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(12) Patent Application Publication (10) Pub. No.: US 2007/0248668A1 Michaelis Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0248668A1 Michaelis Et Al US 2007024.8668A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0248668A1 Michaelis et al. (43) Pub. Date: Oct. 25, 2007 (54) PHARMACEUTICAL COMPOSITIONS AND Related U.S. Application Data USES THEREOF (60) Provisional application No. 60/789,699, filed on Apr. 6, 2006. (76) Inventors: Arthur F. Michaelis, Devon, PA (US); Panayiotis P. Constantinides, Gurnee, Publication Classification IL (US) (51) Int. Cl. A61K 3 1/5383 (2006.01) A61K 3 1/535 (2006.01) Correspondence Address: A 6LX 3L/355 (2006.01) CLARK & ELBNG LLP A6II 3L/22 (2006.01) 101 FEDERAL STREET A6II 3L/07 (2006.01) BOSTON, MA 02110 (US) (52) U.S. Cl. ...................... 424/464; 514/229.5: 514/458: 514/474: 514/546; 514/725 (21) Appl. No.: 11/784,051 (57) ABSTRACT The invention features pharmaceutical compositions includ ing rifalazil, a surfactant, and a lipophilic antioxidant and (22) Filed: Apr. 5, 2007 methods of use thereof. US 2007/024.8668A1 Oct. 25, 2007 PHARMACEUTICAL COMPOSITIONS AND USES 0010. In certain embodiments, the lipophilic antioxidant THEREOF is selected, without limitation, from carotenoids, tocopherols and esters thereof, retinol and esters thereof, ascorbyl esters, CROSS-REFERENCE TO RELATED butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), APPLICATIONS propyl gallate, and mixtures thereof. 0001. The application claims benefit of U.S. Provisional 0011. In one embodiment, the lipophilic antioxidant is an Application No. 60/789,699 filed Apr. 6, 2006, which is antioxidant surfactant, such as pegylated esters and fatty incorporated herein by reference. acid esters of tocopherol, retinol, ascorbic acid (e.g., retinyl palmitate, ascorbyl palmitate, and tocopheryl-PEG-1000 BACKGROUND OF THE INVENTION Succinate), and mixtures thereof. 0012. In one embodiment, the pharmaceutical composi 0002 The present invention relates to the field of anti tion includes from 1 to 50% (w/w) of a first lipophilic microbial therapy. antioxidant selected from retinyl palmitate, ascorbyl palmi 0003 Rifalazil, an ansamycin-class antibiotic, has been tate, and tocopheryl-PEG-1000-succinate and less than 0.1% described in U.S. Pat. No. 4,983,602. (w/w) of a second lipophilic antioxidant selected from 0004. A microgranulated formulation of rifalazil is dis tocopherol, tocopherol acetate, tocopherol nicotinoate, toco closed in U.S. Pat. No. 5,547,683. This microgranulated pherol Succinate, tocotrienol, tocotrienol acetate, tocotrienol rifalazil was shown to exhibit improved oral bioavailability nicotinoate, tocotrienol succinate, carotenoids, BHT, BHA, in comparison to rifalazil crystals, mortar-milled crystals, and propylgallate. Desirably, the pharmaceutical composi and Suspensions of mortar-milled crystals as determined by tion includes from 1 to 20%, 1 to 15%, or 1 to 10% (w/w) the relative AUCs produced for each formulation orally of the first lipophilic antioxidant. administered to beagles. Phase I clinical trials for rifalazil 0013 In another embodiment, the pharmaceutical com are described in U.S. Pat. Nos. 6,566,354 and 6,316,433. position further includes a hydrophilic co-solvent selected from alcohols (e.g., ethanol, propylene glycol, glycerol, and 0005. A stable formulation for the oral administration of mixtures thereof), polyethylene glycols, and mixtures rifalazil that produces more consistent pharmacokinetics and thereof. Desirably, the hydrophilic co-solvent is a polyeth an enhanced degree of bioavailability among Subjects is ylene glycol with a molecular weight of between 200 and desirable. 10,000 Da. The hydrophilic co-solvent is combined with a SUMMARY OF THE INVENTION surfactant, such as PEG-35 castor oil. 0014 Pharmaceutical compositions of the invention 0006 We have discovered that the oral bioavailability of combining both a hydrophilic polymer and a Surfactant can rifalazil is increased and the coefficient of variation in include, for example, from 0.2 to 2.5% (w/w) rifalazil, from pharmacokinetic parameters (e.g., C and AUC.) is 75 to 85% (w/w) PEG-35 castor oil, from 0.5 to 1.5% (w/w) decreased when rifalazil is formulated with a sufficient pluronic F68, from 8 to 15% PEG-400, from 1.5 to 2.5% amount of a surfactant. We have also discovered that the (w/w) ascorbyl palmitate, from 0.01 to 0.05% (w/w) BHT, stability of such formulations is improved by addition of a and from 1.5 to 2.5% (w/w) water. lipophilic antioxidant. 0015. Where the pharmaceutical composition of the 0007 Accordingly, in one aspect, the invention features a invention contains a mixture of surfactants, it is desirable for pharmaceutical composition for oral administration in unit the mixture to include at least one lipophilic Surfactant (i.e., dosage form including rifalazil, one or more Surfactants, and HLB<10) and at least one hydrophilic surfactant (i.e., a lipophilic antioxidant, wherein the Surfactants are from HLB>10). For example, the pharmaceutical composition 20% to 99% (w/w) of the composition. can include PEG-35 castor oil (HLB 12.5), PEG-8 caprylic/ 0008. In a related aspect, the invention features a phar capric glycerides (Labrasol, HLB 14), and PEG-6 apricot maceutical composition for oral administration in unit dos kernel oil (Labrafil M1944, HLB 4). age form including rifalazil and an antioxidant Surfactant. In 0016 Pharmaceutical compositions of the invention certain embodiments, the antioxidant Surfactant is retinyl combining both a lipophilic Surfactant and a hydrophilic palmitate, ascorbyl palmitate, or tocopheryl-PEG-1000-suc surfactant can include, for example, from 0.2 to 2.5% (w/w) cinate. rifalazil, from 22 to 28% (w/w) PEG-35 castor oil, from 45 0009. The invention also features a pharmaceutical com to 50% (w/w) PEG-6 apricot kernel oil, from 20 to 25% position for oral administration in unit dosage form includ PEG-8 caprylic/capric glycerides, from 1.5 to 2.5% (w/w) ing rifalazil, a Surfactant, and a lipophilic antioxidant, ascorbyl palmitate, and from 0.01 to 0.05% (w/w) BHT. wherein the lipophilic antioxidant is present in an amount 0017. In any of the above pharmaceutical compositions sufficient to reduce the oxidation of rifalazil. Desirably, upon the solubility of rifalazil in the surfactants can be greater storage of the unit dosage form at 25° C. and 60% relative than 5 mg/mL. Desirably, the solubility is greater than 8 humidity for a period of one month, six months, or even mg/mL, 10 mg/mL, 12 mg/mL, 14 mg/mL, 15 mg/mL, 16 twelve months, less than 0.2% of the rifalazil is converted to mg/mL, 17 mg/mL, 18 mg/mL. 20 mg/mL, 22 mg/mL, 25 rifalazil N-oxide. In certain embodiments, less than 0.2%, mg/mL, or 30 mg/mL. 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 0018. The pharmaceutical compositions of the invention 25° C. and 60% relative humidity for a period of 1, 2, 3, 4, are in a unit dosage form. Desirably, the unit dosage form is 5, 6, 7, 8, 9, 10, 11, 12, 18, or even 24 months. a liquid-filled or semi-solid filled capsule (i.e., either as a US 2007/024.8668A1 Oct. 25, 2007 hard capsule or a soft capsule). In the case of a hard capsule, Desirably, the coefficient of variation in C is less than the unit dosage form can also be a semi-solid-filled capsule. 55%, 50%, 45%, 40%, 35%, 30%, 25%, or even 20%. Capsule formulations of the invention are, desirably, greater than 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% (w/w) 0025 For any of the pharmaceutical compositions of the one or more Surfactants. invention, the Surfactants are, desirably, present in an amount Sufficient to produce, upon administration to fasted 0019. The pharmaceutical compositions of the invention patients, a coefficient of variation in AUC of less than 40%. can include a gelling agent (i.e., from 0.5 to 50%, 0.5 to Desirably, the coefficient of variation in AUC is less than 25%, 0.5 to 15%, 0.5 to 10%, 0.5 to 5%, or 0.5 to 3% (w/w) 35%, 30%, 25%, or even 20%. gelling agent) to increase the viscosity. Desirably, the gelling agent is a polyoxyethylene-polyoxypropylene block copoly 0026. For any of the pharmaceutical compositions of the mer. These gelling agents are available under various trade invention, the Surfactants are, desirably, present in an names, including one or more of Symperonic PE Series (ICI), amount Sufficient to produce, upon administration to fasted Pluronic R series (BASF), Supronic, Monolan, Pluracare, patients, a mean bioavailability of greater than 30%. Desir and Plurodac. The generic term for these copolymers is ably, the mean bioavailability is greater than 35%, 40%, “poloxamer” (CAS 9003-11-6). These polymers have the 45%, or even 50%. formula (I): 0027. The invention further features a method of treating a bacterial infection in a patient that includes the step of HO(CHO) (CHO)(CHO).H (I) administering a rifalazil pharmaceutical composition of the where “a” and “b' denote the number of polyoxyethylene invention, wherein the rifalazil is administered in an amount and polyoxypropylene units, respectively. These copolymers effective to treat the infection. are available in molecular weights ranging from 1000 to 15000 daltons, and with ethylene oxide?propylene oxide 0028. In any of the above methods, the infection is ratios (a/b) between 0.1 and 3.0 by weight. Formulations of selected from community-acquired pneumonia, upper and rifalazil according to the invention may include one or more lower respiratory tract infections, skin and soft tissue infec of the polyoxyethylene-polyoxypropylene block copoly tions, hospital-acquired lung infections, bone and joint mers above. In certain embodiments, the gelling agent is infections, respiratory tract infections, acute bacterial otitis Pluronic(R) F68, also known as Poloxamer 188 in which media, bacterial pneumonia, urinary tract infections, com a=75, b=30 (HLB-29).
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