WO2012103119A1

WO2012103119A1 - Compositions for administering rifalazil and other anti-tuberculosis agents in unit dosage form for oral administration

Info

Publication number: WO2012103119A1
Application number: PCT/US2012/022404
Authority: WO
Inventors: Chalom Sayada
Original assignee: Activbiotics Pharma, Llc
Priority date: 2011-01-24
Filing date: 2012-01-24
Publication date: 2012-08-02

Abstract

Pharmaceutical compositions including rifalazil, a surfactant, a lipophilic antioxidant, and one or more antibiotics selected from the group consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol are provided in a single unit dosage form for oral administration. The compositions can be used to treat tuberculosis. By placing the multiple antibiotic agents in a single unit dosage form, patient compliance with otherwise complicated treatment regimens can be increased.

Description

COMPOSITIONS FOR ADMINISTERING RIFALAZIL

AND OTHER ANTI-TUBERCULOSIS AGENTS IN UNIT DOSAGE FORM FOR ORAL ADMINISTRATION

BACKGROUND OF THE INVENTION

The present invention relates to the field of antimicrobial therapy.

Rifalazil, an ansamycin-class antibiotic, has been described in U.S. Pat. No. 4,983,602. A microgranulated formulation of rifalazil is disclosed in U.S. Pat. No. 5,547,683. This microgranulated rifalazil was shown to exhibit improved oral bioavailability in comparison to rifalazil crystals, mortar-milled crystals, and suspensions of mortar-milled crystals as determined by the relative AUCs produced for each formulation orally administered to beagles. Phase I clinical trials for rifalazil are described in U.S. Pat. Nos. 6,566,354 and 6,316,433.

Rifalazil is known to be able to treat tuberculosis, particularly when it is combined with one or more antibiotics known to be used in combination therapy to treat tuberculosis, such as isoniazid, streptomycin, pyrazinamide, and ethambutol. However, the insolubility of rifalazil makes it difficult to provide compositions containing rifalazil and these additional antibiotics in a single unit dosage form for oral administration.

It would be advantageous to provide compositions that include rifalazil and isoniazid, streptomycin, pyrazinamide, and/or ethambutol in a stable unit dosage form for oral administration, so as to ease patient compliance. It would also be advantageous to the bioavailability of rifalazil, to overcome the limitations associated with administration of rifalazil in dry microgranulated powder form. The present invention provides such compositions, as well as methods of using the compositions treat tuberculosis.

SUMMARY OF THE INVENTION

The invention features pharmaceutical compositions including rifalazil, a surfactant, a lipophilic antioxidant, and one or more antibiotics selected from the group consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol. The compositions can be used to treat tuberculosis. The oral bioavailability of rifalazil is increased, and the coefficient of variation in pharmacokinetic parameters (e.g., C_max and AUC_∞) is decreased when rifalazil is formulated with a sufficient amount of a surfactant. The stability of such formulations is improved by addition of a lipophilic antioxidant. The presence of the surfactant, and, optionally, the lipophilic antioxidant, does not significantly affect the stability or potency of the isoniazid, streptomycin, pyrazinamide, and/or ethambutol. The permits combination therapy using rifalazil and these other agents to be provided in a single unit dosage form for oral administration, for example, in the form of a capsule.

Accordingly, in one aspect, the invention features a pharmaceutical composition for oral administration in unit dosage form including rifalazil, one or more surfactants, one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, and, optionally, a lipophilic antioxidant, wherein the surfactants are from 20% to 99% (w/w) of the composition.

In a related aspect, the invention features a pharmaceutical composition for oral administration in unit dosage form including rifalazil, one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, and an antioxidant surfactant. In certain embodiments, the antioxidant surfactant is retinyl palmitate, ascorbyl palmitate, or tocopheryl-PEG-1000-succinate.

The invention also features a pharmaceutical composition for oral administration in unit dosage form including rifalazil, one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, a surfactant, and a lipophilic antioxidant, wherein the lipophilic antioxidant is present in an amount sufficient to reduce the oxidation of rifalazil. Desirably, upon storage of the unit dosage form at 25°C and 60% relative humidity for a period of one month, six months, or even twelve months, less than 0.2% of the rifalazil is converted to rifalazil N-oxide. In certain embodiments, less than 0.2%, 0.15%, 0.10%, 0.05%, or 0.02% of the rifalazil is converted to rifalazil N-oxide upon storage of the unit dosage form at 25°C and 60% relative humidity for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, or even 24 months.

In certain embodiments, the lipophilic antioxidant is selected, without limitation, from carotenoids, tocopherols and esters thereof, retinol and esters thereof, ascorbyl esters, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), propyl gallate, and mixtures thereof. In one embodiment, the lipophilic antioxidant is an antioxidant surfactant, such as pegylated esters and fatty acid esters of tocopherol, retinol, ascorbic acid (e.g., retinyl palmitate, ascorbyl palmitate, and tocopheryl-PEG-lOOO-succinate), and mixtures thereof.

In one embodiment, the pharmaceutical composition includes from 1 to 50% (w/w) of a first lipophilic antioxidant selected from retinyl palmitate, ascorbyl palmitate, and tocopheryl-PEG-lOOO-succinate and less than 0.1% (w/w) of a second lipophilic antioxidant selected from tocopherol, tocopherol acetate, tocopherol nicotinoate, tocopherol succinate, tocotrienol, tocotrienol acetate, tocotrienol nicotinoate, tocotrienol succinate, carotenoids, BHT, BHA, and propylgallate. Desirably, the pharmaceutical composition includes from 1 to 20%, 1 to 15%, or 1 to 10% (w/w) of the first lipophilic antioxidant.

In another embodiment, the pharmaceutical composition further includes a hydrophilic co-solvent selected from alcohols (e.g., ethanol, propylene glycol, glycerol, and mixtures thereof), polyethylene glycols, and mixtures thereof. Desirably, the hydrophilic co-solvent is a polyethylene glycol with a molecular weight of between 200 and 10,000 Da. The hydrophilic co-solvent is combined with a surfactant, such as PEG-35 castor oil.

Pharmaceutical compositions of the invention combining both a hydrophilic polymer and a surfactant can include, for example, from 0.2 to 2.5% (w/w) rifalazil, from 0.2 to 10% of one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, from 75 to 85% (w/w) PEG-35 castor oil, from 0.5 to 1.5% (w/w) pluronic F68, from 8 to 15% PEG-400, from 1.5 to 2.5% (w/w) ascorbyl palmitate, from 0.01 to 0.05% (w/w) BHT, and from 1.5 to 2.5% (w/w) water.

Where the pharmaceutical composition of the invention contains a mixture of surfactants, it is desirable for the mixture to include at least one lipophilic surfactant (i.e., HLB<10) and at least one hydrophilic surfactant (i.e., HLB>10). For example, the pharmaceutical composition can include PEG-35 castor oil (HLB 12.5), PEG-8 caprylic/capric glycerides (Labrasol, HLB 14), and PEG-6 apricot kernel oil (Labrafil M1944, HLB 4).

Pharmaceutical compositions of the invention combining both a lipophilic surfactant and a hydrophilic surfactant can include, for example, from 0.2 to 2.5% (w/w) rifalazil, from 22 to 28% (w/w) PEG-35 castor oil, from 45 to 50% (w/w) PEG- 6 apricot kernel oil, from 20 to 25% PEG-8 caprylic/capric glycerides, from 1.5 to 2.5% (w/w) ascorbyl palmitate, and from 0.01 to 0.05% (w/w) BHT.

In any of the above pharmaceutical compositions the solubility of rifalazil in the surfactants can be greater than 5 mg/mL. Desirably, the solubility is greater than 8 mg/mL, 10 mg/mL, 12 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 20 mg/mL, 22 mg/mL, 25 mg/mL, or 30 mg/mL.

The pharmaceutical compositions of the invention are in a unit dosage form. Desirably, the unit dosage form is a liquid-filled or semi-solid filled capsule (i.e., either as a hard capsule or a soft capsule). In the case of a hard capsule, the unit dosage form can also be a semi-solid-filled capsule. Capsule formulations of the invention are, desirably, greater than 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% (w/w) one or more surfactants.

The pharmaceutical compositions of the invention can include a gelling agent (i.e., from 0.5 to 50%, 0.5 to 25%, 0.5 to 15%, 0.5 to 10%, 0.5 to 5%, or 0.5 to 3% (w/w) gelling agent) to increase the viscosity. Desirably, the gelling agent is a polyoxyethylene-polyoxypropylene block copolymer. These gelling agents are available under various trade names, including one or more of Synperonic PE series (ICI), Pluronic®. series (BASF), Supronic, Monolan, Pluracare, and Plurodac. The generic term for these copolymers is "poloxamer" (CAS 9003-11-6). These polymers have the formula (I):HO(C₂H₄0)_a(C₃H₆0)_b(C₂H₄0)_aH (I) where "a" and "b" denote the number of polyoxyethylene and polyoxypropylene units, respectively. These copolymers are available in molecular weights ranging from 1000 to 15000 daltons, and with ethylene oxide/propylene oxide ratios (a/b) between 0.1 and 3.0 by weight. Formulations of rifalazil according to the invention may include one or more of the polyoxyethylene -polyoxypropylene block copolymers above. In certain embodiments, the gelling agent is Pluronic® F68, also known as Poloxamer 188 in which a=75, b=30 (HLB=29).

Where the unit dosage formulation is a liquid or semi-solid-filled capsule, the formulation can include water to prevent dehydration of the capsule. Desirably, the capsule of rifalazil includes between 0.5% and 5%, 1% and 5%, 2% and 5%, 2% and 4%, or 2% and 3% (w/w) water.

Particular surfactants that may be used in the formulations described herein include polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono- ester and di-ester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters and glycerol esters, mono- and diglycerides, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, sorbitan fatty acid esters, lower alcohol fatty acid esters, polyoxyethylenes, and ionic surfactants. Any surfactant described herein may be used in the rifalazil formulations of the invention.

For any of the above pharmaceutical compositions, the composition can include between 0.5 and 100, 1 and 50, 1 and 30, 1 and 20, 1 and 15, 1 and 10, 1 and 5, or 2 and 20 mg of rifalazil. Desirably, the pharmaceutical composition contains about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 10, 12.5, 15, 20, 25, or 30 mg of rifalazil. Conventional doses of the other antibiotics can be used, and such are well known to those of skill in the art.

For any of the above pharmaceutical compositions, the composition can include between 20% and 99%, 30% and 98%, 40% and 98%, 50% and 98%, 60% and 98%, or even 75% and 95% (w/w) surfactant.

For any of the pharmaceutical compositions of the invention, the surfactants are, desirably, present in an amount sufficient to produce, upon administration to fasted patients, a coefficient of variation in Cmax of less than 60%. Desirably, the coefficient of variation in C_max is less than 55%, 50%, 45%, 40%, 35%, 30%, 25%, or even 20%.

For any of the pharmaceutical compositions of the invention, the surfactants are, desirably, present in an amount sufficient to produce, upon administration to fasted patients, a coefficient of variation in AUC_∞ of less than 40%. Desirably, the coefficient of variation in AUC_∞ is less than 35%, 30%, 25%, or even 20%.

For any of the pharmaceutical compositions of the invention, the surfactants are, desirably, present in an amount sufficient to produce, upon administration to fasted patients, a mean bioavailability of greater than 30%. Desirably, the mean bioavailability is greater than 35%, 40%, 45%, or even 50%.

The invention further features a method of treating a tuberculosis infection in a patient that includes the step of administering the pharmaceutical composition described herein, wherein the rifalazil and one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol are administered in an amount effective to treat the infection. The invention also relates to the prevention of the development of tuberculosis in a patient at risk for tuberculosis, such as medical professionals, police, soldiers, and immunocompomised patients. The method includes administering to the patient (i) rifalazil, ii) one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, and (iii) a lipophilic antioxidant simultaneously in an amount, that together, is effective to treat or prevent the development of tuberculosis in the patient.

The invention features a pharmaceutical composition including (i) rifalazil, (ii) one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, and (iii) a lipophilic antioxidant, wherein the rifalazil, one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, and the lipophilic antioxidant are each present in an amount that together is effective to treat tuberculosis when administered to a patient.

The invention further features a kit including (i) a composition including rifalazil, one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, and a lipophilic antioxidant, and (ii) instructions for administering the composition to a patient diagnosed with tuberculosis.

The invention also features a kit including (i) rifalazil; (ii) one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, and (iii) instructions for administering the rifalazil and a lipophilic antioxidant to a patient diagnosed with tuberculosis. In certain of these embodiments, the tuberculosis is multi-drug resistant tuberculosis.

By "in vivo studies" is meant any study in which a pharmaceutical composition or therapeutic regimen of the invention is administered to a mammal, including, without limitation, non-clinical studies, e.g., to collect data concerning toxicity and efficacy, and clinical studies.

As used herein, "bioavailability" refers to the fraction of drug absorbed following oral administration to a patient. Under fasted conditions the bioavailability of rifalazil formulated as described herein is at least 25%, but may be greater than 30%, 35%, 40%, 45%, or even 50% of the dose administered.

By "coefficient of variation" is meant the arithmetic standard deviation divided by the arithmetic mean for a particular pharmacokinetic parameter, wherein the data is obtained from a pharmacokinetic study involving 12 or more patients.

By " C_max " is meant the maximum concentration of rifalazil achieved in the blood after dosing. By "AUCoo" is meant the integrated area under the rifalazil plasma concentration versus time curve from t=0 to∞.

As used herein, "reducing the food effect" refers to narrowing the difference between any one of C_max, T_max AUC_∞, and bioavailability for rifalazil administered under fasted conditions in comparison to rifalazil administered under fed conditions, such that the differences are less than those observed for microgranulated rifalazil.

By "fed" or "fed conditions" is meant a subject has eaten within 30 minutes prior to drug administration.

By "fasted" or "fasted conditions" is meant a subject has not eaten for twelve hours prior and four hours subsequent to drug administration.

As used herein, the term "treating" refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. To "prevent disease" refers to prophylactic treatment of a patient who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease. To "treat disease" or use for "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease to improve or stabilize the patient's condition. Thus, in the claims and embodiments, treating is the administration to a patient either for therapeutic or prophylactic purposes.

By "patient" is meant a human.

As used herein, the term "administration" or "administering" refers to peroral administration of rifalazil and one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, to a patient.

As used herein, "an amount sufficient" refers to an amount of surfactant in a unit dosage formulation of rifalazil and one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, necessary to decrease the coefficient of variation in Cmax, decrease the coefficient of variation in AUC∞, reduce the food effect, or increase bioavailability in comparison to microgranulated rifalazil. The sufficient amount of surfactant used to practice the invention varies depending upon the amount of rifalazil in the unit dosage formulation and the nature of the surfactant or surfactant mixture. The sufficient amount can be determined by performing pharmacokinetic studies as described in Example 8.

The term "unit dosage form" refers to physically discrete units suitable as unitary dosages, such as a pill, tablet, caplet, hard capsule or soft capsule, each unit containing a predetermined quantity of rifalazil one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol. The unit dosage forms of the invention include rifalazil, one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, and a surfactant.

By "hard capsule" is meant a capsule that includes a membrane that forms a two-part, capsule-shaped, container capable of carrying a solid, semi-solid, or liquid payload of drug and excipients.

By "soft capsule" is meant a capsule molded into a single container carrying a liquid payload of drug and excipients.

By "effective" amount is meant the amount of rifalazil and one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, required to treat or prevent a tuberculosis infection. The effective amount of rifalazil used to practice the invention for therapeutic or prophylactic treatment varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.

As used in herein, a "surfactant" refers to any surface-active amphiphilic molecule, natural or synthetic. Surfactants can be amphiphilic molecules, e.g., molecules that are both oil- and water-soluble; lipophilic molecules, e.g., molecules that are soluble in oils, fats, and waxes; and hydrophilic molecules, e.g., molecules having an HLB value greater than 10 and are readily dispersable in water and other aqueous solvents. Surfactants include compounds that are micelle-forming, e.g., form aggregates in aqueous and biological fluids that are formed above certain surfactant concentration known as critical micelle concentration (CMC); compounds that form an emulsion in aqueous solutions, e.g., a colloidal dispersion of two immiscible liquids in the form of droplets, whose diameter, in general, is between 0.1 and 3.0 microns and which is typically optically opaque, unless the dispersed and continuous phases are refractive index matched; and compounds that form a microemulsion in aqueous solutions, e.g., a thermodynamically stable isotropically clear dispersion of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules (i.e., a microemulsion has a mean droplet diameter of less than 200 nm, in general between 10-100 nm). The surfactants useful in the compositions and methods of the invention can be used as part of self-emulsifying drug delivery systems (SEDDS). Such systems include non-aqueous mixtures of oil(s) and surfactant(s), or lipophilic and hydrophilic surfactants as defined herein, with or without a co-solvent which form clear and isotropic solutions.

As used in herein, the term "lipophilic antioxidant" refers to a compound which (1) is at least partially soluble in the one or more surfactants present in the pharmaceutical compositions of the invention and (2) is capable, alone or in combination with another antioxidant, of reducing the oxidation of rifalazil when present in sufficient amounts in a formulation of the invention. Lipophilic antioxidants include, without limitation, tocopherols, tocotrienols, tocopherol acetate, tocopherol nicotinoate, tocopherol succinate, tocotrienol acetate, tocotrienol nicotinoate, tocotrienol succinate, retinol, carotenoids, butylhydroxyamide (BHA), butylhydroxytoluene (BHT), and propyl gallate, as well as compounds which are capable of functioning both as antioxidants and surfactants, such as pegylated tocopherols, pegylated retinols, and fatty acid esters of tocopherols, tocotrienols, retinol, and ascorbic acid. Preferred lipophilic antioxidants for use in the methods and compositions of the invention are tocopherol, tocopherol acetate, tocopherol nicotinoate, tocopherol succinate, tocotrienol, tocotrienol acetate, tocotrienol nicotinoate, tocotrienol succinate, carotenoids, butylhydroxyamide (BHA), butylhydroxytoluene (BHT), retinyl palmitate, ascorbyl palmitate, tocopheryl-PEG- 1000-succinate (TPGS), and mixtures thereof.

As used herein, "carotenoid" refers to naturally-occurring pigments of the terpenoid group that can be found in plants, algae, bacteria, and certain animals, such as birds and shellfish. Carotenoids include carotenes, which are hydrocarbons (i.e., without oxygen), and their oxygenated derivatives (i.e., xanthophylls). Examples of carotenoids include lycopene; beta-carotene; zeaxanthin; echinenone; isozeaxanthin; astaxanthin; canthaxanthin; lutein; citranaxanthin; beta-apo-8'-carotenic acid ethyl ester; hydroxy carotenoids, such as alloxanthin, apocarotenol, astacene, astaxanthin, capsanthin, capsorubin, carotenediols, carotenetriols, carotenols, cryptoxanthin, decaprenoxanthin, epilutein, fucoxanthin, hydroxycarotenones, hydroxy echinenones, hydroxy lycopene, lutein, lycoxanthin, neurosporine, phytoene, phytofluoene, rhodopin, spheroidene, torulene, violaxanthin, and zeaxanthin; and carboxylic carotenoids, such as apocarotenoic acid, betaapo-8'-carotenoic acid, azafrin, bixin, carboxylcarotenes, crocetin, diapocarotenoic acid, neurosporaxanthin, norbixin, and lycopenoic acid. As used herein, the term "antioxidant surfactant" refers to compounds which function both as antioxidants and surfactants. Antioxidant surfactants include pegylated tocopherols, pegylated retinols, and fatty acid esters of tocopherols, tocotrienols, retinol, and ascorbic acid. Preferred antioxidant surfactants for use in the methods and compositions of the invention are retinyl palmitate, ascorbyl palmitate, tocopheryl-PEG-1000-succinate (TPGS), and mixtures thereof.

As used herein, the term "an amount sufficient to reduce the oxidation of rifalazil" refers to an amount of lipophilic antioxidant sufficient to reduce the amount of rifalazil N-oxide formed in a pharmaceutical composition of the invention upon storage for 4 weeks at 40°C and 75% relative humidity ( H) in comparison to the same pharmaceutical composition formulated without a lipophilic antioxidant. The amount of rifalazil N-oxide formed upon storage of any pharmaceutical formulation of the invention can be determined by HPLC analysis as described in Example 8. Desirably, the lipophilic surfactant is present in an amount sufficient to reduce the amount of rifalazil N-oxide present at 4 weeks, 40°C, and 75% RH by 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or even %100 (i.e., below detectable limits) in comparison to the same pharmaceutical composition formulated without a lipophilic antioxidant.

As used herein, "HLB" values refer to the hydrophilic-lipophilic balance of a surfactant and defines the relative hydrophilicity and lipophilicity of the surfactants. Surfactants with lower HLB values are more lipophilic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. For purposes of the present invention, surfactants having an HLB value less than 10 are "lipophilic surfactants," while surfactants having an HLB value greater than 10 are "hydrophilic surfactants." The HLB value derives from a semi-empirical formula used to index surfactants. Its value varies from 1-45 and in the case of non-ionic surfactants from about 1-20. The HLB system is based on the concept that some molecules have hydrophilic groups, other molecules have lipophilic groups, and some have both. Weight percentage of each type of group on a molecule or in a mixture predicts what behavior the molecular structure will exhibit. See, for example, Griffin, W C, J. Soc. Cos. Chem. 1 :311 (1949); and Griffin, W C, J. Soc. Cos. Chem. 5:259 (1954). HLB values for exemplary surfactants which can be used in the methods and compositions of the invention are provided in Table 1 , below. TABLE-US-00001 TABLE 1 Surfactant HLB Surfactant HLB PEG-2 Hydrogenated Castor Oil 1.7 PEG-10 oleyl ether 12.4 Sorbitan Trioleate 1.8 PEG-8 isooctylphenyl ether 12.4 Sorbitan Tristearate 2.1 PEG-10 stearyl ether 12.4 Glyceryl Stearate 3.5 PEG-35 Castor Oil 12.5 Sorbitan Sesquioleate 3.7 PEG-10 cetyl ether 12.9 Labrafil 4.0 Nonoxynol-9 12.9 Sorbitan Oleate 4.3 PEG-40 Castor Oil 13.0 Sorbitan monostearate 4.7 PEG-10 isooctylphenyl ether 13.5 PEG-2 oleyl ether 4.9 PEG-40 Hydrogenated Castor Oil 14.0 PEG-2 stearyl ether 4.9 Labrasol 14 PEG-7 Hydrogenated Castor Oil 5.0 Nonoxynol-15 14.2 PEG-2 cetyl ether 5.3 PEG-12 tridecyl ether 14.5 PEG-4 Sorbitan Stearate 5.5 PEG-18 tridecyl ether 14.5 PEG-2 Sorbitan Isostearate 6.0 Polysorbate 60 14.9 Sorbitan Palmitate 6.7 Polysorbate 80 15.0 Triton SP-135 8.0 PEG-20 Glyceryl Stearate 15.0 Sorbitan monolaurate 8.6 PEG-20 Stearate 15.0 PEG-40 Sorbitan Peroleate 9.5 PEG-20 stearyl ether 15.3 PEG- 4 lauryl ether 9.7 PEG-20 oleyl ether 15.3 Polysorbate 81 10.0 Polysorbate 40 15.6 PEG-40 Sorbitan Hexaoleate 10.0 PEG20 cetyl ether 15.7 PEG-40 Sorbitan Perisostearate 10.0 PEG(20) hexadecyl ether 15.7 PEG-10 Olive Glycerides 10.0 PEG-60 Hydrogenated Castor Oil 16.0 PEG sorbitol hexaoleate 10.2 PEG-30 Stearate 16.5 Polysorbate 65 10.5 Polysorbate 20 16.7 PEG-25 Hydrogenated Castor Oil 10.8 PEG-75 Lanolin 16.7 Polysorbate 85 11.0 PEG23 lauryl ether 16.9 PEG-7 Glyceryl Cocoate 11.0 PEG-40 Stearate 17.3 PEG-8 Stearate 11.1 PEG-50 Stearate 17.7 PEG sorbitan tetraoleate 11.4 PEG40 isooctylphenyl ether 17.9 PEG-15 Glyceryl Isostearate 12.0 PEG-100 Stearate 18.8 PEG-35 Almond Glycerides 12.0 Pluronic F68 29.0

By "bacterial infection" is meant the invasion of a host by pathogenic bacteria. For example, the infection may include the excessive growth of bacteria that are normally present in or on the body of a human or growth of bacteria that are not normally present in or on a human. More generally, a bacterial infection can be any situation in which the presence of a bacterial population(s) is damaging to a host body. Thus, a human is "suffering" from a bacterial infection when an excessive amount of a bacterial population is present in or on the person's body, or when the presence of a bacterial population(s) is damaging the cells or other tissue of the person.

A patient who is being treated for tuberculosis is one who a medical practitioner has diagnosed as having such a disease. Diagnosis may be by any suitable means. A patient in whom the development of tuberculosis is being prevented is one who has not received such a diagnosis, but who, due to proximity to tuberculosis patients, or b y virtue of being immunocompromised, is susceptible to tuberculosis infection. One in the art will understand that these patients can be identified, without examination, as one at high risk due to the presence of one or more risk factors. Thus, prophylactic administration of a pharmaceutical composition of the invention is considered to be preventing the development of tuberculosis.

Tuberculosis has been treated or prevented when one or more tests of the disease (e.g., any of those described above) indicate that the patient's condition has improved or the presence of bacteria causing tuberculosis is no longer observed. However, in one embodiment, patients are treated with a set number of unit dosage forms, and this will be presumed to have treated the disease.

By "immunocompromised" is meant a person who exhibits an attenuated or reduced ability to mount a normal cellular or humoral defense to challenge by infectious agents, e.g., viruses, bacterial, fungi, and protozoa. Persons considered immunocompromised include malnourished patients, patients undergoing surgery and bone narrow transplants, patients undergoing chemotherapy or radiotherapy, neutropenic patients, HIV-infected patients, trauma patients, bum patients, patients with chronic or resistant infections such as those resulting from myelodysplastic syndrome, and the elderly, all of who may have weakened immune systems.

When administered to a human, pharmaceutical compositions described herein can provide an increase in the bioavailability of rifalazil in comparison to the administration of microgranulated rifalazil disclosed in U.S. Pat. No. 5,547,683. The rifalazil formulations also decrease the coefficient of variation in pharmacokinetic parameters (e.g., C_max and AUC_∞) in comparison to the microgranulated formulation.

DETAILED DESCRIPTION

The invention provides stable pharmaceutical formulations including rifalazil, one or more of isoniazid, streptomycin, pyrazinamide, and/or ethambutol, a surfactant, and a lipophilic antioxidant. The formulations are useful for decreasing the coefficient of variation in C_max, decreasing the coefficient of variation in AUC_∞, reducing the food effect, and/or increasing the bioavailability of rifalazil.

Formulation

As described herein, surfactants can be added to rifalazil in a unit dosage form for oral administration. The excipients can increase the solubilization of rifalazil in the gut, increasing overall rifalazil absorption and reducing the variability in the PK parameters observed in a patient population. The excipients used are restricted to those that have a high degree of safety in humans.

A variety of surfactants may be used for the formulation of rifalazil including those disclosed in U.S. Pat. No. 6,365,637, incorporated herein by reference and compounds belonging to the following classes: polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono-ester and di-ester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters and glycerol esters, mono- and diglycerides, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, sorbitan fatty acid esters, lower alcohol fatty acid esters, polyoxyethylenes, and ionic surfactants. Commercially available examples for each class of excipient are provided below.

Polyethoxylated fatty acids may be used as excipients for the formulation of rifalazil. Examples of commercially available polyethoxylated fatty acid monoester surfactants include: PEG 4-100 monolaurate (Crodet L series, Croda), PEG 4-100 monooleate (Crodet O series, Croda), PEG 4-100 monostearate (Crodet S series, Croda, and Myrj Series, Atlas/ICI), PEG 400 distearate (Cithrol 4DS series, Croda), PEG 100, 200, or 300 monolaurate (Cithrol ML series, Croda), PEG 100, 200, or 300 monooleate (Cithrol MO series, Croda), PEG 400 dioleate (Cithrol 4DO series, Croda), PEG 400-1000 monostearate (Cithrol MS series, Croda), PEG-1 stearate (Nikkol MYS-1EX, Nikko, and Coster Kl, Condea), PEG-2 stearate (Nikkol MYS-2, Nikko), PEG-2 oleate (Nikkol MYO-2, Nikko), PEG-4 laurate (Mapeg® 200 ML, PPG), PEG-4 oleate (Mapeg® 200 MO, PPG), PEG-4 stearate (Kessco® PEG 200 MS, Stepan), PEG-5 stearate (Nikkol TMGS-5, Nikko), PEG-5 oleate (Nikkol TMGO-5, Nikko), PEG-6 oleate (Algon OL 60, Auschem SpA), PEG-7 oleate (Algon OL 70, Auschem SpA), PEG-6 laurate (Kessco® PEG300 ML, Stepan), PEG-7 laurate (Lauridac 7, Condea), PEG-6 stearate (Kessco® PEG300 MS, Stepan), PEG-8 laurate (Mapeg® 400 ML, PPG), PEG-8 oleate (Mapeg® 400 MO, PPG), PEG-8 stearate (Mapeg® 400 MS, PPG), PEG-9 oleate (Emulgante A9, Condea), PEG-9 stearate (Cremophor S9, BASF), PEG-10 laurate (Nikkol MYL-10, Nikko), PEG-10 oleate (Nikkol MYO-10, Nikko), PEG-12 stearate (Nikkol MYS-10, Nikko), PEG-12 laurate (Kessco® PEG 600 ML, Stepan), PEG-12 oleate (Kessco® PEG 600 MO, Stepan), PEG-12 ricinoleate (CAS # 9004-97-1), PEG-12 stearate (Mapeg® 600 MS, PPG), PEG-15 stearate (Nikkol TMGS-15, Nikko), PEG-15 oleate (Nikkol TMGO- 15, Nikko), PEG-20 laurate (Kessco® PEG 1000 ML, Stepan), PEG-20 oleate (Kessco® PEG 1000 MO, Stepan), PEG-20 stearate (Mapeg® 1000 MS, PPG), PEG- 25 stearate (Nikkol MYS-25, Nikko), PEG-32 laurate (Kessco® PEG 1540 ML, Stepan), PEG-32 oleate (Kessco® PEG 1540 MO, Stepan), PEG-32 stearate (Kessco® PEG 1540 MS, Stepan), PEG-30 stearate (Myrj 51), PEG-40 laurate (Crodet L40, Croda), PEG-40 oleate (Crodet O40, Croda), PEG-40 stearate (Emerest® 2715, Henkel), PEG-45 stearate (Nikkol MYS-45, Nikko), PEG-50 stearate (Myrj 53), PEG-55 stearate (Nikkol MYS-55, Nikko), PEG-100 oleate (Crodet O-100, Croda), PEG-100 stearate (Ariacel 165, ICI), PEG-200 oleate (Albunol 200 MO, Taiwan Surf.), PEG-400 oleate (LACTOMUL, Henkel), and PEG- 600 oleate (Albunol 600 MO, Taiwan Surf.). Formulations of rifalazil according to the invention may include one or more of the polyethoxylated fatty acids above.

Polyethylene glycol fatty acid diesters may also be used as excipients for the formulation of rifalazil. Examples of commercially available polyethylene glycol fatty acid diesters include: PEG-4 dilaurate (Mapeg® 200 DL, PPG), PEG-4 dioleate (Mapeg® 200 DO, PPG), PEG-4 distearate (Kessco® 200 DS, Stepan), PEG-6 dilaurate (Kessco® PEG 300 DL, Stepan), PEG-6 dioleate (Kessco® PEG 300 DO, Stepan), PEG-6 distearate (Kessco® PEG 300 DS, Stepan), PEG-8 dilaurate (Mapeg® 400 DL, PPG), PEG-8 dioleate (Mapeg® 400 DO, PPG), PEG-8 distearate (Mapeg® 400 DS, PPG), PEG-10 dipalmitate (Polyaldo 2PKFG), PEG-12 dilaurate (Kessco® PEG 600 DL, Stepan), PEG-12 distearate (Kessco® PEG 600 DS, Stepan), PEG-12 dioleate (Mapeg® 600 DO, PPG), PEG-20 dilaurate (Kessco® PEG 1000 DL, Stepan), PEG-20 dioleate (Kessco® PEG 1000 DO, Stepan), PEG-20 distearate (Kessco® PEG 1000 DS, Stepan), PEG-32 dilaurate (Kessco® PEG 1540 DL, Stepan), PEG-32 dioleate (Kessco® PEG 1540 DO, Stepan), PEG-32 distearate (Kessco® PEG 1540 DS, Stepan), PEG-400 dioleate (Cithrol 4DO series, Croda), and PEG-400 distearate Cithrol 4DS series, Croda). Formulations of rifalazil according to the invention may include one or more of the polyethylene glycol fatty acid diesters above.

PEG-fatty acid mono- and di-ester mixtures may be used as excipients for the formulation of rifalazil. Examples of commercially available PEG-fatty acid mono- and di-ester mixtures include: PEG 4-150 mono, dilaurate (Kessco® PEG 200-6000 mono, Dilaurate, Stepan), PEG 4-150 mono, dioleate (Kessco® PEG 200-6000 mono, Dioleate, Stepan), and PEG 4-150 mono, distearate (Kessco® 200-6000 mono, Distearate, Stepan). Formulations of rifalazil according to the invention may include one or more of the PEG-fatty acid mono- and di-ester mixtures above.

In addition, polyethylene glycol glycerol fatty acid esters may be used as excipients for the formulation of rifalazil. Examples of commercially available polyethylene glycol glycerol fatty acid esters include: PEG-20 glyceryl laurate (Tagat® L, Goldschmidt), PEG-30 glyceryl laurate (Tagat® L2, Goldschmidt), PEG- 15 glyceryl laurate (Glycerox L series, Croda), PEG-40 glyceryl laurate (Glycerox L series, Croda), PEG-20 glyceryl stearate (Capmul® EMG, ABITEC), and Aldo® MS- 20 KFG, Lonza), PEG-20 glyceryl oleate (Tagat® O, Goldschmidt), and PEG-30 glyceryl oleate (Tagat® 02, Goldschmidt). Formulations of rifalazil according to the invention may include one or more of the polyethylene glycol and glycerol fatty acid esters above.

Alcohol-oil transesterification products may also be used as excipients for the formulation of rifalazil. Examples of commercially available alcohol-oil transesterification products include: PEG-3 castor oil (Nikkol CO-3, Nikko), PEG-5, 9, and 16 castor oil (ACCONON CA series, ABITEC), PEG-20 castor oil, (Emalex C- 20, Nihon Emulsion), PEG-23 castor oil (Emulgante EL23), PEG-30 castor oil (Incrocas 30, Croda), PEG-35 castor oil (Incrocas-35, Croda), PEG-38 castor oil (Emulgante EL 65, Condea), PEG-40 castor oil (Emalex C-40, Nihon Emulsion), PEG-50 castor oil (Emalex C-50, Nihon Emulsion), PEG-56 castor oil (Eumulgin® PRT 56, Pulcra SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG-100 castor oil, PEG-200 castor oil (Eumulgin® PRT 200, Pulcra SA), PEG-5 hydrogenated castor oil (Nikkol HCO-5, Nikko), PEG-7 hydrogenated castor oil (Cremophor W07, BASF), PEG-10 hydrogenated castor oil (Nikkol HCO-10, Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, Nikko), PEG-25 hydrogenated castor oil (Simulsol® 1292, Seppic), PEG-30 hydrogenated castor oil (Nikkol HCO-30, Nikko), PEG-40 hydrogenated castor oil (Cremophor RH 40, BASF), PEG-45 hydrogenated castor oil (Cerex ELS 450, Auschem Spa), PEG-50 hydrogenated castor oil (Emalex HC-50, Nihon Emulsion), PEG-60 hydrogenated castor oil (Nikkol HCO-60, Nikko), PEG-80 hydrogenated castor oil (Nikkol HCO-80, Nikko), PEG-100 hydrogenated castor oil (Nikkol HCO-100, Nikko), PEG-6 corn oil (Labrafil® M 2125 CS, Gattefosse), PEG-6 almond oil (Labrafil® M 1966 CS, Gattefosse), PEG-6 apricot kernel oil (Labrafil® M 1944 CS, Gattefosse), PEG-6 olive oil (Labrafil® M 1980 CS, Gattefosse), PEG-6 peanut oil (Labrafil® M 1969 CS, Gattefosse), PEG-6 hydrogenated palm kernel oil (Labrafil® M 2130 BS, Gattefosse), PEG-6 palm kernel oil (Labrafil® M 2130 CS, Gattefosse), PEG-6 triolein (Labrafil® M 2735 CS, Gattefosse), PEG-8 corn oil (Labrafil® WL 2609 BS, Gattefosse), PEG-20 corn glycerides (Crovol M40, Croda), PEG-20 almond glycerides (Crovol A40, Croda), PEG-25 trioleate (TAGAT® TO, Goldschmidt), PEG-40 palm kernel oil (Crovol PK- 70), PEG-60 corn glycerides (Crovol M70, Croda), PEG-60 almond glycerides (Crovol A70, Croda), PEG-4 caprylic/capric triglyceride (Labrafac® Hydro, Gattefosse), PEG-8 caprylic/capric glycerides (Labrasol, Gattefosse), PEG-6 caprylic/capric glycerides (SOFTIGEN®767, Huls), lauroyl macrogol-32 glyceride (GELUCIRE 44/14, Gattefosse), stearoyl macrogol glyceride (GELUCIRE 50/13, Gattefosse), mono, di, tri, tetra esters of vegetable oils and sorbitol (SorbitoGlyceride, Gattefosse), pentaerythrityl tetraisostearate (Crodamol PTIS, Croda), pentaerythrityl distearate (Albunol DS, Taiwan Surf.), pentaerythrityl tetraoleate (Liponate PO-4, Lipo Chem.), pentaerythrityl tetrastearate (Liponate PS-4, Lipo Chem.), pentaerythrityl tetracaprylate tetracaprate (Liponate PE-810, Lipo Chem.), and pentaerythrityl tetraoctanoate (Nikkol Pentarate 408, Nikko). Also included in this category of surfactants are esters of oil-soluble vitamins, such as vitamins A, D, E, K, etc. Thus, derivatives of these vitamins, such as tocopheryl PEG-1000 succinate (TPGS, available from Eastman), are also suitable surfactants. Formulations of rifalazil according to the invention may include one or more of the alcohol-oil transesterification products above.

Polyglycerized fatty acids may also be used as excipients for the formulation of rifalazil. Examples of commercially available polyglycerized fatty acids include: polyglyceryl-2 stearate (Nikkol DGMS, Nikko), polyglyceryl-2 oleate (Nikkol DGMO, Nikko), polyglyceryl-2 isostearate (Nikkol DGMIS, Nikko), polyglyceryl-3 oleate (Caprol® 3GO, ABITEC), polyglyceryl-4 oleate (Nikkol Tetraglyn l-O, Nikko), polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S, Nikko), polyglyceryl-6 oleate (Drewpol 6-1-0, Stepan), polyglyceryl-10 laurate (Nikkol Decaglyn 1-L, Nikko), polyglyceryl-10 oleate (Nikkol Decaglyn l-O, Nikko), polyglyceryl-10 stearate (Nikkol Decaglyn 1-S, Nikko), polyglyceryl-6 ricinoleate (Nikkol Hexaglyn PR-15, Nikko), polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN, Nikko), polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-0, Nikko), polyglyceryl-3 dioleate (Cremophor G032, BASF), polyglyceryl-3 distearate (Cremophor GS32, BASF), polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-0, Nikko), polyglyceryl-6 dioleate (Caprol® 6G20, ABITEC), polyglyceryl-2 dioleate (Nikkol DGDO, Nikko), polyglyceryl-10 trioleate (Nikkol Decaglyn 3-0, Nikko), polyglyceryl-10 pentaoleate (Nikkol Decaglyn 5-0, Nikko), polyglyceryl-10 septaoleate (Nikkol Decaglyn 7-0, Nikko), polyglyceryl-10 tetraoleate (Caprol® 10G4O, ABITEC), polyglyceryl-10 decaisostearate (Nikkol Decaglyn 10-IS, Nikko), poly glyceryl- 101 decaoleate (Drewpol 10-10-O, Stepan), polyglyceryl-10 mono, dioleate (Caprol® PGE 860, ABITEC), and polyglyceryl polyricinoleate (Polymuls, Henkel). Formulations of rifalazil according to the invention may include one or more of the polyglycerized fatty acids above.

In addition, propylene glycol fatty acid esters may be used as surfactants for the formulation of rifalazil. Examples of commercially available propylene glycol fatty acid esters include: propylene glycol monocaprylate (Capryol 90, Gattefosse), propylene glycol monolaurate (Lauroglycol 90, Gattefosse), propylene glycol oleate (Lutrol OP2000, BASF), propylene glycol myristate (Mirpyl), propylene glycol monostearate (LIPO PGMS, Lipo Chem.), propylene glycol hydroxystearate, propylene glycol ricinoleate (PROPYMULS, Henkel), propylene glycol isostearate, propylene glycol monooleate (Myverol P-06, Eastman), propylene glycol dicaprylate dicaprate (Captex® 200, ABITEC), propylene glycol dioctanoate (Captex® 800, ABITEC), propylene glycol caprylate caprate (LABRAFAC PG, Gattefosse), propylene glycol dilaurate, propylene glycol distearate (Kessco® PGDS, Stepan), propylene glycol dicaprylate (Nikkol Sefsol 228, Nikko), and propylene glycol dicaprate (Nikkol PDD, Nikko). Formulations of rifalazil according to the invention may include one or more of the propylene glycol fatty acid esters above.

Mixtures of propylene glycol esters and glycerol esters may also be used as lipophilic surfactants for the formulation of rifalazil. One preferred mixture is composed of the oleic acid esters of propylene glycol and glycerol (Arlacel 186). Examples of these surfactants include: oleic (ATMOS 300, ARLACEL 186, ICI), and stearic (ATMOS 150). Formulations of rifalazil according to the invention may include one or more of the mixtures of propylene glycol esters and glycerol esters above.

Furthermore, mono- and diglycerides may be used as lipophilic surfactants for the formulation of rifalazil. Examples of commercially available mono- and diglycerides include: monopalmitolein (CI 6:1) (Larodan), monoelaidin (CI 8:1) (Larodan), monocaproin (C6) (Larodan), monocaprylin (Larodan), monocaprin (Larodan), monolaurin (Larodan), glyceryl monomyristate (C14) (Nikkol MGM, Nikko), glyceryl monooleate (C18:l) (PECEOL, Gattefosse), glyceryl monooleate (Myverol, Eastman), glycerol monooleate/linoleate (OLICINE, Gattefosse), glycerol monolinoleate (Maisine, Gattefosse), glyceryl ricinoleate (Softigen® 701, Huls), glyceryl monolaurate (ALDO® MLD, Lonza), glycerol monopalmitate (Emalex GMS-P, Nihon), glycerol monostearate (Capmul® GMS, ABITEC), glyceryl mono- and dioleate (Capmul® GMO-K, ABITEC), glyceryl palmitic/stearic (CUTINA MD- A, ESTAGEL-G18), glyceryl acetate (Lamegin® EE, Grunau GmbH), glyceryl laurate (Imwitor® 312, Huls), glyceryl citrate/lactate/oleate/linoleate (Imwitor® 375, Huls), glyceryl caprylate (Imwitor® 308, Huls), glyceryl caprylate/caprate (Capmul® MCM, ABITEC), caprylic acid mono- and diglycerides (Imwitor® 988, Huls), caprylic/capric glycerides (Imwitor® 742, Huls), Mono- and diacetylated monoglycerides (Myvacet® 9-45, Eastman), glyceryl monostearate (Aldo® MS, Arlacel 129, ICI), lactic acid esters of mono and diglycerides (LAMEGIN GLP, Henkel), dicaproin (C6) (Larodan), dicaprin (CIO) (Larodan), dioctanoin (C8) (Larodan), dimyristin (C14) (Larodan), dipalmitin (C16) (Larodan), distearin (Larodan), glyceryl dilaurate (C12) (Capmul® GDL, ABITEC), glyceryl dioleate (Capmul® GDO, ABITEC), glycerol esters of fatty acids (GELUCIRE 39/01, Gattefosse), dipalmitolein (C16: l) (Larodan), 1,2 and 1,3-diolein (C18: l) (Larodan), dielaidin (CI 8:1) (Larodan), and dilinolein (CI 8:2) (Larodan). Formulations of rifalazil according to the invention may include one or more of the mono- and diglycerides above.

Sterol and sterol derivatives may also be used as excipients for the formulation of rifalazil. Examples of commercially available sterol and sterol derivatives include: cholesterol, sitosterol, lanosterol, PEG-24 cholesterol ether (Solulan C-24, Amerchol), PEG-30 cholestanol (Phytosterol GENEROL series, Henkel), PEG-25 phytosterol (Nikkol BPSH-25, Nikko), PEG-5 soyasterol (Nikkol BPS-5, Nikko), PEG- 10 soyasterol (Nikkol BPS- 10, Nikko), PEG-20 soyasterol (Nikkol BPS-20, Nikko), and PEG-30 soyasterol (Nikkol BPS-30, Nikko). Formulations of rifalazil according to the invention may include one or more of the sterol and sterol derivatives above.

Polyethylene glycol sorbitan fatty acid esters may also be used as surfactants for the formulation of rifalazil. Examples of commercially available polyethylene glycol sorbitan fatty acid esters include: PEG- 10 sorbitan laurate (Liposorb L-10, Lipo Chem.), PEG-20 sorbitan monolaurate (Tween® 20, Atlas/ICI), PEG-4 sorbitan monolaurate (Tween® 21, Atlas/ICI), PEG-80 sorbitan monolaurate (Hodag PSML- 80, Calgene), PEG-6 sorbitan monolaurate (Nikkol GL-1, Nikko), PEG-20 sorbitan monopalmitate (Tween® 40, Atlas/ICI), PEG-20 sorbitan monostearate (Tween® 60, Atlas/ICI), PEG-4 sorbitan monostearate (Tween® 61, Atlas/ICI), PEG-8 sorbitan monostearate (DACOL MSS, Condea), PEG-6 sorbitan monostearate (Nikkol TS106, Nikko), PEG-20 sorbitan tristearate (Tween® 65, Atlas/ICI), PEG-6 sorbitan tetrastearate (Nikkol GS-6, Nikko), PEG-60 sorbitan tetrastearate (Nikkol GS-460, Nikko), PEG-5 sorbitan monooleate (Tween® 81, Atlas/ICI), PEG-6 sorbitan monooleate (Nikkol TO-106, Nikko), PEG-20 sorbitan monooleate (Tween® 80, Atlas/ICI), PEG-40 sorbitan oleate (Emalex ET 8040, Nihon Emulsion), PEG-20 sorbitan trioleate (Tween® 85, Atlas/ICI), PEG-6 sorbitan tetraoleate (Nikkol GO-4, Nikko), PEG-30 sorbitan tetraoleate (Nikkol GO-430, Nikko), PEG-40 sorbitan tetraoleate (Nikkol GO-440, Nikko), PEG-20 sorbitan monoisostearate (Tween® 120, Atlas/ICI), PEG sorbitol hexaoleate (Atlas G-1086, ICI), polysorbate 80 (Tween® 80, Pharma), polysorbate 85 (Tween® 85, Pharma), polysorbate 20 (Tween® 20, Pharma), polysorbate 40 (Tween® 40, Pharma), polysorbate 60 (Tween® 60, Pharma), and PEG-6 sorbitol hexastearate (Nikkol GS-6, Nikko). Formulations of rifalazil according to the invention may include one or more of the polyethylene glycol sorbitan fatty acid esters above.

In addition, polyethylene glycol alkyl ethers may be used as surfactants for the formulation of rifalazil. Examples of commercially available polyethylene glycol alkyl ethers include: PEG-2 oleyl ether, oleth-2 (Brij 92/93, Atlas/ICI), PEG-3 oleyl ether, oleth-3 (Volpo 3, Croda), PEG-5 oleyl ether, oleth-5 (Volpo 5, Croda), PEG- 10 oleyl ether, oleth-10 (Volpo 10, Croda), PEG-20 oleyl ether, oleth-20 (Volpo 20, Croda), PEG-4 lauryl ether, laureth-4 (Brij 30, Atlas/ICI), PEG-9 lauryl ether, PEG- 23 lauryl ether, laureth-23 (Brij 35, Atlas/ICI), PEG-2 cetyl ether (Brij 52, ICI), PEG- 10 cetyl ether (Brij 56, ICI), PEG-20 cetyl ether (BriJ 58, ICI), PEG-2 stearyl ether (Brij 72, ICI), PEG- 10 stearyl ether (Brij 76, ICI), PEG-20 stearyl ether (Brij 78, ICI), and PEG-100 stearyl ether (Brij 700, ICI). Formulations of rifalazil according to the invention may include one or more of the polyethylene glycol alkyl ethers above.

Sugar esters may also be used as surfactants for the formulation of rifalazil. Examples of commercially available sugar esters include: sucrose distearate (SUCRO ESTER 7, Gattefosse), sucrose distearate/monostearate (SUCRO ESTER 11, Gattefosse), sucrose dipalmitate, sucrose monostearate (Crodesta F-160, Croda), sucrose monopalmitate (SUCRO ESTER 15, Gattefosse), and sucrose monolaurate (Saccharose monolaurate 1695, Mitsubisbi-Kasei). Formulations of rifalazil according to the invention may include one or more of the sugar esters above.

Polyethylene glycol alkyl phenols are also useful as surfactants for the formulation of rifalazil. Examples of commercially available polyethylene glycol alkyl phenols include: PEG-10-100 nonylphenol series (Triton X series, Rohm & Haas) and PEG-15-100 octylphenol ether series (Triton N-series, Rohm & Haas). Formulations of rifalazil according to the invention may include one or more of the polyethylene glycol alkyl phenols above.

Sorbitan fatty acid esters may also be used as surfactants for the formulation of rifalazil. Examples of commercially sorbitan fatty acid esters include: sorbitan monolaurate (Span-20, Atlas/ICI), sorbitan monopalmitate (Span-40, Atlas/ICI), sorbitan monooleate (Span-80, Atlas/ICI), sorbitan monostearate (Span-60, Atlas/ICI), sorbitan trioleate (Span-85, Atlas/ICI), sorbitan sesquioleate (Arlacel-C, ICI), sorbitan tristearate (Span-65, Atlas/ICI), sorbitan monoisostearate (Crill 6, Croda), and sorbitan sesquistearate (Nikkol SS-15, Nikko). Formulations of rifalazil according to the invention may include one or more of the sorbitan fatty acid esters above.

Esters of lower alcohols (C₂ to C₄) and fatty acids (Cs to Cis) are suitable lipophilic surfactants for use in the invention. Examples of these surfactants include: ethyl oleate (Crodamol EO, Croda), isopropyl myristate (Crodamol IPM, Croda), isopropyl palmitate (Crodamol IPP, Croda), ethyl linoleate (Nikkol VF-E, Nikko), and isopropyl linoleate (Nikkol VF-IP, Nikko). Formulations of rifalazil according to the invention may include one or more of the lower alcohol fatty acid esters above.

In addition, ionic surfactants may be used as excipients for the formulation of rifalazil. Examples of useful ionic surfactants include: sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristolate, sodium palmitate, sodium palmitoleate, sodium oleate, sodium ricinoleate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl sulfate (dodecyl), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium glyco cheno deoxycholate, sodium cholylsarcosinate, sodium N-methyl taurocholate, egg yolk phosphatides, hydrogenated soy lecithin, dimyristoyl lecithin, lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidic acid, phosphatidyl glycerol, phosphatidyl serine, diethanolamine, phospholipids, polyoxyethylene-10 oleyl ether phosphate, esterification products of fatty alcohols or fatty alcohol ethoxylates, with phosphoric acid or anhydride, ether carboxylates (by oxidation of terminal OH group of, fatty alcohol ethoxylates), succinylated monoglycerides, sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono/diacetylated tartaric acid esters of mono- and diglycerides, citric acid esters of mono-, diglycerides, glyceryl-lacto esters of fatty acids, acyl lactylates, lactylic esters of fatty acids, sodium stearoyl-2-lactylate, sodium stearoyl lactylate, alginate salts, propylene glycol alginate, ethoxylated alkyl sulfates, alkyl benzene sulfones, alpha-olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, sodium octyl sulfosuccinate, sodium undecylenamideo-MEA-sulfosuccinate, hexadecyl triammonium bromide, decyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyldimethylammonium salts, diisobutyl phenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts, betaines (trialkylglycine), lauryl betaine (N-lauryl,N,N-dimethylglycine), and ethoxylated amines (polyoxyethylene-15 coconut amine). For simplicity, typical counterions are provided above. It will be appreciated by one skilled in the art, however, that any bioacceptable counterion may be used. For example, although the fatty acids are shown as sodium salts, other cation counterions can also be used, such as, for example, alkali metal cations or ammonium. Formulations of rifalazil according to the invention may include one or more of the ionic surfactants above.

Many of the foregoing surfactants are micelle-forming in aqueous and intestinal media. However, with the compositions of the present invention non- micellar aggregates, such as emulsions and microemulsions, can also be formed in aqueous and intestinal media. The formation of micelles can be monitored using any of several standard techniques known in the art, including surface tension measurements, solubilization of water insoluble dye, conductivity measurements, and light scattering, among others. In all of these methods, an abrupt change in some physicochemical property is measured as a function of surfactant concentration. The abrupt change occurs when the concentration of surfactant is sufficient to form micelles. Above this concentration, also known as the critical micelle concentration (CMC), micelles are present in solution. Above the CMC, the concentration of micelles increases whereas the concentration of monomeric surfactant in equilibrium with micelles remains constant.

Various MW sizes of polyoxyethylene glycols (PEG) are suitable hydrophilic co-solvents for use in the invention. Polyoxyethylene glycol polymers which can be used in the methods and compositions of the invention can be from 200 Da to 10,000 Da, more preferably from 200 Da to 2,000 Da, in size. Specific examples include PEG-200, PEG-300, PEG-400, PEG-600, PEG- 800, PEG- 1,000, PEG- 1,200, PEG- 1 ,500, PEG 2000 and combinations thereof.

Methods for making formulations for oral administration are found, for example, in "Remington: The Science and Practice of Pharmacy" (20th ed., ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins). Formulations for oral administration (e.g., tablets, pills, caplets, hard capsules, and soft capsules) may, for example, contain any one or combination of the excipients described above along with other excipients as needed. Liquid-filled capsules can include any of the excipients described herein. The capsule will contain from, for example, 0.1 to about 100 mg of rifalazil. Liquid-filled capsules may, for example, contain either solutions or suspensions of rifalazil, depending upon the concentration of rifalazil within the capsule and the excipients used in the formulation.

The filled formulation can also be a semi-solid formulation, e.g., solid at ambient temperature but liquid at physiological temperature. Semi-solid formulations can be made, for example, by including a sufficient amount of high molecular weight PEG (i.e., greater that 600 Da, preferably 1,500 Da) in the formulation. Alternatively, inclusion of a surfactant having a melting point above 37°C can result in a semi-solid formulation. Formulations of M4 and M5 (see Table 9) are examples semi-solid formulations.

Rifalazil may be formulated as a pharmaceutically acceptable salt, such as a non-toxic acid addition salt or metal complex that are commonly used in the pharmaceutical industry. Examples of acid addition salts include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or the like. Metal complexes include zinc, iron, and the like.

Many strategies can be pursued to obtain sustained or controlled release in which the rate of release outweighs the rate of metabolism of the therapeutic compound. For example, sustained or controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., single or multiple unit capsule compositions, by varying the amount of hydrophilic polymer present in a liquid-filled rifalazil capsule of the invention, or by varying the amount of gelling agent in the formulated capsule or by using a surfactant that is semi-solid at ambient temperature. Other controlled released polymeric excipients can also be used in the compositions of the present invention.

Other Therapeutic Agents

The rifalazil formulations described herein also include a second therapeutic agent, namely, one or more of isoniazid, streptomycin, pyrazinamide, and ethambutol.

All of the therapeutic agents employed in the pharmaceutical compositions of the invention can be used in the dose ranges currently known and used for these agents. Different concentrations may be employed depending on the clinical condition of the patient, the goal of therapy (treatment or prophylaxis), the anticipated duration, and the severity of the infection or disease for which a pharmaceutical composition of the invention is being administered. Additional considerations in dose selection include the type of infection, age of the patient (e.g., pediatric, adult, or geriatric), general health, and comorbidity. Determining what concentrations to employ are within the skills of the pharmacist, medicinal chemist, or medical practitioner formulating pharmaceutical composition of the invention in combination with other therapeutic agents.

In one embodiment, the isoniazid, streptomycin, pyrazinamide, or ethambutol is administered daily for 8 weeks. In another embodiment, the isoniazid, streptomycin, pyrazinamide, or ethambutol are administered daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete a 2-month induction phase, then 2-3 times a week for approximately 7 months.

In addition, or in place of to the conventional treatments, such as isozianid, there are new treatments being developed. One or more of these compounds can be used, in one embodiment, to replace one or more of isoniazid, streptomycin, pyrazinamide, and ethambutol.

These compounds include, for example, the diarylquinoline TMC207 (J&J/Tibotec, previously R207910), analogs of TMC-207, as described, for example, in U.S. Application Publication No. 2006/0142279, entitled "Quinoline derivatives as antibacterial agents," fluoroquinolones, Gatifloxacin (G), Moxifloxacin (M), Nitroimidazopyran PA-824, and new compounds by Otsuka Pharmaceuticals (Otsuka Pharmaceutical's OPC-67683) and Lupin Laboratory (a four-in-one therapy including rifampicin, isoniazide, ethambutol, and pyrazinamide, as well as Sudoterb, a pyrrole derivative). The nitroimidazole derivative PA-824, a Chiron compound, can also be used.

The fluoroquinolone (FQ) compounds are a class of synthetic antibiotic derived from nalidixic acid, with a broad spectrum of activity. This family includes ciprofloxacin and a variety of related compounds, two of which are in the current TB pipeline. FQs are well absorbed orally, and have good tissue penetration and relatively long duration of activity. Quinolones are "broad-spectrum antibacterial agents that block DNA replication and kill bacterial cells" (Drlica K, Lu T, Malik M, Zhao X. Fluoroquinolones as antituberculosis agents. Chapter 53 in Rom WN, Garay SM, Tuberculosis, 2nd edition, Lippincott Williams & Wilkins (2004), 791-806). Some newer fluoroquinolones are effective against non-dividing bacteria as well; they do not have cross-resistance to other classes of TB drugs. Several fluoroquinolones have been studied for their antimycobacterial activities (Pletz MW, De Roux A, Roth A, Neumann KH, Mauch H, Lode H. Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrob Agents Chemother. 2004 Mar;48(3):780-2.; Gradelski E, Kolek B, Bonner D, Fung- Tome J. Bactericidal mechanism of gatifloxacin compared with other quinolones. J Antimicrob Chemother. 2002 Jan;49(l): 185-8).

Further, Pfizer and MicuRx are collaborating on a compound called MRX-1, which is intended to be used in a Phase I clinical trial in the near future.

TMC-207, l-(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2- naphthalen-l-yl-l-phenyl-butan-2-ol, with the following structure:

Analogs of TMC-207 are described, for example, in U.S. Application Publication No. 2006/0142279.

Rifampin can still be included in first line therapy for treating tuberculosis, as can rifapentine. Moxifloxacin can be used to replace isoniazid in first line treatment.

Rifalazil therapy can be combined with protease inhibitor therapy, when the patient is co-infected with HIV and tuberculosis or other lung infection, particularly where the patients to be treated are children.

Combinations of rifalazil and isoniazid, olptoinally also includking rifabutin, rifampicin, or rifapentine, can be used, ideally at a dosage of once per week. The dosage can be for as little as three months, versus daily isoniazid for nine months, for treating latent tuberculosis infection.

Additional antimicrobial compounds that can be added include CPZEN-45 (Microbial Chemistry Research Foundation, Tokyo, Japan, Lilly TB Drug Discovery Initiative, NIAID, IDRI, Lilly, YourEncore), Quinolone DC-159a (Japan Anti- Tuberculosis Association, JATA, Daiichi-Sankyo Pharmaceutical Co.), SQ609 (Sequella), SQ641 (Sequella), Benzothiazinone (New Medicines For Tuberculosis (NM4TB)), Q201-(Quro Science, Inc.), PNU-100480 (Pfizer), SQ109 (Sequella, NIHS), AZD5847 (Astrazeneca), PA-824 (TB Alliance), NCOOl (TB Alliance), and low-dose linezolid, particularly for the Treatment of Multi-Drug Resistant Tuberculosis (TBTC, Pfizer).

In another embodiment, rather than, or in addition to, including rifalazil in absorbable form (i.e., microparticulate form), one can co-administer oral vancomycin. The co-administration of rifalazil can minimize the development of vanco-resistant bacterial infections.

In certain embodiments of the invention, the method includes administering rifalazil and one or more additional antibiotics simultaneously or sequentially. Rifalazil and one or more additional antibiotics can be administered within fourteen days of each other, or within five days, three days, or within twenty-four hours of each other. If desired, the one or more additional antibiotics can be administered via pulmonary administration, though they can also be administered orally or parenterally.

Particularly for treating latent tuberculosis, rifalazil can be used to replace rifapentine in the conventional treatment.

Rifalazil can be combined with TMC 207 (Tibotec/Johnson and Johnson), and both drugs have relatively long half lives. TMC 207 is also useful for treating multidrug resistant tuberculosis (MDR-TB), so combination therapy with TMC 207 can be preferred for this indication.

Therapy

The combination of rifalazil, one or more of isoniazid, streptomycin, pyrazinamide, and ethambutol, and a lipophilic antioxidant described herein can be administered, for example, to effectively treat or prevent tuberculosis infections, including drug resistant tuberculosis infections. Combination therapy with conventional microgranulated rifalazil is difficult to combine with the other antibiotic agents that are used in combination therapy, because the rifalazil is poorly soluble relative to the other antibiotics. The formulations described herein, by solubilizing the rifalazil, enable the preparation of a single unit dosage form that includes all components of the combination therapy, and increases the bioavailability of the rifalazil. The administration of a single unit dosage form is expected to increase patient compliance. The increased bioavailability of rifalazil can result in lower effective doses, thus reducing the side effect profile associated with rifalazil administration, particularly as the rifalazil and other antibiotic agents are administered over a significant period of time.

The dosage of rifalazil in various embodiments can range from 0.01 mg to 100 mg. The dosage of rifalazil is e.g., normally about 1 to 100 mg (desirably about 0.1 to 10 mg, more desirably about 1 to 5 mg). The unit dosage form is administered for a length of time sufficient to treat the subject. Treatment may be for 1 to 31 days, desirably 1 to 21 days, 1 to 14 days or even 1, 3, 5, or 7 days. If desired, treatment can continue for up to a year or even for the lifetime of the subject.

The method can be employed as an initial treatment of a subject having or being at risk for developing a lung infection, for example, health care providers, police officers, and soldiers, particularly those serving in geographic regions where there is a high incidence of TB infection. The method can also be employed when the subject is colonized with TB that is resistant to one or more antibiotics commonly used to treat this disorder.

Co-Administration with Anti-Fungals

Lung infections may include, in addition to a bacterial component, a fungal component. This is particularly true with respect to immunocompromised patients. Representative fungal infections include Pneumocystis jiroveci pneumonia, aspergillosis pulmonary infections, and cryptococcosis.

Pneumocystis jiroveci pneumonia (also referred to as PCP) is the most common opportunistic infection among HIV patients, and is caused by a fungus called Pneumocystis jiroveci. This disease is considered an AIDS-defining illness, because when HIV-infected patients develop PCP, their condition has progressed to AIDS. This disease almost always affects the lungs causing a type of pneumonia, with symptoms such as difficulty breathing, fever, and a dry cough. Other common symptoms include chest discomfort, weight loss, chills, spitting up blood (rare), rapid breathing, fast heart rate, cyanosis (bluish discoloration of the skin), nasal flaring, and intercostal retractions (visible use of muscles between the ribs that indicates labored breathing).

PCP can be treated effectively with antifungal medications. TMP/SMX (Bactrim® or Septra®) is the most effective treatment for PCP. The drug is a combination of two antibiotics, trimethoprim (TMP) and sulfamethoxazole (SMX), which work synergistically to kill the fungus. Patients typically receive treatment for the rest of their lives to prevent the infection from recurring.

The Aspergillus fungus causes aspergillosis pulmonary infections. Although there are more than 100 Aspergillus species, most human illnesses are caused by Aspergillus fumigatus or Aspergillus niger or, less frequently, Aspergillus flavus or Aspergillus clavatus. Aspergillosis is not considered an AIDS-defining illness. This means that patients who develop aspergillosis do not necessarily have AIDS.

There are four main types of aspergillosis: allergic bronchopulmonary aspergillosis (ABPA), chronic necrotizing Aspergillus pneumonia (CNAP), aspergilloma, and invasive aspergillosis. ABPA is a hypersensitive reaction to A. fumigatus, which causes inflammation of the airways and air sacs of the lungs. CNAP is a rare condition that usually occurs in patients who have weakened immune systems. An aspergilloma is a fungus ball (mycetoma) that develops in a preexisting lung cavity (abnormal space between the membranes that line the lungs). Invasive aspergillosis is a rapidly progressive, often fatal infection that occurs in patients who have extremely weakened immune systems.

When a human host inhales the fungus spores, the organism enters the lungs. Macrophages (white blood cells that kill microorganisms that enter the body) and neutrophils (white blood cells that destroy foreign substances that enter the body) will engulf the invading fungus to prevent infection.

However, many species of Aspergillus produce toxic metabolites that may prevent macrophages and neutrophils from engulfing them. Individuals who are taking corticosteroids or have immunodeficiencies (like HIV/ AIDS) have impaired macrophage and neutrophil function, making it even more difficult to fight off the fungus. Consequently, HIV patients are unable to fight off the invading fungus and therefore suffer from pulmonary infections.

Common symptoms include fever, cough, dyspnea (shortness of breath), tachypnea (rapid breathing), chest pain, hypoxemia (low levels of oxygen in the blood), and sometimes hemoptysis (blood in sputum).

Aspergillosis is diagnosed once the fungus has been identified in the patient's tissue. Procedures and tests, such as a sputum sample analysis, bronchoalveolar lavage, lung biopsy, chest X-ray, and computerized tomography (CT) scan, are performed to identify the fungus and to assess the tissue damage.

Treatment varies depending on the specific type of aspergillosis. An antifungal called voriconazole (Vfend®) is commonly used to treat pulmonary aspergillosis. Other antifungals, such as itraconazole (Sporanox®), caspofungin (Cancidas), or amphotericin B formulations (Fungilin®, Fungizone®, Abelcet®, AmBisome®, Fungisome®, Amphocil®, and Amphotec®), have also been used.

Cryptococcus neoformans, a type of yeast found worldwide, can cause pulmonary and central nervous system (CNS) infections that can potentially spread to other areas of the body. This infection is called cryptococcosis. HIV/AIDS patients are especially vulnerable to developing the infection. If the infection spreads from the lungs to the CNS (brain and spinal cord) of an HIV patient, the condition is considered an AIDS-defining illness. This means the patient's condition has progressed to AIDS. Most infections develop after the yeast has been inhaled into the lungs. The fungus strongly resists phagocytosis, so the immune system cells have to work hard to engulf the organism.

Cryptococcosis usually starts with a pulmonary (lung) infection, which then spreads to the CNS. If left untreated, the infection may continue to spread to other organs in the body, including the skin, prostate and medullary cavity of the bones. Common symptoms of pulmonary involvement include fever, general feeling of discomfort, dry cough, pain in the membrane surrounding the lungs, and rarely, hemoptysis (blood in sputum).

Initially, amphotericin B (Amphocin® or Fungizone®), a type of antifungal medication, is administered at 0.7-1 milligrams/kilogram/day for two weeks, with or without two weeks 100 milligrams/kilogram/day of flucytosine. Once initial treatment is completed, a maintenance therapy of 200-400 milligrams/day of fluconazole for life is recommended as a preventative measure against future Cryptococcus infections.

In immunocompromised patients suffering from both fungal and bacterial infections, co-administration of azole antifungals, such as fluconazole, itraconazole, sulfamethoxazole, and voriconazole to treat the fungal infection and rifalazil to treat the bacterial infection can be useful for maintaining the therapeutic efficacy of the azole antifungal. Unlike co-administration of rifabutin or rifampicin, there will not be a massive reduction of systemic exposure to azole antifungals due to induced metabolism.

The anti-fungals can be administered via pulmonary administration, oral administration, or parenteral administration, as appropriate, and the therapy is not expected to interfere with the administration of rifalazil.

VII. Methods of Treating Disorders Other than Tuberculosis

The compositions described herein can be used to treat bacterial infections other than tuberculosis, and disorders mediated by such infections. In one embodiment, the patients are immunocompromised patients.

Where a patient is suffering from a bacterial infection caused by one of the above-listed bacteria, which have an active form as well as an inactive, latent form, and is also being treated for another disorder with an agent that is metabolized by CYP450, the patient can be treated for the bacterial infection by administering rifalazil or a rifalazil analog that does not modulate CYP450. Ideally, the rifalazil or a rifalazil analog is administered for a longer period of time than would be required to treat the active bacteria, so that it can accumulate in the patient's cells, and the drug's persistence in the blood stream and within the cells will enable it to be present to treat the latent form of the bacteria, when it transitions into the active form. In this manner, one can prevent a relapse of a bacterial infection.

The compositions can be used to treat drug resistant Gram-positive cocci, such as methicillin-resistant S. aureus and vancomycin-resistant enterococci, and are useful in the treatment of community- acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital-acquired lung infections, bone and joint infections, and other bacterial infections.

The time sufficient to treat a bacterial infection in the lungs ranges from one week to one year, but it can also be extended over the lifetime of the individual patient, if necessary. In more preferable embodiments, the duration of treatment is at least 30 days, at least 45 days, at least 100 days, or at least 180 days. Ultimately, it is most desirable to extend the treatment for such a time that the bacterial infection is no longer detected.

The compositions described herein can be used as therapy for treating tuberculosis and other bacterial disorders treatable with rifalazil and rifalazil derivatives described herein, in any and all of these patients. When used to treat immunocompromised patients, the treatment with rifalazil can be in combination or alternation with existing therapies used to manage disorders that result in the patient being immunocompromised, such as, for example, cancers, liver disorders, HIV, HBV, and HCV.

Treatment of Asthma Patients

In one embodiment, the compositions can also be used to treat asthma patients suffering from tuberculosis. In this embodiment, the rifalazil is co-administered with an anti-asthmatic, such as ventoline, or steroidal anti-inflammatory agents commonly used to treat asthma. Methods for treating asthma patients suffering from tuberculosis, which involve administering this composition to a patient in need of treatment thereof, are also within the scope of the invention. Treatment of Immunocompromised Patients

The compositions described herein can be used to treat immunocompromised patients, including cancer patients, HIV-positive patients, HBV patients, and HCV patients, suffering from a tuberculosis or other bacterial lung infection, or at risk for being infected with tuberculosis or other bacterial lung infection.

When the immunocompromised patients have an HIV, HBV, and/or HCV infection, and are co-infected with tuberculosis, by using the compositions described herein, the patients can continue their existing HIV, HBV, and/or HCV treatments without fear of complications resulting from induction of CYP450, as is the case with other rifamycins, such as rifampicin and rifabutin.

Treatment of HIV-Positive Patients

Ideally, the management of TB among HIV-infected patients taking antiretroviral drugs includes directly observed therapy, and the availability of experienced and coordinated TB/HIV care givers (CDC, Recommendations and Reports, October 30, 1998 / 47(RR20);1-51, Prevention and Treatment of Tuberculosis Among Patients Infected with Human Immunodeficiency Virus: Principles of Therapy and Revised Recommendations). As described herein, the management of TB also includes the use of a TB treatment regimen that includes rifalazil instead of rifampin. The same holds true for patients with cancer, HBV, HCV, and various liver disorders.

Because the use of rifalazil as an alternative to the use of rifampin or rifabutin for antituberculosis treatment is now available, the previously recommended practice of stopping protease inhibitor therapy to allow the use of rifampin or rifabutin for TB treatment is no longer needed for patients with HIV -related TB.

The use of the anti-tuberculosis regimens described herein may further include an assessment of the patient's response to treatment to decide the appropriate duration of therapy (i.e., 6 months or 9 months). Physicians and patients also should be aware that paradoxical reactions might occur during the course of TB treatment when antiretroviral therapy restores immune function.

Short-course (i.e., 2 months) multidrug regimens (e.g., rifalazil or a rifalazil derivative, combined with pyrazinamide or other anti-TB agents) can be used to prevent TB in persons with HIV infection. The co-treatment of mycobacterium tuberculosis infection and HIV infection can take into consideration the frequency of co-existing TB and HIV infection and rates of drug-resistant TB among patients infected with HIV; the co-pathogenicity of TB and HIV disease; the potential for a poorer outcome of TB therapy and paradoxical reactions to TB treatment among HIV-infected patients; and therapies to prevent TB among HIV-infected persons. Effective treatments for TB patients co- infected with HIV can not only help reduce new cases of TB in general, but also help decrease further transmission of drug-resistant strains and new cases of drug-resistant TB.

The Use of Rifalazil in Combination with Anti-Retroviral Agents

Widely used antiretroviral drugs available in the United States include protease inhibitors (saquinavir, indinavir, ritonavir, and nelfinavir) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, delavirdine, and efavirenz). Protease inhibitors and NNRTIs have substantive interactions with certain rifamycins (rifampin, rifabutin, and rifapentine) used to treat mycobacterial infections. These drug interactions principally result from changes in the metabolism of the antiretroviral agents and the rifamycins secondary to induction or inhibition of the hepatic cytochrome CYP450 enzyme system. Rifamycin-related CYP450 induction decreases the blood levels of drugs metabolized by CYP450. For example, if protease inhibitors are administered with rifampin (a potent CYP450 inducer), blood concentrations of the protease inhibitors (all of which are metabolized by CYP450) decrease markedly, and most likely the antiretroviral activity of these agents declines as well. Conversely, if ritonavir (a potent CYP450 inhibitor) is administered with rifabutin, blood concentrations of rifabutin increase markedly, and most likely rifabutin toxicity increases as well. These undesirable side effects are avoided by using rifalazil or the other rifamycin analogs described herein, instead of rifampin, rifabutin, or rifapentine.

In contrast to the protease inhibitors and the NNRTIs, the other class of antiretroviral agents available, nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, didanosine, zalcitabine, stavudine, and lamivudine) are not metabolized by CYP450. Rifampin (and to a lesser degree, rifabutin) increases the glucuronidation of zidovudine and thus slightly decreases the serum concentration of zidovudine. The effect of this interaction probably is not clinically important, and the concurrent use of NRTIs and rifamycins is not contraindicated.

Because current treatment regimens frequently include two NRTIs combined with a potent protease inhibitor (or, as an alternative, combined with an NNRTI), and the protease inhibitors and NNRTIs are adversely affected by conventional anti-TB agents, the patients receiving dual treatment with these regimens are at risk for developing resistant mutations of HIV. Accordingly, the use of rifampin to treat active TB in a patient who is taking a protease inhibitor or an NNRTI is always contraindicated. Rifabutin is a less potent inducer of the CPY450 cytochrome enzymes than rifampin, and, in modified doses, might not be associated with a clinically significant reduction of protease inhibitors or nevirapine. Rifapentine is not recommended as a substitute for rifampin because its safety and effectiveness have not been established for treating patients with HIV-related TB.

TB treatment regimens that contain no rifamycins, for example, TB treatment regimens consisting of streptomycin and isoniazid, have been proposed as an alternative for patients who take protease inhibitors or NNRTIs. However, these TB regimens have not been studied among patients with HIV infection.

For this reason, the treatment regimens using rifalazil or rifalazil derivatives described herein overcome the limitations of the prior TB treatment for HIV-infected individuals.

In one embodiment, the initial phase of a 9-month TB regimen consists of rifalazil or a rifalazil derivative, along with one or more of isoniazid, streptomycin, pyrazinamide, and ethambutol administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment involves administration of rifalazil or a rifalazil derivative, along with one or more of isoniazid, streptomycin, and pyrazinamide, 2-3 times a week for 7 months.

Another option is a 6-month regimen that includes rifalazil or a rifalazil derivative, along with one or more of isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin). These drugs are administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by 2-3-times-per-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment includes a) isoniazid and rifalazil or a rifalazil derivative administered daily or 2-3 times a week for 4 months. Rifalazil or a rifalazil analog, and one or more of isoniazid, pyrazinamide, and ethambutol (or streptomycin) also can be administered three times a week for 6 months

Pyridoxine (vitamin B6) (25-50 mg daily or 50-100 mg twice weekly) can be administered to all HIV-infected patients who are undergoing TB treatment with isoniazid, to reduce the occurrence of isoniazid-induced side effects in the central and peripheral nervous system.

The CDC's most recent recommendations for the use of treatment regimens is 6 months, to complete a) at least 180 doses (one dose per day for 6 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12 induction doses (two doses per week for 6 weeks) plus 36 continuation doses (two doses per week for 18 weeks). While the use of rifalazil and/or rifalazil derivatives may obviate the need for such lengthy treatment, the CDC guidelines can be useful in determining an appropriate baseline treatment modality, and patient monitoring can be used to determine whether the treatment duration can be shortened.

The minimum duration of short-course rifampin-containing TB treatment regimens can be, for example, 6 months, to complete a) at least 180 doses (one dose per day for 6 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12-18 induction doses (two to three doses per week for 6 weeks) plus 36- 54 continuation doses (two to three doses per week for 18 weeks). The same duration can be used for rifalazil therapy.

Three-times-per-week rifalazil regimens can include at least 78 doses administered over 26 weeks.

The final decision on the duration of therapy should consider the patient's response to treatment. For patients with delayed response to treatment, the duration of rifalazil-based regimens should be prolonged from 6 months to 9 months (or to 4 months after culture conversion is documented).

Interruptions in therapy because of drug toxicity or other reasons should be taken into consideration when calculating the end-of-therapy date for individual patients. Completion of therapy is typically based on the total number of medication doses administered, rather than on duration of therapy alone.

Reinstitution of therapy for patients with interrupted TB therapy might require a continuation of the regimen originally prescribed (as long as needed to complete the recommended duration of the particular regimen) or a complete renewal of the regimen. In either situation, when therapy is resumed after an interruption of greater than or equal to 2 months, sputum samples (or other clinical samples as appropriate) should be taken for smear, culture, and drug- susceptibility testing.

When caring for persons with HIV infection, clinicians should make aggressive efforts to identify those who also are infected with M. tuberculosis. Because the reliability of the tuberculin skin test (TST) can diminish as the CD4+ T- cell count declines, it can be important to screen for TB with TST as soon as possible after HIV infection is diagnosed. Because the risk of infection and disease with M. tuberculosis is particularly high among HIV-infected contacts of persons with infectious pulmonary or laryngeal TB, these persons should be evaluated for TB as soon as possible after learning of exposure to a patient with infectious TB.

Monthly Monitoring of Patients During TB Preventive Treatment

Patients in high-risk areas, in high-risk occupations, such as medical care professionals, police officers, and soldiers, or at high risk for exposure to TB, such as family members, friends, and immunocompromised individuals, may undergo preventative treatment. Patients undergoing preventive treatment for TB can optionally receive a periodic, for example, a monthly clinical evaluation of their adherence to treatment and medication side effects.

In one embodiment, the preventive therapy regimens include the use of a combination of at least two antituberculosis drugs that the infecting strain is believed to be susceptible to (e.g., rifalazil or a rifalazil derivative, in combination with ethambutol pyrazinamide, levofloxacin or ethambutol). The clinician can review the drug-susceptibility pattern of the M. tuberculosis strain isolated from the infecting source-patient before choosing a preventive therapy regimen.

Follow-up of HIV-infected Persons Who Have Completed Preventive Therapy Follow-up care, including chest x-rays and medical evaluations, may not be necessary for patients who complete a course of TB preventive treatment, unless they develop symptoms of active TB disease or are subsequently re-exposed to a person with infectious TB disease.

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to be limiting.

EXAMPLE 1

Preparation of Liquid-Filled Capsules Containing 2.5 mg of Rifalazil

PEG-35 castor oil (Cremophor ELP), ascorbylpalmitate, Pluronic® F68, PEG 400, water, BHT, and rifalazil can be mixed in proportions as provided below. The other antibiotic agents can then be added. Capsules can be filled with the liquid to produce liquid-filled capsules containing 2.5 mg of rifalazil each, and, depending on the other antibiotic, an appropriate unit dosage for that antibiotic. The total fill weight per capsule can be calculated based on target fill volume of 0.6 mL and density of 1.0421 g/mL.

The amount of each component is provided in terms of (mg) per capsule, and percent by weight (i.e., % (w/w)). Rifalazil 2.5 mg, 0.40% Ascorbyl Palmitate 12.46 mg, 1.99%, Cremophor ELP 517.08 mg, 82.70% Pluronic F68, 6.23 mg, 1.00%, PEG 400, 71.73 mg, 11.47%, Water 15.07 mg, 2.41%, BHT, 0.19 mg, 0.03 %, for a total of 625.26 mg, 100.0%. The additional antibiotic(s) can be added to this composition.

EXAMPLE 2

Preparation of Liquid-Filled Capsules Containing 12.5 mg of Rifalazil

PEG-35 castor oil (Cremophor ELP), ascorbylpalmitate, Pluronic® F68, PEG 400, water, BHT, and rifalazil can be mixed in proportions as provided below. The other antibiotic agents can then be added. Capsules can be filled with the liquid to produce liquid-filled capsules containing 12.5 mg of rifalazil each. The total fill weight per capsule can be calculated based on target fill volume of 0.6 mL and density of 1.0421 g/mL. The amount per capsule is shown with weight, and weight percent (% (w/w)): Rifalazil 12.5 mg, 2.00%, Ascorbyl Palmitate, 12.26 mg, 1.96%, Cremophor ELP, 508.77 mg, 81.37%, Pluronic F68, 6.13 mg, 0.98%, PEG 400, 70.59 mg, 11.29 %, Water, 14.83 mg, 2.37 %, BHT, 0.18 mg, 0.03%, for a total of 625.26 mg, 100.0%. The additional antibiotic(s) can be added to this composition.

Additional formulations are described, for example, in U.S. Serial No. 11/784,051, the contents of which are hereby incorporated by reference. EXAMPLE 3

Rifalazil Stability in Various Formulations

The stability of rifalazil in various liquid-filled capsule formulations of the invention can be measured as a function of storage conditions. Following storage under set conditions, each capsule can be cut open using a clean razor blade and the contents dissolved in methanol, sonicated for 5-10 minutes, rinsed, and diluted to a final concentration of about 0.1 mg/mL. The solution can be assayed by reverse phase HPLC (Wavelength: 635 nm and 230 nm; Flow: 1.0 mL/min; Run time: 25 minutes; Mobile Phases: (A) 25 mM pH 5.5 Phosphate Buffer, (B) Methanol; linear gradient (% A/% B, minutes): (25/75,0), (5/95,20), (25/75,20.5), (25/75,25); Injection volume: 20 .mu.L). The relative retention time of rifalazil N-oxide is 0.47 (rifalazil=1.0). The amount of N-oxide impurity present in each sample can be assessed by comparison to a known standard.

The pharmacokinetic parameters of the unit dosage forms can be determined as described, for example, in U.S. Serial No. 11/784,051, the contents of which are hereby incorporated by reference.

All publications, patent applications, and patents mentioned in this specification are herein incorporated by reference.

While the invention has been described in connection with specific embodiments, it will be understood that it is capable of further modifications. Therefore, this application is intended to cover any variations, uses, or adaptations of the invention that follow, in general, the principles of the invention, including departures from the present disclosure that come within known or customary practice within the art.

Other embodiments are within the claims.

Claims

1. A pharmaceutical composition for oral administration in unit dosage form comprising:

a) rifalazil,

b) one or more additional antibiotic agents selected from the group consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol,

c) one or more surfactants, and

d) a lipophilic antioxidant, wherein said one or more surfactants are from 20% to 99% (w/w) of said composition.

2. The pharmaceutical composition of claim 1, wherein said one or more surfactants are from 75% to 95% (w/w) of said composition.

3. The pharmaceutical composition of claim 1, wherein said lipophilic antioxidant is selected from carotenoids, tocopherols and esters thereof, tocotrienols and esters thereof, retinol and esters thereof, ascorbyl esters, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), propyl gallate, and mixtures thereof.

4. The pharmaceutical composition of claim 1, wherein said lipophilic antioxidant is an antioxidant surfactant.

5. The pharmaceutical composition of claim 4, wherein said antioxidant surfactant is retinyl palmitate, ascorbyl palmitate, or tocopheryl-PEG-1000-succinate.

6. The pharmaceutical composition of claim 1, wherein said composition comprises from 1 to 50% (w/w) of a first lipophilic antioxidant selected from retinol, retinyl palmitate, ascorbyl palmitate, tocopherol, tocotrienol and tocopheryl-PEG- 1000-succinate and less than 0.1% (w/w) of a second lipophilic antioxidant selected from tocopherol, tocopherol acetate, tocopherol nicotinoate, tocopherol succinate, tocotrienol, tocotrienol acetate, tocotrienol nicotinoate, tocotrienol succinate, carotenoids, BHT, BHA, and propylgallate.

7. The pharmaceutical composition of claim 6, wherein said composition comprises from 1 to 20% (w/w) of said first lipophilic antioxidant.

8. The pharmaceutical composition of claim 1, further comprising a hydrophilic co-solvent selected from alcohols, polyethylene glycols, and mixtures thereof.

9. The pharmaceutical composition of claim 8, wherein said hydrophilic co- solvent is an alcohol selected from ethanol, propylene glycol, glycerol, and mixtures thereof.

10. The pharmaceutical composition of claim 8, wherein said hydrophilic co- solvent is a polyethylene glycol with a molecular weight of between 200 and 10,000 Da.

11. The pharmaceutical composition of claim 10, comprising PEG-35 castor oil.

12. The pharmaceutical composition of claim 11, comprising from 0.2 to 2.5% (w/w) rifalazil, from 0.2 to 10% (w/w) of one or more of isoniazid, streptomycin, pyrazinamide, and ethambutol, from 75 to 85% (w/w) PEG-35 castor oil, from 0.5 to 1.5% (w/w) pluronic F68, from 8 to 15% PEG-400, from 1.5 to 2.5% (w/w) ascorbyl palmitate, from 0.01 to 0.05% (w/w) BHT, and from 1.5 to 2.5% (w/w) water.

13. The pharmaceutical composition of claim 1, comprising PEG-35 castor oil, PEG-8 caprylic/capric glycerides, and PEG-6 apricot kernel oil.

14. The pharmaceutical composition of claim 13, comprising from 0.2 to 2.5% (w/w) rifalazil, from 0.2 to 10% (w/w) of one or more of isoniazid, streptomycin, pyrazinamide, and ethambutol, from 22 to 28% (w/w) PEG-35 castor oil, from 45 to 50% (w/w) PEG-6 apricot kernel oil, from 20 to 25% PEG-8 caprylic/capric glycerides, from 1.5 to 2.5% (w/w) ascorbyl palmitate, and from 0.01 to 0.05% (w/w) BHT.

15. The pharmaceutical composition of claim 9, wherein the solubility of said rifalazil in said one or more surfactants is greater than 16 mg/mL.

16. The pharmaceutical composition of claim 15, wherein the solubility of said rifalazil in said one or more surfactants is greater than 20 mg/mL.

17. The pharmaceutical composition of claim 1, wherein said unit dosage form comprises from between 1 and 30 mg of rifalazil.

18. The pharmaceutical composition of claim 1, wherein said one or more surfactants is present in an amount sufficient to produce, upon administration to fasted patients, a coefficient of variation in C_max of less than 60%.

19. The pharmaceutical composition of claim 1, wherein said one or more surfactants is present in an amount sufficient to produce, upon administration to fasted patients, a coefficient of variation in AUC_∞ of less than 40%.

20. The pharmaceutical composition of claim 1, wherein said one or more surfactants is present in an amount sufficient to produce, upon administration to fasted patients, a mean bioavailability of greater than 30%.

21. A pharmaceutical composition for oral administration in unit dosage form comprising rifalazil, one or more antibiotics selected from the group consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol, and an antioxidant surfactant.

22. The pharmaceutical composition of claim 21, wherein said antioxidant surfactant is retinyl palmitate, ascorbyl palmitate, or tocopheryl-PEG-lOOO-succinate.

23. A pharmaceutical composition for oral administration in unit dosage form comprising rifalazil, one or more antibiotics selected from the group consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol, a surfactant, and a lipophilic antioxidant, wherein said lipophilic antioxidant is present in an amount sufficient to reduce the oxidation of rifalazil.

24. The pharmaceutical composition of claim 23, wherein upon storage of said unit dosage form at 25°C and 60% relative humidity for a period of one month, less than 0.2% of said rifalazil is converted to rifalazil N-oxide.

25. The pharmaceutical composition of claim 24, wherein upon storage of said unit dosage form at 25°C and 60% relative humidity for a period of six months, less than 0.2% of said rifalazil is converted to rifalazil N-oxide.

26. The pharmaceutical composition of claim 25, wherein upon storage of said unit dosage form at 25°C and 60% relative humidity for a period of twelve months, less than 0.2% of said rifalazil is converted to rifalazil N-oxide.

27. A method of treating a tuberculosis infection in a patient, said method comprising administering to said patient a pharmaceutical composition comprising rifalazil, one or more antibiotics selected from the group consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol, 20% to 99% (w/w) of one or more surfactants, and a lipophilic antioxidant, wherein said composition is administered in an amount effective to treat said infection.

28. The method of claim 27, wherein said tuberculosis infection is by a multidrug resistant tuberculosis bacteria.

29. A method of treating tuberculosis in a patient diagnosed as having said disease, said method comprising administering to the patient (i) rifalazil, (ii) one or more additional antibiotics selected from the group consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol, and (ii) a lipophilic antioxidant in an amount and for a duration effective to treat said disease in said patient.

30. A kit, comprising: (i) a composition comprising rifalazil, one or more additional antibiotics selected from the group consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol, and a lipophilic antioxidant; in a unit dosage form for oral administration, and (ii) instructions for administering said composition to a patient diagnosed with tuberculosis.

31. The kit of Claim 30, wherein the instructions specify administering the unit dosage form for one to fourteen days.

32. The kit of Claim 30, wherein the unit dosage form is administered daily for approximately 8 weeks.

33. The kit of Claim 30, wherein the unit dosage form is administered daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete a 2-month induction phase, then 2-3 times a week for approximately 7 months.

34. Use of rifalazil, one or more additional antibiotics selected from the group consisting of isoniazid, streptomycin, pyrazinamide, and ethambutol, and a lipophilic antioxidant; in the preparation of a medicament for treating tuberculosis, wherein the medicament is a unit dosage form for oral delivery.

35. The use of claim 34, wherein the unit dosage provides between 0.01 and 100 mg of rifalazil.

36. The use of claim 34, wherein the unit dosage provides between 1 and 50 mg of rifalazil.

37. The use of claim 34, wherein the unit dosage provides between 1 and 5 mg/day of rifalazil.