infection models (21-23). 0-24h Interpolating between values, the estimated AUC of 160-190 hours*μg / mL produced by the 125 mg / kg dose used in the combined efficacy studies (Examples 3 and below) is obtained. 0-24h This refers to the steady-state AUC in healthy human volunteers who received 800 mg twice daily (the highest dose administered in recent clinical trials to determine the dose range of the bactericidal activity). 0-24h It is similar to (24). Oxazolidinone is cleared relatively quickly, and 1 / 2 The values ​​ranged from 2.8 to 3.9 hours. AUC from all compounds. 0-24h The value is AUC inf The values ​​were approximately equal to (≧98%). This suggests that accumulation is not expected after multiple doses in BALB / c mice.

[0078] The present invention is further described in the following numbered sections: 1. A pharmaceutical composition comprising linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide, or each of a pharmaceutically acceptable salt thereof in a therapeutically effective amount, and a pharmaceutically acceptable carrier. [Add clinical dosage] 2. Linezolid is the pharmaceutical composition described in item 1, with a dosage of 100 mg / kg. 3. Linezolid is the pharmaceutical composition described in item 1, with a dosage of 50 mg / kg. 4. A method for the treatment of tuberculosis, comprising the step of administering to a patient in need a therapeutically effective amount of linezolid, bedaquiline, and pretomanid, and optionally pyrazinamide, or each of each of these pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier. 5. Linezolid is administered for up to 3 months as described in item 4. 6. Linezolid is administered for up to two months as described in item 4. 7. Linezolid is administered for up to one month as described in item 4. 8. Linezolid is administered at a dose of 100 mg / kg / day for up to 1 to 2 months, as described in item 4. 9. Linezolid is administered at a dose of 50 mg / kg / day for up to 2 months, as described in item 4. 10. Linezolid is administered at a dose of 100 mg / kg / day for up to one month, as described in item 4. 11. Linezolid is administered once daily at a dose of 600 mg for the first one to two months, as described in item 4. 12. Linezolid is re-administered after a drug-free period of 1-2 weeks, as described in item 4. 13. The pharmaceutical composition described in item 1, in which bedaquiline is administered in a dose of 200-400 mg qd. 14. Bedaquiline is administered over two weeks at a dose of 400 mg qd followed by 200 mg tiw, as described in item 4. 15. Linezolid in a dose of 600 mg bid or 1200 mg qd, as described in item 1. 16. Pretomanid is the pharmaceutical composition described in item 1, in a dosage of 100-200 mg qd.

[0079] References

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[0080] It should be understood that the present invention is not limited to the specific embodiments of the invention described above, because variations of those specific embodiments may be made and still fall within the scope of the appended claims.

Claims

1. A single pharmaceutically acceptable dosage form comprising an antibacterial agent and a pharmaceutically acceptable carrier, wherein the antibacterial agent comprises linezolid, bedaquiline, and pretomanid, or pharmaceutically acceptable salts thereof, and each of the linezolid, bedaquiline, and pretomanid is present in the single dosage form in an amount of 1 mg to 1 g, with a dose ratio of linezolid to bedaquiline of 2:1 or 4:1, and a dose ratio of linezolid to pretomanid of 0.5:1 or 1:

1.

2. The pharmaceutically acceptable monodose form according to claim 1, wherein the antibacterial agent further comprises pyrazinamide or a pharmaceutically acceptable salt thereof.

3. The pharmaceutically acceptable single dosage form according to claim 1, wherein linezolid, bedaquiline, and pretomanid are each present in an amount of 10 mg to 500 g in the single dosage form.

4. The pharmaceutically acceptable single dosage form according to claim 1, wherein linezolid, bedaquiline, and pretomanid are each present in an amount of 50 mg to 300 mg in the single dosage form.

5. The pharmaceutically single dosage form according to claim 1, wherein bedaquiline is present in an amount of 200 mg to 400 mg in the single dosage form.

6. The pharmaceutically single dosage form according to claim 1, wherein linezolid is present in an amount of 600 mg in the single dosage form.

7. The pharmaceutically monoform according to claim 1, wherein pretomanid is present in an amount of 100 mg to 200 mg in the monoform.

8. The single pharmaceutically acceptable dosage form according to claim 1, wherein the single dosage form is a tablet or a capsule.

9. The pharmaceutically mono-dosage form according to claim 1, wherein the mono-dosage form comprises 100 mg of pretomanid.

10. The pharmaceutically mono-dosage form according to claim 1, wherein the mono-dosage form comprises 200 mg of pretomanid.

11. A single pharmaceutically acceptable dosage form according to any one of claims 1 to 10, for the treatment of tuberculosis in patients requiring treatment for tuberculosis.

12. The single pharmaceutical dosage form according to claim 11, wherein the dosage form is for administration for up to three months.

13. The single pharmaceutical dosage form according to claim 11, wherein the dosage form is for administration for up to two months.

14. The single pharmaceutical dosage form according to claim 11, wherein the dosage form is for administration for up to one month.

15. The pharmaceutical monoform according to claim 11, wherein the dosage form is for readmission after a drug-free period of one to two weeks.

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