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Wo 2010/096551 A2

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Wo 2010/096551 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 26 August 2010 (26.08.2010) WO 2010/096551 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/4725 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US2010/024576 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 18 February 2010 (18.02.2010) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/153,463 18 February 2009 (18.02.2009) US (84) Designated States (unless otherwise indicated, for every 61/25 1,475 14 October 2009 (14.10.2009) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): RIB-X ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, PHARMACEUTICALS, INC. [-/US]; 300 George TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Street, Suite 301, New Haven, CT 065 11 (US). ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, (72) Inventors; and TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (75) Inventors/Applicants (for US only): LI, Danping ML, MR, NE, SN, TD, TG). [US/US]; 4 Colonial Court, Middlebury, CT (US). BU- RAK, Eric, S. [US/US]; 51 Bone Mill Road, East Had- Declarations under Rule 4.17: dam, CT 06423 (US). DRESBACK, David, S. [US/US]; — of inventorship (Rule 4Λ 7(iv)) 2 1 Elm Street, Stonington, CT 06378 (US). Published: (74) Agents: ELRIFI, Ivor, R. et al; Mintz Levin Cohn Fer ris Glovsky And Popeo, P.C , One Finnancial Center, — without international search report and to be republished Boston, MA 021 11 (US). upon receipt of that report (Rule 48.2(g)) (54) Title: ANTIMICROBIAL COMPOSITIONS Figure 3 Delafloxacin Capsules in 2-Step Dissolution, 45 mg/50 mL ith arginine ith FVP) TPGS Solution Drug) Time (min) (57) Abstract: The present invention relates to pharmaceutical compositions comprising a quinolone carboxylic acid compound and an absorption enhancer. In further embodiments, the compositions further comprise a basifer or a crystallization inhibitor, or both a basifϊer and a crystallization inhibitor. These compositions are useful for treating, preventing, or reducing the risk of infec tion. ANTIMICROBIAL COMPOSITIONS RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Patent Application No. 61/251,475, filed October 14, 2009 and U.S. Patent Application No. 61/153,463, filed February 18, 2009, the disclosures of which are incorporated by reference herein. FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions comprising a quinolone carboxylic acid compound and an absorption enhancer. In further embodiments, these compositions further comprise a basifer or a crystallization inhibitor, or both a basifier and a crystallization inhibitor. These compositions can be formulated for administration via various routes, including oral administration. These compositions are useful for treating, preventing, or reducing the risk of infection. BACKGROUND An appropriate pharmaceutical carrier system is generally a requirement for the safe and effective delivery of a pharmaceutical drug active. The entire pharmaceutical composition, i.e., the pharmaceutical drug active formulated in a pharmaceutical carrier, can affect the bioavailability and also the pharmacokinetics and pharmacodynamics of the drug active. It is therefore important that a pharmaceutical composition be carefully developed and manufactured to deliver the desired pharmaceutical drug active in a safe and effective manner. The delivery of antimicrobial agents for treating or preventing microbial infections can present special challenges. To provide therapeutic efficacy, it is generally desired that the antimicrobial agent be administered to the patient to achieve systemic concentrations in the bloodstream or target organs above a minimum inhibitory concentration (MIC) for a sufficient time against the particular microbial organism or organisms being targeted. Consequently, an antimicrobial agent that otherwise exhibits an effective antimicrobial profile in vitro can be ineffective, or even harmful, unless properly formulated for in vivo administration. When formulating pharmaceutical compositions for oral administration, particularly antimicrobial compositions such as antibiotics, it is important to maximize the delivery of the pharmaceutical active. The reasons for maximizing this delivery is to increase the absorption or bioavailability of the pharmaceutical active and to reduce the amount of the pharmaceutical active remaining in the gastrointestinal tract. By maximizing absorption or bioavailability, more of the pharmaceutical active is transported into the bloodstream and organs of the subject patient for targeting an infection and less of the pharmaceutical active remains, which can cause untoward gastrointestinal side effects such as diarrhea or encourage the growth of resistant, harmful gastrointestinal microorganisms such as Clostridium difficile. The present invention addresses the foregoing and other needs. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows a powder X-ray diffraction pattern of crystalline D-glucitol, 1-deoxy-l- (methylamino)-, l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-l,4-dihydro-7-(3-h- ydroxyazetidin- 1-yl)-4-oxo-3-quinolinecarboxylate (salt). FIG. 2 shows a powder X-ray diffraction pattern of crystalline D-glucitol, 1-deoxy-l- (methylamino)-, l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-l,4-dihydro-7-(3-h- ydroxyazetidin- 1-yl)-4-oxo-3-quinolinecarboxylate trihydrate (salt). FIG. 3 shows the two-step dissolution of delafloxacin meglumine capsules used in a dog study. FIG. 4 shows the two-step dissolution profile of delafloxacin meglumine formulations used in a dog study. SUMMARY OF THE INVENTION The present invention relates to antimicrobial compositions and more specifically compositions of quinolone carboxylic acid compounds. The present invention relates to a pharmaceutical composition comprising a quinolone carboxylic acid compound or a pharmaceutically acceptable salt or ester thereof, and an absorption enhancer. In further embodiments, the compositions further comprise a basifer or a crystallization inhibitor, or both a basifϊ er and a crystallization inhibitor. These compositions can be formulated for administration via various routes, including oral administration. These compositions are useful for treating, preventing, or reducing the risk of infection. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition comprising a quinolone carboxylic acid compound or a pharmaceutically acceptable salt or ester thereof, and an absorption inhibitor. In further embodiments, these compositions further comprise a basifer or a crystallization inhibitor, or both a basifϊ er and a crystallization inhibitor. These compositions are useful for treating, preventing, or reducing the risk of infection. In one embodiment, the present invention relates to a pharmaceutical composition which prior to mixing comprises (a) a quinolone carboxylic acid compound or a pharmaceutically acceptable salt, ester, or prodrug thereof, and (b) an absorption enhancer. In other embodiments, the present invention relates to a pharmaceutical composition comprising (a) a quinolone carboxylic acid compound or a pharmaceutically acceptable salt, ester, or prodrug thereof, and (b) an absorption enhancer. In other embodiments, the present invention relates to a pharmaceutical composition which prior to mixing comprises (a) a quinolone carboxylic acid compound or a pharmaceutically acceptable salt, ester, or prodrug thereof, (b) an absorption enhancer, and (c) a basifϊ er. In other embodiments, the present invention relates to a pharmaceutical composition comprising (a) a quinolone carboxylic acid compound or a pharmaceutically acceptable salt, ester, or prodrug thereof, (b)an absorption enhancer, and (c) a basifϊ er. In other embodiments, the present invention relates to a pharmaceutical composition which prior to mixing comprises (a) a quinolone carboxylic acid compound or a pharmaceutically acceptable salt, ester, or prodrug thereof, (b) an absorption enhancer, and (c) a crystallization inhibitor. In other embodiments, the present invention relates to a pharmaceutical composition comprising (a) a quinolone carboxylic acid compound or a pharmaceutically acceptable salt, ester, or prodrug thereof, (b) an absorption enhancer, and (c) a crystallization inhibitor. In other embodiments, the present invention relates to a pharmaceutical composition which prior to mixing comprises (a) a quinolone carboxylic acid compound or a - A- pharmaceutically acceptable salt, ester, or prodrug thereof, (b) an absorption enhancer, (c) a basifϊ er, and (d) a crystallization inhibitor. In other embodiments, the present invention
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