RU2288700C2 - Warming and non-irritating anhydrous lubricating compositions - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to anhydrous, antifungal, lubricating gel compositions comprising polyhydric alcohol, gelatinizing agent and an antifungal azole compound, and to a method for treatment of a patient with fungal infections comprising administration of indicated composition in a patient. Compositions shows the excellent warming and lubricating effect after its applying on skin and mucosal tissues and provides the effective treatment of fungal infections.

EFFECT: improved and valuable properties of compositions.

21 cl, 2 tbl, 11 dwg, 9 ex

Description

Field of Invention

This invention relates to essentially anhydrous, individual lubricating gel and jelly compositions that are warming and non-irritating when applied to the skin or mucous membranes, in particular to the mucous membrane of the vagina and oral cavity. In some embodiments, the compositions of the present invention are substantially anhydrous and contain one or more polyols. This invention also relates to a method that can be used to test and compare the irritating effects of the compositions of this invention and other individual lubricants known in the art. Unlike previously known compositions that use exothermic reactions to release heat or irritating agents to transfer heat perception, the compositions of the present invention use “solution heat” to release heat. The feeling of warmth produced by the compositions of the present invention is very pleasant and soft compared to previously known compositions. The compositions of the present invention are also more tissue lubricating than previously known warming compositions. In addition, the lubricity of the compositions of the present invention increases after dilution with water; the lubricity of previously known aqueous compositions tends to decrease after dilution with water. Therefore, when applying the compositions of the present invention will be significantly more lubricating than compositions previously known in this field.

BACKGROUND OF THE INVENTION

Humans are warm-blooded animals that maintain a constant body temperature of 98.6 ° F (37 ° C). The skin and external organs of a person have a very effective circulatory system and nervous system, which leads to the fact that the human body can very quickly perceive temperature changes. Individual lubricants and drugs are usually applied to human mucous membranes at room temperature, i.e. 60 ° F to 80 ° F. Since there is a detectable temperature difference between room temperature and human body temperature, users of such lubricants and medicines perceive them as quite cold. This feeling of cold can be quite uncomfortable for the user. From time to time, attempts have been made to develop products that overcome this perception of cold.

A significant number of individual lubricating compositions are known in the art. These compositions are formulations ranging from jelly preparations to liquids and vaginal suppositories, and they range from water to oils and silicone-based compositions. Most of the compositions actually used at present are water-based jellies or aqueous liquids. Almost all individual lubricants and available for use are currently cold to the touch, and this feeling can be uncomfortable.

Compositions that claim to give a warming sensation after being applied to the skin or mucous membrane are commercially known or described in the literature. These compositions are generally divided into several main categories based on the mechanism of action.

Some of these compositions use plant extracts that are irritating to the skin and mucous membranes and give a sensation or perception of warmth due to their irritating effect. Others claim to increase blood flow in order to cause tissue warming. Some others allegedly work on the principle of lowering the freezing point and are well suited for heating in the microwave or cooling in the refrigerator. There is one cosmetic composition, which is given the property of self-heating by the inclusion of a compound containing a bond between boron atoms, which reacts exothermically with water.

In one category of warming compositions, plant extracts or agents, such as methyl salicylate, which irritate the skin or mucous membranes, are used. For example, WO 97/02273 A describes phosphate derivatives that can be used in oral and topical compositions to provide a perceived sensation of warmth. The compositions contain warming components, such as derivatives of vanillyl. The compositions also include an additional warming agent, including ethanol, niacin, jamba, nicotinic acid, zingeron, isopropyl ether of vanillyl alcohol, gingerol, methyl salicylate, shogaol, paradol, zingeron, capsaicin, dihydrocapsaicin, homohydrocapsicin, eudoxynaprocetic, norodigrocapsaicin oil, novigidrocapsaicin oil, nape dihydrocapsaicin peptica, necrohydrocapsaicin oil, naphenhydrocapsaicin oil, naphenhydrocapsaicin oil, naphenhydrocapsaicin oil, naphenhydrocapsicin,

In another category of warming products, the mechanism of increased blood circulation is used. US Pat. No. 5,895,658, entitled “Delivery of L-arginine to induce tissue warming, delayed release of nitric oxide to treat diabetes, stimulate hair growth and heal wounds,” describes a drug for enhancing blood flow in tissues, thereby causing , beneficial effects, such as warming cold tissues of the hands and feet.

In yet another category of warming products, inorganic compounds are used to create exothermic reactions leading to heat generation. For example, WO200260408 A1 relates to anhydrous cosmetic hair care compositions containing inorganic salts such as sodium sulfate, calcium sulfate, aluminum sulfate, calcium chloride, magnesium chloride or calcium oxide, or magnesium sulfate. After mixing with water, these compositions give off heat.

KR 20010227018 describes an exothermic cosmetic product containing active zeolite compositions that stimulate blood circulation and metabolism, giving the skin a sensation of warmth. Active zeolite contains ethoxylated alcohol. JP 63159490 A relates to exothermic cosmetic compositions, in particular for softening hair, containing reducing agents such as sodium sulfite, sodium thiosulfate, sodium pyrosulfite or sodium bisulfite and an oxidizing agent such as sodium bromate, potassium bromate or sodium perbromate.

Document EP 2001306347 relates to compositions for use in preparing shaving hair. The compositions contain at least one substance that undergoes a noticeable chemical change when mixed during shaving. The substance changes temperature, emits a smell, or undergoes oxidation, hydration, a reaction between acid and base, or an exothermic reaction.

In another category of heat-generating products, mechanisms other than the three above categories are used. US20020142015 A1 and JP2002179517 describe warming compositions for cosmetics, toiletries, bath additives and pharmaceuticals that contain a cooling agent and a specific parahydroxybenzaldehyde derivative. The use of this parahydroxybenzaldehyde cooling agent is intended to cause a warming effect for a longer time. FR 2810240 A1 describes cosmetic compositions containing a component that can absorb or release heat, thereby providing a cooling and refreshing effect during exposure to heat or a warming effect during exposure to cold, such as a combination of long-chain hydrocarbon compounds that can absorb thermal energy and store or exchange heat. No. 3,632,516 A describes a heating foam that is rapidly heated by hydrogen peroxide through a redox reaction of thiosulfate.

JP 2001335429 describes gel-like cosmetics that contain 40-75 wt.% Polyethylene glycol, 20-55 wt.% Glycerol and a carboxyvinyl polymer. These compositions are used to generate heat in order to stimulate blood circulation and metabolism in conditions of fatigue and to provide a feeling of warmth during shaving. One example of a commercially available composition, Prosensual ™, distributed by Lexie Trading, Inc., Fairlaw, New Jersey, contains plant extracts such as Cinnamon cassia (cinnamon), Zingiber officinalis (ginger), mint, sandalwood, orange and cloves all of which are known to be skin irritants. Such a composition has the disadvantage of causing mucosal irritation, which can be problematic with respect to the mucous membrane of the vagina or oral cavity, since irritation can promote the growth of unwanted bacteria and cause infection.

Another current WET ™ massage massage oil composition sold by International, Valencia, California uses retinyl palmitate (Vitamin A palmitate), Prunus amygdalis (prunes), Amara (almonds), Persica gratissima (avocado oil), oil Macdamia ternifulia seeds, Kakeri nut oil, Helianthus annus (hybrid sunflower), Cannabis sativa (Hemp) and Aloe vera (aloe) seed oil. Most of these ingredients are known mucosal irritants that are not suitable for use on mucous membranes.

U.S. Patent No. 5,513,629, entitled “Microwave-heated Release and Absorbent Compositions and a Container, Humidifier Including Compliant Gel, Anti-Freezing Point Agent, Gel Sealant, Polyacrylamide Absorber, Corn Starch Binder, Mineral Oil and Plasticizers, Durability, Efficiency "Describes compositions that have high evaporation points and are therefore suitable for heating in a microwave oven or cooling in a freezer and placed in a suitable container or in Nilov packaging, such as hot and cold pack, but not for consumption or use by people.

However, none of the above compositions is truly “warm” or has a relatively higher temperature than the ambient temperature of the product or the environment.

US Pat. No. 4,110,426, entitled “Method for treating skin and hair with self-heating cosmetic, organic boron-oxygen-boron compounds”, describes non-aqueous compositions, such as shaving creams, which are given the property of self-heating by including in them a compound containing at least one boron-oxygen-boron bond such as triethoxyboroxine. The boron-containing compound exothermically reacts with water or other proton-containing material to increase the temperature. Such compositions are not suitable for use in the vagina or in the oral cavity due to the possible toxicity of boron-containing compounds for the human reproductive system (Fail PA, et al., General, reproductive developmental, and endocrine toxicity of boronated compoundes, Reprod toxicol 12: 1, 1- 18, Jan-Feb, 1998).

Forms of physical energy were used to enhance the transport of material across the membrane for therapeutic purposes. Such forms of energy include electricity, ultrasound, and thermal energy (e.g., heat-assisted drug delivery (review by Sun, in "Skin Absorption Enhancement by Physical Means: Heat, Ultrasound, and Electricity", Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc., 1997, pages 327-355)). Local heating of the drug delivery device or composition, as well as skin tissues or mucous membranes, not only increases the thermodynamic energy of the drug molecules and the permeability of the membranes to facilitate the movement of the drug through the barrier membrane, it improves blood circulation in the tissue to accelerate the removal of the drug from local tissue to the systemic circulation. Both processes lead to increased absorption of the drug. Experimental evidence demonstrates that a low level of heating (i.e., tissue temperature of less than about 42 ° C) significantly enhances the absorption of the drug through the skin.

US Pat. No. 5,658,583 describes a heat generating device for improved penetration of pharmaceutical agents through the skin. The device includes a thin reservoir for the drug composition and a heat generating oxidation reaction chamber separated by an impermeable wall. The reservoir for a medicinal composition contains a predetermined amount of a composition containing pharmaceutical agents. The heat-generating / temperature-regulating chamber includes a heat-generating medium consisting of carbon, iron, water and / or salt, which is activated after contact with oxygen in the air. However, a complex heating device, such as the one indicated, is not suitable for use in the vagina or oral cavity due to the apparent insecurity of use.

Locally applied heat (such as a heating pad on the stomach) has also been used to treat dysmenorrhea or menstrual cramps with demonstrated effectiveness (Akin MD et al., Continuous low-level topical heat in the treatment of dysmenorrhea, Obstet Gynecol 97: 3, 343-9 , Mar, 2001).

US Pat. No. 6,019,782 describes disposable thermal pads on the body that produce heat through an oxidation reaction designed to relieve menstrual pain when applied to the skin of the abdomen. There is currently a product on the US market for the treatment of dysmenorrhea based on heating the abdomen, lining for the relief of menstrual cramps with air-activated ThermaCare® thermal wraps manufactured by Procter & Gamble (Cincinnati, OH). However, there are no products or descriptions of localized internal heating for the treatment of dysmenorrhea.

SUMMARY OF THE INVENTION

The compositions and methods of this invention relate to essentially anhydrous, non-irritating gel and jelly compositions. The compositions and methods of the present invention contain gel-forming cellulose derivatives and polyols. Preferably, the gel-forming cellulose derivatives are hydrocolloids. The compositions of the present invention can be used as warming, lubricating compositions that are non-toxic and non-irritating, and which can be used as individual lubricants intended to come into contact with the skin or mucous membrane. When mixed with water, the temperature of the gel and jelly compositions of the present invention increases or heat is generated. This has a facilitating (painkiller) effect on the tissues on which the compositions are applied. This essentially eliminates the sensation or perception of the cold, which when used conveys conventional, individual lubricants.

The compositions of the present invention have excellent lubrication characteristics. The gels and jelly compositions of the present invention have a greater lubricating effect than even the aqueous lubricating products currently on the market. The compositions of the present invention, in particular the jelly-like compositions of the present invention, are new in that their lubricity increases after dilution with water. The lubricity of known commercially available aqueous compositions decreases after dilution with water. This is a particular advantage in that the compositions of the present invention can be used in connection with the wet mucous membrane of the vagina and oral cavity, and they will become increasingly lubricating after contact with moisture in these cavities.

Although anhydrous compositions are generally perceived to be irritating to the skin and mucous membranes, the gel and jelly compositions of this invention are surprisingly non-irritating.

The compositions of the present invention can be applied to the skin or mucous membranes, preferably to the mucous membrane of the vagina or oral cavity. The compositions of the present invention are preferably substantially anhydrous and preferably contain at least one polyhydric alcohol.

The inventors theoretically suggest that when the polyhydric alcohols contained in the compositions of this invention come into contact with water or body moisture in humans, they react with the molecules of the surrounding water in order to cause an increase in temperature or to generate heat, thereby providing , a calming effect on the tissues on which these compositions are applied.

Unexpectedly and in contrast to the general opinion that polyhydric alcohols in the compositions have an irritating effect on the mucous membrane, it was found that the compositions of this invention containing such polyhydric alcohols are non-irritating. The inventors theoretically suggest that the hydrocolloids that can be used in the compositions and methods of the present invention swell when they come in contact with water, forming a lubricating coating gel. This coating physically blocks the irritating effect of other anhydrous elements of the compositions of the present invention. In addition, since the polyhydric alcohols used in the compositions of the present invention are wetting agents and humectants, when the hydrocolloids swell and form thin films on the tissues of the mucous membranes, the films retain the humectants on the surface of the tissues. Thus, the compositions of the present invention overcome dry conditions such as vaginal dryness and dry mouth caused by various factors, including menopause and aging, as well as various pathological conditions.

Thus, the compositions of the present invention are very soft for the skin and mucous membranes. The compositions of the present invention have a calming effect when applied to the mucous membranes of the oral cavity and can function to alleviate slight irritation of the oral cavity and throat.

The combination of polyhydric alcohols in the compositions of this invention can also be used as a carrier for the solubilization of insoluble drugs, including, but not limited to, antifungal agents, antibacterial agents, antiviral agents, painkillers, anti-inflammatory steroids, contraceptives, local anesthetics, hormones and the like. drugs.

Preferably, the acidic pH of the compositions of the present invention is maintained. Acidic pH helps to maintain a healthy vaginal flora and oral cavity, in particular, to maintain Lactobacilli in the vaginal area. Acids or buffers are known to be insoluble in anhydrous compositions. Preferably, the compositions of the present invention contain an organic acid that is soluble in them to maintain an acidic pH. More preferably, the organic acid is lactic acid. Lactic acid is not only soluble in the anhydrous compositions of the present invention, it is a natural acid produced in human tissue, and is very safe for use in the compositions of the present invention. Such an organic acid is particularly useful as an acidifying agent that can help reduce the pH of the tissues to which the compositions of the present invention are applied. This will help maintain the natural acidic environment of the mucous membrane and stimulate the growth of the corresponding flora.

The compositions of the present invention may also preferably contain a heat insulating agent that functions to maintain the temperature rise by maintaining heat within the composition after it has been applied to the skin or mucous membrane. More preferably, honey can be used as a heat insulating agent.

Brief Description of the Drawings

Figure 1 is a graph depicting% viable epidermal cells versus contact time using the composition of Example 1.

Figure 2 is a graph depicting% viable epidermal cells versus contact time using the composition of Example 2.

Figure 3 is a graph depicting% viable epidermal cells versus contact time when using a non-irritating article of the prior art (K-Y Liquid®).

Figure 4 is a graph depicting% viable epidermal cells versus contact time when using a non-irritant article of the prior art (Prosensual®).

Figure 5 is a graph comparing the dynamics over time (s) of the lubricity of the composition of example 1 and three leading individual lubricants available on the market.

6 is a graph showing the results of Differential Scanning Calorimetry tests that were performed to characterize the heat release of the compositions of the invention when they came into contact with water to form a solution. In this study, the energy released by applying a thin film of a specific composition to a thin film of water was measured.

7 is a graph of the lubricity of commercially available KY®Jelly, measured both in its commercially available form and when diluted with water 1: 1.

Fig. 8 is a graph of the lubricity of a composition 14 of the present invention in comparison with the lubricity of the same composition when diluted with water 1: 1.

9 is a comparative graph of the lubricity of KY®Jelly and composition 14 in their original form.

Figure 10 is a graph illustrating the high lubricity of the two gel heating compositions 13 and 14 of the present invention.

11 is a graph showing the lubricity of KY * Ultragel and dilute composition 14.

Detailed Description of Preferred Embodiments

The compositions of this invention are essentially anhydrous, preferably containing less than about 20% water, more preferably containing less than about 5% water, most preferably containing less than about 3% water.

Preferably, the compositions of this invention contain at least one polyhydric alcohol, more preferably 2 polyhydric alcohols. Preferably, at least one of the polyhydric alcohols of the compositions of this invention is one of polyalkylene glycols or other alcohols selected from the following group: glycerol, propylene glycol, butylene glycol, hexalenglycol or polyethylene glycol of various molecular weights and the like and / or a combination thereof. More preferably, the compositions of this invention comprise polyethylene glycol; most preferably, polyethylene glycol can be selected from the following group: polyethylene glycol 400 or polyethylene glycol 300. The compositions of this invention should contain polyhydric alcohols in an amount of from about 80% to about 98% by weight of the composition.

The compositions of this invention should also preferably contain one or more water-soluble, cellulose-derived, film-forming polymers, resins, chitosans or the like. Preferably, such cellulose-derived polymers are hydroxyalkyl cellulose polymers. More preferably, the hydroxyalkyl cellulose polymer is selected from the following group: hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose and the like. Most preferably, the hydroxyalkyl cellulose polymer is hydroxypropyl cellulose, such as Klucel®, from Hercules Incorporated, Wilmington, Delaware. Most cellulose derived polymers are water soluble and insoluble in anhydrous solvents, but hydroxypropyl cellulose is completely soluble in the anhydrous polyhydric portion of the compositions of this invention. Preferably, the compositions of the present invention contain from about 0.15% to about 0.6 wt.% Hydroxypropyl cellulose to produce flowable gels and from about 1% to about 4 wt.% Hydroxypropyl cellulose to produce thixotropic gel-like materials.

The compositions of this invention preferably also contain a heat insulating agent. More preferably, the heat insulating agent should be honey or esters of isopropyl alcohol and high molecular weight saturated fatty acids, such as myristic or palmitic acid, for example, isopropyl myristate and isopropyl palmitate. The heat insulating agent should be present in the compositions of this invention in an amount of from about 1% to about 5% by weight of the composition.

The compositions of this invention are unexpectedly self-preserving and may not require a preservative agent. However, a preservative can be added to provide an additional guarantee against microbial growth. The preservative agent can be selected from preservatives known to those skilled in the art, including, but not limited to, one or more of the following: methylparaben, benzoic acid, sorbic acid, gallic acid, propylparaben, or the like. A preservative agent may be present in the compositions of this invention in an amount of from about 0.01% to about 0.75% by weight of the composition.

The compositions of this invention may also preferably contain an ester. More preferably, the ester is a fatty acid ester. Most preferably, the ester may include, but is not limited to: isopropyl stearate, isopropyl myristate, isopropyl palmitate, isopropyl laurate and the like. Most preferably, the ester is isopropyl myristate.

The compositions of this invention may contain one or more water soluble cellulose derived polymers, resins, chitosans, or the like. Such polymers contribute to the viscosity and biological adhesiveness of the compositions of this invention. More preferably, such cellulose derived polymers are hydroxyalkyl cellulose polymers. More preferably, the hydroxyalkyl cellulose polymer is hydroxypropyl cellulose or Klucel® commercially available from Hercules Incorporated, Wilmington, Dalaware.

Polyhydric alcohols used in the compositions of this invention can theoretically be used as warming and heat-generating agents. Honey functions as a heat insulating agent, protecting the composition from excessive cooling. An ester, preferably a fatty acid ester, functions as an emollient and a lubricant. The cellulosic polymer can be used as a viscosity agent. The compositions of this invention are unique in that they lubricate, warm and soothe the tissues of the user, in particular, the mucous membranes of the vagina and oral cavity, without transmitting a feeling of cold. Moreover, they are soft and lubricating.

The compositions of this invention may be a liquid, semi-solid or solid, depending on its specific intended use. The compositions of this invention can be formulated as syrup-like gel liquids, flowable gels, or high viscosity gels. Preferably, their viscosity should be in the range from about 1000 cP to about 7000 cP for gels and from about 60,000 cP to about 500,000 cP for jelly-like substances. The compositions of this invention may also be formulated into soft or hard gelatin capsules, suppositories, and impregnated into tissues or polymers.

The compositions of this invention can be used as individual lubricants that convey a sensation of warmth. The sensation of warmth produced by the compositions of the present invention has a softening effect on the skin or mucous membranes on which they are applied. The compositions of this invention also have a sweet and pleasant taste, which is especially favorable when these compositions are used orally.

The compositions of this invention can also be used as individual moisturizers that convey a feeling of warmth when applied to the mucous membrane of the vagina or oral cavity. They can be used as moisturizers that convey a feeling of warmth and facilitate dry vagina or dry mouth.

The compositions of this invention can also be used as a carrier for delivering a drug or other therapeutic agents to biological membranes, including, but not limited to, hormones, antimicrobial, antibacterial agents, antibiotics, non-steroidal anti-inflammatory drugs, sperm-destroying agents, immunomodulators, anesthetics, plant extracts, vitamins, corticosteroids or antifungal agents and the like.

Antifungal agents are preferably azoles or imidazoles, including but not limited to miconazole, econazole, terconazole, saperconazole, itraconazole, butaconazole, clotrimazole, thioconazole, fluconazole and ketoconazole, vericonazole, fenticonazole, oxonazole, elubiol, workconazole, isoconazole, flutrimazole, thioconazole and their pharmaceutically acceptable salts and the like. Other antifungal agents may include allylamine or one of the other chemical families, including, but not limited to, ternafine, natrifin, amorolfine, butenafine, cyclopirox, griseofulvin, undecyclic acid, haloprogin, tolnaftate, nystatin, iodine, rilopyrox, purpuricin, iurpuricin, purpurin their pharmaceutically acceptable salts.

Another embodiment of the invention are compositions for use on the vulvovaginal mucosa or other mucous membranes containing one or more antibiotics. The antibiotic can be selected from the group including, but not limited to, metronidazole, clindamycin, tinidazole, ornidazole, secnidazole, refaximin, trospectomycin, purpuromycin and their pharmaceutically acceptable salts and the like.

Another embodiment of the compositions of the present invention includes compositions for use on the vulvovaginal mucosa or other mucous membranes containing one or more antiviral agents. Antiviral agents may preferably include, but are not limited to, immunomodulators, more preferably imihimod, its derivatives, podofilox, podophyllin, alpha interferon, reticolos, cidofovir, nonoxynol-9 and their pharmaceutically acceptable salts and the like.

Still other embodiments of the compositions of the present invention are compositions that include one or more sperm-destroying agents. Sperm disrupters may preferably include, but are not limited to, nonoxynol-9, octoxynol-9, dodecaethylene glycol monolaurate, 10S laurel and methoxypolyoxyethylene glycol 550 laurate and the like.

Still other embodiments of the compositions of the present invention are compositions containing antimicrobial agents. Antimicrobial agents may preferably include, but are not limited to, chlorhexidine gluconate, polystyrene sodium sulfonate, cellulose sodium sulfate, micron and submicron silver particles, silver salts, and other antibacterial agents known in the art.

Other embodiments of the compositions of the present invention are compositions that may include local anesthetics. Local anesthetics may preferably include, but are not limited to, benzocaine, lidocaine, dibucaine, benzyl alcohol, camphor, resorcinol, menthol and diphenylhydramine hydrochloride and the like.

The compositions of the invention may also include plant extracts such as aloe, hazel, chamomile, hydrogenated soybean oil and colloidal oatmeal, vitamins such as vitamin A, D or E, and corticosteroids such as hydrocortisone acetate.

Another embodiment of the compositions and methods of the present invention includes compositions for vulvovaginal administration containing one or more hormones for treating decreased estrogen secretion in women in need of estrogen replacement, such as women with vaginal atrophy. Hormones may preferably include, but are not limited to, estrogen selected from the group consisting of estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, conjugated estrogen, estriol, estrone, estrone sulfate, ethinyl estradiol, estroestrol, estroflurostrol, estroflurostrol, estrofluroestrol, estrofluroestrol and estrofluroestrol.

Another embodiment of the compositions and methods of the present invention includes compositions for vulvovaginal administration containing one or more analgesics and / or non-steroidal anti-inflammatory drugs for the treatment of dysmenorrhea or menstrual cramps. Pain relievers and non-steroidal anti-inflammatory drugs may preferably include, but are not limited to, aspirin, ibuprofen, indomethacin, phenylbutazone, bromfenac, phenamate, sulindac, nabumeton, ketorolac and naproxen and the like.

In another embodiment of the compositions and methods of the present invention, the compositions themselves can be used to treat sexual dysfunction in women, since they can serve to increase blood flow to the areas to which they are applied by increasing the temperature in them. Alternatively, they may contain agents known in the art for treating sexual dysfunction in women (including various aspects of sexual dysfunction in women, such as sexual dysfunction in women, disorders with reduced sexual arousal, orgasm disorder, and the like) as well as drugs that treat dyspareunia and / or vaginismus or vulvodynia, and to relieve pain during intercourse. Such agents include hormones such as estrogen, prostaglandin, testosterone, calcium channel blockers, cholinergic modulators, alpha adrenergic receptor antagonists, beta adrenergic receptor agonists, cAMP dependent protein kinase activators, peroxide neutralizers, potassium channel activators, compounds like estrogen compounds like testosterone, benzodiazepines, adrenergic nerve inhibitors, HMG-CoA reductase inhibitors, smooth muscle relaxants, adenosine modulators -receptor and adenylyl cyclase activators. Such agents include phosphodiesterase-5 inhibitors and the like.

Another embodiment of the compositions and methods of the present invention includes compositions for use on the mucous membranes of the oral cavity, vulvovaginal region or other mucous membranes, and relates to a method for enhancing the absorption of active agents from the applied compositions onto the mucous membrane by increasing the temperature of the composition and mucous membrane tissue through the interaction of polyhydric alcohols in compositions and moisture on the mucous membrane and subsequently the generated heat.

Another embodiment of the compositions of the present invention includes compositions for vulvovaginal administration and relates to compositions and methods for preventing and / or treating dysmenorrhea by intravaginal heating or heating. Preferably, the composition heats the intravaginal region to a temperature of preferably from about 37 ° C to about 42 ° C, more preferably from about 38 ° C to about 41 ° C. Compositions of the invention for use in such a method may optionally contain active agents, such as painkillers and non-steroidal anti-inflammatory drugs for the treatment of dysmenorrhea. The composition of the invention can be administered directly into the vagina with an applicator or impregnated into vaginal devices, such as a tampon, for intravaginal applications.

The compositions of the present invention can be made in the form of a tampon coating or dispersed according to the material of the absorbent tampon, or enclosed inside as the core of the tampon. Compositions of the present invention for a warming swab for preventing and / or treating dysmenorrhea preferably include a mixture of polyethylene glycols of various molecular weights manufactured by The Dow Chemical Company (Midland, MI) under the trade names (CARBOWAX SENTRY PEG 300 NF, CARBOWAX SENTRY PEG 400 NF, CARBOWAX SENTRY PEG 600 NF, CARBOWAX SENTRY PEG 900 NF, CARBOWAX SENTRY PEG 1000 NF, CARBOWAX SENTRY PEG 1450 NF, CARBOWAX SENTRY PEG 3500 NF, CARBOWAX SENTRY PEG 4000 NF, CARBOWAX SENTRY PEG 4600 NF and CARBOWAX SENTRY PEG 4600 NF. The compositions of the present invention for the prevention and treatment of dysmenorrhea may contain one or more water soluble polymers and resins derived from cellulose gels that form gels around polyhydric alcohols, such as glycerin, propylene glycol and polyethylene glycols, thereby reducing the dissolution of polyhydric alcohols, prolonging heat generation due to solvation and adjusting the elevated temperature in the preferred temperature range.

The present invention also relates to a method for determination and comparison using EpiDerm ™ skin model analysis, as described in Example 1, of relative amounts of irritation caused by certain sources, such as compositions applied to skin cells or mucous membranes. The following example 1 illustrates the use of the method of the present invention.

Example 1

EpiDerm ™ Skin Model Analysis to Test Lubricant Irritation

The method, designated as EpiDerm ™ skin model analysis, uses epithelial cells derived from human skin as target cells and is commercially available from MatTek Corporation. This analysis is described in Berridge, M.V., et al. (1996) The Biochemical and Cellular Basis of Cell Proliferation Assays That Use Tetrazolium Salts. Biochemica 4: 14-19. Test materials are applied directly to the surface of the epithelial cell culture. This test has not previously been used to determine the toxicity of test materials. The toxicity of the test material is evaluated based on the dynamics over time of the relative viability of the tissue. Actual tissue viability is determined by MTT reduction (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) NAD (P) H-dependent microsomal enzyme in cultures treated with the control and test product. The negative control used in this analysis was deionized water, and the positive control was Triton X-100. The contacted cell culture was incubated for 4, 8, 16 and 24 hours and analyzed to detect MTT recovery. The data are presented below in FIGS. 1-4 in the form of a relationship of relative survival (relative MTT recovery) versus contact time. The relative irritation in this analysis is expressed as the survival in% of epidermal cells over a period of 24 hours. Products with a higher relative survival are less toxic or less irritating, while products with a lower survival are more toxic or more irritating. Survival using the four compositions of this invention ranged from 81.3% to 90.3%, indicating that the compositions of the present invention are substantially non-irritating.

Figure 1-4 summarizes the results of a biological analysis of a model of the epidermis of the skin. The data is a graph of% viable cells versus contact time in the range of 4 to 24 hours. Figures 1 and 2 show the results for two compositions of the present invention, respectively, compositions 1 and composition 2. Figure 3 presents the results of using the K-Y® Liquid product, which is a recognized individual lubricant available commercially. When tested in animals and humans and a long history of use in humans, it was found that the K-Y® Liquid is safe and non-irritating. The results of using the product K-Y® Liquid showed 100.3% of viable cells after 24 hours of contact (figure 3).

Example 1 of the invention (figure 1) and example 2 of the invention (figure 2) showed respectively 91.1% and 96.9% of viable cells. Figure 4 shows the results of using a warming composition known in the market. This product uses plant materials like cinnamon, cloves, ginger and orange and others to feel warm. The results show only 37.6% of viable cells after 24 hours of contact with the specified product. This indicates that such compositions will irritate the skin and mucous membranes. Compositions 1 and 2 of this invention, providing respectively 91.1% and 96.9% of viable cells, will be practically non-irritating. The positive control (Triton X-100) has only 22.4% viable cells at 8-hour intervals.

Example 2

Heat release

The compositions of the present invention are anhydrous and contain one or more polyols. When combined with water, the polyhydric alcohols used in the compositions of the present invention cause an increase in temperature, which has a calming effect on the tissues on which these compositions are applied. In actual use, the compositions of the invention interact with the moisture of the vaginal mucosa and the oral cavity, thereby increasing the temperature or creating a feeling of warmth.

The “Heat Generation” data summarized in Table 1 below was obtained by mixing 20 ml of each of the ingredients in composition 1 and composition 2 of the present invention with 20 ml of water. The product temperature and water temperature were recorded before adding water to the product. After adding water, the mixture was stirred for 2 minutes and the actual temperature was recorded. The ingredients of composition 1 are glycerin, propylene glycol and honey. From table 1 it is clear that when mixed with water, the temperature of the mixture increases by 9.0 ° F for glycerol, 13.5 ° F for propylene glycol, 17.0 ° F for polyethylene glycol 400 and 12.5 ° F for the composition of example 1 of the present invention . The calculated temperature rise for composition 1 based on the temperature rise and the amount of each individual ingredient in% wt./wt. in the composition was 10.875 ° F. The actual recorded temperature rise for composition 1 was 12.5 ° F, which is 1.625 ° F higher than expected, indicating that there is an unexpected temperature increase as a result of the combination of ingredients.

Table 1
Heat release data (temperature rise in ° F) by mixing an equal amount of each product with water The product's name Product Temperature (° F) Water temperature (° F) Average Expected Temperature (° F) Actual Temperature (° F) Temperature Rise (° F) (expected minus actual) Glycerol analysis 69.0 71.0 70.0 79.0 9.0 Propylene Glycol Analysis 72,4 71.0 71.7 85,2 13.5 Honey 74.0 71.0 72.5 74.0 1,5 K-Y Warm® 74.0 71.0 72.5 85.0 12.5 Isopropyl myristate 75.0 74.1 74.5 75,2 0.7 Polysorbate 60 70.9 74.1 72.5 83.1 10.6 Polyethylene glycol 400 72.0 71.0 71.5 88.5 17.0

Calculated temperature rise: to determine the expected temperature rise caused by each composition, the percentage of each component in such a composition is multiplied by the temperature increase caused by such a component separately to obtain its expected contribution to the temperature increase. These values are added together to calculate the total expected temperature rise. Then these values are compared with the actual rise in temperature caused by each composition. For example, the calculated temperature rise caused by the K-Y Warm® composition in the table above was found as follows and compared with the actual temperature rise to determine an unexpectedly higher heat production by the composition:

Propylene glycol (50% of 13.5) = 6.75 Glycerin (45% of 9.0) = 4.05 Honey (5% of 1.5) = 0.075 Total 10,875 Difference: 12.5-10.875 = 1.625

Example 3

Effect of water content on heat generation

After contact with moisture or water, the heat of the solution is responsible for the warming effect of the compositions of the present invention. There is concern that accidental water contamination or prolonged contact with excess moisture may adversely affect the warming ability of the product. In accordance with this example, water is added to the compositions of this invention, varying from about 1% to about 10%, as emphasized in table 2 below. The contents are thoroughly mixed and the samples are allowed to remain at room temperature for 24 hours, after which heat production determine, as emphasized in the next paragraph. The results show that the temperature rise decreases proportionally depending on the amount of water added, but there is still an increase of 8.5 ° F in temperature when approximately 10% of water is added.

The results of this example are summarized in table 2 below.

table 2
Effect of water content on heat generation for KY Warm® composition The product's name Sample Temperature (° F) Water temperature (° F) Average Expected Temperature (° F) Actual Temperature (° F) Temperature Rise (° F) (expected minus actual) Without water 73.80 70.00 71.90 83.50 11.60 1% water 73.90 70.00 71.95 82,20 10.25 2% water 72.30 70.00 71.95 81.70 9.85 3% water 72.30 70.00 71.15 80.40 9.25 4% water 72,20 70.00 71.10 80.70 9.60 5% water 71.60 70.00 70.80 80.40 9.60 6% water 71.60 70.00 70.80 80.40 9.60 7% water 71.50 70.00 70.75 80,20 9.45 8% water 71.60 70.00 70.80 80,20 9.40 9% water 70.90 70.00 70.45 79.50 9.05 10% water 70.50 70.00 70.25 79.00 8.05

Example 4

Perception of warmth when used in humans

A study of human use was performed in 246 individuals. The data obtained in this study are summarized in table 3 below. Individuals were asked to use the compositions of this invention. They were asked the following 3 questions regarding the perception of heat when using a product:

1. Does it warm on contact?

2. Does it give a feeling of warmth?

3. He does not give a feeling of cold?

Individuals were asked to register their response in the form of “excellent”, “very good”, “good”, “good” and “bad”. Positive responses are summarized in table 2.

Table 3
The perception of heat in a study of use in 246 people using the composition of example 1 of the invention Asked Question Positive answer (%) Heats on contact A great 25.12 Very good 31.88 Good 24.64 Total 81.64 Gives a feeling of warmth A great 30.88 Very good 28.92 Good 25.98 Total 85.78 Does not give a feeling of cold A great 54.37 Very good 29.61 Good 10.19 Total 94.53

As shown in table 3 above, 81.64% of people reported a positive response that the product “warms upon contact”, 85.78% of people felt that the product “gives a feeling of warmth”, while 94.53% of people reported that the product "Does not give a feeling of cold."

Example 5

Lubricity Comparison

Ahmad et al. US Pat. No. 6,139,848, which is incorporated herein by reference, describes a method for testing the lubricity of various individual lubricants known on the market. In the described test method, the lubricity of various commercially available individual lubricants was determined over a period of 300 s (5 min). The lubricity data disclosed in this patent indicates that the K-Y Liquid® lubricant had a higher lubricity and lasted longer for a 300 s test period than competing products. The lubricity data set forth in US Pat. No. 6,139,848 has a negative sign (-) during the “on my own” phase of the experiment and a positive sign (+) during the “on my own” phase of the experiment. The compositions of this invention were tested using the lubricity test presented in US patent No. 6129848. However, the test duration was successfully continued up to 16 min (960 s), and the data was processed to “fit the curve” in order to eliminate the negative (-) sign. The lubricity data of composition 1 of the present invention are compared in the K-Y Liquid® data in FIG. The data indicate that composition 1 of the present invention has a higher lubricity compared to K-Y Liquid®, and that composition 1 retains a high lubricity for an extended period of 16 hours (960 minutes) and therefore is longer acting.

Example 6

Heat solution

It is believed that the warming effect of the compositions of the present invention is caused by heat generation by the solution, in contrast to the creation of conditions for exothermic reactions. Exothermic reactions lead to heat generation due to a chemical reaction between two chemicals and are uncontrolled. As a result of such an exothermic chemical reaction, new products or chemical structural units can be obtained, some of which may not be suitable for human tissues. In contrast, when a solution is formed, a change in energy occurs due to the difference between the attractive forces of dissimilar and similar molecules. In particular, the bonds between the molecules of each mixed component are destroyed, and new bonds are formed between neighboring molecules of the product or solution mixture. This mechanism is different from the heat of reaction because there is no chemical rearrangement of the atoms of the ingredients to form products from the reactants. As can be seen from the following experiment, the maximum heat generated or the maximum temperature rise is not more than 18.8 ° F, which makes these compositions very soft and safe.

The dissolution process for the compositions of the present invention (COMPOSITION 15 of example 9 below), for example, in vaginal fluids ("X H ₂ O") can be represented by the following physical equation:

COMPOSITION 15 (1) + Н ₂ О (1) → COMPOSITION 15 (Х Н ₂ О)

The designation “COMPOSITION 15 (X H ₂ O)” represents that the product is a solution of 1 (mol) of COMPOSITION 15 in X (mol) H ₂ O. Thus, when using COMPOSITION 15, the composition in accordance with the present invention as an individual lubricant means does not change the existing amount of naturally occurring vaginal fluids. It just forms a solution with them.

The maximum temperature increase possible as a result of heat production using the compositions of the present invention can be measured using thermodynamic principles. For example, differential scanning calorimetry (DSC) was used to characterize the heat released by the compositions of the present invention when they come into contact with water to form a solution. In this test, the energy released when a thin film of a particular composition was applied to a thin film of water was measured. The results of a typical test are presented in Fig.6. The exothermic (i.e., negative) peak area represents the total energy released during the formation of a solution of the composition of the present invention and water. Table 4 summarizes the energy released in this series of experiments.

Table 4
Summary of DSC measurements of heat generated by composition 15 / water Experiment The composition of the invention (mg) Released Energy (mJ) one 17.85 398,878 2 22.5 355,108 3 28.32 267,229 average value 22.89 340,405 Standard deviation 5.25 67,045

The energy release measured by DSC is a representative indicator of the maximum energy that would be observed on the surface of the vaginal tissue. This is because the heat current (energy flow) into the thin film of water during the formation of the solution, measured by DSC, is equal to the heat current (energy flow) that would be on the surface of the vaginal tissue. Therefore, thermodynamics can be used to calculate the maximum possible temperature rise as follows:

where Q _max represents the maximum released energy during contact (formation of a solution) of the composition 15 and water; C _pm represents the specific heat of a solution of composition 15 and water; and ΔT _max represents the maximum temperature rise. Thus, by rebuilding equation 1, it is possible to calculate ΔT _max , the maximum temperature rise, based on the known or measured values of the maximum released energy and heat capacity of the solution of composition 15 as follows:

By assuming a normal distribution, the experimental results presented in Table 1 can be used to arrive at an estimate of the worst case maximum value Q _max as follows:

(Using this as the upper limit, the upper limit of confidence represents 99.73% for the normal distribution).

In the case of C _{pm, a} smaller value of C _p for composition 15 and C _p for water can be used to arrive at an estimate of the worst case of its minimum value. Insofar as

then

Therefore, to assess the worst case of a maximum increase in temperature, possible as a result of heat production by composition 15, one can come up using a combination of equations 2, 3 and 4 as follows:

Thus, the maximum heat released after applying the composition 15 is a maximum of about 10.5 ° C or 18.8 ° F, a relatively small heat release, indicating that the temperature increase carried out by the compositions of the present invention is safe and comfortable for the user .

Example 7

Heat release

Compositions 10, 11 and 12 were tested in accordance with the following procedure to determine the extent to which said compositions give off heat after mixing with water. Data was obtained by mixing 20 ml of each composition with 20 ml of water. The temperature of the composition and the temperature of the water were recorded before adding water to the composition, after adding water, the contents were mixed for 2 minutes and the actual temperature was recorded. The results are presented in the following table 5:

Heat release data (temperature rise in ° F) by mixing an equal amount of each composition with water The product's name Product Temperature (° F) Water temperature (° F) Average Expected Temperature (° F) Actual Temperature (° F) Temperature Rise (° F) (Expected Minus Actual) Temperature rise for compositions of the invention Composition 10 73.00 70.3 71.6 87.3 15.7 Composition 11 73.00 70.3 71.6 83,2 11.6 Composition 12 73.00 70.3 71.6 87.1 15,5 Temperature rise for individual components of compositions Polyethylene glycol 400 72.0 71.0 71.5 88.5 17.0 Propylene glycol 72,4 71.0 71.7 85,2 13.5 Glycerol 69.0 71.0 70.0 79.0 9.0

The calculation of the temperature rise for compositions 10, 11 and 12:

Composition 10

Propylene glycol (38% of 13.5) = 5.13

Polyethylene glycol 400 (61.5% of 17.0) = 10.45

Total: 15.58 ° F

Composition 11

For composition 11, the calculated temperature rise is 15.58 ° F.

Composition 12

For composition 12, the calculated temperature rise is 15.15 ° F.

The calculated temperature for all three compositions is very close to the actual temperature rise.

Example 8

Lubricity Comparison

Using the method of testing and comparing the lubricity of various individual lubricants described in Example 3 above, the lubricity of the compositions of the present invention was determined. The following is a summary of the results.

The gel compositions of the present invention have the same lubricity as the aqueous gel compositions described in US Pat. No. 6,139,848 to Ahmad et al. 7, the lubricity of a commercially available KY® Jelly product was measured both in its commercially available form and in a 1: 1 dilution with water. After dilution, the lubricity was not significantly increased.

The jelly-like compositions of the present invention have greater lubricity compared to prior art aqueous jellies known in the market. Composition 14 of the present invention was measured in terms of lubricity in its original form and when diluted 1: 1 with water. Surprisingly, its lubricity is significantly increased (approximately 4 times) after dilution. These data are presented in Fig. 8. Thus, the jelly-like compositions of the present invention become more lubricating or their lubricity is increased when these compositions are diluted with water in a ratio of 1: 1. Figure 9 shows a comparison of the lubricity values of the KY® Jelly product and composition 14 in their original form. Figure 10 illustrates the lubricity values of two warming gel-like compositions of the present invention, compositions 13 and 14, exhibiting their high lubricity values. 11 shows the product KY * Ultragel and the diluted composition 14.

Example 9

Compositions of the invention

The following compositions of the present invention were prepared as follows: firstly, propylene glycol and glycerin were mixed. Then, a preservative agent and a heat insulating agent were added to the mixture in the same container. Then the mixture was heated to a temperature of from about 35 ° C to about 45 ° C to completely dissolve the preservative agent. Then the mixture was cooled. Gel and jelly compositions were prepared by mixing propylene glycol, polyethylene glycol and hydroxypropyl cellulose in a high speed mixer at a temperature of from about 60 ° C to about 70 ° C to obtain a soft gel or jelly. The resulting gel or jelly was cooled to a temperature of from about 45 ° C to about 55 ° C and lactic acid was added. The mass was continuously stirred for 15 minutes or until lactic acid was dissolved. Then the mass was cooled to room temperature.

Composition 1: Propylene glycol 50.0% Glycerol 45.00% Honey 5.00% Composition 2: Propylene glycol 50.0% Glycerol 20.00% Isopropyl myristate 27.00% Polysorbate 60 3.00% Composition 3: Propylene glycol 95.0% Honey 5.00% Composition 4: Propylene glycol 50.0% Glycerol 20.00% Isopropyl myristate 29.50% Klucel hf 0.50% Composition 5: Propylene glycol 99.50% Klucel hf 0.50% Composition 6: Propylene glycol 49.80% Glycerol 45.00% Honey 5.00% Preserving agent 0.20% Composition 7: Miconazole nitrate 2.00% Propylene glycol 49.80% Glycerol 43.00% Honey 5.00% Preserving agent 0.20% Composition 8: Fluconazole 2.00% Propylene glycol 49.80% Glycerol 43.00% Honey 5.00% Preserving agent 0.20% Composition 9: Metronidazole 3.00% Propylene glycol 49.80% Glycerol 42.00% Honey 5.00% Preserving agent 0.20% Composition 10 (Gel): Propylene glycol 38.00 Polyethylene glycol 400 61.05 Lactic acid 00.20 Hydroxypropyl cellulose 0.75 Composition 11 (Jelly): Propylene glycol 37.00 Polyethylene glycol 400 61.05 Lactic acid 0.20 Hydroxypropyl cellulose 1.75 Composition 12 (Gel): Propylene glycol 48.00 Polyethylene glycol 400 51.30 Lactic acid 0.20 Hydroxypropyl cellulose 0.50 Composition 13 (Jelly): Propylene glycol 48.55 Polyethylene glycol 400 50.00 Lactic acid 0.20 Hydroxypropyl cellulose 1.25 Composition 14 (Jelly): Propylene glycol 98.55 Lactic acid 0.20 Hydroxypropyl cellulose 1.25 Composition 15 (Jelly): Polyethylene glycol 400 98.55 Lactic acid 0.20 Hydroxypropyl cellulose 1.25 Composition 16 (Gel): Polyethylene glycol 400 99.50 Lactic acid 0.20 Hydroxypropyl cellulose 0.30 Composition 17 (Gel): Propylene glycol 74.50 Glycerol 25.00 Lactic acid 0.20 Hydroxypropyl cellulose 0.30 Composition 18 (Gel): Propylene glycol 74.50 Polyethylene glycol 400 25.00 Lactic acid 0.20 Hydroxypropyl cellulose 0.30 Composition 19 (Gel): Propylene glycol 69.50 Polyethylene glycol 400 15.00 Glycerol 15.00 Lactic acid 2.00 Hydroxypropyl cellulose 0.30 Composition 20 (Jelly): Propylene glycol 73.55 Polyethylene glycol 400 25.00 Lactic acid 0.20 Hydroxypropyl cellulose 1.25

Claims (21)

1. Anhydrous antifungal gel composition comprising at least one polyhydric alcohol and a gelling agent and an antifungal azole compound. 2. The composition of claim 1, wherein said antifungal compound comprises an imidazole compound. 3. The composition according to claim 2 in which the imidazole compound is selected from the group consisting of miconazole, econazole, terconazole, saperconazole, itraconazole, butaconazole, clotrimazole, thioconazole, fluconazole and ketoconazole, vericonazole, fenticonazole, sertaconazole, oxazonazole, posacon , elubiol, workconazole, isoconazole, flutrimazole, thioconazole and their pharmaceutically acceptable salts. 4. The composition of claim 1, further comprising a pH adjusting agent. 5. The composition according to claim 1, wherein said polyhydric alcohol is selected from the group consisting of glycerol, alkylene glycol, polyethylene glycol and mixtures thereof. 6. The composition according to claim 1, wherein said gelling agent is hydroxypropyl cellulose. 7. The composition according to claim 4, in which the pH regulating agent is an organic acid. 8. The composition according to claim 7, in which the organic acid is alpha-hydroxy acid. 9. The composition of claim 8, wherein said alpha-hydroxy acid is lactic acid. 10. The composition of claim 5, wherein said polyethylene glycol is selected from the group consisting of polyethylene glycol 300, polyethylene glycol 400, and mixtures thereof. 11. The composition according to claim 1, which includes from about 75 to about 99 wt.% Polyhydric alcohol, from about 0.1 to about 4 wt.% Hydroxypropyl cellulose and from about 0.1 to about 1 wt.% Lactic acid and about 0.25 to about 20 wt.% antifungal agents. 12. The composition according to claim 1, which is a transparent, colorless gel. 13. The composition according to claim 7, which brings the pH of the vagina to an acidic pH from about 2 to about 5. 14. The composition according to claim 1, comprising at least one polyhydric alcohol and a gelling agent and an antifungal azole compound, the gel containing less than 5% water. 15. The composition of claim 14, wherein the antifungal agent comprises an imidazole compound. 16. The composition according to p. 15, in which the imidazole compound is selected from the group consisting of miconazole, econazole, terconazole, saperconazole, itraconazole, butaconazole, clotrimazole, thioconazole, fluconazole and ketoconazole, vericonazole, fenticonazole, sertaconazole, bacon sulconazole, elubiol, workonazole, isoconazole, flutrimazole, thioconazole and their pharmaceutically acceptable salts. 17. A method of treating a patient with fungal infections, comprising administering to a patient in need thereof a composition according to claim 1. 18. The method according to 17, characterized in that the infection is vulvovaginal candidiasis. 19. The method according to 17, where the patient has vulvovaginal candidiasis. 20. The method according to 17, where the patient has an oral fungal infection. 21. The method according to 17, where the patient has a fungal infection of the nails.

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