US 2006O140990A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0140990 A1 Bortz et al. (43) Pub. Date: Jun. 29, 2006 (54) COMPOSITION FOR TOPICAL TREATMENT (60) Provisional application No. 60/507,138, filed on Oct. OF MIXED VAGINAL INFECTIONS 1, 2003. Provisional application No. 60/504,017, filed on Sep. 19, 2003. (75) Inventors: Jonathan Bortz, Saint Louis, MO (US); R. Saul Levinson, Chesterfield, Publication Classification MO (US); Mitchell Kirschner, St. (51) Int. Cl. Louis, MO (US); Robert C. Cuca, A61K 3 1/7034 (2006.01) Glen Carbon, IL (US) A6IR 9/00 (2006.01) Correspondence Address: (52) U.S. Cl. .............................................. 424/400: 514/35 HARNESS, DICKEY, & PIERCE, P.L.C (57) ABSTRACT 7700 BONHOMME, STE 400 ST. LOUIS, MO 63105 (US) A pharmaceutical composition comprises (a) an antibacterial agent in an antibacterially effective amount, illustratively (73) Assignee: Drug Tech Corporation, Wilmington, comprising clindamycin or a pharmaceutically acceptable salt or ester thereof, and (b) an antifungal agent in an DE (US) antifungally effective amount, illustratively comprising (21) Appl. No.: 11/326,979 butoconazole or a pharmaceutically acceptable salt or ester thereof. The composition is adapted for application in a unit (22) Filed: Jan. 5, 2006 dose amount to a Vulvovaginal Surface and has at least one nonlipoidal internal phase and at least one lipoidal external Related U.S. Application Data phase that is bioadhesive to the vulvovaginal surface. The composition is useful for administration to a Vulvovaginal (63) Continuation-in-part of application No. 10/944,416, Surface to treat a mixed bacterial vaginosis and Vulvovaginal filed on Sep. 20, 2004. candidiasis infection. US 2006/O 140990 A1 Jun. 29, 2006 COMPOSITION FOR TOPCAL TREATMENT OF increased susceptibility to viral infection including HIV and MIXED VAGINAL INFECTIONS HSV-2, and, in pregnant women, premature birth, preterm 0001. This application is a continuation-in-part of appli rupture of membranes, intra-amniotic fluid infection, pre cation Ser. No. 10/944,416, filed on Sep. 20, 2004, which term labor and postpartum endometritis. claims priority of provisional application Ser. No. 60/507, 0010 Bacterial and candidal infections can coexist. 138, filed on Oct. 1, 2003 and provisional application Ser. Mixed bacterial and candidal (herein “BV/VVC) infection No. 60/504,017, filed on Sep. 19, 2003. Each of the above occurs in up to about one-fifth of vaginitis cases. For cited applications is incorporated in its entirety herein by example, Redondo-Lopez et al. (1990), Sex. Transm. Dis. reference. 17(1):51-53, reported that in 132 episodes of symptomatic vaginitis in 35 patients with recurring symptoms, 15% were FIELD OF THE INVENTION found to involve a mixed BV/VVC infection. 0002 The present invention relates to pharmaceutical 0011. In another study, Ferris et al. (2002), Obstet. compositions suitable for vaginal delivery of an antifungal Gynecol. 99(3):419–425, reported that of 95 women who agent and an antibacterial agent. The invention further were about to treat themselves for VVC, 34% were con relates to therapeutic methods of use of Such compositions firmed to have VVC alone, 19% had BV alone, and 19% had in women having mixed fungal and bacterial infections of a mixed BV/VVC infection. the Vulvovaginal system. 0012. A significant problem is that such mixed infections BACKGROUND OF THE INVENTION are underdiagnosed, and self-medication or prescribed treat ment occurs as if for fungal or bacterial infection alone. Both 0003 Infective vaginitis covers a range of conditions fungi such as Candida albicans and bacteria Such as Gard involving microbial infection of the vagina, and inflamma merella vaginalis are opportunistic pathogens, therefore in tion associated therewith, that sometimes extends to the case of a mixed infection removal of one can lead to rapid Vulva. It accounts for an estimated 15 million physician population growth of the other. Thus, for example, a mixed office visits a year in the U.S., and with availability of BV/VVC infection treated topically only with an antifungal over-the-counter remedies particularly for candidal infec agent such as butoconazole can quickly become a serious tions, many additional cases are medicated without profes BV infection, which then requires follow-up antibacterial sional diagnosis. treatment, either as a further topical application or as sys temic (e.g., oral antibiotic) therapy. Implications of such 0004 Agents of infection implicated in vaginitis include: misdiagnosis can be nontrivial, especially considering the 0005 (a) fungi, more particularly yeasts, especially Can serious conditions to which BV can lead if untreated. dida spp. including one or more of C. albicans, C. dublin iensis, C. glabrata, C. kefir, C. krusei, C. lusitaniae, C. 0013 Thus a need exists in the art for a medicament and neoformans, C. parasilopsis and C. tropicalis, of which the method of use thereof that conveniently and effectively most common is C. albicans, treats mixed BV/VVC infections. 0006 (b) bacteria, commonly a variety of species includ 0014 U.S. Pat. No. 4,551,148 to Riley et al. proposes a ing one or more of Bacteroides spp., Gardnerella vaginalis, controlled release system for vaginal drug delivery, com Mobiluncus spp., Mycoplasma hominis and Peptostrepto prising unit cells having a nonlipoidal internal phase and a coccus spp., most commonly with G. vaginalis predominat lipoidal continuous external phase. An active agent is ing; and present at least in the internal phase. 0007 (c) protozoa, especially Trichomonas vaginalis. 0.015 U.S. Pat. No. 5.266,329 to Riley proposes such a vaginal delivery system having an antifungal imidazole, 0008 Candidal infections, herein referred to collectively exemplified by metronidazole, as the active agent. as vulvovaginal candidiasis (VVC), are the best known cause of vaginitis and are believed to affect about 75% of 0016 Thompson & Levinson (2002), Drug Delivery Sys women at least once during their lifetime. VVC is generally tems & Sciences 2(1), 17-19, describe a bioadhesive topical not sexually transmitted. Bacterial vaginosis (BV), a collec drug delivery system known therein as the VagiSite system tive term used herein for vaginal or Vulvovaginal conditions as a high internal phase ratio water-in-oil emulsion system, caused by bacterial infection, is generally considered a providing a delivery platform for administration of active sexually transmitted disease although other modes of trans drug entities in the vaginal cavity. They disclose that the mission can occur. Symptoms of VVC and BV include VagiSite system is incorporated in Gynazole-1(R) antifungal irritation (manifesting, for example, as redness, burning vaginal cream, which contains 2% by weight butoconazole and/or itching), dyspareunia and abnormal discharge, which nitrate. in the case of BV tends to have a fishy odor. Other diagnostic 0017 U.S. Patent Application Publication No. 2003/ criteria include a vaginal pH lower than about 4.7 in VVC, 0180366 of Kirschner et al. discloses a composition suitable or higher than about 4.7 in BV, and presence of "clue cells' for vaginal drug delivery, comprising an essentially pH (epithelial cells having a granular appearance) in BV. neutral emulsion having an internal water-soluble phase and 0009 VVC is typically a nuisance, often very troubling an external water-insoluble phase, wherein the internal to the patient but relatively rarely implicated in development phase comprises an acidic buffered phase comprising a drug, of more serious or life-threatening conditions. On the other which can illustratively be an antifingal agent or an anti hand, BV, if untreated, can lead to serious conditions. Such bacterial agent. Example I therein provides such a compo as cerviciitis, pelvic inflammatory disease, cervical dyspla sition comprising the antibacterial agent metronidazole in an sia, urinary tract infections, postoperative infections, amount of 0.75% by weight. Example II therein provides US 2006/O 140990 A1 Jun. 29, 2006 Such a composition comprising the antibacterial agent clin U.S. Patent Application Publication No. 2003/0180366, or damycin phosphate in an amount of 2.8% by weight. as further described herein. Such a water-in-oil emulsion can 0018 U.S. Pat. No. 5,055.303 to Riley describes a solid be presented in a Solid form, for example as a vaginal composition, for example a Suppository, comprising a water Suppository, or in a semi-solid form, for example as a in-oil emulsion that can carry an active agent. The compo vaginal cream, and has bioadhesive properties. sition is stated to be suitable for insertion into a body orifice 0029 A“vulvovaginal surface herein denotes any exter and to melt at body temperature to form a cream having nal or internal Surface of the female genitalia, including controlled release and bioadherent properties. mucosal Surfaces in the vaginal cavity and nonmucosal 0019 U.S. Patent Application Publication No. 2003/ Surfaces of the Vulva and immediately Surrounding areas of 0225,034 of Floros et al. mentions that, for treatment of skin. In some embodiments, the composition is more spe vaginitis, Surfactant lipids can be administered in conjunc cifically adapted for application to a vaginal mucosal Sur tion with one or more medications including antibiotics and face, and the external phase of the composition is bioadhe antifungals. Examples of antibiotics said to be suitable sive, i.e., mucoadhesive, to Such a surface. include amplicillin, ceftriaxone, clindamycin, metronidazole 0030. In one embodiment, the composition is formulated and tetracycline. Examples of antifungals said to be suitable as a bioadhesive vaginal delivery system as described by include miconazole, clotrimazole, econazole, butoconazole, Thompson & Levinson (2002), op. cit. under the name tioconazole and terconazole. VagiSite, or a vaginal delivery system Substantially equiva lent thereto, including as active agents an antibacterial agent SUMMARY OF THE INVENTION and an antifungal agent. 0020. There is now provided a pharmaceutical composi 0.031) International Patent Publication No.