BACKGROUND OF THE INVENTION Sexual dysfunctions, particularly impotence, affect a substantial number of patients. As used herein, the term"sexual dysfunction"refers to certain disorders of the cavernous tissue of the penis and the associated fascia, which produce impotence, the inability to attain a sexually functional erection when desired. For example, impotence is estimated to affect approximately 30 million American men (U. S. Patent No. 6,007,824) and can result from any of numerous physiological or psychological factors which cause the blood flow to and from the penis to remain in balance thereby preventing retention of sufficient blood to cause rigid dilation of the corpus cavernosa and spongiosa.

Erection takes place when the smooth muscles of the corpora cavernosa relax in response to sexual stimulation of the penis allowing the vessels to become engorged with blood. Sexual dysfunction or the inability to obtain erection results from a defect in the neuro- vascular pathways that produce erection. See e. g., U. S. Patent No. 5,583,144. Female sexual dysfunction is a significant age-related, progressive and highly prevalent problem that affects a substantial number of women in the United States. The female sexual response cycle is initiated by neurotransmitter-mediated vascular and nonvascular smooth muscle relaxation resulting in increased pelvic blood flow, vaginal lubrication, and clitoral and labial engorgement.

These mechanisms are mediated by a combination of neuromuscular and vasocongestive events. Physiological impairments that interfere with the normal female sexual response bring about complaints associated with diminished sexual arousal, libido, vaginal lubrication, genital sensation, and ability to achieve orgasm. Berman et al., 38 (1) EUR. UROL. 20-9 (2000). The cause of impotence in men is multi-factorial, including psychopathology, diabetic neuropathy, aging and arteriosclerosis. Treatments for impotence include psychosexual therapy, oral sildenafil (Viagra0, Pfizer), intracavernosal injections or transurethral administration of the prostaglandin alprostadil, external vacuum devices, and implanted penile prostheses. Implants, requiring surgical insertion, are reserved for those who cannot be adequately treated by the less invasive measures. Ralph and McNicholas, 2000 (321) BRIT MED J. 499-503 (2000). Even the non-invasive treatments have disadvantages as well as advantages.

The success of psychosexual therapy depends on the motivation of the patient because it requires him to work with the therapist to discover what prevents him from experiencing normal sexual arousal. A review of all outcome studies in psychosexual therapy published since 1970 showed successful outcomes in 50-80% of patients. Psychosexual therapy may be used in conjunction with physical therapies. Id. Sublingual apomorphine has been used to produce erection via stimulation of the mid-brain dopamine receptors. See U. S. Patent No.

5,985,889.

Oral sildenafil, trademarked as Viagra0, has been shown to be an effective treatment for erectile dysfunction. Improvement in erectile response has been reported by 50-88% of patients, but onset is slower than with alprostadil. Clinical safety has been evaluated in more than 3,700 patients. Side effects are predominantly mild and transient, and it is non-invasive. It is contraindicated, however, in patients taking nitrates and in patients with severe hepatic impairment, hypotension, hereditary degenerative retinal disorders, and recent stroke or myocardial infarction. Ralph (2000). Several cardiovascular deaths have been spontaneously reported. However, sexual intercourse alone is known to precipitate heart attack in persons with cardiovascular disease. Whether the deaths were an adverse reaction to the drug, or the drug allowed a cardiac patient to have intercourse, which precipitated a heart attack, is unknown.

Kloner, 86 (2A) AM. J. CARDIO. 57F-61F (2000).

Intracavernosal prostaglandin (alprostadil) injections are available from companies such as Upjohn of Kalamazoo, Michigan and Pharmacia of Peapack, NJ that offer different injection systems to administer via the intracavernosal route. Ease of use affects patient's and partner's satisfaction and therefore compliance. Alprostadil may also be given transurethrally in systems developed by Vivus, Inc. of Menlo Park, CA that have been proven effective in providing erections adequate for intercourse. In patients with erectile dysfunction from organic causes, 65.9% achieved erections that were sufficient for intercourse during testing at a clinic and 64.9% of a subgroup of these responders were able to achieve intercourse at least once during the three months that they treated themselves at home. Ralph (2000). Various other devices and compounds may be used for transurethral administration. See e. g., U. S. Patent Nos. 6,037,346, and 6,127,363, regarding a method for transurethral administration of phosphodiesterase inhibitors. Phosphodiesterase inhibitors may also be given topically or transdermally.

Prostaglandin E has also been used topically to promote female sexual response. U. S. Patent No. 5,891,915.

Intracavernosal administration of phosphodiesterase type 5 inhibitors, such as sildenafil, or short-acting alpha-adrenergic receptor antagonists, such as phentolamine, in the absence of sexual stimulation do not initiate penile erection. In contrast, intracavernosal administration of Prostaglandin El or papaverine induces erection independent of sexual stimulation. Oral agents are not direct mediators of smooth muscle relaxation and act to facilitate relaxation in response to sexual stimulation, while intracavemosal agents directly mediate smooth muscle relaxation, independent of sexual stimulation. Lue et al., 12 (Suppl 1) INT'LJ. IMPOTENCERES.

S81-88 (2000). Although intracavernous injection of vasoactive drugs can produce a relatively rapid onset of erection in patients suffering from impotence attributable to venous leakage or arterial insufficiency, patients often find the injections psychologically disturbing, painful, traumatic or inconvenient, as evidenced by a high discontinuance rate. Althof et al., 5 (2) J. SEX & MARITAL THERAPY 121-29 (1989). Adverse side effects include priapism, corporeal nodules and diffuse fibrosis, drug tolerance, bruising and hematoma. Swelling and ulceration of penile skin at the injection site have also been reported.

Other agents have been used topically, by intracavernosal injection, transurethral, topical and dermal administration. Piperoxan has been used by intracavernosal or transurethral injection. U. S. Patent No. 5,583,144. Mono-or di-nitrates have also been utilized by topical routes. See U. S. Patent No. 6,056,966.

A vacuum device consisting of an external cylinder fitted over the penis to allow air to be pumped out results in engorgement of the penis with blood. A constriction ring is then fitted to the base of the penis to maintain this"erect"state. Vacuum therapy is suitable for a wide range of patients with chronic or occasional erectile dysfunction, whatever the cause. One study reported an overall clinical success rate of about 90%, with more than 80% of patients continuing with the device. In another study, however, only 23% of patients asked for a prescription after a two-week trial and only 53% of these reported complete or reasonable satisfaction. The incidence of side effects is low and the devices are suitable for long-term use and in a wide range of patients, including those who have failed other therapy. Disadvantages include contraindication in patients with bleeding disorders, lack of spontaneity and cumbersome quality. In addition, use of the devices may produce uncomfortable erections and ejaculation may be impaired, pivoting may occur at the base of penis, and partners report a "cold penis."A cross over study showed the ability to attain orgasm and the overall satisfaction of patient and partner lower with vacuum devices in comparison to injection therapy. Ralph (2000).

Other external devices used to induce and maintain an erection include the invention described in U. S. Patent No. 5,855,548: a venous flow control device comprising a tubular structure adapted to be secured in a loop configuration about the penis to provide an adjustable radial constrictive force about the base of the penis. U. S. Patent No. 4,175,554 discloses a device comprising a sleeve-like body enclosed at one end and having the other end open for receiving the penis.

Penile prostheses are semi-rigid, malleable or inflatable implants, which are surgically inserted into the penis to allow an erect state. Prostheses are considered in patients whose impotence has an organic cause and who are unwilling to consider, fail to respond to, or are unable to continue with medical treatment or external devices. Technical success rates are high.

For example, a revision rate of 2.5% and a removal rate of 4.4% were reported in a two year follow up study; patient and partner satisfaction in confidence and device rigidity were reported as 80%. But insertion requires surgery and sepsis is the most common complication with rates ranging from 2-16%, although other complications, such as erosion, migration, and penile necrosis, are rare. Ralph (2000).

Natural and holistic compositions are also used to restore potency: a mixture of lyophilized roe and a dry powdered extract from leaves of Ginkgo biloba (U. S. Patent No.

5,730,987); a combination of the edible Andean tuber (Lepidium meyenii), commonly known as maca, with deer or elk antler (U. S. Patent No. 6,093,421); L-arginine, ginseng and Zizyphi fructus with or without Saw Palmetto, Gingko biloba, Glutamic acid and L-lysine (U. S. Patent No. 6,007,824); a combination of Muira pauma, Yohimbe, Epimedium, L-arginine and Tribulus terrestris (Erect-X by Amassed Data of Los Angeles, CA); milled seeds from Aframomum stipulatum (U. S. Patent No. 5,879,682).

A serious shortcoming of the injection and external device methods is that they are cumbersome and unnatural, requiring the patient and his partner to"play doctor"at a time that they are seeking romance. While potentially correcting the physical disability, they extract a price in destroying the delicate interplay between mood and sexual desire. Viagra (D suffers, in addition to its possible dangers, from the requirement that it be taken an hour before its effects are desired, thus destroying any romantic mood with a"waiting period." To be easily accepted, a prosexual treatment must be both easy and simple to use, without requiring embarrassing medical procedures, and rapidly effective. According to our invention, we have provided methods and dosage forms for the treatment of sexual dysfunctions which are painless and capable of rapidly, safely and effectively producing erection of the penis in the case of impotence without the above described adverse side effects with a high degree of patient acceptability.

Nutritional supplements and pharmaceutical agents are typically provided in solid dosage formulations that are taken orally. Examples of solid dosage forms include coated tablets, compressed tablets, compressed capsules and two piece gelatin capsules. Such forms have the advantage of being easy and relatively inexpensive to produce, readily dispensable, and fairly stable. Dosage form is an important factor that influences the absorption and bioavailability of a compound. Solid dosage formulations of drugs and nutritional supplements have the disadvantage that stomach acids degrade many of the ingredients in the supplement.

Degradation can be an important factor that limits the effectiveness of drugs and nutritional supplements, such as plant extracts, which are taken for medicinal purposes.

The rate or speed of absorption and the extent or ratio of the amount of active material absorbed over the amount administered depends on several factors. Drugs given in aqueous solution are more rapidly absorbed than those given in oily solution, suspension, or solid form are, because they mix more readily with the aqueous phase at the absorptive site. For those given in solid form, the rate of dissolution may be the limiting factor in their absorption. The area of the absorbing surface to which a drug is exposed is one of the more important determinants of the rate of drug absorption. Drugs are absorbed very rapidly from large surface areas such as the pulmonary alveolar epithelium, the intestinal mucosa, or, in a few cases after extensive application, the skin. The route of administration determines the absorbing surface.

GOODMAN & GILMAN s THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (J. Hardman & L.

Lipman, 9th ed. 1996) [Hereinafter"J. Hardman"], Section I, Chap. 1.

Liposomes were discovered in 1961 when Alec D. Bangham of the Agricultural Research Council's Institute of Animal Physiology in Cambridge, England was evaluating the effect of phospholipids on blood clotting. Dr. Bangham noticed that when he put water in a flask containing a phospholipid film, the water forced the molecules to arrange themselves into what he later discovered were microscopic closed vesicles composed of a bilayered phospholipid membrane surrounding water. Phospholipids form closed, fluid-filled spheres when mixed with water in part because the molecules are amphipathic having a hydrophobic tail and a hydrophilic or polar head. Two fatty acid chains, each containing from 10 to 24 carbon atoms, make up the hydrophobic tail of most naturally occurring phospholipid molecules.

Phosphoric acid bound to any of several water-soluble molecules composes the hydrophilic head. When phospholipids are mixed with water in a high enough concentration, the hydrophobic tails spontaneously herd together to exclude water, whereas the hydrophilic heads bind to water. The result is a bilayer in which the fatty acid tails point into the membrane's interior and the polar head point outward. As the liposome forms, any water-soluble molecules that have been added to the water are incorporated into the aqueous spaces in the interior of the spheres and lipid-soluble molecules added to the solvent are incorporated into the lipid bilayer.

Ostro, 256 (1) Sci. AMER. 103-11 (1987).

The separation between the bilayers is determined by the balance between the repulsive forces between the layers, probably mainly electrostatic interactions between headgroups and hydration forces of the head-groups, and attractive forces which are consistent with the expected van der Waal's forces between the layers. The equilibrium distance between the bilayers of pure egg phosphatidyl choline in water is 2.75 nm. Tyrrell et al., 457 BIOCHIMICA ETBIOPHYSICAACTA259-302 (1976). When solutes are sequestered into liposomes, the rate at which they leak out depends on both the nature of the solute and the composition of the liposome. By modification of the composition of the lipid bilayers it is possible to reduce the leakage of particular molecules.

Depending on the number of lipid layers, size, surface charge, lipid composition and methods of preparation, various types of liposomes have been utilized. Multilamellar lipid vesicles (MLV) were first described by Bangham et al., (13 J. MOL. BIOL. 238-52 (1965)). A wide variety of phospholipids form MLV on hydration. MLV are composed of a number of bimolecular lamellar interspersed with an aqueous medium. U. S. Patent No. 4,485,054.

Unilamellar vesicles consist of a single spherical lipid bilayer entrapping aqueous solution.

According to their size they are referred to as small unilamellar vesicles (SUV) with a diameter of 200 to 500 A; and large unilamellar vesicles (LUV) with a diameter of 1000 to 10,000 A.

The small lipid vesicles are restricted in terms of the aqueous space for encapsulation, and thus they have a very low encapsulation efficiency for water soluble biologically active components.

The large unilamellar vesicles, on the other hand, encapsulate a high percentage of the initial aqueous phase and thus they can have a high encapsulation efficiency.

A variety of liposomal products are known to enhance uptake or facilitate delivery of various products. For example, the parental and topical uses of liposomal carriers were reported to protect a drug against hostile environments and to provide controlled release of the drug while circulating in the blood or after immobilization at a target tissue such as the skin.

LIPOSOM TECHNOLOGY (Gregoriadis, ed. 2nd Ed, Vol. I 1993). The topical administration of drugs such as Minoxidil has been reported by Mezei, U. S. Patent No. 4,897,269, as well as the pulmonary administration of liposomes-encapsulated opiod analgesic agents, U. S. Patent No. 5,451,408. Mezei also has developed a topical liposomal local anesthetic product said to be useful in producing local anesthesia of mucous membrane-covered surfaces, U. S. Patent No. 4,937,078, a method for preparing multilamellar lipid vesicles described in U. S. Patent No.

4,485,054, and a method to formulate a biologically active ingredient in a concentration above its water and lipid solubility. U. S. Patent No. 4,761,288.

Some biologically active compounds are delivered sublingually to achieve a rapid onset and greater bioavailability. For example, by administering nitroglycerin tablets under the tongue, rapid onset is achieved by virtue of quick absorption into the blood stream through the highly vascularized capillary plexus. In addition, this route avoids the liver where the compound is highly metabolized on first exposure to metabolic enzyme systems. Another example of a compound that is administered orally for absorption in the mouth is methyltestosterone.

Supplied in tablet form that is designed for absorption through the buccal mucosa into systemic circulation, this route provides twice the androgenic activity of oral tablets. U. S. Patent No.

5,891,465.

The mucosa of the mouth and throat is highly vascularized and well suited for the absorption of lipophilic, nonionized compounds. These routes of absorption are particularly advantageous for compounds that are needed to have a rapid onset of action or are not well absorbed when taken orally. This route of administration circumvents exposure of compounds to digestive enzymes and the high acidity of the gastrointestinal tract that can be damaging to compounds and render them inactive.

Despite the foregoing advantages of sublingual and buccal routes of administration and of the use of lipid encapsulation, these two methods have not been combined to deliver nutrients to treat sexual dysfunction, particularly in an aerosol or spray delivery form that provides the rapid onset required for treating sexual dysfunction. This invention provides novel delivery systems for administering nutrients, such as prosexual herbs, testosterone precursors, and aromatase and 5-alpha reductase inhibitors whereby the agent is encapsulated into lipid vesicles or liposomes and placed in a solution. The nutrient solution can be administered as an aerosol or spray into the mouth for subsequent absorption in the mouth, the throat and/or the gastrointestinal tract; such formulations provide increases in the bioavailability and improved therapeutic response.

SUMMARY OF THE INVENTION The present invention relates to prosexual compositions encapsulated in liposomes and methods for treating sexual dysfunction, improving sexual function, improving energy, enhancing sexual responsiveness and increasing testosterone levels, and muscle strength and mass. The inventor has now discovered that by encapsulating prosexual herbs, testosterone precursors, with or without aromatase and 5-alpha reductase inhibitors, a fast-acting treatment for sexual dysfunction can be made. It is pleasant and convenient to use, and may be used when needed, requiring only a spray in into the mouth either sublingually or into the buccal cavity, or may be administered topically to the genitals, or by dermal patch.

The compositions of the present invention comprise liposome encapsulated Pausinystalia yohimbe with or without one or more additional prosexual herbs or testosterone precursors encapsulated within said liposomes. The prosexual herbs and testosterone precursors are preferably selected from the group consisting of Epimedium saggitatum, Tribulus terrestris, Ptychopetalum Olacoids (Muira puama), Serenoa repens (saw palmetto), 4-androstenedione, 5-androstenedione, 5-androstenediol, and 4-androstenediol. The composition may optimally comprise chrysin, a substance that controls aromatase activity and thus the production of estradiol and estrone.

In another embodiment of the invention, the prosexual herbs are provided in at least 0.5 mg per unit dose, either as herb or standardized extract. Preferably, the Pausinystalia yohimbe is an 8% standardized extract, the Tribulus terrestris extract is a 45% steroidal saponin standardized extract of the fruit, the Ptychopetalum olacoides extract is a 12 : 1 standardized extract, the Epimedium saggitatum extract is a 5% icariin standardized extract of the leaf, and the Serenoa repens extract is a 20-25% fatty acids and sterols standardized extract of the fruit.

In yet another embodiment, the composition further comprises at least 0.5 mg of one or more testosterone precursors, preferably 5-androstenedione or 5-androstenediol. 4-androstenedione or 4-androstenediol may optionally be used. The chrysin, if present, is also provided in 0.5 mg per unit dose, either as herb or standardized extract. Preferably, the prosexual herbs and testosterone precursors are present in amounts between 0.5 mg and 2 gm, and more preferably between 0.5 mg and 1 gm or between 0.5 and 50 mg. In the most preferred embodiment, a unit dose of the liposomal composition comprises 15 mg of Pausinystalia yohimbe, 30 mg of Epimedium saggitatum, about 25 mg of Tribulus terrestris, about 10 mg Ptychopetalum olacoides root (Muira puama), about 10 mg Serenoa repens (saw palmetto), 10 mg of chrysin, about 4 mg of 5-androstenedione and about 2 mg of 5-androstenediol.

The liposome-encapsulated herbs may be multilamellar, unilamellar, or multivesicular lipid vesicles or a multiphase liposomal system and may be prepared using a phospholipid preferably selected from the group consisting of phosphatidylcholines, lysophosphatidylcholines, phosphatidylserines, phosphatidylethanolamines, phosphatidylinositols and mixtures thereof. Preferably, the phospholipid is natural soybean lecithin. The phospholipid may also be provided in admixtures with a cholesterol, stearyl amine, stearic acid, or tocopherol.

In another embodiment of the invention, the prosexual agents and testosterone precursors are present in amounts sufficient to treat sexual dysfunction or improve sexual function. Alternatively, in yet another embodiment of the invention, the prosexual herbs and testosterone precursors are present in amounts sufficient to improve muscle strength.

A method for delivering a liposome-encapsulated prosexual agent to a target cell is another embodiment of the invention, comprising the steps of: encapsulating prosexual agents in a liposome ; immersing a solution of liposomes into an appropriate pharmaceutical carrier ; administering the solution to a human; and contacting a target cell with the liposome for a sufficient time that the prosexual agents are transported into the target cell.

The invention also describes methods for enhancing sexual function, sexual response, and sexual performance in a human, preferably a male, by administering Pausinystalia yohimbe encapsulated in liposomes, with one or more testosterone precursors and with or without one or more additional prosexual herbs with or without chrysin. In another embodiment, a method for treating human sexual dysfunction is described. More particularly, methods are described to enhance human vitality, increase genital blood flow, increase genital engorgement of erectile tissues, enlarge the corpora cavernosa, induce erectogenesis, normalize testosterone levels, strengthen orgasms, improve libido, and relax smooth muscle in erectile tissue.

In yet another embodiment of the invention, methods are provided for improving human male erectile turgidity, tumescence, frequency, or strength, or enlarging the corpora cavernosa of a human male.

In yet another embodiment, methods are provided for increasing muscle mass and increasing muscle strength by the administration of the composition. The invention also provides methods for delivering one or more prosexual agents and testosterone precursors to a human in need of said preparation by administering a pharmaceutically effective amount of the liposomal composition of prosexual herbs and testosterone precursors, with or without chrysin.

The administration may be made buccal, oral or sublingual spray, topical application to the genitals, or by dermal patch.

Another embodiment of the invention further includes herbs that inhibit 5-alpha reductase thus reducing undesirable levels of dihydrotestosterone. Another embodiment further includes chrysin, which inhibits aromatase and the production of estrogenic steroids.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to liposomal compositions and methods for treating sexual dysfunction, enhancing sexual function, and improving muscle strength and mass. The liposomes are preferably dispersed in a pharmaceutically acceptable carrier and comprise yohimbe and testosterone precursors, with or without additional prosexual herbs. It is understood that the present invention is not limited to the particular methodology, protocols, reagents, etc., described herein, as these may vary. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. It must be noted that as used herein and in the appended claims, the singular forms"a,""and,"and"the"include plural reference unless the context clearly dictates otherwise.

Compositions Pausinystalia yohimbe The only FDA approved medicine for impotence is yohimbine, an alkaloid isolated from the bark of the yohimbe tree (Pausinystalia yohimbe) native to tropical West Africa. It has been used for 70 years to treat both male and female sexual difficulties. Riley, 48 (3) BR. J.

CLIN. PRACT. 133-36 (1994). Yohimbine hydrochloride increases libido, but its primary action is to increase blood flow to erectile tissue. The mechanisms for male erection and female arousal are the same: the engorgement of genital tissues in the corpora cavernosa of the male and the clitoris of the female; and yohimbine is effective in both sexes. In the composition designed to enhance the rate and efficiency of adsorption and uptake by target tissues claimed in this invention, the yohimbine alkaloid of yohimbe will increase genital engorgement and clitoral erectogenesis in a human female.

Yohimbine is a selective alpha-2 receptor antagonist. Contrary to a popular misconception, yohimbine has no effect on testosterone levels. Anonymous 1 (3) AM. J. NAT.

MED. 8 (1994). Yohimbine improves the ejaculatory response through antagonism of the alpha-2, and to a lesser extent alpha-1, adrenoceptors. Sonda et al., 16 (1) J. SEX & MARITAL THERAPY 15-21 (1990); Steers et al., 131 J. UROL. 799-802 (1984).

The alpha-1 adrenoreceptors are believed to be located on smooth muscle membranes to mediate contraction and the alpha-2 receptors are thought to be located on nerve terminals mediating the inhibition of transmitter release. Since relaxation of the corpus cavernosa muscle initiates erection, alpha-1 antagonism results in relaxation in vitro. The alpha-adrenergic blocking properties of yohimbine were shown by in vitro studies of human corpus cavernosa tissue from transsexual patients in which contractions induced by norepinephrine are antagonized in a dose-related manner at concentrations between 10 7 to 10-'4 M. These authors also injected 9 rabbits with yohimbine hydrochloride at 1 mg/kg and 2 mg/kg and killed the animals 2 hours or 48 hours later. Corporal tissues assayed showed no statistically significant differences in norepinephrine content between treated and control rabbits, but all rabbits had peripheral vasodilation of ear veins and 2 rabbits at the 2 mg/kg dose had erections.

Yohimbine probably partially antagonizes an alpha-1 postsynaptic mediated effect. Id.

In a study of the erectile and ejaculatory response to manual penile stimulation in 8 male dogs, each animal served as his own unmedicated control and receiving all doses of vehicle,. 01,. 03,. 10,. 30, and 1.00 mg/kg of yohimbe at 4 day intervals. The amount of ejaculate was measured and found to increase in a dose dependent manner at low doses up to . 10 mg/kg with decreases at the higher doses, but erectile potency was unchanged. Yonezawa et al., 48 LIFE SCIENCEF, PL 103-9 (1991). In a specific embodiment of the invention, a unit dose of the liposomes provides 15 mg of yohimbe, equivalent to a. 5 mg/kg dose in a 75 kg male.

Central effects have also been demonstrated. With intracerebro-ventricular and intraperitoneal injection, the response of male rats in mount latency, ejaculation latency, intromission latency, and ejaculation frequency is parabolic, improving and decreasing after a maximally effective dose. The maximal dose is less than 10 mg/kg with intracerebroventricular injection and 1.00 mg/kg with intraperitoneal injection, suggesting that stimulation with yohimbine is central rather than genital. This is further supported by a study of sexually vigorous male rats that were injected intraperitoneally with yohimbine or vehicle at 2 mg/kg and later anesthetized in the genital area. Treated rats exhibited about twice as much mounting behavior as controls, suggesting that it is a potent stimulator of arousal even in the absence of feedback from the genitalia. Clark et al., 225 SCIENCE 847-48 (1984).

Studies of yohimbine in castrated and female rats show that it decreases latencies to initial mount, intromission and ejaculation in castrated rats with and without testosterone treatment up to 91 days and 51 days after castration, respectively, and induces mounting in intact nonreceptive females. This is felt to further support the suggestion that alpha-2 adrenoreceptors are involved in modulation of sexual arousal with yohimbine. Results have not been consistent in all species. In a study in male Nile crocodiles, treated groups showed increased headslap display frequency (a courtship ritual), earlier peak activity with longer courtship and mating period, and increased egg fertility. However, there was no increase in the number of matings. Morpurgo et al., 43 PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR 449-52 (1992).

Human trials have confirmed the effects seen in animals. Sonda et al. performed a double-blind crossover study of placebo vs. 5.4 mg yohimbine in forty patients complaining of impotence of a 3-months duration defined as inability to achieve sufficient erection for vaginal penetration. Each drug was given for 4 weeks with a 1-week washout between treatments, and testing was done by snap gauge and questionnaire on sexual desire, erection quality and orgasm. Thirty-three (33) patients completed the study without side effects, of whom 11 (33%) had subjective improvement only on yohimbine, 5 (15%) on both yohimbine and placebo, 5 (15%) only on placebo and 12 (36%) on neither. These differences approached statistical significance (p <. 07 on chi-squared test). Of the 11 responders, 9 reported only improved desire and 4 improved orgasm. However, the 11 responders included 9 of 10 (45%) of those whose impotence was organic as opposed to psychological and 8 of these 20 showed objective response in increased snap gauge breakage on yohimbine but not placebo (p<. 01 by chi-squared test). Id., at 15-21.

Sonda et al. also performed a study of the records of 215 patients with organic impotence who were treated with yohimbine at 16.2 mg per day or 21.6 mg per day if no initial response was obtained. Response was characterized as complete, with full erection and ability to initiate and maintain intercourse; partial, with improvement not sufficient to restore performance on each occasion; or none. Treatment was for six (6) weeks. Ten of the 215 (5%) reported complete improvement on the lower dose, and those with no or only partial improvement were administered the higher dose. Of the 72 (33%) with initial partial improvement, 21 were given the higher dose, of whom 13 improved further and 4 of whom exhibited complete improvement. Of the 133 (62%) who had no improvement on the lower dose, 25 were administered the higher dose, leading to further improvement in 11 and complete improvement in 2 of those. Id., at 15-21.

In this invention, yohimbe is provided encapsulated in liposomes to enhance and hasten its adsorption. By this means, the herb or herbal extract is used to treat sexual dysfunction; or to improve or enhance sexual function, response, performance, libido, or vitality, in a human, especially a male. In further embodiments of the invention, liposome encapsulated yohimbe is used to increase genital blood flow, relax human smooth muscle in erectile tissue, increase engorgement of erectile tissues, increase enlargement of the corpora cavernosa, improve erectile frequency in a human, strengthen orgasms, or improve libido in a human, especially a male.

Epimedium sagittatum Epimedium sagittatum is used in Traditional Chinese Medicine and translates as"the herb for the man that likes sex too much, like a goat,"or simply"passionate goat weed." RADIANT HEALTH, 162-63 (Teeguarden, R., 1998). It was used historically for impotence, and is believed to increase sexual activity, increase sperm production, stimulate the sensory nerves and increase desire. CHINESE HERBAL MEDICINE MATERIA MEDICA (Bensky, D., and Gamble, A., Rev. Ed. 1993).

Several groups of Chinese researchers have confirmed the benefits of Epimedium sagittatum on sexual function and muscles. In a mouse study"Yang-insufficiency"was induced by hydroxyurea in two groups of rats, that also received Epimedium and Cistanche and a third untreated control group."Yang-insufficiency"mice showed slowed activity, weakness, decreased body hair, localized baldness, reduced muscle tone and cold tail. After 13 days of treatment, 1 control mouse, 5 mice in the"Yang-insufficiency"group, and only 2 from the treated group died. The untreated"Yang-insufficiency"group showed remarkable weight loss, while others gained weight. Liu, 4 (8) CHUNG His I CHIEH Ho TSA CHIH 488-90 (1984).

Results were confirmed in humans by Liao et al. (15 (4) CHUNG Kuo CHUNG Hls I CHEH HoTsA CHIH 202-4 (1995)), who studied the effects of Epimedium sagittatum, 16 g/kg/day for 4 months, in 34 hemodialysis patients, 12 controls and 22 treated patients, 17 of whom were impotent. Of the impotent group, 2 became free of impotence, 2 noted improved sexual function, 5 had achieved an erection and 1 had night emission.

The effects of this plant may be explained by the anti-platelet aggregating properties of its constituents. The Epimedium sagittatum plant has been shown by Taiwanese researchers to contain several prenylflavone compounds, yinyanghuo 1 and 2, identified by nuclear magnetic resonance (NMR), that have significant inhibition of platelet aggregation in response to arachidonic acid. Chen et al., 59 (4) J. NAT. PROD. 412-14 (1996). Arachidonic acid plays an important role in producing erection by releasing eicosonoids that control the relaxing effect of nitric oxide. Fisher, 2 FRONTIERS IN BIOSCIENCE 482-500 (1997). However, it also promotes platelet aggregration that may inhibit blood flow. Thromboxane, one of three metabolites of arachidonic acid (Gryglewski et al, 12 (6) HYPERTENSION 530-48 (1988)), promotes the aggregation of platelets in the capillaries and arterioles that is believed to be a primary cause of vasculogenic impotence. Prostacyclin opposes this effect and inhibits aggregation of platelets.

Lin et al., 148 (2 Pt 1) J. UROL. 311-13 (1992). The inhibition of platelet aggregation by the prenylflavones in Epimedium sagittatum suggests that they inhibit the production of thromboxane and inhibit the platelet aggregation that would otherwise interfere with the production of an erection. In another embodiment of the invention, the prosexual herb Epimedium sagittatum to yohimbe is encapsulated in liposomes with the yohimbe. This embodiment is preferred when used to increase genital blood flow or engorgement of erectile tissues; enlarging the corpora cavernosa ; or inducing erectogenesis in a human.

Numerous other flavonoids have been isolated, including icariin. Zhau et al., 19 (1) CHuNG-HuACHuNGLtuTsACHtH [ChineseJ. Oncol.] 53-55 (1997).

Tribulus terrestris Tribulus terrestris is an ancient folk medicine in Asia and Bulgaria for illnesses including spermatorrhea and sexual impotence that has been found to contain steroidal saponins. Tomova et al., 34 PLANTA MEDICA 188-91 (1978).

Its prosexual effects were studied in 21 male rams with sexual impotence and deficient sperm count, at 250 mg 2 or 3 times per day for 20 or 40 days. The plant was administered to 6 of 8 animals with preserved sexual reflexes, 6 with disorders of sexual reflexes and lack of libido and 7 with disorders of sperm production. Sperm production in the controls decreased over the course of the mating season. In those rams with preserved sexual reflexes that were treated, ejaculate was nearly twice that of controls and did not decrease during the mating season. Moreover, all six of the impotent rams were restored to sexual potency after 8 days of treatment, and sperm counts improved in 3 of the 7 rams with deficiencies. Testosterone increased in both preserved and impotent treated rams (p < 0.001). Dimitrov et al., 24 (5) VETERINARY SCIENCE 102-9 (1997).

A three-fold increase in testosterone levels (p < 0.001), was similarly observed in humans, along with a 1.5 fold increase in estradiol (p < 0.001), and leutenizing hormone (p < 0.001), 8 and 12 hours after the administration of 250 mg Tribulus. Milanov et al., 4 MED.

BIOL. INFORMATION 27-29 (1985). Two additional studies in infertile human males revealed an increase in the percentage of motile sperm. Protich et al., 22 (4) AKUSH GINEKIL 326-29 (1983); Tsvetkov et al., 6 KHIRURGIYA 49-52 (1989).

In further embodiments of the invention, Tribulus terrestris is added to the liposome encapsulated composition, especially when the composition is used to treat sexual dysfunction, enhance sexual function or response, or to improve libido.

Ptychopetalum Olacoids (Muira puama) Ptychopetalum olacoides has been used in folk lore for centuries as an aphrodisiac (Mowrey, Feb. ENERGYTlMES MAGAZINE (1996)) and is known also as"potency wood". It is described as a powerful aphrodisiac herb indigenous to South America that helps stimulate male libido and overcome erectile dysfunction. Anonymous, GAIA SYMPOSIUM PROCEEDINGS, NATUROPATHIC HERBAL MEDICINE, HERBAL HEALING WISDOM FOR THE FUTURE (May 29-31, 1993). Brazilian tribes use the roots and bark taken internally as a tea for treating sexual debility and impotency, neuromuscular problems, rheumatism, grippe, cardiac asthenia, gastrointestinal asthenia and to prevent baldness. A POCKETBOOK OF BRAZILIAN HERBS (Bernardes, A., 1984). It is considered by naturopaths to be one of the best herbs to use for erectile dysfunction or lack of libido. Its mechanism of action is unknown, but some researchers feel that it may enhance both psychological and physical aspects of sexual function.

Anonymous 1 (3) AMJ. NAT. MED. 8 (1994).

A recent study has validated its safety and effectiveness in improving libido and sexual function in some patients. At the Institute of Sexology in Paris, France, a clinical study with 262 patients complaining of lack of sexual desire and the inability to attain or maintain an erection demonstrated Muira puama extract to be effective in many cases. Within two weeks, at a daily dose of 1 to 1.5 grams of the extract (4: 1), 62% of patients with loss of libido claimed that the treatment had dynamic effect while 51% of patients with"erection failures"felt that Muira puama was of benefit. ETHNOPHARMACOLOGY, (Ed. Rivier L., & Anton, R., 1990); Waynberg, J., PROCEEDINGS OF THE FIRST INTERNATIONAL CONGRESS ON ETHNOPHARMACOLOGY, STRASBOURG, FRANCE, June 5-9,1990.

Active constituents are free long-chain fatty acids, sterols, cumarin, alkaloids and essential oils. Chemically, Muira puama contains. 05% muirapuamine,. 4% fat,. 5% alkaloids, . 6% pholbaphene,. 6% alpha-resinic acid,. 7% beta resinic acid,. 5% of a mixture of esters including behenic acid, lupeol and beta-sitosterol, as well as tannin, volatile oils and fatty acids.

CRC HANDBOOK OF MEDICINAL HERBS (Duke, J. 1985). Proper preparation methods must be employed to preserve the active constituents found in the natural bark. The extract is produced by high heat for at least 20 minutes or longer in alcohol necessary to dissolve and extract the volatile and essential oils, terpenes, gums and resins found in the bark and root.

In further embodiments of the invention Ptychopetalum olacoides is added to the liposome encapsulated composition for improved results especially when used to treat sexual dysfunction, induce erectogenesis, or improve libido in a human.

Testosterone precursors Testosterone and its derivatives have been shown to increase blood testosterone levels, treat sexual dysfunction, improve sexual function and improve feelings of well-being. A significant decrease in free testosterone, androstenedione, and 5-androstenediol accompanies aging. Testosterone levels decline slowly and continuously throughout adult life in men, but the levels of dihydrotestosterone do not decrease with age. Partin et al., 145 J. UROL. 405-9 (1991). Benign hyperplastic tissue in the prostate also increases with age, and has been correlated with circulating levels of free testosterone, estriol and estradiol, but not dihydrotestosterone.

The testosterone precursors are normally metabolized from dehydroepiandro-sterone (DHEA). This has been studied in people with panhypopituitarism (lack of adrenal and gonadal steroids) by administering 50 mg or 200 mg of DHEA. This induces an increase of both steroids to supraphysiological plasma levels and a small increase of delta 5- androstenediol. In contrast, the increase of plasma delta 4-androstenedione was significant and dose dependent. DHEA was also converted into testosterone. The administration of a 50 mg dose of DHEA restored plasma testosterone to levels similar to those observed in young women. The 200 mg dose induced an important increase of plasma testosterone, slightly below the levels observed in normal men. The increase of plasma dihydrotestosterone levels was small at both doses of DHEA, in contrast with the large conversion of DHEA into androsterone glucuronide and androstanediol glucuronide. Finally, DHEA administration induced a significant and dose dependent increase of plasma estrogens and particularly of estradiol.

Young et al., 82 (8) J. CLIN. ENDOCRINOL. & METABOL. 2578-85 (1997).

4-androstenedione and 4-androstenediol The androgens 4-androstenediol and 4-androstenedione are natural testosterone precursors. The biosynthesis of testosterone takes place within the testicular Leydig cells in two metabolic pathways. During the progesterone-pathway (8-4 pathway), pregnenolone is metabolized to progesterone by the 3-0-hydroxy-steroid deydrogenase and an isomerase.

Progesterone is then changed to 17-a-hydroxyprogesterone by the 17-oc-hydroxylase and Cl7C2,-lyase to androstenedione, then to testosterone by reduction of the 17-keto-group by 17- 0-hydroxy-steroid dehydrogenase. The DHEA-pathway (8-5 pathway) leads from pregenolone to 17-a-hydroxypregnenolone to dehyroepiandrosterone (C, 7C2,-lyase), to 5-8- androstenediol. Wichmann et al., 83 (3) Exp. CLIN. ENDOCRINOL. 283-290 (1984).

As a testosterone pro-hormone and metabolite, 4-androstenedione may be used by athletes and bodybuilders to improve muscle mass. Levels of 4-8-androstenedione increase significantly with moderate exercise in healthy men. Velardo et al., 97 (1) Exp. & CLIN.

ENDOCRINOL. 99-101 (1991). Additionally, supplementation with 4-androstene-dione has been known to produced elevations in serum testosterone. Mahesh et al., 41 (3-8) J. STEROID BIOCHEM. MoL. BIOL. 495-513 (1992).

4-androstenediol is also metabolized into testosterone and is produced by conversion of dehyroepiandrosterone. Inaba et al., 13 (2) ENDOCRINOLOGIA JAPONICA 160-72 (1966). It was first shown to produce elevations in human serum testosterone levels in 1965, and this was also demonstrated in in vitro studies in animals (Kundu, 6 (5) STEROIDS 543-51 (1965)) and human fibroblast cultures (Faredin et al. 32 (2) ACTA MEDICA ACADEMIAE SCIENTIARUM HUNGARICAE 139-52 (1975)). Supplementation with 4-androstenedione, 4-androstenediol, and 19-nor-4- androstenedione has been studied to determine whether a rise in testosterone is produced.

Uralets et al., 23 ANAL. ToxicoL. 357-366 (1999); U. S. Patent No. 5,880,117.

Testosterone is excreted in the urine unchanged and is metabolized through Sa-and (3- DHT as 5a-and (3-androstanediol, while androstenedione is similarly excreted as androsterone and etiocholanolone. Both the final excreted steroid and the intermediaries stanediones and DHT intraconvert so that androsterone, 5a-and P-androstanediol and etiocholanolone are seen in urine. Supplementation with 4-androstenediol produced a 10-fold greater urine testosterone concentration than 4-androstenedione. Uralets (1999).

5-androstenediol and 5-androstenedione The steroids 5-androstenedione and 5-androstenediol are secreted by the adrenal gland and in the testes, and are metabolites of as well as precursors to testosterone. See Munabi et al., 63 (4) So. J. CLIN. ENDOCRINOL. & METABOL. 1936-40 (1986); Moger, 80 (3) J. ENDOCRINOL.

321-32 (1979). 5-androstenediol is a natural hormone with androgenic activity. Chang et al.

96 (20) PROC. NAT'L ACAD. Scl. 1173-77 (1999); Rosner et al., 15 (1) STEROIDS 181-93 (1970).

In vitro studies reveal that 5-androstenediol is a precursor of both androstenedione and testosterone. Sulcova et al., 70 (1) ENDOKRINOLOGIE 6-12 (1977).

The 4-and 5-androstenediols are part of two different pathways that predominate differently in different mammalian species. Precursors of the 8 5-pathway (DHEA, androstenediol) are low in the red deer, dog, cat, rat and guinea pig. In comparison, precursors of the 8 4-pathway (progesterone, 17-hydroxprogesterone, androstenedione) are lower in the bull, boar, ram, stallion and rabbit. Wichmann et al., 83 (3) CLIN. ENDOCRINOL. 283-90 (1984).

5-androstenediol is reported to have minimal androgenic activity and the potential to bind to estrogen receptors in several systems in women. Bird et al., 99 ACTA ENDOCRINIOLGICA 309-13 (1982).

Conversion of 5-androstenediol to radiochemically pure testosterone was demonstrated in the pituitary, some brain structures, and ventral prostate of adult castrated male rats.

Formation of dihydrotestosterone and dehydroepiandrosterone was also detected in these animals. The may in part explain the behavioral and brain virilization effects of 5- androstenediol. Perez et al., 29 (5) STEROIDS 627-33 (1977). 5-androstenediol has been considered to be important in the human male as an intermediate in the biosynthesis of testosterone by testicular tissue. In women as well, it is metabolised into DHEA, 4- androstenedione, and testosterone in both post-menopausal and young women. Bird (1982).

Over the past few years, use of testosterone precursors and the derivatives of has become popular amongst life-extensionists as well as athletes. Testosterone precursors are available in bulk from companies such as Eiselt Research (Sweden), and from additional suppliers well known to those with ordinary skill in the art. For instance, androstenedione may be obtained from Great Earth Vitamins of Medford, Oregon, and companies such as American Sports Nutrition of Meriden, CT, and SportsOne, Inc. of Woodbridge, CT sell 4- androstenediol.

In the invention, one or more testosterone precursors are included in the liposome encapsulated composition to normalize testosterone levels, improve muscle mass, or improve muscle strength in a human, preferably a male. In another specific embodiment, said testosterone precursors are selected from the group consisting of 4-androstenedione, 5- androstenedione, 5-androstendiol, and 4-androstenediol.

Chrysin Although increased testosterone levels show positive effects on sexual function and muscle mass, increased testosterone levels also produce increased levels of estrogen and dihydrotestosterone. These can produce feminizing effects, benign prostate hypertrophy (BPH) and hasten male pattern baldness (MPB). When BPH volume and hormone levels were corrected for age, BPH volume correlated positively with free testosterone, estradiol, and estriol.

Partin et al., 145 (2) J. UROL. 405-09 (1991). Similarly, estrogenic hormones have undesirable effects on the human male, which may be lessened by combining an aromatase inhibitor with supplements of testosterone pro-hormones. Aromatase enzyme plays a crucial role in the production of estrone from testosterone and estradiol from androstenedione. GOODMAN & GILMAN (1996). The pro-hormones, or precursors, are also precursors to estradiol via metabolism by aromatase.

Chrysin controls aromatase activity, and thus the production of estradiol and estrone.

The compositions of the present invention may further comprise a substance that controls 5- alpha reductase, and thus its production of dihydrotestosterone (DHT).

Other aromatase inhibitors include substituted androstenediones. There is also evidence that aromatase is involved in the production of DHT, which is well known for its negative effects on the prostate and male pattern baldness. An in vitro rat testis cell suspension model was used to investigate the metabolism of tritiated testosterone, dihydrotestosterone, and androstenedione. In the presence of aromatase inhibitors and androstenedione, the metabolism was shifted towards 17-keto forms. This suggests that androstenedione and the derived aromatase inhibitors activate the 17-beta-hydroxysteroid-dehydrogenase in a product-activating manner. Thus, aromatase inhibitors may regulate the intratissuelar levels, not only of estrogens, but also of other hormonally active steroids like DHT and 5-androstenedione. Schroder et al., 31 (4B) J. STERorDBIocHEM. 685-90 (1988).

Because of the usefulness of inhibiting aromatase in breast cancer patients, several synthetic aromatase inhibitors have been developed. See e. g., U. S. Patent No. 4,954,446.

There are natural substances, however, such as chrysin, that have similar activity. Chrysin is a bioflavonoid found in propolis (bee pollen) and honey that has been demonstrated to be as potent and effective in inhibiting aromatase as the popular pharmaceutical, aminoglutethimide (AG). In aromatase enzyme assays, chrysin, 7,8 benzo-flavone (ANG), AG, flavone and genistein 4'-methyl ether (5,7-dihydroxy-4'-methoxyisoflavone, Biochanin A) were shown to inhibit aromatase. Chrysin and AG inhibited the enzyme by 50% at a concentration of 4.6 uM and 7.4 uM respectively, and only ANG had a high Iso of 0.5 uM. Both Flavone and Biochanin A inhibited aromatase, but to a lesser degree. Campbell et al., 46 (3) J. STEROID BIOCHEM. MOL. BIOL. 381-88 (1993). In screening for potential cancer preventatives, chrysin was one of the three of flavonoids with the greatest aromatase-inhibiting activity, with an inhibitory concentration (IC) of 1. 1, ug/ml. Jeong et al., 22 (3) ARCHIVES PHARMA RES 309-12 (1999).

In one or more embodiments to the invention, chrysin is included in the liposome encapsulated composition to control the production of estradiol and estrone. Chrysin is available commercially from suppliers well known to those skilled in the art. For instance, chrysin may be obtained from Mass Quantities, Inc. (New York, NY) and Netrition, Inc. (NY).

5-alpha reductase inhibitors As noted above, testosterone supplementation may be linked to benign prostatic hypertrophy (BPH) because it elevates levels of free testosterone, dihydrotestosterone, estradiol, and estriol. Partin (1991). Moreover, in 64 men with prostate cancer, ages 42 to 71 years old, it was shown that with age there was a significant increase in the volume of BPH and a significant decrease in the serum levels of free testosterone, androstenedione, dehydroepiandrosterone (DHA), dehydroepi-androsterone sulphate (DHA-S), delta 5- androstenediol, and 17-hydroxypregnenolone, and a significant increase in sex hormone- binding globulin (SHBG), luteinizing hormone (LH), and follicle stimulating hormone (FSH).

When BPH volume and hormone levels were corrected for age, BPH volume correlated positively with free testosterone, estradiol, and estriol. These data indicate that, with age, patients with larger volumes of BPH have higher serum androgen and estrogen levels, suggesting that serum androgen and estrogen levels may be factors in the persistent stimulation of BPH with age. Therapeutic attempts at lowering plasma testosterone levels, reducing estrogen levels, or blocking androgenic stimulation through other mechanisms may interfere with the progression of BPH with age. Id.

Serenoa Repens In its peripheral target structures, testosterone must be converted into 5a-androstan- 17ß-ol-3-one (androstanolone or dihydrotestosterone, or CHT), 5a-androstane-3a, 470-diol (3alpha-diol) and Sa-androstane-3p, 17p-diol (3p-diol) to become fully active. Massa et al., 6 J. STEROID BlOCHEM. 567-571 (1975). The metabolism of testosterone to DHT is catalyzed by 5-alpha reductase, an enzyme found in the hypothalamas. In target tissues, such as the prostate and hair follicles, the active medabolite is the 5-oc-reduced testosterone, DHT. This compound differs from testosterone only in that the double bond between carbons 4 and 5 is hydrogenated into a single bond. For this reason, several products are available by prescription that inhibit the 5-alpha reductase and the formation of DHT. See Wilson et al., 6 PROSTATE SUPPLEMENT 88-92 (1966); U. S. Patent Nos. 5,998,427; 5,372,996; and 5,017,568. Finasteride (Proscar (E)), the most popular alpha reductase blocker, is a 4-aza steroid that selectively and competitively inhibits the activity of 5-alpha reductase.

Serenoa repens is one of the most widely studied 5-alpha reductase inhibitors, used in Europe as a medical treatment of BPH. See e. g., Swoboda et al., 149 (8-10) WIENER MEDIZINISCHE WOCHENSCHRIFT 235 (1999); Di Silverio et al., 37 (2) PROSTATE 77-83 (1998); Plosker et al., 9 (5) DRUGS & AGING 379-95 (1996); Carraro et al., 29 (4) PROSTATE 231-40, at 241-2 (1996). Poor prostate health is associated with sexual dysfunction. Serenoa repens is available commercially, in bulk and wholesale, from suppliers well known to those skilled in the art.

Another embodiment of the invention relates to methods for improving sexual function, improving mood, enhancing feelings of well being and for increasing muscle mass comprising administering to a human a liposomal composition comprising extract of Pausinystalia yohimbe and extracts of Epimedium saggitatum, Tribulus terrestris, Ptychopetalum olacoides root (Muira puama), and Serenoa repens (Saw palmetto), chrysin, 5-androstendione and 5- androstenediol. In a specific embodiment, the liposomes are multilamellar and about 5000 A in diameter. In another specific embodiment, the components of the composition are between 0.5 mg and 50 mg each.

The administration of the composition is preferably in accordance with a predetermined regimen, which may be only on an as needed ("PRN") basis, or at least once daily and over an extended period of time for chronic treatment, and could last for one year or more, including the life of the subject. The dosage administered will depend upon the frequency of the administration, the blood level desired, other concurrent therapeutic treatments, the severity of the condition, whether the treatment is for improving sexual function or muscle strength and mass, the age of the patient, the degree of increase in testosterone desired, and the like.

In one or more embodiments of the invention, Serenoa repens is included in the liposome encapsulated composition to control the production of dihydrotestosterone.

Liposomes Liposomes are lipid vesicles composed of membrane-like lipid layers surrounding aqueous compartments. Liposomes are widely used to encapsulate biologically active materials for a variety of purposes, e. g., they may be used as drug carriers. Depending on the number of lipid layers, size, surface charge, lipid composition and methods of preparation various types of liposomes have been utilized. Methods for the encapsulation of pharmaceuticals in lipid vesicles for administration as an aerosol or liquid droplet spray are numerous and well known to those of ordinary skill in the art. Any of the known methods for preparing a liposome encapsulated composition may be employed within the spirit and scope of this invention.

The earliest processes included the steps of drying the lipid under vacuum from organic solvent as a very thin film on the walls of a rotary evaporator flask, then suspending it by adding an aqueous solution and gently shaking the flask. The lipid swells spontaneously and then gradually falls from the walls of the flask into aqueous suspension as very large multilamellar liposomes of about 1, um in diameter. Tyrrell et al., at 263-4.

As is generally known, varying the specific lipid mixtures/ratios can generate a variety of liposome and lipid vesicle types in the various methods used in generating the liposomes or lipid vesicle. For example, the lipid vesicle may be formed as a micelle, whereas the liposome may be formed as a multilamellar lipid vesicle (MLV) which is composed of a number of bimolecular lamellae interspersed with an aqueous medium; a unilamellar lipid vesicle which is composed of a single spherical lipid bilayer entrapping aqueous solution; and/or a multivesicular lipid vesicle that is composed of a number of vesicles. U. S. Patent No.

5,128,139. Liposome forming lipids include phospholipids (Bedu-Addo FK, et al., 13 (5) PHARM. RES. 710-17 (1996) such as soy phosphatidylcholine and phosphatidylethanolamine.

However, other phospolipids used in the various embodiments of the invention include natural soybean lecithin, phosphatidylcholines, lysophosphatidylcholines, phosphatidylserines, phosphatidylinositols and mixtures thereof. Other types of lipids may be used in the various embodiments of the invention including cholesterols, stearyl amines, stearic acid, tocopherols, and mixtures thereof.

A method of encapsulating biologically active materials in multilamellar lipid vesicles is described in U. S. Patent No. 4,485,054. In a preferred embodiment of the invention, large multilamellar vesicles are prepared according to the method of Brown et al., U. S. Patent No.

5,128,139. The lipids or lipophilic substances are dissolved in an organic solvent. The solvent is removed under vacuum by rotary evaporation. The lipid residue forms a film on the wall of the container. An aqueous solution generally containing electrolytes and/or hydrophilic biologically active materials is added to the film. Agitation produces larger multilamellar vesicles. Small multilamellar vesicles can be prepared by sonication or sequential filtration through filters with decreasing pore size. Small unilamellar vesicles can be prepared by more extensive sonication. Alternatively, any of several reported techniques to make unilamellar vesicles may be employed. The sonication of an aqueous dispersion of phospholipid results in microvesicles (SUV) consisting of bilayer or phospholipid surrounding an aqueous space.

Papahadjopoulos and Miller, 135 BIOCHEM BIOPHYS ACTA 624-238 (1968). Multilamellar, unimallelar, multivesicular vesicles and a multiphase liposomal system may be used in different embodiments of the invention.

Alternate methods for the preparation of small unilamellar vesicles that avoid the need of sonication are the ethanol injection technique (Batzri, S. and Korn, E. 298 BIOCHEM BIOPHYS ACTA 1015-1019 (1973)) and the ether injection technique (Deamer, D. and Bangham, A. 443 BIOCHEM BIOPHYS ACTA 629-634 (1976)). In these processes, the organic solution of lipids is rapidly injected into a buffer solution where it spontaneously forms liposomes of the unilamellar type. The injection method is simple, rapid and gentle. However, it results in a relatively dilute preparation of liposomes and it provides low encapsulation efficiency. Another technique for making unilamellar vesicles is the so-called detergent removal method, Liposome Technology 79-107 (G. Gregoriadis, 1984). In this process, the lipids and additives are solubilized with detergents by agitation or sonication yielding defined micelles. The detergents then are removed by dialysis.

Liposomes have been used to provide efficient administration of various pharmaceuticals and nutraceuticals. U. S. Patent No. 4,937,078 describes a method for administering liposomal encapsulations of opiods via the pulmonary route for superior analgesia. Aqueous dispersions of anti-cancer drugs may also be delivered in liposomes via small particle aerosol to the respiratory tract of a patient. U. S. Patent No. 6,090,407.

Well known in the art are several methods to prepare liposomes containing vitamins and herbal extracts that are suitable for practice with the present invention. U. S. Patent No.

4,089,801, which is expressly incorporated herein by reference, describes a method that may be used in a more preferred embodiment of the present invention. A mixture of a lipid, an aqueous solution of the material to be encapsulated, and a liquid which is insoluble in water, is subjected to ultrasonication, whereby aqueous globules enclosed in a monomolecular lipid layer form liposome precursors. The lipid vesicles are then prepared by combining the first dispersion of liposome precursors with a second aqueous medium containing amphiphilic compounds, and subjecting the mixture to centrifugation, whereby the globules are forced through the monomolecular lipid layer, and forming the biomolecular lipid layer characteristic of liposomes.

Another embodiment of the present invention provides periodic release of the prosexual agents and testosterone precursors entrapped within a liposome complex. Periodic release is accomplished, in part, by the use of multilamellar (multilayered) liposomes, formed in multiple layers of liposomes or in clusters. Because liposomes are inherently unstable, they tend to break apart, thus releasing the contents within. When liposomes are layered together, or are in clusters, those liposomes that are confined within or are sandwiched between outer layers of liposomes are more likely to remain stable. Thus, the outer liposomes tend to break apart releasing their contents while protecting the inner liposomes for later degradation and release.

U. S. Patent No. 5,128,139.

U. S. Patent No. 5,891,465, to Keller et al., describes another method for encapsulation particularly designed to be used with nutritional supplements that may be used in a further embodiment of this invention.

As noted above, the lipid encapsulated compositions of the present invention can either be a mixture of a variety of types and sizes of liposomes and lipid vesicles or compositions containing one or more predominant types and sizes. For the latter types of compositions, a variety of methods are available for separating the liposomes formed into groups based on size and type. These include, but are not limited to, separation using sedimentation, gel filtration, or extrusion through straight pored filters. To make compositions that contain a mixture of liposomal types or sizes, after liposome formation, procedures for separation of the liposome into size/type groups are not employed. See U. S. Patent No. 5,128,139.

Administration by the sublingual, buccal, oral spray or dermal route further avoids the first-pass effect from hepatic enzymes of the compounds of the present invention. The term first-pass effect is used to characterize the fraction of the drug that is metabolized during the first exposure to the gut wall and the liver. All compounds that are absorbed from the gastrointestinal tract go to the portal vein and the liver before entering the systemic circulation.

This means that before a drug that has been absorbed across the membrane of the gastrointestinal mucosa can reach the general circulation it has to pass through the liver. U. S.

Patent No. 5,891,465. In another embodiment of the invention, the composition is administered orally, and held in the mouth before swallowing to permit sublingual adsorption.

In a specific embodiment, the liposomal compositions of the present invention may be administered as an aerosol or spray. These include coarse sprays, colloidal suspensions of liquid droplets in a gaseous carrier, such as oxygen, nitrogen or a hydrocarbon propellant, or temporary suspensions of liquid droplets in the carrier. A variety of devices are currently available that allow for the efficient delivery of liquid compositions such as aerosols or sprays.

Such devices include, but are not limited to, pump actuated devices and pressurized devices such as liquefied gas systems, compressed gas systems, and separate propellant/concentrate systems. REMINGTON'S PHARMACEUTICAL SCIENCES 1644 (15th Ed., Hoover, J. E., ed. 1975).

Examples of commercially available aerosol delivery devices include the Sprayette IV by Calmar Dispensing Systems, Inc. of City of Industry, California. In a specific embodiment, the compositions of the present invention may be administered by mechanical pump devices.

In another specific embodiment, the compositions of the present invention may be administered by topical application to the genitals.

The liposomal compositions of the present invention are non-invasive and the lipid encapsulation and aerosol or spray administration of an aqueous solution provides enhanced absorption properties for the agent. When administered, the compositions of the present inventions may be in the oral cavity for a period of time sufficient for absorption of the agent sublingually. The period of time needed to attain absorption will vary based mainly on the type of lipid particle, the lipids that make up the lipid coat, the agent encapsulated, and delivery system used. A skilled artisan can readily determine the time needed to achieve absorption, e. g., sublingual, and vary these parameters to optimize delivery of the composition. The invention will be further illustrated by the following non-limiting examples: EXAMPLE 1 A composition of the following formulation was prepared by the method of Schneider, U. S. Patent No. 4,089,801, as described above: Yohimbe is obtained as cut bark, in bulk, from TSN Labs, Inc., Midvale Utah; muira puama is obtained as root, in bulk, from Almira Alchemy in Alachua, Florida; Epimedium sagittatum obtained as a 5% standardized extract, Tribulus terrestris obtained as a 45% standardized extract, and Serenoa repens obtained as a 35% extract are obtained from Gourmet Nutrition, in Ste. Julie, Quebec, Canada; chrysin is obtained from LKT Laboratories, Inc., of St.

Paul MN ; and 5-androstenedione and 5-androstenediol are obtained from Eiselt Research in Jarfalla Sweden. Extracts are prepared from bulk plant by methods well-known in the art.

An aqueous solution of nutrients comprising 30 mg of Epimedium saggitatum, 25 mg of Tribulus terrestris, 15 mg of Yohimbe, 10 mg Ptychopetalum olacoides root (Muira puama), 10 mg Serenoa repens (Saw palmetto), about 10 mg chrysin, 4 mg of 5-androstenedione and about 2 mg of 5-androstenediol per milliliter of solution is encapsulated in an aqueous sodium chloride solution (0.15 M/1).

Lecithin (54 mg) and the aqueous nutrient solution (0.1 ml) are added to dibutyl ether (3 ml) and the heterogeneous mixture thus obtained is subjected to ultrasonic (or near- ultrasonic) vibration (17 kHz frequency; output: 70 Watts) for 2 minutes while maintaining a temperature less than 30 C by means of a cooling bath.

A transparent liquid, apparently homogeneous and having a bluish reflection, is obtained. A layer of this liquid is placed in a centrifuge tube on a layer of 1.5 ml of an aqueous solution of sodium chloride (0.15 M/1). There is thus obtained a 2-phase"mixture"comprising a lower layer formed by an aqueous phase (the sodium chloride solution) and an upper layer formed by the organic phase obtained in the first step of the process by ultrasonic vibration of the mixture of dibutyl ether, lecithin and the nutrient solution.

The 2-phase mixture is then centrifuged at 30,000 rev/min. for 30 minutes. The upper layer (organic phase) is then removed and the lower layer (aqueous phase) is submitted to a further centrifugation at 30,000 rev/min. for 30 minutes. A faintly bluish clear liquid is obtained together with a very small amount of residue comprising non-dispersed lipid (lecithin), which is rejected. The clear liquid comprises a suspension of liposomes (having colloidal dimensions) containing the aqueous nutrient solution, in a 0.15 M sodium chloride solution, and also contains a small quantity of non-encapsulated nutrients.

Depending on how the suspension is to be used, it is possible to use the suspension as formed or after elimination of non-encapsulated nutrients by gel chromatography (for example on a sepharose (dextran) gel).

EXAMPLE 2 : A clinical trial is conducted at the International Academy of Alternative Health and Medicine. Two groups of six men are given samples of a liposome nutrient composition with a unit dose of. 75 mL comprising 30 mg of Pausinystalia yohimbe ; 30 mg of Epimedium sagittatum extract of leaf, 5% icarrin ; 25 mg of Tribulus terrestris fruit extract, 45% steroid saponins; Ptychopetalum olacoides herb extract, 12: 1; Serenoa repens fruit extract, 20-25% fatty acids and sterols; 4 mg of androstenedione; and 2 mg of 4-androstenediol. Subjects are instructed to administer two full sprays under their tongues three times a day and to hold the solution under the tongue for 20 seconds.

1) Group 1: Subjects, six men, aged 42-73, are told that the product was aimed at being prosexual, but that it might also affect their capacity to work out at the gym. They were given a 4 point rating scale from 0 (no effect) to 3 (very effective) and asked to rate the composition's effectiveness as a pro-sexual. Five of six subjects find that the composition had some effect.

Ratings were as follows: SubjectRating 1 2 2 1 3 3 4 2 5 0 6 1 The men all report that they felt that the product improved their work-out, so a second trial is performed.

2) Group 2: Six men, aged 46 to 73,4 of whom will have already used the composition as part of Group 1 and two additional subjects, are asked to rate its effectiveness in improving work-out in the gym, both as ease of work-out and how strong they felt. All men report some effectiveness in both of the parameters, and one subject (3) finds the composition very effective in promoting ease of workout.

Subject Ease Strength 1 2 1 1 2 2 2 3 3 2 5 1 1 5 1 1 6 2 1 Four of the six men state that it was easier to maintain or increase muscle mass, and this was synonymous with"feeling stronger." EXAMPLE 3 A study of the effect of Muira puama, Epimedium sagittatum, Pausinystalia Yohimbe, Tribulus terrestris, 5-androstenedione, 5-androstenediol, Serenoa repens and chrysin in men with age-related decline in testosterone levels, sexual dysfunction and muscle weakness is conducted over a six-month period. A statistical analysis is performed to compare the resulting testosterone levels of the test and a control (placebo) group to determine if a significant improvement in testosterone levels results from administration of the test preparation. Sixty men having total reduced testosterone and complaining of loss of libido are selected for inclusion in the statistical study. Two weeks prior to the start of the study, each subject completes a self-administered questionnaire to assess sexual function in men with erectile dysfunction. Subjects are asked to rate on a five-point scale the following items: frequency (per week) of morning erections, erectile firmness, ejaculatory frequency (per week) and libido.

Baseline blood samples are drawn on two separate days, measuring free and bound serum testosterone, with standard hemogram and blood chemistry; and the subjects are assigned randomly to one of two treatment groups: the test solution or matching placebo solution. Both groups continue on their basal diet and administer two. 75 ml sprays of the test solution three times per day.

The effects of the dietary supplementation on total free and bound testosterone, and sexual function as measured by the self-assessment scale, are evaluated using multiple linear regression analysis and a standard student's T-test. In each analysis, the baseline value of the outcome variable is included in the model as a covariant. Treatment by covariant interaction effects is tested by the method outlined by Weigel and Narvaez 12 CONTROLLED CLINICAL TRIALS 378-94 (1991). If there are no significant interaction effects, the interaction terms are removed from the model. The regression model assumptions, normality and homogeneity of variance of residuals, are evaluated by inspecting the plots of residuals versus predicted values.

Detection of the temporal outset of effects is done sequentially, by testing for the presence of significant treatment effects at 18,12, and 6 weeks, proceeding to the earlier time in sequence only when significant effects have been identified at each later time-period. Additionally, differences between groups in nutrient intake, physical activity, and body mass index at each time point are compared using one-way analysis of variance. Changes from the baseline within each group are evaluated using paired T-tests. In additionally, variance analysis is performed on all baseline measurements and measurable subject characteristics to assess homogeneity between groups. All statistical procedures are conducted using the Statistical Analysis System (SAS Institute Inc., Cary, NC). An alpha level of 0.05 is used in all statistical tests.

A statistically significant increase in testosterone and improved sexual function are observed in the blood of the treated subjects but not the controls upon completion of the study.

The differences between the levels of testosterone in the treated subjects and controls are statistically significant.

The invention has been described in detail with particular reference to preferred embodiment thereof. However, it will be appreciated that those skilled in the art, upon consideration of this disclosure, may make variations and modifications within the spirit and scope of the invention.

All patent references and other published documents identified in this specification are hereby incorporated by reference in their entirety.