KR20040012779A - Composition comprising antifungal agents for treating vulvovaginitis and vaginosis - Google Patents

Abstract

The present invention relates to compositions and methods for treating vulvovaginitis and vaginosis. The compositions of the present invention include not only antifungal agents, but also buffer systems that maintain a pH to create a beneficial environment that helps the flora grow properly when administered to the vagina of the patient. Useful antifungal agents in the compositions of the present invention include azole antifungal agents. The buffer system comprises gluconodeltalactone.

Description

Composition comprising antifungal agents for treating vulvovaginitis and vaginosis

This application is filed on March 28, 2002, based on U.S. Provisional Patent Application No. 60 / 287,942, filed May 1, 2001 (Agency Ref. No. PPC 833) (provisional application). This is not part of the continuous application.

Field of invention

The present invention relates to compositions and methods of treatment for treating vulvitis and vaginosis using antifungal agents in pharmaceutically acceptable buffer compositions. Such antifungal agents may be applied or intravaginally administered to the vaginal and vulvar regions of vulvitis patients to alleviate the symptoms and to treat vulvitis, vaginal candidiasis and / or bacterial vaginosis in optimal conditions.

Background of the Invention

Bacterial vaginosis is a change in flora, the cause of which is still unknown in most cases. Bacterial vaginosis has generally been used to indicate changes in the vaginal flora that cause the assumed loss of lactobacillus. However, whether such flora is genetically normal in quality in all women is insufficiently defined. Most of the recommended therapies for bacterial vaginosis in infertile women are often successful in the short term, but usually not successful in the case of long term treatment. Bacterial vaginosis is generally thought to be an endogenous disease, but various behavioral factors may be involved, such as the use of contraceptives and personal hygiene products and lifestyles. Bacterial vaginosis is not considered to be a true sex-borne infection but can be associated with a number of sex partners. Therefore, there is a growing demand for the development of products that are effective against bacterial vaginosis and other vaginal disorders.

Often, patients mistakenly think that their vaginal infections are a type of fungal infection, such as Candida albicans, which can be treated with over-the-counter (OTC) antifungal products. However, these OTC antifungal products are not effective treatments for bacterial vaginosis, and the chronic condition of bacterial vaginosis is estimated to be much more common than candidiasis.

Vulvaritis (vulvar candidiasis or VVC) due to fungal infections is usually treated with azole antifungal agents administered intravaginally or orally. Intravaginally administered azole antifungal drugs in semisolid or solid dosage forms usually maintain their effective concentrations in the vagina for several days. For example, Odds, F.C. and MacDonld, F., Br. J. Vener. Dis., 57: 6, pages 400-401, Dec., 1981, reported that bioconcentration of myconazole in vaginal secretions obtained from 16 healthy women aged 20 to 27 years for at least 48 hours after insertion of a single myconazole vasculature. It is reported that it is maintained at the possible concentration. Daneshmend, TK (J. Antimicrob, Chemother., 18: 4, pages 507-511, Oct, 1986) is a healthy female 11 hours after insertion of a single 1200 mg vaginal pessary. Serum concentrations of myconazole were measured in persons. The average elimination half life was found to be 57 hours. Myconazole half-life after intravenous administration is only 24 hours [Janssen, F.A.J. and Van Bever, W.F.M. in Pharmacological and Biochemical Properties of Drug Substances, Vol. 2, Goldberg, M.E. Ed., Am. Pharm. Assoc. Acad. Pharm. Sci., Pages 336-337], the results of vaginal administration of daneshmend indicate that the concentration of myconazole remaining in the vagina after intravaginal administration can last for at least 5 days.

An effective and over-the-counter azole antifungal agent for vulvovaginitis caused by Candida albicans is a good candidate to be formulated as a product for the treatment of bacterial vaginosis and is a compound such as myconazole, especially active in the vaginal pH environment. . The effects of selected azole compound (s) can be enhanced and the environment controlled to mitigate microbial growth. The present invention describes formulations comprising a buffered myconazole nitrate system for treating VVC, bacterial vaginosis, or VVC / bacterial vaginal complex infections.

Under stable conditions, lactobacillus, found primarily in normal vagina, inhibits the growth of anaerobic and other bacteria by producing hydrogen peroxide and lactic acid from vaginal glycogen to keep the vagina acid. It is considered normal for the pH of the vagina of a woman having a menstrual cycle to be 4-5. Bacterial vaginosis is one of the most common infectious diseases affecting women and accounts for 45% of symptomatic cases and is present in 15% of asymptomatic sexually active women.

Clinically, bacterial vaginosis is a multi-microbial vaginal infection caused by an increase in the number of anaerobic microorganisms resulting in a relatively reduced vaginal lactobacillus. Diagnosis of bacterial vaginosis is based on several manifestations: i) dilute homogeneous discharge, ii) elevated vaginal pH (> 4.5), iii) fishy smell from vaginal discharge, and iv) a) 10% potassium hydroxide (amine). Some specific criteria such as testing and the presence of b) labeled cells. Currently, only two compounds, metronidazole (MetroGel-Vaginal ^R ) or clindamycin (Cleocin ^R ), have been used to treat bacterial vaginosis locally. These two compounds are classified as antibacterial agents and metronidazole is also an antiprotozoal agent. These can only be purchased with a prescription. Since bacterial vaginosis is a life-free disease and self-diagnosis is not clearly identified, consumers have two options for treating their bacterial vaginal infections: i) Wait days or even weeks for a doctor's diagnosis. Or ii) self-treat the infection with an OTC product.

The likelihood of misdiagnosis by self-diagnosing women or even doctors is very high. In general, self-treatment with OTC antifungal products can treat VVC in women with multiple infections, but they are likely to continue with symptoms. Moreover, such coexisting infections require clinical and research assessments as well as treatment that takes into account all aspects of disease symptoms.

In addition, the study revealed that about 15-30% of patients with BV may experience VVC infection after treatment due to changes in normal vaginal flora. Thus, there is a great need for a single product or treatment regimen that can treat bacterial vaginosis while preventing future fungal overgrowth.

U.S. Patent 5,536,743, for example, describes buffered metronidazole containing compositions. However, the composition only treats bacterial vaginosis because metronidazole is effective only against bacteria and not against fungi.

Vaginal pH is known to be an important factor in maintaining a healthy vaginal ecology. To compare the effect of polycarbophil, a gel-type bioadhesive polymer, on the recovery of physiological vaginal pH in women with vaginal pH above 4.5 and suspected of bacterial vaginosis, compared with the effect of acid vaginal douche. The study was performed by Milani et al. Of Mipharm SpA, Milan, Italy. Both physical and microbiological signs of bacterial vaginosis were improved in the polycarbophil group. Vaginal polycarbophil gels have been shown to reduce vaginal pH rise to physiological levels for 80 hours and to reduce vaginal pH in women suspected of bacterial vaginosis compared to acidic vaginal lavage. However, the study does not mention a means of treating mixed infections.

Products marketed in Mexico to treat both VVC and BV contain two active ingredients, for example itraconazole and secnidazole. As such, this product contains one active ingredient for treating fungal infections and one active ingredient for treating bacterial infections. The combination product may be insufficient for sequential infection treatment in case of bacterial infection following fungal infection or when the fungal component of the mixed infection is not blocked by vaginal infection treatment. This therapy also requires two active ingredients in one product to treat both infections.

Therefore, there is a need for a doctor-free product that is effective in treating both vulvitis and bacterial vaginosis simultaneously or sequentially.

Summary of the Invention

The compositions and methods of the present invention are directed to products containing antifungal compounds, active buffer compounds and pharmaceutically acceptable carriers. The buffered compositions of the present invention are expected to have surprising effects in treating both fungal infections and bacterial vaginosis. The pH of the composition of the present invention is preferably maintained at about 2.5 to about 5.5. More preferably, the pH should be maintained at about 3 to about 5, most preferably about 3 to about 4.5. In this pH range, both the antifungal compound and the vaginal environment serve to treat and prevent fungal and bacterial vaginosis infections.

The buffer according to the invention can be applied to the vagina before, during or after treatment with intravaginal antifungal drugs. The buffer may be co-administered with antifungal azoles in the same composition. It may also be administered as two different or separate compositions but is administered substantially simultaneously. In addition, each antifungal azole composition and buffer composition may be administered sequentially and individually at specific time intervals.

Accordingly, the compositions and methods of the present invention are directed to compositions for treating vulvovaginitis and vaginosis, comprising (a) an antifungal agent and (b) a buffer system. More preferably, the present invention relates to a composition for treating vulvovaginitis and vaginosis, comprising a buffer system comprising (a) an azole antifungal agent and (b) gluconodeltalactone. The present invention also relates to a composition for treating vulvitis and vaginosis, comprising (a) an azole antifungal agent, (b) a buffer system and (c) a pharmaceutically acceptable carrier. The composition of the present invention comprises an emulsion for treating vulvovaginitis and vaginosis, comprising (a) an azole antifungal agent, (b) a buffer system comprising gluconodeltalactone, (c) a carbomer and (d) a pharmaceutically acceptable carrier. A composition as well as a gel composition for treating vulvitis and vaginosis, comprising (a) an azole antifungal agent, (b) a buffer system, (c) polyethylene glycol and (d) a pharmaceutically acceptable carrier. The compositions and methods of the present invention also comprise (a) a lipophilic or oily phase comprising an azole antifungal agent and a pharmaceutically acceptable lipophilic carrier and (b) a buffered system and a pharmaceutically acceptable hydrophilicity. A dual-phase composition for treating vulvitis and vaginosis, comprising a carrier. The method of the present invention relates to a method for treating vulvitis and vaginosis, comprising administering to the vaginal mucosa a composition comprising an azole antifungal agent and a buffer system. The compositions and methods of the present invention may also be useful for the prevention, ie prevention of vaginal infections, according to the compositions and methods mentioned above. The compositions of the present invention are also soothing, containing not only the compositions according to the invention, but also anti-irritants, anti-inflammatory agents, emollients, antifungals, preservatives and similar ingredients that can be applied to the vulva to help soothe, protect and heal the skin. The kit containing the composition can be filled.

Surprisingly, even though myconazole nitrate is generally ineffective against bacterial infections, it has been found that its antimicrobial activity is markedly enhanced by buffering.

Detailed Description of the Preferred Embodiments

Vaginal infections, such as candidiasis related infections, require active antifungal compounds in the dosage form to treat the infection. Azole type antifungal agents are known to be effective in treating vaginal fungal infections without disrupting vaginal flora. Several azole compounds that have been proven effective for fungal infections, including vaginal products containing myconazole nitrate, thioconazole or clotrimazole, are acceptable for OTC. Therefore, these azole products are recognized as safe.

Although the efficacy of these VVC effective azole products for treating infections associated with bacterial vaginitis has not been demonstrated, these safe antifungal effective compounds against vaginal infections, such as candidiasis, bacterial vaginosis and mixed infections, using the compositions of the present invention Can be developed.

The novel composition of the present invention, which combines the antifungal efficacy of the antifungal component with the buffered carrier composition, maintains or regulates vaginal pH at healthy levels and serves to treat and potentially prevent both vulvar vaginitis and bacterial vaginosis.

Dosages of antifungal agents for the treatment of vulvar vaginitis and bacterial vaginosis vary depending on the antifungal active ingredient used and its efficacy. The amount of antifungal component effective to treat an infection is referred to as a "therapeutically effective amount." Preferably, the antifungal agent in the composition of the present invention should be present in a therapeutically effective amount. Preferably, the antifungal agent is present in an amount of about 0.01 to about 90 weight percent, more preferably about 0.1 to about 50 weight percent, even more preferably about 0.4 to about 10 weight percent, based on the total weight of the composition. It must exist in quantity. The buffer in the composition is present in an amount of about 0.01 to about 50 weight percent, more preferably about 0.1 to about 20 weight percent, and most preferably about 1 to about 5 weight percent, based on the total weight of the composition. Should be.

Other ingredients such as water, antioxidants, chelating agents, preservatives, oils, waxes, surfactants, emulsifiers, viscosity enhancers, solvents, wetting agents, solubilizers and bioadhesives / mucoadhesives, etc. may be present in the compositions of the present invention. . The relative amounts of these ingredients may vary depending on the desired properties and roughness of the composition, including creams, ointments, waxy suppositories, gelatin capsules, anhydrous polymeric suppositories, and the like.

Preferred buffered forms of the compositions of the invention may be emulsions, gels or biphasic or dual dosage forms. Preferably, one hydrophilic phase is present in the composition of the present invention to provide a composition section in which it can be buffered. Three preferred buffered dosage form designs containing active antifungal compounds are (i) a hydrophilic cream, (ii) a hydrophilic gel, and (iii) a phase 2 dosage form for treating vaginal infections as described above. Will alleviate consumer demand for immediate and effective treatment. The buffering capacity of each formulation is formulated to maintain a pH between about 3 and about 5.5, more preferably between about 3 and about 4.5.

The buffer according to the invention can be applied vaginally before, during or after treatment with an intravaginal antifungal agent. Buffers can be co-administered with antifungal azoles in the same composition or can be administered together or substantially simultaneously as two different or separate compositions. For example, the buffer can be incorporated directly into a composition containing an antifungal azole compound. In such cases, the buffer and azole compound are preferably administered to the patient simultaneously during application. The buffer may be coated on the outer surface of the vaginal suppository (eg wax or fatty acid based antifungal vaginal suppository) or gelatin capsule suppository containing an antifungal agent. Buffers may also be incorporated into the gelatin walls of antifungal gelatin capsules.

Alternatively, each antifungal azole composition and buffer composition may be administered sequentially and individually over a specific period of time. For example, the composition for vaginal application may contain only a buffer without any antifungal azole. Such buffer compositions may be administered vaginally when antifungal azoles are present in the vagina. The azoles already present in the vagina by prior intravaginal or oral antifungal treatment, and the buffer (s) act to expand the intended therapeutic efficacy to treat or prevent the development of bacterial vaginosis. Since the antifungal azoles in the vaginal tissue and fluid typically last several days after intravaginal or oral administration, the buffer composition is preferably from 1 hour to about 10 days, more preferably from about 8 hours to about 7 days of administration of the antifungal agent. Most preferably, from about 12 hours to about 5 days.

Dosage regimens vary depending on the particular antifungal agent used in the products of the present invention. A therapeutically effective or prophylactically effective dose should be used.

The buffer may also be administered before and / or after intravaginal antifungal treatment. Preferably, the buffer is selected from certain polymeric or biopolymer adhesive materials such as gelatin, chitosan and derivatives thereof, hydrophilic cellulose (preferably hydroxyalkylcellulose, more preferably hydroxymethylcellulose, hydroxy). Ethylcellulose, or the like) and polyacrylate-polyacrylic acid polymers such as carbomers and the like. Hydrophilic polymers containing buffers can act as gelling agents in gel-like compositions or as viscosity enhancers in emulsion-like compositions, for example, in oil-in-water creams.

In addition, the buffer encapsulated hydrophilic polymer may be suspended in a lipophilic composition containing an antifungal agent (eg, ointment, wax- / fatty-acid suppository or water-in-oil emulsion). In vaginal applications, hydrophilic polymers adhere to the vaginal mucosa, keeping the vaginal pH in the desired pH range for a long time, even for a long time after the antifungal agent is removed or released from the vagina. This long-term maintenance of nitric acidity ensures the reestablishment of healthy fungal flora (eg, Lactobacillus spp.) And inhibits pathogenic yeast (eg Candida albicans), which occurs only when the vaginal immune system is weakened. do.

The composition of the present invention should contain at least one active antifungal component, preferably an azole antifungal component. More preferably, the compound is myconazole nitrate, terconazole, butaconazole, itraconazole, barleyconazole, ketoconazole, econazol, thioconazole, fluconazole, poconazole, labuconazole, clotrimazole and the like. .

In addition, the compositions of the present invention should contain at least one buffer system or buffer. Preferably such buffer is gluconodeltalactone ("GDL"). GDL is a neutral cyclic gluconate ester. When added to an aqueous solution, GDL dissolves rapidly and then slowly hydrolyzes to gluconic acid. Other buffer systems or buffers may also be used in the compositions and methods of the present invention. As used herein, the term “buffer system” or “buffer” refers to a solute or agent that stabilizes the solution against large changes in pH (or hydrogen ion concentration) when an acid or base is added, in aqueous solution. . The solute (s) are used to inhibit changes in the initial buffered pH value around pH 4 as are preferably used in the compositions and methods of the present invention. In general, the buffers used in the compositions of the present invention include any physiologically acceptable organic acid and corresponding salts thereof, either liquid or solid (determined depending on the intended application). Preferably, the pK _a of such buffer is at pH about 3 to about 5. Buffers preferably used in the compositions and methods of the present invention include, but are not limited to, acetic acid, fumaric acid, lactic acid, citric acid, propionic acid, malic acid, succinic acid, gluconic acid, ascorbic acid, tartaric acid, and the like. For example, polymers with ionizable functional groups and buffering capacity comprising carboxylic acid or amine groups can also be used as polymeric buffers according to the invention. Examples of polymeric buffers which are preferably used in the compositions and methods of the present invention are B. F. Carbomer ^R or Carbopol ^R and Carboxymethyl Cellulose available from BF Goodrich Co. (Akron, Ohio). Virtually any pharmaceutically acceptable buffer system can be used in the compositions and methods of the present invention to achieve a pH in the range desired for topical application.

Buffer formulations suitable for application to the vagina according to the present invention and consisting of azoles suitable for achieving the desired therapeutic action and physiological pH of about 4 vagina, include, but are not limited to, suspensions, emulsions, Non-flowable forms including clear and opaque gels, ointments, pastes, oil-in-water (o / w) creams, semisolid emulsions with an internal solid phase, semisolid systems with internal fluid phase semisolid emulsions, vaginal suppositories, intercalated tablets, soft Or in hard gelatin capsules or the like.

Surprisingly, buffered gels containing the azole antifungal agent myconazole nitrate have been found to exhibit improved buffering capacity over buffered gels that do not contain myconazole nitrate by a pH in the range of about 3 to about 5.5.

The compositions of the present invention may also contain other components for use in emulsified gels or two-phase systems. For example, the emulsion may contain surfactants, oils, humectants, pH adjusters, waxes, polymer carriers, bioadhesives and water, which are known to those skilled in the art. Gel formulations may contain oils, humectants, carbomers, celluloses, polyalkylene glycols, and water, in addition to the active ingredients and buffer systems. The compositions may be in the form of creams, suppositories, gels or two phase combinations.

Phase 2 dosage forms of the invention are not limited to the natural or physical state of the substance as a pharmaceutically acceptable carrier. For example, phases containing antifungal azoles may be solid (eg suppositories consisting of waxy, fatty, polymeric or lyophilized) or semisolids (eg emulsions, oil-in-water creams, water-in-oil creams, ointments or aqueous gels). Can be. Likewise, the phase containing the buffer (s) may be solid or semisolid in various pharmaceutical dosage forms. One example of such a biphasic dosage form preferably contains a buffer gel and a hydrophobic antifungal component in the delivery system. The hydrophobic phase of the blend is an internal stability delivery system and is designed to dissolve at body temperature. Such dosage forms can be delivered together in both phases using an applicator that can be inserted into the vaginal cavity. Advantageously, a biphasic dosage form can deliver antifungal drugs and buffer gels simultaneously into the vagina to provide therapeutic capacity for both bacterial and bacterial infections. While antifungal drugs inhibit bacterial infectious agents, the pH of the vagina is lowered and maintained in a healthy range by the buffer gel.

Fungal vulvitis and bacterial vaginosis are treated by the methods using the compositions of the present invention. The composition is administered intraperitoneally. Preferably, the bioadhesive component in the composition of the present invention maintains the active ingredient and the buffer system in the vaginal mucosa. All abnormal floras, including fungi and / or bacteria, are removed and the composition can be reapplied daily until the infection is treated.

The following examples merely illustrate some possible compositions of the invention. Although the compositions of the following examples all contain both antifungal azoles and buffer (s) for simultaneous intravaginal administration, the antifungal azoles of this composition are purified water. Can be substituted to form a buffer composition for sequential administration as mentioned above. The examples are merely illustrative of the compositions of the present invention and methods for their preparation and are not intended to be limiting.

Example 1 Hydrophilic Cream

ingredient % (w / w) (1A) % (w / w) (1B) % (w / w) (1C) % (w / w) (1D) Stearyl alcohol 8.500 8.500 8.500 8.500 Cetyl alcohol 3.000 3.000 3.000 3.000 Polysorbate 60 3.000 3.000 3.000 3.000 Isopropyl myristate 1.000 1.000 1.000 1.000 Propylene glycol 20.000 20.000 20.000 20.000 Benzoic acid 0.200 0.200 0.200 0.200 Potassium hydroxide 0.055 0.055 0.055 0.055 Gluconodeltalactone (GDL) 1.000 1.000 1.800 0.900 Carbomer (Cabopol 974P) - 2.000 - 0.900 Myconazole Nitrate 4.000 4.000 4.000 4.000 Purified water 59.245 57.245 58.445 58.445

The composition of this example can be prepared according to the following procedure:

1. Water and propylene glycol are added to the vessel and heated to about 70 to about 75 ° C. with low speed mixing with a paddle stirrer. Once the mixture reaches the desired temperature, benzoic acid is added with continued mixing. When benzoic acid is dissolved, potassium hydroxide is added and mixed until dissolved.

2. Once potassium hydroxide is dissolved, polysorbate 60 is added and mixed for about 1 minute while maintaining the batch temperature at 70-75 ° C. Stop the mixer and add isopropyl myristate, cetyl alcohol and stearyl alcohol. The batch is mixed again at about 70 to about 75 ° C. until all the components in the vessel are completely dispersed.

3. Remove the vessel from the heat source and continue mixing with the homogenizer for about 2 minutes. After homogenization, the batch is mixed with a paddle stirrer while cooling to about 40 ° C.

4. When the temperature reaches about 40 ° C., add myconazole nitrate to the vessel with mixing. After addition of myconazole nitrate, gluconodeltalactone is added to the vessel and the mixture is homogenized for about 4 minutes or until the myconazole nitrate is completely dispersed. After homogenization, continue mixing with a paddle stirrer for about 5 minutes.

Example 2: Buffered Placebo Cream

ingredient % (w / w) (2A) % (w / w) (2B) Stearyl alcohol 8.500 8.500 Cetyl alcohol 3.000 3.000 Polysorbate 60 3.000 3.000 Isopropyl myristate 1.000 1.000 Propylene glycol 20.000 20.000 Benzoic acid 0.200 0.200 Potassium hydroxide 0.055 0.055 Gluconodeltalactone (GDL) - 1.800 Carbomer (Cabopol 974P) - - Myconazole Nitrate - - Purified water 64.245 62.445

The composition of this example can be prepared using the following process.

1. Add water and propylene glycol to the vessel and heat to about 70 to about 75 ° C. with low speed mixing with a paddle stirrer. If the mixture reaches the desired temperature, continue mixing and benzoic acid is added. If benzoic acid is dissolved, add potassium hydroxide and mix until dissolved.

2. When potassium hydroxide is dissolved, add polysorbate 60 and mix for about 1 minute while maintaining the bath temperature at 70-75 ° C. The mixer is then stopped and isopropyl myristate, cetyl alcohol and stearyl alcohol are added. The bath is mixed again at about 70 to about 75 ° C. to ensure complete dispersal of all ingredients in the vessel.

3. Remove the vessel from the heat source and continue mixing using the homogenizer for about 2 minutes. After homogenization, the bath is mixed with a paddle stirrer while cooling to about 40 ° C.

4. Once the temperature reaches about 40 ° C., optionally add gluconodeltalactone to the vessel and homogenize the mixture for about 4 minutes or until the myconazole nitrate is completely dispersed. After homogenization, continue mixing with a paddle stirrer for about 5 minutes.

Example 3: Single-Carbomer Gel

ingredient % (w / w) placebo, (3A) in the case of containing a% (w / w) azole compound, (3B) Potassium chloride 0.16 0.16 EDTA 0.02 0.02 Carbomer 974P (Cabopol 974P, B.F.Goodrich) 2.08 2.08 Sodium hydroxide 0.17 0.17 Myconazole Nitrate - 4.00 Purified water 97.57 93.57

The composition of this example can be prepared using the following process.

1. Carbomer 974P is added to water and mixed at room temperature using a high speed mixer (eg homogenizer).

2. Then add potassium chloride, EDTA and sodium hydroxide and mix using a slow mixer (eg paddle mixer).

3. For formulations containing azole compounds, myconazole nitrate is added to the mixture and mixed using both homogenizers and paddles to ensure uniform dispersion of myconazole nitrate in the formulation.

Example 4: Multi-Carbomer Gel

ingredient % (w / w) (4A) % (w / w) placebo, (4B) % (w / w) (4C) % (w / w) placebo, (4D) Carbomer 971 2.00 2.00 2.00 2.00 Mineral oil 4.20 4.20 4.20 4.20 Griserin 12.90 12.90 - - Carbomer 974 1.00 1.00 1.00 1.00 Distilled monoglycerides 1.00 1.00 1.00 1.00 Sorbic acid 0.08 0.08 0.08 0.08 Polyethylene Glycol 400 - - 12.90 12.90 Myconazole Nitrate 4.00 - 4.00 - pure 74.82 78.82 74.82 78.82

The composition of this example can be prepared using the following procedure:

1. Glycerin, mineral oil (or polyethylene glycol 400), distilled monoglycerides (e.g. miberol), and sorbic acid are added to a suitable vessel and heated to 65-70 ° C. Carbomer 971 and 974 are then added to the vessel and mixed.

2. The water is individually heated to 55-60 ° C. and then added to the mixture of (1). After mixing for about 3 minutes myconazole nitrate is added to the vessel.

3. Mix the batch with a paddle stirrer while cooling to about 45 ° C. When the temperature is about 45 ° C., mix the batch for about 2 minutes using a homogenizer.

4. Switch to paddle stirrer and mix while cooling the batch to room temperature.

Example 5: Carboxymethylcellulose Gel

ingredient % (w / w) (5A) % (w / w) placebo, (5B) Gluconodelta-lactone (GLD) 2.50 2.50 Sodium hydroxide 0.25 0.25 Methylparaben 0.20 0.20 glycerin 17.00 17.00 Hydroxyethylcellulose 3.00 3.00 Myconazole Nitrate 4.00 - Purified water 73.05 77.05

The composition of this example can be prepared using the following procedure:

1. Add hydroxyethylcellulose to water and mix at room temperature using a high speed mixer such as a homogenizer.

2. Glycerin, methylparaben, sodium hydroxide and gluconodelta-lactone are then added and mixed using a slow mixer such as a paddle mixer.

3. Add myconazole nitrate to the mixture and mix using both homogenizers and paddles to uniformly disperse myconazole nitrate in the formulation.

Example 6: Adhesive / hydrophobic suppositories

ingredient % (w / w) (6A) % (w / w) (6B) Xanthan rubber 1.00 1.00 Sodium Carboxymethylcellulose 7HF 8.00 8.00 Colloidal silicon dioxide 1.00 1.00 Wecobee M 12.00 15.00 Wacoby FS 54.00 67.00 Myconazole Nitrate 24.00 8.00

The composition of this example can be prepared using the following procedure:

1. Wecoby M and FS (these are hard fat bases consisting mainly of a mixture of triglyceride esters of highly saturated fatty acids with varying proportions of mono- and diglycerides) are dissolved at 50-60 ° C. in a suitable container. Xanthan gum, colloidal silicon dioxide, and carboxymethylcellulose 7HF are added to the vessel and mixed appropriately. Mixing using a homogenizer is continued for about 2 minutes or until the additives are completely dispersed.

2. Add myconazole nitrate to the batch, mixing with a homogenizer. While cooling with a slow mixer, the batch is cooled to room temperature. The batch is solidified at a temperature below 35 ° C.

Example 7: Buffer Capacity

In order to measure the buffer capacity of the composition of the present invention, the following process is used.

The amount of 0.1 N sodium hydroxide that varied the pH of the samples described in Examples 1-5 was determined by titration method. The amount of sodium hydroxide added to this sample is shown in the graph below on a molar-equivalent basis.

Samples generated from Example 6 do not have a buffer capacity between 3.0 and 5.5 and are designed to be delivered with a placebo buffer gel (Example 5) to the applicator. This is an example of the two phase delivery system described above. Data obtained from buffered Metrogel-Virginal Treatment (source: 3M Corporation, Minneapolis, Minn., USA) for the treatment of bacterial vaginosis is provided for comparison as shown in the figure as a comparison.

1 and 2 demonstrate the buffering capacity for the cream formulations of Examples 1 and 2 described above. Monostart 3 vaginal cream is used as a control. As shown, Examples 1A, 1B, 1C, 1D and 2B have relatively good buffering capacity, while Comparative Example 2A and Monostart 3 vaginal cream do not. Example 2A does not contain any buffer or carbomer. The buffering capacity of the cream base is remarkably improved after adding 1.8% or more of the combination of gluconodeltalactone or gluconodeltalactone and carbomer. In addition, better buffering capacity is observed for formulations containing myconazole nitrate compared to placebo (Example 1C compared to Example 2B). It is surprising that myconazole nitrate can increase buffering capacity in the cream formulations described above.

3 and 4 demonstrate the effectiveness of the buffered gel formulations of Examples 3 and 4 as compared to the commercially available formulation Metrogel-Virgin for treating bacterial vaginosis. Formulations 3A, 4B and 4D do not contain myconazole nitrate and are relatively poorly buffered than other formulations containing myconazole nitrate (3B, 4A and 4C).

5 demonstrates the effect of the buffered gel formulation of Example 5. Formulation 5B does not contain myconazole nitrate and is relatively poorly buffered than other examples.

6 is a commercial formulation of metronidazole containing metronidazole for topical treatment of bacterial vaginosis, and a commercial formulation of monistat 3 vaginal cream containing myconazole nitrate for topical treatment of vulvar candidiasis, and the present invention The comparative test results between Formulations 1C and 4C, which are preferred buffered formulations, are shown. As demonstrated, the compositions of the present invention have a greater ability to maintain normal pH than commercially available products due to their buffering capacity.

Example 8 In Vitro Evaluation of Antimicrobial Vaginal Organism Activity

The ability of selected vaginal anaerobes to survive in a mixture of the described formulations and supplemented Brucella gravy was also studied. Brucella gravy supplemented with vitamin K and hemin was prepared at twice the concentration to be diluted with the formulation of the present invention. The organisms studied were taken from the freezer and sub-cultured more than once to ensure purity and good growth. The following procedure was used to perform in vitro evaluation.

Method: Steer's Replicator Assay (survival time in hours)

1. Add 1 ml of dimethyl sulfoxide ("DMSO") to 1 g of test sample and mix. One of the formulations must be dissolved at 40-46 ° C. and mixed thoroughly before dissolving in DMSO. Prepare 18 ml. Remove a small amount and measure and record the pH. Place in an anaerobic chamber for at least 2 hours.

2. While operating in the chamber, prepare a suspension corresponding to the # 1 McFarland equivalence turbidity standard for each anaerobic organism in Brussela gravy (˜3 × ^{10 8} cfu / ml) supplemented at twice the concentration. . Add 0.5 ml to the steer replicator well. One BBA (Brussela blood agar) culture dish is stamped as a control before growth.

3. Using a multi-channel pipettor, add 0.5 ml of cream solution to each broth for each well. Mix thoroughly by pipetting up and down. When complete, record the time it takes to inoculate the entire replicator head (the first well will have a longer contact time than the last well). As "0" time, one BBA culture dish is stamped. Use one steer replicator head for each of the creams. On each day of the experimental setup, a control replicator was prepared with an suspension of the organisms that had added Brucella gravy and DMSO (1 + 9) but no cream added.

4. Incubate with prongs in the wells.

5. Stamp another BBA every hour and label the time in hr on the petri dish. Incubate at 36 ° C.

6. Continue for 24 hours.

7. Examine the stamped culture dish after 72 hours of incubation and record whether growth or non-growth is present or whether there is a growth pattern that can show damaged cells, ie, little or no colony growth.

8. Finally, record the time, in hr, for the organism to survive in the presence of each of the samples in Table I below.

For the azole compounds studied, myconazole, terconazole and fluconazole are proven azoles for treating the vulva and vulvovaginal candidiasis. Metronidazole and tinidazole are known compounds that are useful for treating bacterial vaginosis. However, an unexpected finding from this in vitro evaluation of azole compounds is that myconazole actually has better activity against bacterial vaginosis organisms than terconazole and fluconazole.

The activity of the described formulations against bacterial vaginitis organisms is shown in Table II below. Of the formulations studied, Examples 2A, 2B, 4B and 4D are formulations without myconazole nitrate. Example 2A with the lowest buffer capacity has the least effect on the organisms studied. Example 2B is the buffered placebo formulation of Example 1C and Example 4D is the buffered placebo formulation of Example 4C. Activity against the studied organisms is significantly enhanced by incorporating myconazole nitrate into Example 1C. The same result is obtained by incorporating myconazole nitrate in Example 4D.

Example 9 Pilot Clinical Study of Two Buffered Myconazole Vaginal Formulations

Phase II in an in vivo pilot study demonstrates the therapeutic efficacy of two preferred buffered (4%) myconazole nitrate formulations (Model Nos. 1 and 2) for treating bacterial vaginitis (BV) when administered intravaginally. Performed for evaluation in comparison with the original gel. All products are administered daily for 5 days. Efficacy parameters for this pilot study are therapeutic treatment rate (combined clinical and microbial treatment), clinical treatment (reduction of signals and signs) and microbiological treatment (Nugent score of 3 or less). Therapeutic, clinical and microbiological treatment rates for scheduled visits to the clinic 21 to 30 days after the initial administration of the therapeutic agent are similar for myconazole nitrate buffered cream and metrogel-vaginal. Therefore, administration of buffered myconazole cream product for 5 days appears to be effective in treating bacterial vaginitis. Vulvar side effects are known to occur in 50-60% of patients treated with myconazole and 21% in patients treated with metrogel. Most side effects are mild in intensity.

Model Number 1: Buffered Myconazole Nitrate Vaginal Cream

ingredient % (w / w) Stearyl alcohol 8.5 Cetyl alcohol 3 Polysorbate 60 3 Isopropyl myristate One Propylene glycol 20 Benzoic acid 0.2 Potassium hydroxide 0.055 Gluconodeltalactone (GDL) 1.8 Myconazole Nitrate 4 Purified water 58.445

Model Number 2: Buffered Myconazole Nitrate Vaginal Gel

ingredient % (w / w) Carbomer 971 2 Mineral oil 4.2 Carbomer 974 One Distilled monoglycerides One Sorbic acid 0.08 Polyethylene Glycol 400 12.9 Myconazole Nitrate 4 Purified water 74.82

Claims (21)

(a) a therapeutically effective amount of an antifungal agent and (b) a composition for simultaneous treatment of vulvitis and vaginosis, comprising a buffer system capable of maintaining the pH of the infection site to which the composition is applied at about 2.5 to about 5.5. (a) azole antifungal agents and (b) Simultaneous vulvitis and vaginosis, comprising a buffer system comprising a buffer selected from the group consisting of gluconodeltalactone, acetic acid, fumaric acid, lactic acid, citric acid, propionic acid, malic acid, succinic acid, gluconic acid, ascorbic acid and tartaric acid Therapeutic composition. (a) a therapeutically effective amount of an azole antifungal agent, (b) a buffer system and (c) A composition for simultaneous treatment of vulvitis and vaginosis, comprising a pharmaceutically acceptable carrier. (a) a therapeutically effective amount of an azole antifungal agent, (b) a buffer system comprising gluconodeltalactone, (c) carbomer and (d) An emulsion composition for treating vulvitis and vaginosis, comprising a pharmaceutically acceptable carrier. (a) a therapeutically effective amount of an azole antifungal agent, (b) a buffer system, (c) polyethylene glycol and (d) A gel composition for treating vulvitis and vaginosis, comprising a pharmaceutically acceptable carrier. (a) an oil phase comprising an azole antifungal and an oil, (b) an aqueous phase comprising a buffer system and water and (c) A dual-phase composition for the treatment of vulvovaginitis and vaginosis, comprising a pharmaceutically acceptable carrier. A method of treating vulvitis and vaginosis, comprising administering to a mucosa a composition comprising an azole antifungal agent and a buffer system. The composition of claim 1, wherein the buffer system maintains the pH at about 3 to about 5. The composition of claim 1, wherein the buffer system maintains the pH at about 3 to about 4.5. 8. The method of claim 7, wherein the mucosa is a vagina. 8. The method of claim 7, wherein the mucosa is an oral cavity. (a) a therapeutically effective amount of an antifungal agent and (b) a composition for preventing vulvitis and vaginosis, comprising a buffer system capable of maintaining the pH of the infection site to which the composition is applied at about 2.5 to about 5.5. (a) azole antifungal agents and (b) vulvovaginitis and vaginosis prevention, comprising a buffer system comprising a buffer selected from the group consisting of gluconodeltalactone, acetic acid, fumaric acid, lactic acid, citric acid, propionic acid, malic acid, succinic acid, gluconic acid, ascorbic acid and tartaric acid Composition. (a) a therapeutically effective amount of an azole antifungal agent, (b) a buffer system and (c) A composition for treating vulvitis and vaginosis, comprising a pharmaceutically acceptable carrier. (a) a therapeutically effective amount of an azole antifungal agent, (b) a buffer system comprising glocono deltalactone, (c) carbomer and (D) vulvitis and vaginal disease preventing emulsion composition comprising a pharmaceutically acceptable carrier. A gel composition for preventing vulvitis and vaginosis comprising (a) a therapeutically effective amount of an azole antifungal agent, (b) a buffer system, (c) polyethylene glycol and (d) a pharmaceutically acceptable carrier. A method for preventing vulvitis and vaginosis, comprising applying a prophylactically effective amount of the composition according to claim 1 to the vulva or vagina. 18. The method of claim 17, comprising applying the composition according to claim 5 to the vulva or vagina. Kit for treating vulvitis and vaginosis, comprising the composition according to claim 1 and a composition for soothing irritated skin. Vulvaritis or vaginosis, which comprises applying a prophylactic or antimicrobial effective amount of the composition according to claim 1 comprising at least one antimicrobial active ingredient to the vulva or vagina, and then separately applying a second composition comprising at least one buffer Method of treatment or prevention. The method of claim 20, wherein the second composition further comprises one or more antimicrobial active ingredients.