KR20050062466A - Warming and nonirritating anhydrous lubricant compositions - Google Patents

Abstract

The present invention relates to a substantially anhydrous, warm, non-toxic and non-irritating lubricant composition comprising one or more polyhydric alcohols and gelling agents, as well as related gel and jelly compositions. The present invention also relates to methods of using such lubricating compositions, methods of administering active ingredients, and methods for preventing or treating dysmenorrhea.

Description

Warming and nonirritating anhydrous lubricant compositions

The present invention relates to a substantially anhydrous personal lubricant gel and jelly composition which is warm and non-irritating when applied to the skin or mucosa, in particular the vaginal or oral mucosa. In some embodiments, the compositions of the present invention are substantially anhydrous and contain one or more polyhydric alcohols. The invention also relates to methods that can be used to test and compare the compositions of the invention with other personal lubricants known in the art. Unlike known compositions which use exothermic reactions to generate warmth or stimulants to sense warmth, the compositions of the present invention use "heat of dissolution" to generate warmth. The warm feeling produced by the compositions of the present invention is very pleasant and soft compared to known compositions. The compositions of the present invention also have a higher lubricity to tissues than existing known warmable compositions. In addition, while the lubricity of the compositions of the present invention increases upon dilution with water, the lubricity of existing known aqueous compositions tends to decrease upon dilution with water. Therefore, in practical use, the compositions of the present invention will be considered to have a higher lubricity compared to existing compositions known in the art.

Humans are warm-blooded animals whose body temperature is kept constant at 98.6 ° F. (37 ° C.). Human skin and external organs have a very efficient circulatory and nervous system that can recognize temperature changes very quickly. Personal lubricants and agents are usually administered to the human mucosa at room temperature, i. Because of the significant temperature difference between room temperature and human body temperature, users of these lubricants and drugs feel that the lubricants and drugs are quite cold. This feeling of cold can cause significant discomfort to the user. At times, attempts have been made to develop products to overcome this perceived cold.

Many personal lubricant compositions are known in the art. Such compositions are a category of intravaginal administration suppositories ranging from jelly to liquids, ranging from aqueous to oily silicone substrates. Most compositions currently used in practice are aqueous jelly or aqueous liquids. Almost all personal lubricants known and available for use today can be cold and unpleasant to the touch.

Many compositions that claim to impart warmth upon administration to the skin or mucous membranes are known in the art or described in the literature. These compositions fall into several main categories, which are usually based on mechanisms of action.

Some of these compositions use plant extracts that irritate skin and mucous membranes and give warmth or such awareness due to the action of irritants. Other compositions claim to increase blood flow to warm tissue. Another composition is believed to act on the principle of freezing point drop and is very suitable for heating in a microwave or cooling in a refrigerator. There is a cosmetic composition that is self-heated by enclosing a compound containing a boron-boron bond that exothermicly reacts with water.

One category of warmable compositions uses plant extracts or agents that stimulate the skin or mucous membranes, such as methyl salicylate. For example, WO 97 / 02273A describes phosphate derivatives useful in oral and topical compositions for recognizing warmth. The composition contains a warming component such as vanylyl derivative. The composition also contains ethanol, niacin, latent, nicotinic acid, gingeron, vanylyl alcohol isopropyl ether, gingerol, methyl salicylate, sogaol, paradol, gingeron, capsaicin, dihydrocapsaicin, nordihydrocapsaicin Additional warming agents are included, including homocapsaicin, tintuer capsicum, eucalyptus oil.

Another category of warmable products is the use of mechanisms that increase blood circulation. The invention of "L-Arginine to cause tissue warming, sustained release of nitric oxide to cause tissue warming, delayed release of nitric oxide for treating diabetes, stimulating hair growth, and wound healing. US Pat. No. 5,895,658, treat effects of diabetes, stimulate hair growth and heal wounds, describes agents that increase the blood flow of tissues, thereby causing beneficial effects such as warming cold tissue of the hands and feet.

Another category of warm products uses inorganic compounds that produce an exothermic reaction that causes heat release. WO 200260408 A1 relates to anhydrous cosmetic hair care compositions containing inorganic salts such as, for example, sodium sulfate, calcium sulfate, aluminum sulfate, calcium chloride, magnesium chloride, calcium oxide or magnesium sulfate. When mixed with water, these compositions generate heat.

KR 20010227018 describes a pyrogenic cosmetic containing an active zeolite composition which promotes blood circulation and metabolism by imparting warmth to the skin. JP 63159490A relates to a pyrogenic cosmetic composition which contains a reducing agent such as sodium sulfite, sodium thiosulfate, sodium pyrosulfite or sodium hydrogen sulfite and an oxidizing agent such as sodium bromide, potassium bromide or sodium perbromide and is especially used for hair softening. .

EP 2001306347 relates to a composition used to prepare shaving hair. The composition contains one or more substances that undergo significant chemical changes when mixed during shaving. The material changes temperature, releases odors and undergoes oxidation, hydration, acid based reactions or exothermic reactions.

Another category of heat generating products uses mechanisms different from the three categories described above. US 20020142015 A1 and JP 2002179517 A describe warming compositions for pharmaceuticals, bath additives, bathroom articles and cosmetics containing coolants and certain p-hydroxybenzaldehyde derivatives. The reason for using such p-hydroxybenzaldehyde coolant is to give the product a warming effect for a longer period of time. FR 2810240 A1 is a component that can either absorb or release heat, giving it a cool refreshing effect when exposed to heat, or a warming effect when exposed to low temperatures (e.g., a long-chain hydrocarbon compound that can absorb or store heat to absorb heat). It describes a cosmetic composition containing a. US 362516A describes self heating lathers which are rapidly heated by hydrogen peroxide via a thiosulfredox reaction.

JP 2001335429 describes gel cosmetics containing 40 to 75% by weight polyethylene glycon, 20 to 55% by weight glycerol and carboxyvinyl polymer. These compositions are used to generate heat to promote blood circulation and metabolism in the tired state and to warm up during shaving. One example of a composition known under the trade name Prosensual ^R , distributed by Lexy Trading, Inc., Fairro, NJ, USA, is Cinnamon cassia (Cinnamon), Zinziber. Contains plant extracts known as skin irritants such as Zingiber officinalis (ginger), peppermint, sandalwood, oranges and cloves. Such compositions can cause irritation of the mucosa, causing problems with the vaginal or oral mucosa as the stimulation promotes the growth of undesired bacteria and causes infection.

As another commercial composition, WET ^™ heated massage oils, distributed by International, Valencia, CA, include retinyl palmitate (vitamin A palmitate), Prunus amygdalis; Purness), Amara (almond), Persica gratissima (avacca oil), Macdamia termifulia seed oil, Cakeri fruit oil, Helianthus annus (hybrid) Sunflower), Cannabis sativa (hemp) seed oil and aloe vera. Many of these components are known stimulants that are not suitable for use on mucous membranes.

Heat-Resisting and Absorbing Compositions and Containers for Use in Microwave Ovens, " Flexible Gels, Wetting Agents, Freezing Point Lowering Agents, Gel Sealers, Polyacrylamide Absorbers, Corn Starch Binders, Mineral Oil and Plasticizers, Durable, Efficient {Microwavable heat releasing and absorbing compositions and container, pliable gel comprising humectant, freezing point depressant, gel sealer, polyacrylamide absorbent, corn starch binder, mineral oil and plasticizers, durability, efficacy}. Describe compositions that are suitable for heating, cooling in a cooler, or placed in suitable containers or vinyl packaging (eg, hot and cold packs), but not suitable for human consumption or use.

However, none of these compositions is substantially "warm" or relatively higher than the ambient temperature of the product or the surrounding environment.

The invention is entitled "Method of treating skin and hair with a self heated cosmetic, organic boron-oxygen-boron compounds}" US Pat. No. 4,110,426 describes a non-aqueous composition such as a shaving cream that is self-heated by containing a compound containing one or more boron-oxygen-boron bonds, such as triethoxyboroxine. Boron containing compounds react exothermicly with water or other protic substances to increase the temperature. Such compositions are not suitable for intravaginal or oral use due to the potential toxicity of boron containing compounds to human reproduction systems [Fail PA, et al., General, reproductive, developmental, and endocrine toxicity of boronated compounds., Reprod toxicol 12: 1, 1-18, Jan-Feb, 1998].

Physical energy forms have been used to increase the transport of material across membranes for therapeutic purposes. Such energy forms include electricity, ultrasound and heat energy (eg, heat assisted drug delivery), which have been reviewed in the literature by Sun [Skin absorption Enhancement by Physical Means: Heat, Ultrasound, and Electricity ", Transdermal and Topical Drug Delivry Systems, Interpharm Press, Inc., 1997, pages 327-355. Local heating of the skin or mucosal tissue, as well as the drug delivery system of the composition, increases the thermodynamic energy of the drug molecules and mucosal permeability to promote drug transport through the barrier membrane, as well as improve blood circulation within the tissues, thereby improving systemic circulation from local tissues to systemic circulation. It also promotes drug elimination. These two processes increase drug absorption. Experiments have demonstrated that low levels of heating (ie, tissue temperatures below about 42 ° C.) significantly increase transdermal drug absorption.

U.S. Patent 5,658,583 describes a heat generating device that improves the transdermal penetration of a medicament. The apparatus includes a thin drug formulation reservoir and a heat generating chamber of oxidation reaction separated by a non-permeable wall. The drug formulation reservoir stores a predetermined amount of formulation containing the medicament. The heat generation / temperature control chamber comprises a heat generation medium consisting of salts activated by contact with oxygen in carbon, iron, water and / or air. However, such complex heating means are not suitable for use in the vaginal cavity or oral cavity due to the apparent safety concerns.

Locally applied heat (eg abdominal heating patches) has been used to treat dysmenorrhea or dysmenorrhea with proven efficiency. See 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 a disposable heating element pad that generates heat through oxidation to relieve dysmenorrhea when applied to abdominal skin. Currently on the market for the treatment of dysmenorrhea on the basis of abdominal heating [ThermaCare ^R air activated heating wrap, menstrual pain, manufactured by Proctor & Gamble, Cincinnati, Ohio, USA. Mitigation patch]. However, there is no product that describes internal local heating to treat dysmenorrhea.

Summary of the Invention

The compositions and methods of the present invention relate to non-irritating gel and jelly compositions in a substantially anhydrous state. The compositions and methods of the present invention contain cellulose gelling derivatives and polyhydric alcohols. Preferably, the cellulose gelling derivative is hydrocolloid. The composition of the present invention can be used as a warming lubricant composition which can be used as a personal lubricant designed to be non-toxic, non-irritating and in contact with the skin or mucous membranes. When mixed with water, the gel and jelly compositions of the present invention increase the temperature to produce warmth. This has a soothing effect on the tissues to which these compositions are applied. This substantially eliminates the cold air or the detection of such cold air that comes with use of existing personal lubricants.

The composition of the present invention is excellent in lubrication properties. The gel and jelly compositions of the present invention are more lubricious than commercially available aqueous lubricant products. The composition of the invention, in particular the jelly composition of the invention, is novel in that the lubricity is increased upon dilution with water. Known commercial aqueous compositions have reduced lubricity upon dilution with water. This is particularly useful in that the compositions of the present invention can be used in connection with wet vaginal or oral mucosa and can further increase lubricity upon exposure to moisture in the vagina or oral cavity.

Although anhydrous compositions are commonly recognized to stimulate skin and mucous membranes, the gel and jelly compositions of the present invention are surprisingly nonirritating.

The composition of the present invention may be applied to the skin or mucosa, preferably to the vagina or oral mucosa. The composition of the present invention is preferably substantially anhydrous and preferably contains one or more polyhydric alcohols.

The inventors have found that when the polyhydric alcohols contained in the compositions of the present invention come into contact with water or human body fluids, they react with surrounding water molecules to increase the temperature or create warmth, thereby exerting a calming effect on the tissue to which these compositions are applied. Theorized.

Surprisingly, contrary to the general belief that polyhydric alcohols in the composition irritate the mucosa, the compositions of the present invention containing such polyhydric alcohols have been found to be non-irritating. We theorized that hydrocolloids useful in the compositions and methods of the present invention swell when contacted with water to produce a lubricity coated gel. Such coatings physically block the stimulating action of other anhydrous atoms of the compositions of the present invention. Additionally, as polyhydric alcohols useful in the compositions of the present invention that are humectants and humectants, when hydrocolloids are flattened to form a thin film against mucosal tissue, the thin film retains a moisturizer on the tissue surface. Thus, the compositions of the present invention overcome drying symptoms such as vaginal dryness and dry mouth caused by various diseases as well as various factors including menopause and aging.

Thus, the compositions of the present invention are very soft to the skin and mucous membranes. When the composition of the present invention is applied to the oral mucosa, it has a sedative effect, and may act to relieve slight irritation of the oral cavity and neck.

Mixtures of polyhydric alcohols in the compositions of the present invention can be used as vehicles for solubilizing other insoluble drugs including, but not limited to, antifungal, antibacterial, antiviral, analgesic, anti-inflammatory steroids, contraceptives, local anesthetics, and hormones. have.

Preferably, the composition of the present invention is maintained at acidic pH. Acidic pH is very helpful for maintaining healthy vagina and oral flora, especially Lactobacilli in the vaginal region. Existing acids or buffers are known to be insoluble in anhydrous compositions. Preferably, the compositions of the present invention contain organic acids that are soluble therein to maintain acidic pH. More preferably, the organic acid is lactic acid. Lactic acid is not only soluble in the anhydrous composition of the present invention, but is also a natural acid produced in human tissue and is very safe for use in the composition of the present invention. Such organic acids are particularly useful as acidifying agents which may be helpful in lowering the pH of the tissue to which the composition of the present invention is applied. This will help maintain the natural acidic environment of the mucosa and encourage the growth of suitable flora.

It may be desirable for the composition of the present invention to contain an insulating agent which, after being applied to the skin or mucous membrane, acts to preserve the temperature increase by maintaining heat inside the composition. More preferably, honey can be used as insulation.

1 is a graph depicting epithelial cell viability versus time of exposure using the composition of Example 1. FIG.

FIG. 2 is a graph depicting epithelial cell viability versus time of exposure using the composition of Example 2. FIG.

FIG. 3 is a graph depicting% epithelial cell viability versus exposure time using a high technology non-irritating product (KY Liquid ^™ ).

FIG. 4 is a graph depicting% epithelial cell viability versus exposure time using a high-tech warmable product (Progressive ^R ).

5 is a graph comparing the lubricity versus time (seconds) of the composition of Example 1 and three commercially available personal lubricants.

The composition of the present invention is substantially anhydrous and preferably contains less than about 20% by weight of water, more preferably less than about 5%, most preferably less than about 3%.

Preferably, the composition of the present invention contains at least one polyhydric alcohol, more preferably two polyhydric alcohols. Preferably, at least one polyhydric alcohol of the composition of the present invention is polyalkylene glycol or other selected from the group consisting of glycerin, propylene glycol, butylene glycol, hexylene glycol or polyethylene glycol of various molecular weights and / or mixtures thereof. Polyhydric alcohol. More preferably, the composition of the present invention contains polyethylene glycol, most preferably the polyethylene glycol may be selected from polyethylene glycol 400 and polyethylene glycol 300. The composition of the present invention should contain the polyhydric alcohol in an amount of about 80% to about 98% of the composition.

The composition of the present invention preferably contains one or more water soluble cellulose derived film forming polymers, rubber, chitosan and the like. Preferably, such cellulose derived polymers are hydroxyalkylcellulose polymers. More preferably, the hydroxyalkyl cellulose polymer is selected from the group consisting of hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like. Most preferably, the hydroxyalkylcellulose polymer is hydroxypropyl cellulose, such as Klucel ^R commercially available from Hercules Incorporated, Wilmington, Delaware. Most of the cellulose derived polymerizations are water soluble and insoluble in anhydrous solvents, but hydroxypropylcellulose can be completely dissolved in the anhydrous multivalent fraction of the compositions of the present invention. Preferably, the compositions of the present invention contain about 0.15 to about 0.6 weight percent hydroxypropyl cellulose to provide a flowable gel, and about 1 to about 4 weight percent hydroxypropyl cellulose provide thixotropic jelly. .

The composition of the present invention preferably also contains an insulation. More preferably, the insulation should be an ester of honey or isopropyl alcohol with saturated high molecular weight fatty acids such as myristic acid or palmitic acid, such as isopropyl myristate and isopropyl palmitate. The insulation should be present in the composition of the present invention in an amount of about 1 to about 5 weight percent of the composition.

The compositions of the present invention are exceptionally self-preserving and do not require preservatives. However, preservatives may be added to further ensure that the microorganisms do not grow. Preservatives may be selected from preservatives known to those skilled in the art, examples of which include, but are not limited to, one or more of methylparaben, benzoic acid, sorbic acid, gallic acid, propylparaben, and the like. Preservatives may be present in the compositions of the present invention in an amount from about 0.01 to about 0.75% by weight of the composition.

The composition of the present invention may also preferably contain an ester. More preferably, the ester is a fatty acid ester. Most preferably, the ester may comprise isopropyl stearate, isopropyl myristate, isopropyl palmitate, isopropyl laurate and the like. Most preferably, the ester is isopropyl myristate.

Compositions of the present invention may contain one or more water soluble cellulose derived polymers, rubber, chitosan, and the like. Such polymers contribute to the viscosity and biological adhesion of the compositions of the present invention. Preferably, such cellulose derived polymers are hydroxyalkylcellulose polymers. More preferably, the hydroxyalkylcellulose polymer is Clucell ^R commercially available from hydroxypropylcellulose or Hercules Incorporated, Wilmington, Delaware, USA.

The polyhydric alcohols used in the compositions of the present invention are theorized to be useful as warming and heat generating agents. Honey acts as an insulation to protect the composition from overcooling. Esters, preferably fatty acid esters, act as softeners and lubricants. The compositions of the present invention are unique in that they lubricate, warm and soothe the tissues of their users, especially the oral and vaginal mucosa, while not giving cold air. Moreover, they are soft and lubricious.

The composition of the present invention may be liquid, semisolid or solid, depending on the particular intended use. The composition of the present invention may be formulated as a syrup type liquid-gel, flowable gel or high viscosity jelly. Preferably, their viscosity ranges from about 1,000 to about 7,000 cps for gel and from about 60,000 to about 500,000 cps for jelly. The compositions of the present invention may also be formulated into soft or hard gelatin capsules, suppositories and impregnated into fabrics or polymers.

The composition of the present invention can be used as a personal lubricant to give warmth. The warmth produced by the compositions of the present invention has a calming effect on the skin or mucous membranes to which they are applied. The compositions of the present invention also have a sweet and refreshing flavor, which is particularly advantageous when these compositions are used orally.

The compositions of the present invention can also be used as personal moisturizers that give warmth when administered to the vagina or oral mucosa. They can be used as moisturizers to give warmth and relieve vaginal dryness or dry mouth.

Compositions of the invention also include, but are not limited to, hormones, antimicrobials, antibacterial agents, antibiotics, nonsteroidal anti-inflammatory agents, spermicides, immunodilators, anesthetics, plant extracts, vitamins, corticosteroids or antifungal agents, etc., in biological membranes. Can be used as a vehicle for delivering a drug or other treating agent.

Antifungal agents are preferably myconazole, econazol, terconazole, saperazole, itraconazole, butaconazole, clotrimazole, trioconazole, fluconazole and kenoconazole, vericonazole, penticonazole, sertaconazole, Posaconazole, biponazole, oxyconazole, sulfonazole, elrubiol, borconazole, isoconazole, flutrimazole, thioconazole, and pharmaceutically acceptable salts thereof. Not azole or imidazole. Other antifungal agents include allylamine or ternapine, naphthypine, amololpin, butenapin, cyclopyrox, griffulbin, undecylclinic acid, haloprogin, tolnaftate, nystatin, iodine, lilopy And other pharmaceuticals, including but not limited to Rox, BAY 108888, furfuromycin, and pharmaceutically acceptable salts thereof.

Another aspect of the invention is a vulva or other mucosal composition containing one or more antibiotics. Such antibiotics include, but are not limited to, metronidazole, clindamycin, tinidazole, ornidazole, cecinidazole, refaximin, trosfectomycin, furfuromycin, and pharmaceutically acceptable salts thereof. Can be selected.

Another aspect of the composition of the present invention includes a vulva or other mucosal composition containing one or more antiviral agents. The antiviral agent is preferably an immunomodulatory agent, more preferably imiquimod and its derivatives, grapephylox, grapephylline, interferon alfa, reticulose, sidopovir, nonoxynol-9 and pharmaceutically acceptable thereof Salt, and the like, but is not limited thereto.

Another aspect of the compositions of the present invention is a composition comprising one or more spermicides. Spermicides may preferably include but are not limited to nonoxynol-9, octocinol-9, dodecaethyleneglycol monolaurate, lauret 10S and methoxypolyoxyethyleneglycol 550 laurate, and the like. Does not.

Another aspect of the composition of the present invention is a composition containing an antimicrobial agent. The antimicrobial agents preferably include chlorohexidine gluconate, sodium polystyrene sulfonate, sodium cellulose sulfate, silver particles of micrometer size or smaller than micrometers, silver salts and other antibacterial agents known in the art. It is possible, but not limited to.

Another aspect of the compositions of the present invention is a composition that may include a local anesthetic. Local anesthetics 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 present invention also include plant extracts such as aloe, witch hazel, chamomile, hydrogenated soybean oil and colloidal oatmeal; Vitamins such as vitamins A, D and E; And corticosteroids such as hydrocortisone acetate.

Another aspect of the compositions and methods of the present invention includes a composition for vulva containing one or more hormones to treat a decrease in estrogen secretion in a woman in need of estrogen replacement, such as a woman with reduced vaginal function. The hormone is preferably estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, conjugated estrogen, estriol, estrone, estrone sulfate, ethynyl estradiol, est And estrogens selected from the group consisting of rofurate, quinestrol and mestranol.

Another aspect of the compositions and methods of the present invention includes a composition for vulvovaginia containing at least one analgesic and / or nonsteroidal anti-inflammatory agent for treating dysmenorrhea or dysmenorrhea. Analgesics and nonsteroidal anti-inflammatory agents may preferably include, but are not limited to, aspirin, ibuprofen, indomethacin, phenylbutazole, bromfenac, phenamate, sulindac, nabumethone, ketorolac and naproxen, and the like. .

In another aspect of the compositions and methods of the methods of the invention, the compositions may increase blood flow to these areas by increasing the temperature of the areas to which they are applied, and by themselves would be useful in treating female sexual dysfunction. Can be. In addition, they treat female sexual dysfunctions (including various aspects of female sexual dysfunctions such as female sexual arousal disorders, hypoactive sexual desire disorders, orgasm disorders) as well as sexual dysplasia and / or vaginal or vulvar pain and relieve pain during sexual intercourse. To be known to those skilled in the art. Such agents include hormones such as estrogen, prostaglandins, testosterone; Calcium channel blockers, choline modulators, alpha-adrenergic receptor antagonists, beta-adrenergic receptor agonists, cAMP-dependent protein kinase activators, superoxide scavengers, potassium channel activators, estrogen-type compounds, testosterone-type compounds, benzodiazepines, adrenergic neurosuppressors , HMG-CoA reductase inhibitors, relaxation muscle relaxants, adenosine receptor modulators and adenylyl cyclase activators. Such agents include phosphodiesterase-5 inhibitors and the like.

Another aspect of the compositions and methods of the present invention includes a composition for use in oral and vulvar or other mucosal applications, wherein the composition is through the interaction of the polyhydric alcohol in the composition with water on the mucosa and subsequently heat released. And a method of increasing the uptake of the active agent into the mucosa from the administered composition by increasing the mucosal tissue temperature.

Another aspect of the composition of the present invention comprises a composition for vulva, and relates to compositions and methods for preventing and / or treating dysmenorrhea by vaginal warming or heating. Preferably, the composition heats the vaginal region preferably to a temperature in the range of about 37 to about 42 ° C, more preferably about 38 to about 41 ° C. Compositions of the invention for use in such methods may optionally contain active agents such as nonsteroidal anti-inflammatory and analgesic agents for the treatment of dysmenorrhea. The composition of the present invention may be administered directly into the vagina by an applicator or impregnated into a vaginal device such as tampon for vaginal application.

The composition of the present invention may be prepared as a coating of the probe, dispersed entirely in the absorbent tampon material or embedded as a core of the tampon. Compositions of the invention for use in warm tampons to prevent and / or treat dysmenorrhea are preferably trademarked by CARBOWAX SENTRY PEG by The Dow Chemical Company, Midland, Mich. 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 4500 NF, Carbowax Sentry PEG 4600 NF and Carbowax Sentry PEG 8000 NF, including a mixture of polyethylene glycols of various molecular weights. The composition of the present invention for the prevention and treatment of dysmenorrhea forms a gel around polyhydric alcohols such as glycerin, propylene glycol and polyethylene glycol, thereby reducing the decomposition rate of the polyhydric alcohol, prolonging solvation heat release and increasing the temperature rise in the preferred temperature range. It may contain one or more water soluble cellulose derived polymers and rubbers to regulate.

The invention also measures and compares the relative amount of stimulation induced by a particular source (e.g., a composition applied to skin or mucosal cells) using an EpiDerm ^™ skin model assay as described in Example 1. It is about how to. The following example 1 illustrates the case where the method of the present invention is used.

Example 1 EpiDerm ^™ Skin Model Assay for Test Stimulation of Lubricant

The method designated as the Epiderm ^™ skin model assay uses epithelial cells derived from human skin as target cells and commercially available from MattTek Corporation. The assay was Bridge M. Berridge, MV et al., The Biochemical and Cellular Basis of Cell Proliferation Assays That Use Tetrazolium Salt. Biochemica 4: 14-19]. The test material is applied directly to the epithelial cell culture surface. This test has never been used to determine the toxicity of test materials. Toxicity of the test material is assessed based on relative tissue viability over time. Actual tissue viability is measured by NAD (p) H-dependent microsomal enzyme of MTT in control cultures and cultures treated with the test product. The negative control culture used is deionized water and the positive control culture is Triton X-100. The exposed cell culture is incubated for 4 hours, 8 hours, 16 hours and 24 hours, and the rate of decrease of MTT is assayed. The data are shown in FIGS. 1-4 in the form of relative survival (relative MTT reduction) relative to exposure time. Relative stimulation in this assay is represented by% survival of epithelial cells over 24 hours. Products with higher relative survival are less toxic or less irritant, while lower survival is more toxic or irritant. The survival rates of the four compositions of the present invention range from 81.3 to 90.3%, indicating that the compositions of the present invention are basically non-irritating.

1-4 summarize the results of epithelial model biological assays. The data are plotted as% cell viability over time of exposure ranging from 4 to 24 hours. 1 and 2 show the results of each of the two compositions of the present invention, namely Composition 1 and Composition 2. 3 shows the results of KY ^R , a personal lubricant established on the market. KY ^R Liquid is established to be safe and non-irritating in animal and human testing and from human use for a long time. The results of KY ^R Liquid show 100.3% cell viability after 24 hours of exposure (FIG. 3).

Example 1 (FIG. 1) of the present invention and Example 2 (FIG. 2) of the present invention have cell viability of 91.1% and 96.9%, respectively. 4 shows the result of a warmable composition known under the trade name. The product uses plant materials such as cinnamon, cloves, ginger cloves and oranges and other warming ingredients. The test result is only 37.6% cell viability after 24 hours of exposure to this product. This indicates that such compositions irritate the skin and mucous membranes. Compositions 1 and 2 of the present invention having cell viability of 91.1% and 96.9%, respectively, are substantially non-irritating. Positive control (Triton X-100) has only 22.4% cell viability after 8 hours.

Example 2: Warmth Generation

The composition of the present invention is anhydride and contains one or more polyhydric alcohols. When mixed with water, the polyhydric alcohols used in the compositions of the present invention have a soothing effect on the tissues to which these compositions are applied. In practical use, the compositions of the present invention interact with moisture in the vaginal or oral mucosa, thereby raising the temperature or creating warmth.

The "generation of warmth" data summarized in Table 1 below is generated by mixing 20 ml of each component of Composition 1 and Composition 2 of the present invention with 20 ml of water. Record the temperature of the product and the temperature of the water before adding water to the product. After addition of water, the mixture is mixed for 2 minutes and the actual temperature is recorded. Glycerin, propylene glycol and honey are components of composition 1. It is evident from Table 1 that when mixed with water the temperature of the mixture rises at 9.0 ° F. for glycerin, 13.5 ° F. for propylene glycol, 17.0 ° F. for polyethylene glycol 400 and 12.5 ° F. for the composition of the present invention. The temperature rise calculated for Composition 1 based on the weight / weight percent of each individual component of the composition and the temperature rise is 10.875 ° F. The actual rise in temperature recorded for Composition 1 is 12.5 ° F., which is 1.625 ° F. higher than the estimate indicating the temperature increase prediction generated from the mixture of components.

Calculated Temperature Rise: To determine the temperature rise prediction from each composition, the percentage of each component in such a composition is multiplied by the temperature rise produced by this component alone to obtain the expected contribution to the temperature increase. These numbers are summed to calculate the overall temperature rise prediction. These values are then compared to the actual temperature rise produced by each composition. For example, the temperature rise estimates produced by the KY ^R Warm ^™ composition in the table were found to be as follows, which are compared with the actual temperature rises to determine the exceptionally high warmth generation of 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 the Generation of Warmth

Upon contact with water or water, the heat of dissolution causes a warming action of the composition of the present invention. Accidental contamination with water or prolonged exposure to excessive moisture can adversely affect the warming performance of the product. According to this example, about 1 to about 10% of water is added to the composition of the present invention as schematically shown in Table 2 below. The contents are mixed homogeneously, the sample is allowed to stand at room temperature for 24 hours and then the production of warmth is measured as outlined in the next paragraph. The result is that the temperature rise decreases proportionally with the quality of the added water, but the temperature rise is still 8.5 ° F. when about 10% water is added.

The results of this example are shown in Table 2 below.

Example 4 Detection of Warmth in Human Use

Human use studies are performed on 246 subjects. The data generated by this study is summarized in Table 2 below. Subjects are required to use the compositions of the present invention. As they use this product, they are asked three questions about the detection of warmth:

1. Was it warm on contact?

2. Did you feel warmth?

3. Didn't you feel cold?

The subject is required to record the response as excellent, very good, good, good or bad. Positive reactions are summarized in Table 2.

As shown in Table 3 above, 81.64% of the subjects showed a positive response to feeling "warm on contact" with the product, and 85.78% of the subjects felt "warmth" in the product, while 94.53% of the subjects in the product It was recorded as "not feeling cold".

Example 5: Comparison of Lubricants

United States Patent No. 6,139,848 to Ahmad et al., Incorporated herein by reference, describes a method for testing the lubricity of various personal lubricants known under the trade names. In the test method described, the lubricity of various commercially available personal lubricants is measured for 300 seconds (5 minutes). The lubrication data described in this patent indicated that the lubrication of the KY Liquid ^™ lubricant was higher and lasted longer for the 300 second test period compared to the comparative product. Lubricity data shown in US Pat. No. 6,139,848 shows a negative sign during "push" in the experiment and a positive sign during the "pull" phase. The compositions of the present invention were tested using the lubricity test shown in US Pat. No. 6,129,848. However, the test period was successfully extended to 16 minutes (960 seconds) and the data was processed as "curve-fit" to remove the negative sign. Lubricity data for Composition 1 of the present invention is compared with data for KY Liquid ^R in FIG. 5. The data indicate that Composition 1 of the present invention is more lubricious than KY Liquid ^R , and that Composition 1 lasts longer because it maintains high lubricity for an extended period of 16 minutes (960 seconds).

Example 6: heat of dissolution

The warming effect of the compositions of the present invention is believed to be induced by generating heat of dissolution as opposed to creating conditions for exothermic reactions. Exothermic reactions are not controlled due to the release of heat due to chemical reactions between the two drugs. Such exothermic chemical reactions may produce new products or chemical entities, some of which may not be suitable for human tissue. In contrast, when a solution is formed, there is an energy change due to the difference between the molecules and different or similar attractive forces. Specifically, the bonds between the molecules of each component to be mixed are broken and new bonds are formed between adjacent molecules of the product mixture or solution. This mechanism is different from the heat of reaction because the constituent atoms do not chemically rearrange to form products from the reactants. As can be seen from the following experiments, the maximum heat is produced or the maximum temperature rise is 18.8 ° F. or less, which makes these compositions very mild and safe.

The dissolution process for the composition of the present invention (composition 15 of Example 9) can be represented, for example, by the following scheme 1 in vaginal body fluids ("XH ₂ O").

Composition 15 (1) + XH ₂ O (1) → Composition 15 (XH ₂ O)

In Scheme 1 above, “Composition 15 (XH ₂ O)” indicates that the product is a solution in which 1 (mole) of composition 15 is dissolved in H ₂ OX (mole). Thus, using composition 15, the composition according to the invention as a personal lubricant does not change the existing amount of natural vaginal fluid. It simply forms a solution with them.

The maximum temperature increase possible from heat generation by using the compositions of the present invention can be measured using thermodynamic principles. For example, differential scanning calorimetry (DSC) is used to characterize the heat released by a composition of the invention when it is in contact with water to form a solution. In this test, the energy released when a thin film of a particular composition is applied to a thin film of water is measured. Typical test results are shown in FIG. 6. The exothermic (ie negative) peak region represents the total energy released during the formation of a solution of water with the composition of the present invention. Table 1 summarizes the energy released for this series of experiments.

The energy release measured by DSC represents the maximum energy that can appear on the surface of vaginal tissue. This is because the heat flux (energy flow) into the thin film of water in solution formation as measured by DSC can correspond to the heat plus (energy flow) that may be in the fluid on the surface of the vaginal tissue. Therefore, thermodynamics can be used to estimate the maximum possible temperature, as in the following equation.

Q _max = C _pm ΔT _max

In Equation 1 above,

Q _max represents the maximum energy released during contact of composition 15 with water (solution formation),

C _pm represents the heat capacity of the solution of composition 15 and water,

ΔT _max represents the maximum temperature rise.

Thus, by rearranging Equation 1, the inventors calculated the maximum temperature rise, ΔT _max , based on the maximum energy released and the known or measured value of the heat capacity of the solution of composition 15, as shown in Equation 2 below. can do.

ΔT _max = Q _max / C _pm

By estimating the normal distribution, the test results in Table 1 can be used to estimate the maximum value of Q _max in the worst case as in Equation 3 below.

Q _max = {tested average energy release + 3 × (standard deviation of tested energy release)} / (average amount of composition 15) = {(340.405mJ) + (3) (67.045mJ)} / (22.89mg) = (541.539mJ / 22.89mg)

(If used as an upper limit, this represents an upper confidence limit of 99.73% for a normal distribution.)

For C _pm, the more the C _p and C _p of water to the composition 15 the enemy use it can reach the estimate of the minimum value of the worst case, as shown in equation (4).

C _p (Composition 15) = 0.54 cal / (g- ° C)

C _p (Composition 15) = 1.00 cal / (g- ° C)

C _pm (Minimum value in worst case) = 0.54cal / (g- ℃)

Therefore, the worst case estimate of the maximum possible temperature increase from heat generation by composition 15 can be reached using equations (2), (3) and (4) as follows.

Thus, the maximum heat released upon use of Composition 15 is relatively low at most about 10.5 ° C. or 18.8 ° F., which indicates that the temperature increase exerted by the compositions of the present invention is safe and indicates comfort to the user.

Example 7: Warmth Generation

Compositions 10, 11 and 12 are tested according to the following procedure to determine the extent to which these compositions generate warmth when mixed with water. Data is generated by mixing 20 ml of each composition with 20 ml of water. The temperature of the composition and the temperature of the water are recorded before adding water to the composition. After the addition of water, the contents are mixed for 2 minutes and the actual temperature is recorded. The results are shown in the following table.

We estimated temperature rises 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 ℉

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 temperatures calculated for all three compositions are very close to the actual temperature rise.

Example 8: Lubricity Comparison

The lubricity of the compositions of the present invention is measured using the method of testing and comparing the lubricity of the various personal lubricants shown in Example 3 above. The results are summarized below:

The gel composition of the present invention has lubricity on the order of the aqueous gel composition described in US Pat. No. 6,139,848 to Ahmad et al. In Figure 7, the lubricity of the commercial KY ^R jelly is measured for both the commercial form and the form diluted 1: 1 with water. Upon dilution, the lubricity does not substantially increase.

The jelly composition of the present invention has a higher lubricity compared to the state of aqueous jelly in the art known under the trade name. Composition 14 of the present invention was measured for lubricity in the initially prepared state and for lubricity when diluted 1: 1 with water. Surprisingly, its lubricity increased significantly (about 4 times) upon dilution. This data is shown in FIG. 8. Thus, the jelly compositions of the present invention have greater lubricity when these compositions are diluted 1: 1 with water. Figure 9 shows the results of comparing the lubricity of KY ^R jelly and composition 14 in the initial form. FIG. 10 shows the high lubricity of two warmable gel compositions of the present invention, namely composition 13 and composition 14. FIG. 11 is KY ^* ultragel and diluted composition 14.

Example 9 Compositions of the Invention

The following composition of the invention is prepared as follows: First, propylene glycol and glycerin are mixed. The preservative and insulation are then added to the mixture in the same container. The mixture is then heated from about 35 ° C. to about 45 ° C. to completely dissolve the preservative. Then the mixture is cooled. The gel and jelly compositions are prepared by mixing propylene glycol, polyethylene glycol and hydroxypropylcellulose at a temperature of about 60 to about 70 ° C. in a high speed mixer until a smooth gel and jelly are obtained. The resulting gel or jelly is cooled to about 45 ° C. to about 55 ° C. and lactic acid is added. The material is mixed continuously for about 15 minutes or until the lactic acid is dissolved. The material is then cooled to room temperature.

Composition 1:

Propylene Glycol 50.00%

Glycerin 45.00%

5.00% honey

Composition 2:

Propylene Glycol 50.00%

Glycerin 20.00%

Isopropyl Myristate 27.00%

Polysorbate 60 3.00%

Composition 3:

Propylene Glycol 95.00%

5.00% honey

Composition 4:

Propylene Glycol 50.00%

Glycerin 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%

Glycerin 45.00%

5.00% honey

Preservative 0.20%

Composition 7:

Myconazole nitrate 2.00%

Propylene Glycol 49.80%

Glycerin 43.00%

5.00% honey

Preservative 0.20%

Composition 8:

Fluconazole 2.00%

Propylene Glycol 49.80%

Glycerin 43.00%

5.00% honey

Preservative 0.20%

Composition 9:

Metronidazole 3.00%

Propylene Glycol 49.80%

Glycerin 42.00%

5.00% honey

Preservative 0.20%

Composition 10 (Gel):

Propylene Glycol 38.00%

Polyethylene Glycol 400 61.05%

Lactic acid 0.20%

Hydroxypropylcellulose 0.75%

Composition 11 (jelly):

Propylene Glycol 37.00%

Polyethylene Glycol 400 61.05%

Lactic acid 0.20%

Hydroxypropylcellulose 1.75%

Composition 12 (gel):

Propylene Glycol 48.00%

Polyethylene Glycol 400 51.30%

Lactic acid 0.20%

Hydroxypropylcellulose 0.50%

Composition 13 (jelly):

Propylene Glycol 48.55%

Polyethylene Glycol 400 50.00%

Lactic acid 0.20%

Hydroxypropylcellulose 1.25%

Composition 14 (jelly):

Propylene Glycol 98.55%

Lactic acid 0.20%

Hydroxypropylcellulose 1.75%

Composition 15 (Jelly):

Polyethylene Glycol 400 98.55%

Lactic acid 0.20%

Hydroxypropylcellulose 1.25%

Composition 16 (Gel):

Polyethylene Glycol 400 99.50%

Lactic acid 0.20%

Hydroxypropylcellulose 0.30%

Composition 17 (gel):

Propylene Glycol 74.50%

Glycerin 25.00%

Lactic acid 0.20%

Hydroxypropylcellulose 0.30%

Composition 18 (Gel):

Propylene Glycol 74.50%

Polyethylene Glycol 400 25.00%

Lactic acid 0.20%

Hydroxypropylcellulose 0.30%

Composition 19 (gel):

Propylene Glycol 69.50%

Polyethylene Glycol 400 15.00%

Glycerin 15.00%

Lactic acid 2.00%

Hydroxypropylcellulose 0.30%

Composition 20 (Jelly):

Propylene Glycol 73.55%

Polyethylene Glycol 400 25.00%

Lactic acid 0.20%

Hydroxypropylcellulose 1.25%

This application is a partial continuing application of US Patent Application No. 10 / 137,509 and co-pending US Patent Application No. _______ (Agent Dock No. PPC 834 CIP 1), which is incorporated herein by reference.

Claims (19)

A lubricant composition in a substantially anhydrous state comprising at least one polyhydric alcohol and a gelling agent. The lubricant composition of claim 1 further comprising a pH adjuster. The lubricant composition of claim 1 wherein the polyhydric alcohol is selected from glycerin, alkylene glycol, polyethylene glycol, and mixtures thereof. The lubricant composition of claim 1 wherein the gelling agent is hydroxypropyl cellulose. 4. The lubricant composition of claim 3 wherein the alkylene glycol is selected from the group consisting of propylene glycol, butylene glycol and hexalene glycol. The lubricant composition of claim 4 wherein the polyethylene glycol is selected from the group consisting of polyethylene glycol 300, polyethylene 400, and mixtures thereof. The lubricant composition of claim 1 wherein the gelling agent is lactic acid. 6. The composition of claim 5 comprising about 75 to about 99 weight percent polyhydric alcohol, about 0.1 to about 4 weight percent hydroxypropyl cellulose and about 0.1 to about 1 weight percent lactic acid. The lubricant composition of claim 1 wherein the viscosity is from about 1,000 to about 7000 cps. The lubricant composition of claim 1 wherein the viscosity is from about 60,000 to about 500,000 cps. The lubricant composition of claim 1 further comprising an antimicrobial agent. The lubricant composition of claim 11 wherein the antimicrobial agent is an antifungal agent. The lubricant composition of claim 11 wherein the antimicrobial agent is an antibacterial agent. The lubricant composition of claim 11 wherein the antimicrobial agent is an antiviral agent. The lubricant composition of claim 1 further comprising a spermicide. The lubricant composition of claim 1 further comprising a local anesthetic. A method of treating or preventing dysmenorrhea, including intravaginally administering a composition according to claim 1. The lubricant composition of claim 1 wherein the temperature rises upon moisture exposure. 8. The lubricant composition of claim 7, wherein the pH is adjusted to between about 2 and about 6.