MX2008008638A - Medicament for topical use - Google Patents

Abstract

A pharmaceutical composition comprises (a) an antibacterial agent in an antibacterially effective amount, illustratively comprising clindamycin or a pharmaceutically acceptable salt or ester thereof;and (b) an antifungal agent in an antifungally effective amount, illustratively comprising butoconazole or a pharmaceutically acceptable salt or ester thereof. The composition is adapted for application in a unit dose amount to a vulvovaginal surface and has at least one nonlipoidal internal phase and at least one lipoidal external phase that is bioadhesive to the vulvovaginal surface. The composition is useful for administration to a vulvovaginal surface to treat a mixed bacterial vaginosis and vulvovaginal candidiasis infection.

Description

MEDICATION FOR TOPICAL USE FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions suitable for vaginal delivery of an antifungal agent and an antibacterial agent. The invention further relates to therapeutic methods for the use of such compositions in women who have mixed fungal and bacterial infections of the vulvovaginal system. BACKGROUND OF THE INVENTION Infectious vaginitis encompasses a range of conditions involving microbial infection of the vagina, inflammation associated therewith, which in some cases extends to the vulva. It represents an estimated number of 15 million visits to medical consultations per year in the United States, and with the availability of over-the-counter remedies particularly for candida infections, many additional cases are medi- cated without professional diagnosis. Infectious agents involved in vaginitis include: (a) fungi, more particularly yeast, especially Candida spp., Including one or more of C. albicans, C. dubliniensis, C. glabra ta, C. kefyr, C. krusei, C. lusi taniae, C. neoformans, C. parasilopsis and C. tropicalis, of which the most common is C. albicans; (b) bacteria, commonly a diversity of species including one or more of Bacteroides spp., Gardnerella vaginalis, Mobil uncus spp., Mycoplasma hominis and Peptostreptococcus spp., Most commonly with G. vaginalis predominantly; and (c) protozoa, especially Trichomonas vaginalis. Candid infections, collectively referred to herein as vulvovaginal candidiasis (VVC), are the best-known cause of vaginitis and are believed to affect approximately 75% of women at least once during their lifetime. VVC is not usually transmitted sexually. Bacterial vaginosis (BV), a collective expression used herein for vaginal or vulvovaginal conditions caused by a bacterial infection, is generally considered a sexually transmitted disease although other means of transmission may occur. The symptoms of VVC and BV include irritation (manifesting, for example, as redness, burning and / or pruritus), dyspareunia and an abnormal discharge, which in the case of BV tends to have a fishy smell. Other criteria diagnoses include a lower vaginal pH of about 4.7 at VVC or greater than about 4.7 in BV, and the presence of "indicium cells" (epithelial cells that have a granular appearance) in BV. Typically, VVC is a nuisance, often very uncomfortable for the patient, but is relatively rarely involved in the development of more serious or life-threatening conditions. On the other hand, BV, if left untreated, can lead to serious conditions, such as cervicitis, pelvic inflammatory disease, cervical dysplasia, urinary tract infections, postoperative infections, increased susceptibility to viral infections, including HIV and HSV-2, and, in pregnant women, preterm delivery, preterm rupture of membranes, intra-fluid amniotic infection, preterm delivery and postpartum endometritis. Bacterial and candid infections can coexist. The mixed bacterial and candidiasic infection (in the present report "BV / VVC") occurs in up to about one fifth of the cases of vaginitis. For example, Redondo-Lopez et al. (1990), Sex. Transm. Dis. 17 (1): 51-53, reported that in 132 episodes of symptomatic vaginitis in 35 patients with recurrent symptoms, it was observed that 15% involved a mixed BV / VCV infection.

In another study, Ferris et al, (2002), Obstet. Gynecol. 99 (3): 419-425, reported that of 95 women who were about to be treated for VVC, it was confirmed that 34% had VVC alone, 19% had BV alone and 19% had a mixed BV infection. / VVC. A significant problem is that such mixed infections are underdiagnosed and self-medication or prescription treatment occurs as for fungal or bacterial infection alone. Both mushrooms, such as Candida to lbicans, as bacteria, such as Gardnerella vaginalis, are opportunistic pathogens, therefore, in the case of a mixed infection, the elimination of one can lead to the rapid development of the other's population. Thus, for example, a mixed infection of BV / VVC treated only topically with an antifungal agent such as butoconazole can rapidly become a serious BV infection, which then requires an antibacterial follow-up treatment, as an additional topical application. or a systemic therapy (for example, oral antibiotic). The implications of such misdiagnosis may not be trivial, especially considering the serious conditions to which the BV can lead if left untreated. Therefore, there is a need in the art for a medication and a method to use the same one that treats in a practical way and in an efficient way BV infections and mixed BV / VVC. U.S. Patent No. 4,551,148 to Riley et al. proposes a controlled release system for vaginal drug delivery, comprising unit cells having a non-lipoid internal phase and a continuous lipoidal external phase. An active agent is present at least in the internal phase. U.S. Patent No. 5,266,329 to Riley proposes a vaginal delivery system of this type having an antifungal imidazole, illustrated by metronidazole, as the active agent. Thompson & Levinson (2002), Drug Delivery Systems & Sciences 2 (1), 17-19, describes a bioadhesive topical drug delivery system known herein as the VagiSite system, which has a water-in-oil emulsion system with a high internal phase ratio, which provides a platform of supply for the administration of active pharmacological entities in the vaginal cavity. They describe that the VagiSite system is incorporated in Gynazole-1® antifungal vaginal cream, which contains 2% by weight of butoconazole nitrate.

U.S. Patent Application Publication No. 2003/0180366 to Kirschener et al. discloses a composition suitable for vaginal drug delivery, comprising an essentially pH neutral emulsion having an internal water-soluble phase and an external water-insoluble phase, wherein the internal phase comprises an acid buffered phase comprising a drug, which may be, by way of example, an antifungal agent or an antibacterial agent. Example I in that document provides such a composition comprising the antibacterial agent metronidazole in an amount of 0.75% by weight. Example II in that document provides such a composition comprising the antibacterial agent clindamycin phosphate in an amount of 2.8% by weight. U.S. Patent No. 5,055,303 to Riley discloses a solid composition, for example, a suppository, comprising a water-in-oil emulsion that can carry an active agent. It has been determined that the composition is suitable for insertion into a body orifice and that it melts at body temperature to form a cream having a controlled release and bioadherent properties.

U.S. Patent Application Publication No. 2003/0225034 to Floros et al. mentions that for the Treatment of vaginitis can be administered surfactant lipids together with one or more medications, including antibiotics and antifungals. Examples of antibiotics that are said to be suitable include ampicillin, ceftriaxone, clindamycin, metronidazole and tetracycline. Examples of antifungals that are said to be suitable include miconazole, clotrimazole, econazole, butoconazole, thioconazole and terconazole. SUMMARY OF THE INVENTION A pharmaceutical composition comprising (a) an antibacterial agent in an antibacterially effective amount is now provided; and (b) an antifungal agent in an antifungally effective amount. The composition is adapted for application to a vulvovaginal surface, for example, a vaginal mucosal surface and has at least one non-lipoid internal phase and at least one lipoidal external phase that is bioadhesive to that surface. In one embodiment, the antibacterial agent comprises clindamycin or a pharmaceutically acceptable salt or ester thereof, for example, clindamycin phosphate; and the antifungal agent comprises butoconazole or a pharmaceutically acceptable salt or ester thereof, for example, butoconazole nitrate.

The composition is typically a water-in-oil emulsion and may be presented by way of example in a semi-solid form described in the pharmaceutical art as a cream. There is further provided a vaginal antibacterial and antifungal delivery system comprising such a cream and an applicator to facilitate administration to a vaginal mucosal surface. In addition, a method for treating a mixed BV / VVC infection is additionally provided., the method comprising administering a pharmaceutical composition, as described herein, to a vulvovaginal surface, eg, a vaginal mucosal surface. In some embodiments, such a method can provide a "one dose for cure" treatment for the mixed infection. These and other embodiments are described in more detail in the following detailed description. DETAILED DESCRIPTION The particular form of a composition useful herein is not limited and may be, for example, a cream, a gel, a foam, a tablet, ovule or vaginal suppository, a tampon, an implant such as a ring, etc. However, a composition in the form of a water-in-oil emulsion as is generally described in any of US Pat. No. 4,551,148, U.S. Patent No. 5,055 is of particular interest herein. .303, U.S. Patent No. 5,266,329 or U.S. Patent Application Publication No. 2003/0180366 referred to above or as described hereinafter. Such a water-in-oil emulsion may be presented in a solid form, for example, as a vaginal suppository, or in a semi-solid form, for example, as a vaginal cream, and has bioadhesive properties. A "vulvovaginal surface" in the present specification indicates an external or internal surface of the female genitalia, including mucosal surfaces in the vaginal cavity and non-mucous surfaces of the vulva and of immediately surrounding areas of the skin. In some embodiments, the composition is more specifically adapted for application to a vaginal mucosal surface and the external phase of the composition is bioadhesive, ie mucoadhesive to such a surface. In one embodiment, the composition is formulated as a bioadhesive vaginal delivery system as described by Thompson & Levinson (2002), in the work cited with the name VagiSite or a vaginal delivery system substantially equivalent thereto, including as active agents an antibacterial agent and an antifungal agent. International Patent Publication No. WO 2005/087270, incorporated herein by reference but without admitting that it is a prior art of the present invention, mentions the VagiSite system as an option for the delivery of a combination of antivaginitis drugs. Bioadhesion, for example, to a surface of the vaginal mucosa, is an important property of the compositions of the invention. It is believed, without adhering to a theory, that bioadhesion allows a sustained and controlled supply of the antibacterial agent, the antifungal agent or both over time. The advantages over conventional vaginal delivery systems that show less or do not exhibit bioadhesion include one or more of: (a) minimization of composition loss from the application site; (b) suitability for the application at any time of the day, not being limited to bedtime; (c) decreased exposure to the active agent, in particular, systemic exposure, during the course of therapy; (d) decrease in the total active agent dose that provides an acceptable clinical response; (e) continuous release of the active agent for a prolonged period; (f) faster relief of symptoms; and (g) potential for single dose therapy. It is believed, without adhering to a theory, that the bioadhesive property of a composition of the invention resides, at least in part, in the lipoidal nature of the external phase of the composition, which repels moisture and, therefore, resists dilution and elimination by normal vaginal discharge. It is also believed, again without adhering to a theory, that the external lipoidal phase serves to sequester the internal phase not lipodea; in embodiments where the antibacterial agent, the antifungal agent or both are partially or completely present in the internal phase, the active agent loading is similarly sequestered, allowing the release of the active agent to slowly graduate over time . The bioadhesive and controlled release properties or sustained composition that incorporates a vaginal delivery system known as the Site Reléase® (SR) system useful herein has been demonstrated in studies summarized by Merabet et al. (2005), Expert Opin. Drug Deliv. 2 (4): 769-777, incorporated herein by reference but without admitting that they are antecedent technique of the present invention. A "conventional" vaginal cream, used, for example, as a comparative composition for evaluating a vaginal cream composition performing the SR cream, herein refers to a semi-solid emulsion having an aqueous or non-lipoidal continuous phase and a discontinuous or non-aqueous dispersed phase. or lipoidal, that is, an oil in water emulsion, in which the active agent is solubilized or dispersed in the continuous phase. Typically, this allows immediate contact of the active agent with the vulvovaginal surface to which the composition is applied, but also allows for dilution, rinsing and loss of composition from that surface, decreasing contact time with the surface and with the bacterial and / or fungal pathogens to which it is directed. Conventional vaginal creams comprising an antibacterial agent and / or an antifungal agent, therefore, must be administered generally repeatedly, for example, approximately 3 to 7 times per week, to provide a clinically acceptable response. Such repeated application increases the potential for systemic delivery of the active agent and, therefore, increases the potential for adverse side effects and also increases the likelihood of tissue irritation. Weinstein et al. (1994), Clin. Ther. 16 (6): 930-934, studied the retention time of vaginal creams containing 2% butoconazole nitrate. A total of 16 healthy women were treated intravaginally with a conventional vaginal cream or a SR bioadhesive cream and were monitored daily for 7 days to determine the amount of residual cream detected within the vaginal cavity using a gynecological swab. A mean retention time of 4.2 days was reported for the SR cream, compared with approximately 2.5 days for the conventional cream. Thomson and Levinson (2002), in the cited work, described a study in which 28 healthy women received intravaginal treatment with a conventional antifungal vaginal cream or a SR bioadhesive cream containing the same antifungal agent, in each case, as a single dose . The women carried minipills for a period of 48 hours to evaluate the loss of product from the vaginal cavity. At each time studied (3, 6, 24 and 48 hours after the administration), it was described that the loss of product was greater with the conventional cream than with the SR cream. Overall, the loss was reduced by more than 50% with the SR cream. Conventional vaginal creams commonly require application at bedtime to utilize the advantage of a patient's supine position for several hours, which can help retain the cream within the vaginal cavity. The bioadhesive property and the improved vaginal retention therefore of a vaginal cream of the invention can allow application at any convenient time of the day. Thomson and Levinson (2002), in the aforementioned work, also described in vitro analyzes of butoconazole nitrate release properties of a conventional vaginal cream and a cream that incorporates the SR system, using an acetate buffer of pH 4.3 designed to simulate the vaginal fluid. It was described that the conventional cream disintegrates rapidly and begins to release the active agent immediately, with substantially all the payload of the active agent being released in the range of 1 to 4 hours. On the contrary, it described that SR cream released the active agent continuously over approximately 7 days. The bioadhesive and sustained release properties of a vaginal cream of the invention may allow a relatively low dose of an active agent to provide a clinically acceptable response at least substantially equal to that provided by a much larger dose of the active agent administered in the form of a conventional cream. In particular, a single administration of a cream of the invention can provide a clinically acceptable response at least substantially equal to that provided by a conventional cream administered more than once, e.g., repeatedly from about 3 to about 7 times as over a week. In this regard, it is pointed out that adverse drug reactions are generally dose-related, with the appearance of new adverse effects or the exacerbation of existing adverse effects when the dose is increased. Therefore, a composition of the invention has the potential to provide an improved safety profile. This is especially true with respect to the adverse effects resulting from the systemic supply. The dosage effect of the drug with a sustained release profile allowed by the present compositions the systemic delivery tends to decrease, although it still provides a therapeutically effective delivery at the site of administration. A composition of the invention comprises, typically, a multiplicity of unit cells, which are the basic repeating units of the delivery system and are not divisible without losing at least some of the useful properties herein. Each unit cell has internal and external phases, corresponding to the internal and external phases of the composition referred to above. The compositions of the invention can be described using conventional classifications, for example, as emulsions, emulsions / dispersions, double emulsions, suspensions within emulsions, suppositories, foams, creams, ovules, inserts, etc. The usual compositions of the invention are in the form of water-in-oil emulsions having a medium to high internal phase ratio (expressed as a percentage of the total volume occupied by the internal phase), for example, greater than about 60% , greater than about 70% or greater than about 75% by volume. The compositions of the invention include liquids or semi-solids having a viscosity of about 5,000 to about 1,000,000 centipoise, for example, from about 100,000 to about 800,000 centipoise. In certain embodiments, the composition is a vaginal cream having a viscosity of about 5,000 to about 750,000 centipoises, for example, from about 350,000 to about 550,000 centipoises. Generally, a vaginal cream is a semi-solid water-in-oil emulsion and comprises an emulsifying agent. It is believed, without being bound by theory, that the bioadherence of the composition to the vulvovaginal surface, for example, the vaginal mucosal surface, requires that the composition have sufficient viscosity to retain its integrity when applied to such a surface. Optional ingredients that can increase viscosity, among other properties, include microcrystalline wax, colloidal silicon dioxide and various pharmaceutically acceptable polymers including polysaccharides, cellulosic polymers such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, etc., polyethylene glycol, acrylate polymers and the like. Solid compositions comprising a water-in-oil emulsion typically melt at the temperature temporary to form a bioadhesive cream substantially as described above. The internal phase is typically discontinuous and, as indicated above, is non-lipoidal. The non-lipoid character of the internal phase makes it miscible with water. By way of example, the internal phase comprises water, glycerin, propylene glycol, sorbitol or a combination of two or more thereof. Generally, the internal phase has a high osmotic pressure. The internal phase can be by itself monophasic, biphasic or multiphasic, adopting the form, for example, of a solution, suspension, emulsion or combination thereof. The internal phase optionally comprises one or more suspended solids, emulsifying and / or dispersing agents, osmotic enhancers, crosslinkers, diluents, buffering agents, chelating agents, preservatives, fragrances, colors and other materials. Optionally, the internal phase is buffered with acid to an internal pH of from about 2.0 to about 6.0, for example, from about 2.5 to about 5.5 or from about 3.5 to about 5.0. In one embodiment, the internal phase is buffered with acid to an internal pH that is substantially optimal for the vaginal environment, i.e., a pH that does not cause irritation, itching or other substantial discomfort and / or makes the vaginal environment less favorable for common pathogens including fungal and bacterial pathogens. Typically, said pH is from about 4.0 to about 5.0, for example about 4.5. The external phase is typically continuous (in such systems, the adjacent unit cells have common external phases) and, as indicated, is lipoidal. The term "lipoid" herein may concern any of a group of organic compounds including neutral fats, fatty acids, waxes, phosphatides, petrolatum, fatty acid esters of monoprotic alcohols, mineral oils, etc. that has the following properties: insoluble in water; soluble in alcohol, ether, chloroform and other fatty solvents; and that shows an oily appearance. Examples of suitable oils are mineral oils having a viscosity of about 5.6 to about 68.7 centistokes, for example, about 25 to about 65 centistokes, and vegetable oils such as coconut oils, palm kernel oil, butter cocoa, cottonseed, peanut, olive, palm, sunflower, sesame, corn, safflower, rapeseed (rapeseed) and soybean and fractionated liquid triglycerides of short-chain fatty acids of natural origin. The term "lipoid" may also refer to amphiphilic compounds, including, for example, natural and synthetic phospholipids. Suitable phospholipids may include, for example, phosphatidylcholine esters such as dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC).; phosphatidylethanolamine esters such as dioleylphosphatidylethanolamine and dipalmitoylphosphatidylethanolamine (DPPE); phosphatidylserine; phosphatidylglycerol; phosphatidylinositol; etc. In one embodiment, the external phase comprises a phospholipid component, for example, a lecithin component, more particularly, a refined lecithin component. Without being bound by theory, it is believed that refined lecithins or other phospholipid materials can remain at the oil-water interface of a water-in-oil emulsion and confer improved stability to the emulsion, especially when an active agent is present which It has surfactant properties that tend to alter the stability of the emulsion. A preferred lecithin comprises not less than about 70%, for example, not less than about 80% phosphatidylcholine. Content Phosphatidylcholine from lecithin can be as high as approximately 93% or even higher. Food grade lecithin can not be considered acceptable in specific formulations. An example of a refined lecithin that is generally suitable is Phospholipon 90 ™, available from American Lecithin Co. The amphiphilic compounds other than phospholipids may also optionally act together with a phospholipid as emulsifying agents in a composition of the invention. Any pharmaceutically acceptable emulsifying agent or combination thereof including, but not limited to, medium and long chain monoglycerides and diglycerides, such as glyceryl monooleate, glyceryl monostearate, glyceryl monoisostearate and glyceryl monopalmitate, polyglyceryl esters of acids, may be used. fatty acids, such as polyglyceryl-3 oleate and polyethylene glycol esters and diesters of fatty acids such as dipolyhydroxy-stearate PEG-30. Said agents can also function as emollients in the composition. Emulsifying agents soluble in the external phase are generally preferred. In one embodiment, a mixture of mono and diglycerides alone or with the addition of a metallic soap such as aluminum stearate is used.

The water-in-oil emulsion compositions of the invention are typically deformable at physiological temperatures (about 37 ° C) although, unlike conventional creams, they do not rapidly lose their integrity upon application to a vaginal mucosal surface. In general, therefore, they do not result in offensive or otherwise unacceptable losses from the vaginal cavity after administration. Since the physical decomposition of said compositions occurs over a prolonged period, the non-aqueous components are absorbed or released from the vaginal cavity at a generally undetectable rate, without constituting a substantial increase with respect to the normal rates of vaginal secretion. The release of the antibacterial agent, the antifungal agent or both from a composition of the invention can occur by one or more mechanisms, none of which is limiting of the present invention. Such mechanisms can include diffusion, for example, from the internal phase through the external phase to the vaginal mucosa; the rupture of the unit cells; the dissolution of solid particulates, etc. The release dynamics can be linear or non-linear.

Composition factors that affect the rate of release of each active agent may include relative amounts of the active agent present in the internal and external phases; the internal phase proportion; osmotic pressure of the internal phase; pH of the internal phase; selection and relative amounts of lipoid compounds, including amphiphilic compounds and the external phase, influence of the diffusibility of each active agent inside; particle size where the active agent is in the form of a solid particulate; viscosity of the composition; etc. Each of these factors can be routinely modified by one skilled in the art based on what is described herein to optimize the release rate for specific situations. In a composition having the active agent in the internal phase and having a relatively small internal phase ratio, the external phase tends to form a relatively thick membrane through which the second active agent must pass to be released; consequently, the rate of release can be significantly slowed down in said composition. Physiological factors that affect the rate of release of each active agent include factors that affect the rate of physical degradation or loss of integrity of the composition such as amount of and chemical nature of the fluids and enzymes, pH, chemical equilibrium, temperature and shear forces that arise from the movement of the body. It is believed that shear forces do not affect the integrity of the compositions of the invention as rapidly or severely as in the case of conventional vaginal creams. The composition is typically adapted to release the antibacterial agent, the antifungal agent or both for a period of about 3 hours to about 10 days, after application to a vulvovaginal surface, for example, a vaginal mucosal surface. Based on the description of this specification, including the document description incorporated by reference thereto, in particular the aforementioned U.S. Patent Nos. 4,551,148 and 5,266,329, U.S. Patent Application Publication No. 2003/0180366 and the main application of this partial continuation (published as U.S. Patent Application Publication No. 2005/0095245 although not admitted as a prior art for the present invention), one skilled in the art without too much experimentation can adjust the release rate of each active agent in the composition for get a release period of about 3 hours to about 10 days. In various embodiments, the release period is from about 12 hours to about 10 days, from about 1 to about 10 days, from about 2 to about 10 days, or from about 3 to about 7 days. Therefore, a wide range of release profiles for each active agent is possible. In one embodiment, at least one of the active agents exhibits, on day 1 after administration, from about 2% to about 25% release; at 2 days after administration, from about 15% to about 50% release; at 3 days after administration, from about 25% to about 75% of the release; and at 4 days after administration, approximately 45% to 100% release. The rate of release can be determined by in vivo tests or by any suitable in vi tro method. An illustrative in vi tro method uses an open chamber diffusion cell system such as a Franz cell system, typically fitted with a membrane suitable inert synthetic such as polysulfone, mixed ester of cellulose acetate / nitrate or polytetrafluoroethylene of suitable thickness, for example, 70 μm. The receptor medium must be one in which the active agent of interest is soluble, for example, a water / ethanol medium. A test composition is uniformly placed on the membrane (illustratively, about 300 mg of a semi-solid composition such as a cream constitutes an amount suitable for placement in a membrane of 25 mm diameter) and is kept occluded to avoid evaporation of the membrane. solvent and composition changes. This corresponds to an infinite dose condition. An aliquot of the receptor fluid is removed for analysis at appropriate intervals and replaced with an aliquot of fresh receptor fluid, so that the membrane remains in contact with the receptor fluid throughout the period of the release study. A release rate study such as that described above is typically replicated and can be performed using a standard composition having known release properties for comparison. A "release period" or equivalent expression is referred to herein as a period during which the active agent becomes available for absorption and pharmacological effect (in the present case, antibacterial or antifungal), said effect typically occurring at or near the site of absorption, for example in the vaginal cavity. In this manner, the "release period" begins when the release substantially begins (eg, immediately to about 1 hour after administration or later in the case of a delayed release composition) and ends when there is substantially no more agent active available for release (eg, from about 3 hours to about 10 days after the start of the release period). The antibacterial agent, the antifungal agent or both may be present in one or both of the internal and external phases. In one embodiment, both agents are present at least in part in the internal phase of the composition and may be in dispersed form, for example, in solution or suspension therein, or in undispersed form. Optionally, substantially all of the antibacterial agent and / or substantially all of the antifungal agent may be present in the internal phase. The solubilization of one or both agents can be achieved, for example, by using a cosolvent and / or surfactant. Some agents, for example, the antibacterial agents metronidazole and phosphate clindamycin, are easily soluble in water or are easily solubilized and said agents are present, typically, at least in part in solution in the internal phase. Habitually, however, one or both agents may be present at least in part in the form of particulates, for example, in micronized form or in the form of nanoparticles and may be dispersed as a particulate suspension in the internal and / or external phase. In various embodiments, the antibacterial agent, the antifungal agent or both are present in aggregates or liposomes within the internal and / or external phase. In compositions having one or both active agents in solid particulate form, any suitable particle size can be used. Typically, however, it can be difficult to achieve good physical stability where a substantial part of the particles of any agent is greater than about 250 μm in diameter. Thus, a Dgo particle size (in which 90% by weight of the particles are smaller than the specified size) not greater than about 250 μm is generally desirable for the antibacterial agent and the antifungal agent. Preferably, at least 99% by weight of the particles are not greater than about 250 μm in diameter.

Particle sizes less than about 5 μm may be useful although the expense of particle size reduction may not be justified by some improvement in the stability or effectiveness of said particle sizes. Regardless, particle sizes of less than 0.4 μm (400 nm) or even less than 50 nm can be used if desired. The antibacterial agent can comprise any antibacterial known in the art that is useful in the treatment of bacterial infections of the vulvovaginal system. The antibacterial can be one directed predominantly to a particular category of pathogenic bacteria, eg, aerobic, anaerobic, gram-negative, gram-positive, etc. Illustrative examples of antibacterials that may be useful include, without limitation, acriflavine, ampicillin, ceftriaxone, chloramphenicol, chlorquinaldol, clindamycin, iodoquinol, metronizadol, nimorazole, ornidazole, pivampicillin, secnidazole, spiramycin, tetracycline, tinidazole, pharmaceutically acceptable salts and esters of the same, mixtures thereof and the like. In one embodiment, the antibacterial agent comprises or consists essentially of clindamycin, or a pharmaceutically acceptable salt or ester of it, for example, clindamycin hydrochloride or clindamycin phosphate. In a particular embodiment, the antibacterial agent comprises or consists essentially of clindamycin phosphate. The antibacterial agent is present in the composition in an antibacterially effective amount. The amounts of clindamycin or a salt or ester thereof is expressed herein as equivalent amounts of clindamycin (free base) unless otherwise indicated by the context. Any antibacterially effective amount of clindamycin or salt or ester thereof may be used, but typically an amount equivalent to clindamycin of from about 0.5% to about 6% by weight, for example, will be found useful in a vaginal cream preparation. , from about 1% to about 3% by weight. The antifungal agent can comprise any antifungal known in the art which is useful in the treatment of fungal infections, especially candidiasias, of the vulvovaginal system. Illustrative antifungal agents include, without limitation, atovaquone, griseofulvin, nystatin, polymyxin B, terbinafine, and imidazole and triazole compounds such as butoconazole, clotrimazole, econazole, fluconazole, isoconazole, itraconazole, ketoconazole, miconazole, oxiconazole, ravuconazole, saperconazole, sertaconazole, sulconazole, terconazole, thioconazole, voriconazole, pharmaceutically acceptable salts and esters thereof, mixtures thereof and the like. In one embodiment, the antifungal agent comprises or consists essentially of butoconazole or a pharmaceutically acceptable salt or ester thereof. In a particular embodiment, the antifungal agent comprises or consists essentially of butoconazole nitrate. The antifungal agent is present in the composition in an antifungally effective amount. The amounts of butoconazole or of a salt or ester thereof are expressed herein as equivalent amounts of butoconazole nitrate unless otherwise indicated by the context. Any antifungally effective amount of butoconazole or a salt or ester thereof may be used, but an equivalent amount of butoconazole nitrate of about 0.5% to about 6% by weight will typically be useful in a vaginal cream preparation, for example, from about 1% to about 3% by weight. Those skilled in the art will understand that the "Antibacterial" or "antifungal" terms, applied to an active agent herein, are not necessarily mutually exclusive. A particular agent can show, to some degree, both antifungal and antibacterial activity. Some agents, for example, certain imidazoles including metronidazole, are used herein primarily for their antibacterial activity, but also possess a useful degree of antifungal activity (including anti-calycease) and, in some cases, antiprotozoal (including antithrombomyotic). When such an agent is included in a composition of the invention as an antibacterial agent, therefore, some additional benefits in complementing the activity of an antifungal agent (eg, butoconazole) against a fungal pathogen such as C. albicans. In one embodiment, an active agent, e.g., antibacterial metronidazole, is present at least in a substantial part in the internal phase of the composition and is substantially solubilized therein, and another active agent, e.g., butoconazole nitrate antifungal, is also present at least in a substantial part in the internal phase but is substantially in particulate form and Suspended therein A particular example of a vaginal cream composition of the invention comprises clindamycin phosphate in an equivalent amount of clindamycin of about 2% by weight and butoconazole nitrate in an amount of about 2% by weight. The composition has (i) at least one non-lipoidal internal phase, (ii) at least one lipoidal external phase that is bioadhesive to a vaginal mucosal surface; and (iii) an emulsifying agent, for example, comprising a phospholipid. Clindamycin phosphate and butoconazole nitrate are present in at least a substantial part of the internal phase. Another particular example of a vaginal cream composition of the invention comprises metronidazole in an amount of about 0.75% by weight and butoconazole nitrate in an amount of about 2% by weight. The composition has (i) at least one non-lipoidal internal phase, (ii) at least one lipoidal external phase that is bioadhesive to a vaginal mucosal surface; and (iii) an emulsifying agent, for example, comprising a phospholipid. Clindamycin phosphate and butoconazole nitrate are present in at least a substantial part of the internal phase.

By way of example, the excipient ingredients in a vaginal cream composition of the invention may include water, sorbitol (eg, in the form of a sorbitol solution), lecithin, at least one long chain monoglyceride, eg, monooleate of glyceryl, glyceryl monostearate, glyceryl monoisostearate or glyceryl monopalmitate, at least one polyglyceryl or polyethylene glycol fatty acid ester, for example, polyglyceryl-3-oleate or PEG-30 dipolyhydroxystearate, a chelating agent, for example, edetate disodium , at least one antimicrobial preservative, for example, methylparaben and / or propylparaben, mineral oil and microcrystalline wax. A unit dosage amount of a composition of the invention is an amount suitable for a single administration to a vulvovaginal surface, for example, a vaginal mucosal surface, as described herein. In a much more practical way for the patient, the composition is provided in aliquots of unit doses, typically individually packaged, but this is not a requirement of the present invention. A convenient unit dose aliquot of a vaginal cream is an amount of about 1 to about 10 g, although if desired it can be used larger or smaller amounts, for example, as small as about 0.1 g or as large as about 25 g. A particularly suitable unit dosage amount of a vaginal cream is from about 3 to about 6 g, e.g., about 5 g. When a unit dosage amount is less, it may be desirable to increase the concentration of active agent in the composition and vice versa. Practically, a unit dosage amount of a vaginal cream of the invention can be provided in a pre-filled container or applicator, for example, an applicator similar to that used for the Gynazole-1® vaginal cream from KV Pharmaceutical Co. , St. Louis, MO. An antibacterial and antifungal delivery system comprising a vaginal cream composition of the invention, for example, a disposable applicator, more particularly a disposable applicator pre-filled with a unit dosage amount of the composition, is an embodiment of the invention. A composition of the invention can be prepared in the form of a vaginal cream by discontinuous or continuous processes known for preparing pharmaceutical creams. As in the preparation of conventional emulsions, it is applied shear force to the components using a mixer, homogenizer, mill, shock surface, ultrasound, agitation or vibration. However, unlike conventional emulsions, the water-in-oil emulsions of the invention should normally be prepared using shear mixing at a relatively low level to avoid destruction of the emulsion by an excess of energy. As an example, the internal and external phases are prepared first of all separately. In a typical batch process, the internal phase is added to the external phase while mixing in a planetary or other suitable mixer until a stable emulsion is formed. Addition rates and mixing rates can be adjusted to optimize the formation and viscosity of the emulsion. In a typical continuous process, the external phase is introduced into a continuous mixer comprising a plurality of vanes, until it reaches the level of the lower vane in the mixing chamber. The two phases are then introduced simultaneously through the bottom of the mixer in a suitable proportion as the blades rotate to apply shear to the components. The finished emulsion emerges through the top of the mixer. The flow through the mixing chamber and the Mixing speed can be adjusted to optimize the formation and viscosity of the emulsion. A composition of the invention can be administered typically to external surfaces of the vulva and / or to surrounding areas of the skin. In addition or as an alternative, the composition can be administered intravaginally. In one embodiment, the composition is a vaginal cream and is administered intravaginally in a unit dosage amount, as defined above, to a vaginal mucosal surface. A vaginal cream of the invention can be administered to contact a mucosal surface in the vaginal cavity by, for example, an applicator that is optionally preloaded with a single unit dosage amount of the cream. With the patient in a supine position, the tip of the applicator can be gently inserted deep into the vagina, for example, into the posterior vaginal cul-de-sac, and the cream can be released at the tip by pressing on a plunger of the applicator. One method of the invention for treating a BV / VVC mixed infection comprises administering a pharmaceutical composition, e.g., a vaginal cream composition, as described herein, to a surface vulvovaginal, for example, a surface of the vaginal mucosa. Such a method can also be used to treat a secondary condition arising from a mixed infection of that type. Such a method may involve the repeated administration of a unit dosage amount of the composition until a clinically acceptable response is obtained; however, an advantage of at least some compositions of the invention with respect to conventional vaginal creams is that often a clinically acceptable response can be obtained with a single administration. A method in which a single administration of a unit dosage amount provides a clinically acceptable response is often referred to as a "one dose for cure" therapy, but it will be understood that the term "cure" in the present context is not It necessarily refers to the total or permanent elimination of the infection or the total or permanent relief of all symptoms. A clinically acceptable response or "cure" herein may be evidenced, by way of example, by one or more of the following results: (a) resolution of the four clinical "Amsel criteria", namely, normal vaginal discharge , vaginal pH < 4.7, < 20% of indicator cells in a wet preparation and "hiff" test (negative test), as described by Amsel et al. (1983) Am. J. Med. 74: 14-22; (b) a "Nugent score" < 4 by the gram stain interpretation method of Nugent et al. , (1991), J.

Clin. Microbiol. 29: 297-301; and (c) a negative response from a physician to the question: "In your opinion, does the patient require additional treatment for BV / VVC at this time?". In one embodiment, a therapeutic method using a composition of the invention provides, by a single administration, a "cure" rate at least substantially equal to that provided by from about 3 to about 7 applications of a conventional vaginal cream composition. which contains the same antibacterial and antifungal agents at the same concentration as the composition of the invention, over a week. A method of the invention can be used for the treatment of any combination of bacterial and fungal infections present in the vulvovaginal system, including, without limitation, infections that involve: (a) fungi, more particularly yeast, especially Candida spp., including one or more of C. albicans, C. dubliniensis, C. glabra ta, C. kefyr, C. krusei, C. lusi taniae, C. neoformans, C. parasilopsis and C. tropi calis, those that the most common is C. albicans; and (b) bacteria, commonly a diversity of species including one or more of Bacteroides spp., Gardnerella vaginalis, Mobiluncus spp., Mycoplasma hominis and Peptostreptococcus spp., Most commonly with G. vaginalis predominantly. An additional list of bacterial species identified in women with BV has been described by Fredricks et al. (2005) N. Engl. J. Med. 353: 1899-1911, incorporated herein by reference but without admitting that it is antecedent technique of the present invention. EXAMPLES The following examples are illustrative only and do not limit this description in any way. The vaginal cream compositions detailed below can be prepared by any method known in the art for preparing semi-solid emulsions, including batch and continuous processes as described hereinabove.

Example 1: Vaginal cream, clindamycin + butoconazole * equivalent to 2.00% clindamycin Example 2: Vaginal cream, metronidazole + butoconazole All patents and publications cited herein are incorporated by reference in this application in their entirety. The words "comprise" or "comprise" and "comprising" must be interpreted as inclusive rather than exclusive.

Claims (36)

1. The use of a pharmaceutical composition comprising: (a) an antibacterial agent in an antibacterially effective amount, and (b) an antifungal agent in an antifungally effective amount; in the preparation of a medicament for administration to a vulvovaginal surface to treat a mixed infection of bacterial vaginosis and vulvovaginal candidiasis; wherein the composition has at least one non-lipoidal internal phase and at least one lipoidal external phase that is bioadhesive to the vulvovaginal surface.

2. The use of claim 1, wherein the antibacterial agent comprises clindamycin or a pharmaceutically acceptable salt or ester thereof.

3. The use of claim 1, wherein the antifungal agent comprises butoconazole or a pharmaceutically acceptable salt or ester thereof.

4. The use of claim 1, wherein the internal phase of the composition is buffered with acid to an internal pH of about 2.0 to about 6.0.

5. The use of claim 1, wherein the internal phase of the composition is acid buffered to an internal pH that is substantially optimal for the vaginal environment.

6. The use of claim 1, wherein the vulvovaginal surface to which the composition is administered is a vaginal mucosal surface.

7. The use of claim 6, wherein after application of the composition to the vaginal mucosal surface, the antibacterial and antifungal agents each have a release period of from about 3 hours to about 10 days.

8. The use of claim 6, wherein after the application of the composition to the vaginal mucosal surface, the antibacterial and antifungal agents each have a release period of from about 12 hours to about 10 days.

9. The use of claim 6, wherein at least one of said agents shows, on day 1 after administration, from about 2% to about 25% release; at 2 days after administration, from about 15% to about 50% release; at 3 days after administration, from about 25% to about 75% of the release; and at 4 days after administration, approximately 45% to 100% release.

10. The use of claim 6, wherein the composition is in the form of a vaginal cream.

11. The use of claim 10, wherein the antibacterial agent comprises clindamycin or a pharmaceutically acceptable salt or ester thereof, and the antifungal agent comprises butoconazole or a pharmaceutically acceptable salt or ester thereof.

12. The use of claim 11, wherein the clindamycin or salt or ester thereof is present in an equivalent amount of clindamycin from about 0.5% to about 6% by weight.

13. The use of claim 11, wherein the clindamycin or salt or ester thereof is present in an equivalent amount of clindamycin from about 1% to about 3% by weight.

14. The use of claim 11, wherein the butoconazole or the salt or ester thereof is present in an equivalent amount of butoconazole nitrate of from about 0.5% to about 6% by weight.

15. The use of claim 11, wherein the butoconazole or the salt or ester thereof is present in an equivalent amount of butoconazole nitrate of from about 1% to about 3% by weight

16. The use of claim 10, wherein the antibacterial agent comprises clindamycin phosphate and the antifungal agent comprises butoconazole nitrate.

17. The use of claim 10, wherein the composition is applied in a single effective dosage amount to provide an acceptable clinical response.

18. The use of claim 17, wherein the single dosage amount is from about 1 to about 10 g.

19. The use of claim 17, wherein a single dosage amount of about 5 g of a vaginal cream composition comprising clindamycin phosphate in an equivalent amount of clindamycin of about 2% by weight and butoconazole nitrate in an amount about 2% by weight is administered to a vaginal mucosal surface; the vaginal cream composition (i) having at least one non-lipoidal internal phase, (ii) at least one external lipoidal phase which is bioadhesive to the vaginal mucosa surface; and (iii) an emulsifying agent; where clindamycin phosphate and butoconazole nitrate are present at least in a substantial part in the internal phase.

20. The use of claim 17, wherein the emulsifying agent comprises a phospholipid.

21. A pharmaceutical composition comprising: (a) clindamycin or a pharmaceutically acceptable salt or ester thereof in an equivalent amount of clindamycin from about 0.5% to about 6% by weight of the composition; (b) butoconazole or a pharmaceutically acceptable salt or ester thereof in an equivalent amount of butoconazole nitrate of from about 0.5% to about 6% by weight of the composition; the composition being a vaginal cream having at least one non-lipoid internal phase and at least one lipoidal external phase that is bioadhesive to a vaginal mucosal surface.

22. The composition of claim 21, wherein after application of the composition to a vaginal mucosal surface, clindamycin and butoconazole each have a release period of from about 3 hours to about 10 days.

23. The composition of claim 21, wherein after application of the composition to a vaginal mucosal surface, clindamycin and butoconazole each have a release period of approximately 12 hours to approximately 10 days.

24. The composition of claim 21, wherein at least one of clindamycin and butoconazole shows, on day 1 after administration, from about 2% to about 25% release; at 2 days after administration, from about 15% to about 50% release; at 3 days after administration, from about 25% to about 75% of the release; and at 4 days after administration, approximately 45% to 100% release.

25. The composition of claim 21, wherein the clindamycin or salt or ester thereof is present in an equivalent amount of clindamycin from about 1% to about 3% by weight.

26. The composition of claim 21, wherein the butoconazole or the salt or ester thereof is present in an equivalent amount of butoconazole nitrate of from about 1% to about 3% by weight.

27. The composition of claim 21, wherein clindamycin is present in the clindamycin phosphate form and butoconazole is present in the butoconazole nitrate form.

28. The composition of claim 21, wherein the internal phase is acid buffered to an internal pH of from about 2.0 to about 6.0.

29. The composition of claim 21, wherein the internal phase is acid buffered to an internal pH that is substantially optimal for the vaginal environment.

30. The composition of claim 21, comprising clindamycin phosphate in an equivalent amount of clmdamicin of about 2% by weight and butoconazole nitrate in an amount of about 2% by weight, composition (i) having at least one non-lipoid internal phase, (n) at least one external lipoidal phase that is bioadhesive to the vaginal mucosa surface; and (m) an emulsifying agent; wherein the clmdamicin phosphate and the butoconazole nitrate are present at least in a substantial part in the internal phase.

31. The composition of claim 30, wherein the emulsifying agent comprises a phospholipid.

32. An antibacterial and antifungal vaginal delivery system comprising the composition of claim 21 and an applicator.

33. The delivery system of claim 32, wherein the applicator is disposable.

34. The delivery system of claim 32, wherein the applicator is preloaded with a quantity of unit dose of the composition.

35. The delivery system of claim 34, wherein the amount of unit dose of the composition is from about 1 to about 10 g.

36. The delivery system of claim 34, wherein the amount of unit dose of the composition is from about 3 to about 6 g.