WO2006127057A1

WO2006127057A1 - Non-systematic vaginal administration of estrogen and an androgen for the treatment of sexual dysfunction

Info

Publication number: WO2006127057A1
Application number: PCT/US2006/002185
Authority: WO
Inventors: John W. Lyle
Original assignee: Lyle Corporate Drvelopment, Inc.
Priority date: 2005-05-24
Filing date: 2006-01-20
Publication date: 2006-11-30

Abstract

Methods and formulations for treating female sexual dysfunction are provided. A pharmaceutical composition for topical non-systemic administration is formulated so as to contain a selected estrogen and/or androgen agent administered to the vagina, vulvar area of the individual undergoing treatment.

Description

NON-SYSTEMATIC VAGINAL ADMINISTRATION OF ESTROGEN AND AN ANDROGEN FOR THE TREATMENT OF SEXUAL DYSFUNCTION

CLAIM FOR PRIORITY

[0001] This application claims priority to U.S. provisional application no. 60/684,574, filed on May 24, 2005, the contents of which are incorporated by reference herein.

1. Technic ±al Field

[0002] This invention relates generally to methods and pharmaceutical formulations for treating female sexual dysfunction, and more particularly relates to the acute, non-systemic administration of an estrogen and/or androgen to the vaginal, vulvar and/or urethral area of a female patient, in need of such treatment. The invention further relates to methods of using the present pharmaceutical formulations, including, but not limited to, the improved vaginal cell health as determined by vaginal tissue blood flow, regeneration of vaginal cells, and number of healthy vaginal cells present.

2. Description of the Related Art

[0003] The present invention is directed to a new, highly effective non-systemic method of treating sexual dysfunction in women. The method involves an acute administration of a pharmaceutical formulation to the vaginal, vulvar and/or urethral area of a female containing an estrogen and androgen or the like.

[0004] Drug therapy for treating female sexual dysfunction has been described. For example, U.S. Pat. No. 4,521,421 to Foreman describes the treatment of sexual dysfunction in male and female individuals using the stereoisomers of octahydropyrimido[4,5-g]quinolines, centrally acting dopamine agonists.

[0005] U.S. Pat. No. 5,190,967 to Riley describes the treatment of sexual disorders in male and female individuals using heterocyclic benzodioxinopyrrole compounds, which, like the drugs described in the aforementioned patents, are centrally acting agents.

[0006] U.S. Patent No. 5,460,820 to Ebert et al. discloses a method of providing testosterone replacement therapy to a woman in need of such therapy comprising applying a testosterone-delivering patch.

[0007] U.S. Pat. Nos. 5,565,466 to Gioco et al., 5,731,339 to Lowrey, and 5,773,457 to Nahoum pertain to methods for modulating the human sexual response, with the Gioco et al. and Lowrey patents emphasizing the utility of phentolamine as an active agent.

[0008] U.S. Patent No. 5,877,216 to Place et al. discloses methods and formulations for treating female sexual dysfunction using a pharmaceutical formulation containing " selective vasodilating agents and the co-administration of testosterone to the vaginal area of the patient.

[0009] U.S Patent No. 6,395,744 to Adams et al. describes a method of treating sexual dysfunction in a female by stimulating peripheral pelvic nerve release of nitric oxide. The- preferred compound for the method described therein is apomorphine, with or without a potentiating amount of an androgen compound.

[0010] U.S. Patent No. 6,294,550 to Place et al. describes a method and formulations for treating female sexual dysfunction using selected vasoactive agents administered to the vaginal area of the patient undergoing treatment.

[0011] U.S. Patent No. 6,306,841 to Place et al. discloses methods and formulations for the treatment of female sexual dysfunction using selected vasoactive agents administered to the vaginal area of the patient undergoing treatment. [0012] U.S. Patent No. 6,756,407 to Heaton et al. discloses a method of treating sexual dysfunction in females by stimulating peripheral nerve release of nitric oxide. The method comprises the administration of apomorphine alone or with an apomorphine potentiating amount of an androgen.

[0013] Problems associated with prior art therapies stem from their chronic, systemic administration. For example, hormone replacement therapy (i.e. estrogen and progestin to replace the hormones lost at menopause) is administered systemically to relieve hot flashes, night sweats, and vaginal dryness and to improve women's health. However, their systemic administration can cause an increased risk in breast cancer, heart attacks, strokes, and blood clots as reported in one study published in the July 17, 2002, Journal of the American Medical Association. As disclosed therein, hormone replacement therapy side effects cause a 26% risk of invasive breast cancer, 41% risk of having a stroke, a 100% risk of blood clots, and a 29% risk of heart attack.

[0014] Testosterone administered as tablets, injection, implanted pellet, or skin patch may produce side effects such as, masculinisation with acne and excess body hair, scalp hair loss, fluid retention, deepening of the voice, enlargement of the clitoris and adverse effects on blood cholesterol. Further, systemic use of vasodialators in the treatment of sexual dysfunction have reported side effects of headache, nausea, facial flushing, diarrhea and potentially fatal drug interactions.

[0015] There are, accordingly, a number of background references relating to treatment of female sexual dysfunction, with vaginal, cervical or uterine administration of various medicinal agents. However, the present method for treating female sexual dysfunction, by way of non-systemic vaginal, vulvar delivery of an estrogen and/or androgen, is completely novel and unsuggested by the art. SUMMARY OF THE INVENTION

[0016] The present invention provides a method of treating a female patient exhibiting one or more symptoms associated with a condition of sexual dysfunction and who is not receiving chronic hormonal therapy.

[0017] Specifically, the present invention is a method of treating sexual dysfunction in a human female which comprises administering directly to the vaginal tissue of a human female exhibiting one or more symptoms associated with a condition of sexual dysfunction and who is not receiving chronic hormonal therapy, prior to the

_* female engaging in sexual intercourse, an effective sexual dysfunction treatment amount of a composition comprising at least one hormone selected from the group consisting of estrogen and androgen and/or pharmaceutically acceptable salt and ester thereof.

[0018] In a second embodiment of the present invention, the method comprises administering directly to the vaginal tissue, prior to the female engaging in sexual intercourse, an effective non-systemic sexual dysfunction treatment amount of a composition comprising at least one hormone selected from the group consisting of estrogen and androgen and/or pharmaceutically acceptable salt or ester thereof, wherein said non-systemic amount does not enter the blood stream of the female.

[0019] In a third embodiment of the present invention, the method comprises administering on an acute administrative basis directly to the vaginal tissue, prior to the female engaging in sexual intercourse, an effective non-systemic sexual dysfunction treatment amount of a composition comprising at least one hormone selected from the group consisting of estrogen and androgen and/or pharmaceutically acceptable salt or ester thereof, wherein said acute administrative basis comprises administering said amount directly to the vaginal tissue of the female, from about 5 minutes to about 6 hours, before the female engages in sexual intercourse. [0020] In a forth embodiment of the present invention the composition further comprises an effective amount of a vasodilating agent.

[0021] In a fifth embodiment of the present invention, a method of promoting vaginal cell health, enhancing vaginal lubrication, and minimizing sexual problems resulting from vaginal cell hypoxia, involving vaginal, vulvar administration of a composition comprising a pharmaceutical formulation containing a selected estrogen and/or androgen agent, in combination with a pharmaceutically acceptable vehicle.

[0022] In yet another embodiment of the present invention, the claimed method further comprises the use of a water-soluble lubricant.

[0023] In still another embodiment of the present invention, pharmaceutical formulations useful in conjunction with the aforementioned methods are provided.

[0024] Accordingly, a method is provided herein for the treatment a female patient in need of such treatment exhibiting one or more symptoms associated with a condition of sexual dysfunction and who is not receiving chronic hormonal therapy which comprises applying an sexual dysfunctional treatment amount of a pharmaceutical formulation comprising at least one hormone selected from the group consisting of an estrogen and androgen and/or pharmaceutically acceptable salt or ester thereof, directly to the vaginal tissue of the female patient, prior to the female engaging in sexual intercourse, such that sexual dysfunction is treated.

DEFINITIONS

[0025] In describing and claiming the present invention, the following terminology will be used.

[0026] "Administration," and "administering" refer to the manner in which a drug is presented to a subject. Administration can be accomplished by various routes well- known in the art, however, as contemplated herein, non-oral methods, such as topical application is the preferred method.

[0027] The term "acute" as used herein is for short-term administration of the formulations described herein. Short-term, or acute, administration is carried out prior to engagement in sexual intercourse. Alternately stated, acute administration is the application of the formulations described herein minutes to hours prior to the act of sexual intercourse. Conversely, long-term or chronic administration would be carried out for a period of at least three days to a week to many weeks, months, or even years. In preferred embodiments, the inventive formulations are administered on an acute basis prior to sexual intercourse.

[0028] "Androgenic steroid," or "androgen," refer to a steroid, natural or synthetic, which exerts its biological or pharmacological action primarily by binding to androgen receptors. Examples include, but are not limited to: testosterone, methyltestosterone, androstenedione, adrenosterone, dehydroepiandrosterone, oxymetholone, fluoxymesterone, methandrostenolone, testolactone, pregnenolone, 17 α- methylnortestosterone, norethandrolone, dihydrotestosterone, danazol, androsterone, nandrolone, stanozolol, ethylestrenol, oxandrolone, bolasterone, mesterolone, testosterone propionate, testosterone cypionate, testosterone phenylacetate, and testosterone enanthate, testosterone acetate, testosterone buciclate, testosterone heptanoate, testosterone decanoate, testosterone caprate, testosterone isocaprate, as well as esters, derivatives, prodrugs, and isomers thereof.

[0029] "Coadministration" and similar terms refer to administration of multiple substances to one individual, either simultaneously or sequentially. Thus, with reference to estrogen and androgen, the term includes any situation in which women are receiving non-oral estrogen and non-oral androgen.

[0030] "Estrogen," and "estrogenic hormone" refer to any substance, natural or synthetic, that exerts a biological or pharmacological action primarily by binding to estrogen receptors. Examples include but are not limited to: 17-β-estradiol, 17-α- estradiol, estriol, estrone, and phytoestrogens. These estrogens may be derivatized or modified to form, for example, conjugated equine estrogens, esterified estrogens, ethinyl estradiol, etc. Examples of esterified estrogens include but are not limited to: estradiol- 3,17-diacetate, estradiol-3 -acetate, estradiol- 17-acetate, estradiol-3,17-divalerate, estradiol-3 -valerate, estradiol- 17-valerate. The estrogens may also be present as salts, (e.g.,as sodium estrogen sulfate), isomers, or prodrugs.

[0031] Also included, are phytoestrogens which are plant-derived estrogens. Isoflavones are one major form of phytoestrogen and have a common diphenolic structure that resembles the structure of potent synthetic estrogens such as diethylstilbesterol and hexestrol. Major isoflavones found in humans include, but are not limited to genistein, diadzein, and equol.

[0032] The term "effective amount" is used throughout the specification to describe concentrations or amounts of compounds according to the present invention which may be used to produce a favorable change in the symptomology, disease or condition treated, whether that change is a decrease in or reversal of the effects of symptomology or disease state depending upon the disease state or condition treated. In the present invention, in preferred aspects, an effective amount is that amount which is used to treat the symptomology associated with sexual dysfunction. An effective amount for purposes of treating one or more symptoms of the present invention, includes the non- systemic manner in which an active compound is administered to a patient.

[0033] The terms "formulation" and "composition" are used interchangeably herein. The terms "pharmaceutical" and "drug" are also used interchangeably to refer to a pharmacologically active substance or composition. These terms of art are well-known in the pharmaceutical and medicinal arts.

[0034] "Improved vaginal cell health" refers to reducing, improving, or preventing the incidence and/or intensity of symptoms associated with estrogenic or androgenic steroid deficiency of the vaginal tissue. Examples of such symptoms include but are not limited to: sexual dysfunction, which can manifest in loss of sexual desire, decreased sensitivity to sexual stimulation, decreased arousability and capacity for orgasm, diminished vital energy, depressed mood, diminished sense of well-being, increased shyness, loss of muscle mass and function, and a combination thereof.

[0035] Many evaluations may be employed for measuring the achievement of desired effects in the case of androgen and estrogen delivery to the vaginal cells, which are well known in the art. Such evaluations may be performed by a physician, or other qualified medical personnel, and may include physical examination, blood tests, tissue samples and histological examination.

[0036] "Local administration" means administration by a non-systemic route at or in the vicinity of the site of an affliction, disorder or complication.

[0037] The term "menopause" is used throughout the specification to describe the period in a human female's life between the ages of approximately 45 and 50 after which menstruation (menses) naturally ceases. The symptomology associated with menopause which is particularly relevant to the present invention includes bone loss associated with osteoporosis and most importantly, vaginal dyspareunia.

[0038] The term "non-systemic" refers to local administration such that the compound being administered does not significantly enter the blood stream.

[0039] By "systemic" administration is meant oral, intravenous, intraperitoneal and intramuscular administration of a compound that provides a significant blood level.

[0040] By "topical administration" is meant non-systemic administration and includes the application of the compounds of the invention externally to the epidermis and instillation of such a compound into the vagina of a female, and where it does not significantly enter the blood stream. [0041] "Testosterone" refers to the compound having the IUPAC names (17 β)- 17-Hydroxyandrost-4-en-3-one, and Δ4 -androsten-17β-ol-3-one, as well as their isomers. Testosterone is listed in the Merck Index, entry no. 9322, at page 1569, 12th ed., (1996).

[0042] "Therapeutic effect" refers to a desired result which is achieved to some degree. In the context of estrogen and androgen supplementation as presented in the present patent application, a number of desired results are referred to as "improving vaginal cell health." In one aspect, therapeutic effects may be achieved by delivering a non-systemic "effective amount" of a substance capable of achieving the desired result to a selected degree. While the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a subjective decision.

[0043] The term "vaginal dyspareunia" is used throughout the specification to describe a symptom or condition of menopause wherein vaginal atrophy, dryness and pain during sexual intercourse occurs.

[0044] "Vaginal application" means a composition in which the drug may be placed for direct application to the vaginal skin surface and from which an effective amount of drug is released. Examples of topical formulations include but are not limited to ointments, creams, gels, sprays, vaginal rings, and pastes.

[0045] ' Vaginal administration can be accomplished by applying, pasting, rolling, attaching, pouring, pressing, rubbing, etc., of a topical preparation onto the vaginal skin surface. These and additional methods of administration are well-known in the art.

[0046] "Woman" refers to a human female who benefits from an androgen or estrogen administration in any way. In one aspect, the female may be pre, peri or post menopausal due to age, oophorectomy, or ovarian failure. In yet another aspect, the female may display a deficiency, or imbalance of the vaginal cells which may benefit from the topical non-systemic administration of an estrogen and/or androgenic hormone.

[0047] Concentrations, amounts, solubilities, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.

DETAILED DESCRIPTION

[0048] The present invention provides a method a method of treating sexual dysfunction in a human female which comprises administering directly to the vaginal tissue of a human female exhibiting one or more symptoms associated with a condition of sexual dysfunction and who is not receiving chronic hormonal therapy, prior to the female engaging in sexual intercourse, an effective sexual dysfunction treatment amount of at least one hormone selected from the group consisting of estrogen and androgen and/or pharmaceutically acceptable salt and ester thereof.

[0049] The pharmaceutical formulations of the invention will include at least one member selected from the group consisting of estrogen and androgen, or a pharmaceutically acceptable salt, ester, or pro-drug thereof. "Pharmaceutically acceptable salts, esters, or inclusion complexes" refer to those salts, esters and inclusion complexes ■ which retain the biological effectiveness and properties of the base compounds and which are not biologically or otherwise undesirable.

[0050] Salts, esters and inclusion complexes of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base (typically wherein the neutral form of the drug has a neutral NH₂ group) using conventional means, involving reaction with a suitable acid.

[0051] ■ Estrogens will generally be selected from the group consisting of, pharmaceutically acceptable salts and esters of any of the foregoing, and mixtures thereof. Specifically, such steroids include estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estriol, estrone, estrone benzoate, ethynyl estradiol, and mestranol, in the estrogen family, and acetoxypregnenolone, ethisterone, fluorogestone acetate. Additionally, with pharmaceutical formulations adapted for vulvar administration, it may be desirable to include an androgenic agent such as testosterone, dihydrotestosterone, testosterone analogues such as dehydroepiandrosterone ("DHEA") and DHEA sulfate, or the like.

[0052] 4. The pharmaceutical formulations used in the methods of the present invention may also include one or more pharmacologically active agents other than the estrogen and androgen. For example, the formulations may contain a vasodilating agent. Preferred vasodilating agents are naturally occurring prostaglandins or hydrolyzable lower alkyl esters of a naturally occurring prostaglandin, as well as other vasodilators known in the art.

[0053] The pharmaceutical formulations used in the methods of the present invention may also include one or more lubricants. For example, selected from the group consisting of pullulan, ammonium poly(meth)acrylate, arabian gum, dextran, tamarindo gum, furcelieran, sodium starch-glycoUic acid, sodium polyacrylate, hyaluronic acid and polyvinyl pyrrolidone.

[0054] The pharmaceutical formulations used herein will typically contain one or more pharmaceutically acceptable carriers (also termed "excipients" or "vehicles") suited to the particular type of formulation, i.e., gel, ointment, suppository, or the like. The vehicles are comprised of materials of naturally occurring or synthetic origin that do not adversely affect the estrogen, androgen, vasodilating agent or other components of the formulation. Suitable carriers for use herein include water, silicone, waxes, petroleum jelly, polyethylene glycol, propylene glycol, liposomes, sugars such as mannitol and lactose, and a variety of other materials, depending, again, on the specific type of formulation used.

[0055] The compositions used herein may be in the form of an ointment, cream, emulsion, lotion, gel, solid, sprays, solution, suspension, foam or liposomal composition; such formulations may be used for clitoral, vulvar or vaginal delivery. Alternatively, the compositions may be contained within a vaginal ring, tampon, suppository, sponge, pillow, puff, or osmotic pump system; these platforms are useful solely for vaginal delivery. Methods for preparing various dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed. (Easton, Pa.: Mack Publishing Company, 1990).

[0056] Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, supra, at pages 1399-1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no welter and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, reference may be had to Remington: The Science and Practice of Pharmacy for further information.

[0057] Lotions are preparations that may be applied without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of solids, and preferably, for the present purpose, comprise a liquid oily emulsion of the oil-in- water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethyl-cellulose, or the like.

[0058] Pharmaceutical emulsion formulations are generally formed from a dispersed phase (e.g., a pharmacologically active agent), a dispersion medium and an emulsifing agent. If desired, emulsion stabilizers can be included in the formulation as well. A number of pharmaceutically useful emulsions are known in the art, including oil- in-water (o/w) formulations, water-in-oil (w/o) formulations and multiple emulsions such as w/o/w or o/w/o formulations. Emulsifying agents suitable for use in such formulations include, but are not limited to, TWEEN 60®, Span 80®, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0059] Pharmaceutical creams, are, as known in the art, viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water- washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. [0060] A typical gel composition is formulated by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer to a solution. The preferred concentration of the gelling agent may range from 0.1 to 4 percent by weight of the total composition.

[0061] The compositions used herein can further comprise one or more additional ingredients, such as one or more thickening agents, medicinal agents or pharmaceuticals, bioadhesive polymers, inert carriers, lipid absorbents, viscosity stabilizers, chelating agents, buffers, anti-fading agents, stabilizers, moisture absorbents, fragrances, colorants, film-forming materials, and refatting agents, etc. One of skill in the art will readily be able to choose such additional excipients based on the physical and chemical properties desired in the final topical formulation. Of course, a single excipient may have multiple functions and properties.

[0062] Thickening agents are used to increase viscosity and improve bioadhesive properties. When present in a composition of the invention, the amount of thickening agent is preferably from about 1% to 10% by weight of the total composition weight, more preferably from about 2% to about 5% by weight.

[0063] Tissue penetration enhancers are contemplated herein, and are employed to improve the permeability of an active ingredient into the vaginal tissue and not into the patient's blood stream. Penetration enhancers employed are those recognized in the art as safe for topical application to exposed tissue, for example one or more nonvolatile organic solvents such as, for example, amides, e.g., pyrrolidones; polyol ethers, e.g., glycol ethers; polyols, e.g., glycols, and derivatives thereof, etc.

[0064] To obtain the desired effect in female patients, the sexually therapeutic effective amount or sexually useful effective amount of the pharmaceutical formulation(s) disclosed herein, should be administered from about 0.5 hours to about 8 hr prior to sexual activity. It is preferred that the pharmaceutical formulation be administered from about 15 minutes to about 1 hour prior to sexual activity. Most preferably, the pharmaceutical formulation is to be administered about 5 minutes to about 30 minutes prior to sexual activity. Sexual activity includes sexual intercourse with or without orgasm, ejaculation, masturbation and sexual foreplay.

[0065] The amount of active agent administered is at least the minimum necessary to treat the dysfunction, e.g., excitement stage dysfunctions such as touch sensation impairment, loss of clitoral sensation, vaginal dryness, and concomitant dyspareunia. In the treatment of dyspareunia and other female sexual dysfunction symptoms, as contemplated herein, estrogen and analogues thereof are administered at a level sufficient to exceed naturally occurring levels at the point of administration. For example, an amount of estrogen having estrogenic activity equivalent to from about 0.001 micrograms to about 100 micrograms ethinyl estradiol is applied directly to the vaginal tissue. Preferably, an applied dosage amount of estrogen having estrogenic activity equivalent to from about 0.01 micrograms to about 50 micrograms ethinyl estradiol is applied directly to the vaginal tissue. Most preferably, an applied dosage amount of estrogen having estrogenic activity equivalent to from about 0.1 micrograms to about 35 micrograms ethinyl estradiol is applied directly to the vaginal tissue prior to sexual intercourse.

[0066] In the treatment of dyspareunia and other female sexual dysfunction symptoms, as contemplated herein, androgen and analogues thereof are administered in an amount having androgenic activity equivalent to from about 0.001 milligrams to about 3.00 milligrams methyltestosterone. Preferably, an applied dosage amount of androgen having androgenic activity equivalent from about 0.01 milligrams to about 2.0 milligrams methyltestosterone is applied directly to the vaginal tissue. Most preferably, an applied dosage amount of androgen having androgenic activity equivalent to from about 0.1 milligrams to about 1.5 milligrams is applied directly to the vaginal tissue prior to sexual intercourse. [0067] The use one or more vasodilator agents, as contemplated herein, are administered in a dosage that is at least the minimum necessary to treat the dysfunction.

[0068] It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description as well as the examples which follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

[0069] Experimental: Topical estrogen and/or androgen cream, suppository, ointment and gel formulations are prepared:

EXAMPLE 1

Vaginal cream:

One application unit is equivalent to one (1) gram of cream. The application unit comprises 5 meg of ethenyl estradiol and 0.5mg of methyl testosterone.

One gram of cream has^~the following composition: ethinyl estradiol 5 meg methyl testosterone 0.5mg

Sorbitan monostearate 45.0 mg

Polysorbate 60 (Tween 60) 15.0 mg

Cetyl palmitate (Cutina CP-A) 30.0 mg

Viscous paraffin 130.46 mg

Cetylstearyl alcohol 100.0 mg

Hyaluronic acid 50.0 mg

Purified water 630.0 mg

EXAMPLE 2 Suppository: Prepared by fusion or melt molding wherein one suppository unit comprises 15 meg of ethenyl estradiol and l.Omg of methyl testosterone.

Per suppository the following components are combined: ethinyl estradiol 15 meg methyl testosterone l.Omg

Polyethylene glycol 1000 1.70Og

Polyethylene glycol 4000 0.07Og

EXAMPLE 3 Vaginal ointment:

One application unit is equivalent to one (1) gram of ointment. The application unit comprises . 5 meg of ethenyl estradiol and 0.5mg of methyl testosterone. One gram of ointment has the following composition: ethinyl estradiol 5.00 meg methyl testosterone 1.OOmg N-Methyl Pyrolidone

(Pharmasolye) 50. OOmg

White Wax (White Bees Wax) 67.50 mg

Mineral Oil (Liquid Paraffin) 144.00mg

Paraffin (Hard Paraffin) 30.00mg

Petrolatum, White 707.00mg

EXAMPLE^" 4

Vaginal gel:

One application unit is equivalent to one (1) gram of gel. The application unit comprises

5 meg of ethenyl estradiol and 0.5mg of methyl testosterone. ethinyl estradiol 5 meg methyl testosterone 0.5mg

Hydroxypropylmethylcellulose (HPMC) 0.5 g

Carbopol RTM 934 0.25 g

Glycofurol 75 0.2 g

Aqua purificata 30ml

Claims

WE CLAIM:

1. A method of treating sexual dysfunction in a human female which comprises administering directly to the vaginal tissue of a human female exhibiting one or more symptoms associated with a condition of sexual dysfunction and who is not receiving chronic hormonal therapy, prior to the female engaging in sexual intercourse, an effective sexual dysfunction treatment amount of a composition comprising at least one hormone selected from the group consisting of estrogen and androgen and/or pharmaceutically acceptable salt and ester thereof.

2. The method of Claim 1 further comprising administering directly to the vaginal tissue, prior to the female engaging in sexual intercourse, an effective non- systemic sexual dysfunction treatment amount of a composition comprising at least one hormone selected from the group consisting of estrogen and androgen and/or pharmaceutically acceptable salt or ester thereof, wherein said non-systemic amount does not enter the blood stream of the female.

3. The method of Claim 2 further comprising administering on an acute administrative basis directly to the vaginal tissue, prior to the female engaging in sexual intercourse, an effective non-systemic sexual dysfunction treatment amount of a composition comprising at least one hormone selected from the group consisting of estrogen and androgen and/or pharmaceutically acceptable salt or ester thereof, wherein said acute administrative basis comprises administering said amount directly to the vaginal tissue of the female, from about 5 minutes to about 6 hours, before the female engages in sexual intercourse.

4. The method of Claim 1 wherein said estrogen is selected from the group comprising 17 β-estradiol, estrone, estriol, ethinyl estradiol, estropipate, equilin, Δ8,9 - dehyroestrone, 17α-estradiol, 17α-dihydroequilin, 17β-dihydroequilin, 17β-estradiol, equilenin, 17α-dihydroequilin, and 17β-dihydroequilenin, and combinations thereof.

5. The method of Claim 4 wherein said estrogen is selected from the group consisting of 17 β -estradiol, estrone, estriol, ethinyl estradiol, and pharmaceutically acceptable salts, esters and pro-drugs thereof.

6. The method of Claim 1 wherein said androgen is selected from the group consisting of testosterone, dihydro-testosterone (DHT), methyltestosterone, dehydroepiandrostenedione (DHEA), and pharmaceutically acceptable salts, esters and pro-drugs thereof.

7. The method of Claim 6 wherein said androgen is selected from testosterone and pharmaceutically acceptable salts, esters and pro-drugs thereof.

8. The method of Claim 1 wherein the composition further comprises a pharmaceutically acceptable carrier suited to vaginal tissue drug administration.

9. The method of Claim 8 wherein the pharmaceutical carrier is selected from the group consisting of ointment, cream, suppository, gel, lotion, solution, paste, and mixtures thereof.

10. The method of Claim 9 wherein the pharmaceutical carrier further comprises at least one. of bioadhesive, water-soluble lubricant and vasodilator agent.

11. The method of Claim 10 wherein the pharmaceutical carrier further comprises hyaluronic-acid.

12. The method of Claim 1 wherein the female patient in need of such treatment exhibiting one or more symptoms associated with sexual dysfunction is pre-menopausal, peri-menopausal, or post-menopausal.

13. The method of Claim 1 wherein the estrogen is administered in a dosage amount having estrogenic activity equivalent to from about 0.001 micrograms to about 100 micrograms ethinyl estradiol.

14. The method of Claim 1 wherein the estrogen is administered in a dosage amount having estrogenic activity equivalent to from about 0.01 micrograms to about 50 micrograms ethinyl estradiol.

15. The method of Claim 1 wherein the estrogen is administered in a dosage amount having estrogenic activity equivalent to from about 0.1 micrograms to about 35 micrograms ethinyl estradiol.

16. The method of Claim 1 wherein the androgen is administered in a dosage amount having androgenic activity equivalent to from about 0.001 milligrams to about 3.00 milligrams methyl testosterone.

17. .The method of Claim 1 wherein the androgen is administered in a dosage amount having androgenic activity equivalent to from about 0.01 milligrams to about 2.00 milligrams methyl testosterone.

18. The method of Claim 1 wherein the androgen is administered in a dosage amount having androgenic activity equivalent to from about 0.1 milligrams to about 1.50 milligrams methyl testosterone.

19. A method of promoting vaginal cell health, enhancing vaginal lubrication, and for minimizing sexual dysfunction problems resulting from vaginal cell hypoxia, in a human female exhibiting one or more symptoms associated with a condition of sexual dysfunction and who is not receiving chronic hormonal therapy comprising administering directly to the vaginal tissue of a human female, prior to the female engaging in sexual intercourse, an acute, effective, non-systemic sexual dysfunction treatment amount of at least one hormone selected from the group consisting of estrogen and androgen and/or pharmaceutically acceptable salt or ester thereof.

20. A method of treating sexual dysfunction in a human female comprising the steps of; a) administering directly to the vaginal tissue of the human female, prior to the female engaging in sexual intercourse, a non-systemic sexual dysfunction treatment amount of at least one hormone selected from the group consisting of estrogen and androgen and/or pharmaceutically acceptable salt or ester thereof; and b) assessing a change in the physiological conditions to the said female's vaginal cells and response in the patient to sexual activity, an improvement indicating sexual dysfunction in said patient.