SEXUAL HEALTH ENHANCEMENT COMPOSITION

Abstract

A topical composition and method comprising administering physiological effective amounts of at least two active components forskolin combined with one or more lubricating base components. Active components may include one or more of L-arginme free base, hydrochloride salt, ethyl ester or combinations thereof.

Claims

1. A topical composition comprising physiological effective amounts of at least two active components comprising one or more of L-arginine free base, hydrochloride salt, ethyl ester or combinations thereof, and forskolin combined with one or more lubricating base components.

2. The topical compositional of claim 1 consisting essential of physiological effective amounts of at least two active components comprising one of L-arginine free base, hydrochloride salt, or ethyl ester and forskolin, combined with one or more lubricating base components.

3. The topical composition of claim 1 consisting of physiological effective amounts of L-arginine free base, hydrochloride salt, ethyl ester, or combinations thereof, and forskolin in a gel comprising one or more lubricating base components.

4. The topical composition of claim 1 where in the lubricating base components comprising at least one lubricating pharmaceutically acceptable glycol.

5. The topical composition of claim 1 wherein the effective amount of L-arginine free base, hydrochloride salt, ethyl ester, or combination s thereof comprises about 15-80 wt %, preferably about 20-40 wt %, or more preferably about 30 wt %, based on the weight of the topical composition.

6. The topical composition of claim 1 wherein the effective amount of forskolin comprises about 0.01-1 wt %, preferably about 0.1-0.5 wt %, or more preferably about 0.1 wt % based on the weight of the topical composition.

7. The topical composition of claim 1 wherein an amount of one or more base components in the composition in the composition comprises about 19-85 wt %, prefer about 60-80 wt %, or more preferably about 60-70 wt %, based on the total weight of the topical composition.

8. The topical composition of claim 1 wherein the base components are selected from glycols including propylene glycol, or polyethylene glycol 400 NF, butylene glycol, ethylene glycol, diethylene glycol, pentylene glycol, or a combination thereof, in an oil-in-water emulsions, water in-oil emulsions, anhydrous silicone bases, lipophilic foam bases, or transdermal cream bases.

9. The topical composition of claim 1 comprising about 75 wt % propylene glycol and about 25 wt % polyethylene glycol 400 NF based on the weight of the lubricating base components.

10. The topical composition of claim 1 comprising greater than 75 wt % propylene glycol and less than about 25 wt % polyethylene glycol.

11. The topical composition of claim 1 comprising less than 75 wt % propylene glycol and greater than about 25 wt % polyethylene glycol.

12. The topical composition of claim 1 wherein the one or more base components comprise dermal penetration enhancers.

13. The topical composition of claim 1 wherein the dermal penetration enhancers comprise essential oils, fatty acids, or polysaccharides.

14. The topical composition of claim 1 wherein the base component are selected from glycols, oil-in-water emulsions, water-in-oil emulsions, lipophilic foams, water, anhydrous silicone base, lipophilic foam base, transdermal cream base, and mineral oils.

15. A topical composition comprising an effective amount of one or more of L-arginine free base, hydrochloride salt, ethyl ester, or combinations thereof, and forskolin to provide one or more of the follow conditions for sexual health enhancement: increased nitric oxide (NO) production, increased blood flow by creating nitric oxide, increased cAMP induced relaxation, relaxed state for stimulation, or enhanced relaxation.

16. A packaged sexual health composition comprising a single use sachet containing a topical gel composition having physiological effective amounts of one or more of L-arginine free base, hydrochloride salt, ethyl ester, or combinations thereof, and forskolin, wherein the gel comprises pharmaceutically acceptable additives selected from mineral oils, benzoyl peroxide, diethanolamine, monoethanolamine, triethanolamine, dioxin, parabens, phthalates, sodium lauryl sulfate, sodium laureth sulfate, tridosan, avobenzone, benzphenone, ethoxycinnamate, and PABA.

17. A method of enhancing sexual health comprising topically administering an effective amount of a topical composition consisting essentially of L-arginine ethyl ester and forskolin to a subject, wherein the effective amount of L-arginine ethyl ester and forskolin generates nitric oxide for increased blood flow in the subject, or provides a relaxation state for stimulation of the subject, or both increased blood flow and relaxation state of the subject.

18. The method of claim 17 further comprising use of a transdermal electrically polarized conductive pad attached to an electro-stimulation power controlled device, wherein the effective amount of L-arginine ethyl ester and forskolin in combination with an electric field or current to enhance skin penetration generates nitric oxide for increased blood flow in the subject, or provides a relaxation state for stimulation of the subject, or both increased blood flow and relaxation state of the subject.

Description

DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 is a diagram that illustrates biological processes that have synergistic effects with L-arginine and forskolin.

DETAILED DESCRIPTION

[0028] Forskolin, a diterpene natural product that is produced by the Indian Coleus plant, Coleus forskohlii, has been used to raise levels of cyclic adenosine monophosphate (cAMP) in the study and research of cell physiology. Forskolin activates the enzyme, adenylyl cyclase, and increases intracellular levels of cAMP.

[0029] Important molecular mechanisms of sexual stimulation may include activation of the parasympathetic nervous system, which causes stimulation of endothelial nitric oxide synthase (eNOS), which increases the production of NO in the endothelial cells. NO diffuses to smooth muscle tissues causing relaxation and erection.

[0030] L-arginine is a physiological precursor of nitric oxide (NO), which stimulates eNOS. High doses can restore NOS activity in conditions with endothelial cell dysfunction such as aging, atherosclerosis and diabetes mellitus. Forskolin stimulates cAMP formation and activates nNOS phosphorylation. Based on these important biological processes, natural products such as adenosine donors (purines) and/or forskolin (adenylate cyclase inducers), may have important synergistic effects with L-arginine (precursor of NO) on, for example, penile tissues causing an erection. The diagram in FIG. 1 highlights these pathways.

[0031] L-arginine free base has been studied for treatment of ED. L-arginine is a physiological precursor of nitric oxide (NO) and stimulates eNOS. L-arginine is available in numerous commercially available products in both oral and topical formulations. However, the effectiveness of these products has not been carefully studied with appropriate pharmacokinetic and pharmacodynamic considerations. High oral doses (>6 gm) are required to restore eNOS activity in conditions with endothelial dysfunction such as aging, atherosclerosis and diabetes mellitus. L-Arginine is a zwitter ion and having the properties of a zwitter ion it cannot cross human squamous epithelium to any significant degree. Some reported L-arginine preparations may contain menthol which is an irritant to human skin. By irritating the skin these products will allow some of the L-arginine to cross the skin barrier but again not to any significant degree. In some embodiments, L arginine hydrochloride salt may be substituted for the L-arginine free base. In other embodiments, in order to nullify the charge effect for example, L-arginine ethyl ester may be substituted for the L-arginine free base because the ethyl ester compound crosses squamous epithelium to a significant degree. For example, US Patent Application Pub. No. 2013/0184233 to Carter et al., Personal Lubricant Compositions reports a skin lubricant containing L-arginine ethyl ester. In another example, U.S. Pat. No. 7,629,384 to Fossel et. al., Topical Delivery of L-arginine to Cause Beneficial Effects reports a penetrating cream containing L-arginine along with sodium chloride or other salts at concentrations sufficient to produce a hostile biophysical environment and when applied to the penis induced a firm and natural erection. Intrigue Laboratories have developed a proprietary L-arginine ethyl ester based cream (40% Aquaphor) to enhance penetration of L-arginine for the treatment of sexual dysfunction in women.

[0032] Administration of L-arginine by intravenous infusion (IV) or orally at doses of from about 6 to about 30 gm induced peripheral vasodilation in humans and improved endothelium-dependent vasodilation, resulting in improved muscle blood flow. [0033] L-arginine hydrochloride (HCl) has known physiological properties including: [0034] L-arginine HC1 was administered orally (12 capsules of 0.5 gm of L-arginine HCL) Bioavailability was 50 to 87% with a time to Cmax of 40 to 60 minutes [0035] Mean Cmax: 623 and 822 ttmol/L for 30 gm and 6 gm IV, and 310+/?152 ?mol/L for 6 gm oral [0036] Half-life 60 (IV) to 90 (PO) minutes [0037] No significant changes in hemodynamics at 6 gm doses; blood pressure and total peripheral resistance were significantly decreased after 30 gm IV [0038] Increased urinary cGMP and nitrate excretion (correlate with plasma concentrations) with about from 6 gm to about 30 gm IV, causing significant increases [0039] Numerous over the counter products (gels and creams) are available with or without other agents such as ginseng, niacin and L-citrulline (at concentrations up to 5%).

[0040] Since an oral dose of 10 gm of L-arginine produces a peak arginine plasma concentration of 200 to 300 ?M and the Km of NOS activity for endothelial cells is approximately 30 to 40 ?M, a 10 gm oral dose produces plasma concentrations that are 10-fold above the Km. Therefore, topical administration of arginine needs to be delivered at concentrations greater than about 30 to 40 ?M to achieve the desired physiological effects. Suitable topical formulations should deliver at least about 50 to 70 mg/L (50 to 70 ?g/ml) to the endothelial cell membrane to achieve desired effective amounts of arginine. In some embodiments, the L-arginine includes about 20 wt % to 40 wt % of the total weigh of the topical composition.

[0041] Forskolin is a naturally occurring alkaloid derived from the Indian herb Coleus forskohlii that has been shown to induce smooth muscle relaxation in in vitro studies using canine corporeal tissue and penile erection after intracavernosal administration in a canine model. Forskolin binds directly and stimulates adenylate cyclase increasing cAMP concentrations, and can directly reduce intracellular calcium concentrations in smooth muscle causing relaxation in a NO-independent pathway. cAMP formation by forskolin also activates nNOS phosphorylation which may contribute to sustained erection in concert with phosphorylated eNOS stimulation.

[0042] The activity of forskolin was studied in vitro and in vivo in humans and animals compared to PGE1, papaverine and phentolamine. In vitro forskolin and prostaglandin E1 alone caused concentration dependent relaxation of human CC with an EC50 of approximately 200 nm and 16 nm, respectively. When forskolin and prostaglandin E1 were combined, the concentration response curve for relaxation shifted to the left. cAMP production was highest in cells treated with prostaglandin E1 and forskolin and was unaffected by papaverine or phentolamine. In three animals (New Zealand White rabbits) administered intracavernosal forskolin, equilibrium intracavernosal pressure and duration of erection had a dose dependent increase.

[0043] Forskolin is water soluble and affects multiple different pathways to increase cAMP which has synergistic activity with prostaglandin E1, papaverine and phentolamine. Forskolin may also have synergistic activity with L arginine (NO donor); (and also increase the efficacy PDES inhibitors). In some embodiments, the forskolin is in a pure state and pure, when used with respect to a material containing forskolin, means having at least a technical grade of purity or at least a reagent grade of purity. Suitable purity includes ?70%, 75%, 80%, 85%, 90%, 95% or 99% pure forskolin. In other embodiments, the forskolin is in a crude state and crude, when used with respect to a material containing forskolin, means forskolin that has not been fully refined and can contain components in addition to forskolin having a purity of ?40%, 45%, 50%, 55%, 60%, or 65% pure forskolin.

[0044] Suitable dermal penetration enhancers include, for example, volatile oils (e.g. essential oils), fixed oils (e.g. fatty acids) and polysaccharides. Essential oils are volatile, odoriferous substances found in the flowers, fruit, leaves and roots of certain plants. Fatty acids, on the other hand, are composed of aliphatic hydrocarbon chains, which can be either saturated or unsaturated, and include a terminal carboxyl group.

[0045] Essential oils are a complex mixture of many diverse and unique chemical compounds. Essential oils can include compounds classified as:

[0046] nitrogen- and sulphur-containing compounds (e.g., allyl isothiocyanate found in mustard oil);

[0047] aromatic compounds, which are benzene derivatives (e.g., eugenol which is the main constituent of clove oil);

[0048] terpenes (e.g., 1,8-cineole in eucalyptus oil) and terpenoids; and

[0049] miscellaneous compounds (includes long-chain unbranched substances).

[0050] Exemplary essential oils include niaouli oil, eucalyptus oil, alpinia oxyphylla oil, turpentine oil, sweet basil and tulsi oil, cardamom oil, peppermint oil, fennel oil, and black cumin oil.

[0051] Terpenes, which is a constituent of an essential oil can be isolated from essential oils and are also suitable skin penetration enhancers. Terpenes do not have aromatic character but contains carbon and hydrogen atoms with or without oxygen. Exemplary terpenes include the following classes along with specific examples in that particular class:

TABLE-US-00001 TABLE 1 Class Example(s) of terpene Source ACYCLIC Geraniol and nerol Geraniol is an unsaturated primary MONOTERPENES alcohol found in geranium and other (Alcohols) essential oils. It is found as esters and as a glucoside, but mainly occurs in the free form. Nerol is the isomeric alcohol and is found in various essential oils, primarily in neroli and bergamot oils Palmarosa oil contains more geraniol than any other oil and for nerol it is catnip and rose oil. Linalol Linalol is found as (+) and (?) forms in the oil of Linaloe (a plant found in Central America), but can also be found free and as esters in numerous other essential oils. Rosewood oil contains more linalol than any other oil. MONOCYCLIC Limonene The optically active limonene is MONOTERPENES widespread in nature and is found in (Hydrocarbons) its (+) and (?) forms in various essential oils such as bergamot, caraway, lemon and orange oils. The signature oils for d-limonene and l-limonene is grapefruit and fleabane, respectively. MONOCYCLIC ?-Terpineol Found in many essential oils such as MONOTERPENES camphor, neroli and petitgrain oil. The (Alcohols) Alcohols signature oil is lemon eucalyptus. related to ?-terpineol ?-Terpineol Isomeric with ?-terpineol, but is not isolated from natural sources. Found in commercial terpineol. ?-Terpineol Second isomer of ?-terpineol and is found in at least one essential oil and commercial terpineol. MONOCYCLIC Menthol Menthol is a constituent of numerous peppermint MONOTERPENES oils and is found as its (?)-form. (Alcohols) Alcohols derived from thymol MONOCYCLIC Carveol Carveol is found in caraway oil. MONOTERPENES (Alcohols) Alcohols derived from carvacrol MONOCYCLIC Menthone (?) form is found in numerous peppermint oils, MONOTERPENES (+) form also occurs naturally. (Ketones) Pulegone Found in pennyroyal and many other Ketones related to essential oils as its (+) form. menthone iso-Pulegone Often an accompaniment of pulegone in essential oils. Piperitone Occurs in numerous eucalyptus oils as (+)- and (?) forms. MONOCYCLIC Carvomenthone Isomeric with menthone and is a MONOTERPENES saturated ketone. (?) form is found in (Ketones) numerous essential oils. Ketones related to Carvone Occurs in its (+), (?) and (?) forms and carvomenthone Unsaturated is the main constituent of caraway and ketone dill oils. It can also be found in spearmint oil. MONOCYCLIC 1,8-Cineole Widespread in essential oils, particularly MONOTERPENES in eucalyptus and wormseed oil. (Oxides) BICYCLIC ?-Thujene Found in numerous essential oils. MONOTERPENES (Hydrocarbons) BICYCLIC Car-3-ene Found in several turpentine oils. MONOTERPENES (Hydrocarbons) BICYCLIC ?-Pinene Widespread in nature, found in most MONOTERPENES essential oils of Coniferae. It is the (Hydrocarbons) main constituent of turpentine oil. Secreted by conifers, turpentine oil consists of resinous material dissolved in turpentine oil. ?-Pinene (Nopinene) Isomeric with ?-pinene. Its signature oil is galbanum. BICYCLIC Verbenol, verbenone Verbenol and verbenone has been found MONOTERPENES and verbanone in nature, with the latter being found in (Oxygenated verbena oil. The signature oil for derivatives) verbenone is rosemary verbenone. BICYCLIC Camphor Not widely distributed in nature, is the MONOTERPENES major constituent of camphor oil, (Ketones - camphane obtained from the leaves and wood of group) the camphor tree (Cinnamomum camphora). BICYCLIC Fenchone Occurs as the optically active forms in MONOTERPENES fennel, thuja and cedar leaf oils. (Ketones - fenchane group SESQUITERPENES Farnesol Widely distributed in flower oils, in (Alcohol) particular those of the acacia, cyclamen and the rose. Nerolidol Isomeric with farnesol and found in neroli oil. (?) Guaiol A crystalline alcohol found in guaiacum wood oil. (+) Cedrol Cedarwood oil. (?) ?-Bisabolol Camomile oil. SESQUITERPENES Bisabolene Widespread in nature, found in bergamot (Hydrocarbon) and myrrh oils. Also in many other essential oils. The Azulenes All hydrocarbons are derived from (Unsaturated azulene (C.sub.10H.sub.8), a parent hydrocarbon. hydrocarbons) Most of those attained from natural origin have the molecular formula C.sub.15H.sub.18. Azulenes is responsible for the blue color of certain essential oils, or when essential oils become blue/violet when undergoing processes which might result in dehydrogenation (+) Longifolene Tricyclic sesquiterpene found in the essential oil of Pinus longifolia. ?-Caryophyllene Main hydrocarbon constituent of clove oil. (+)- Eucalyptus oil. (+) ?-Cedrene Cedarwood oil. ACYCLIC Phytol Found in rosemary oil. DITERPENES (Alcohol) ACYCLIC Squalene It is found in the unsaponifiable fraction TRITERPENES of shark liver oil and in several plant (Hydrocarbon) sources such as vegetable oils and several fungi. Jasmine is the signature oil.

[0052] In some embodiments, the terpene menthol is used as a skin penetration enhancer in a composition containing L-arginine.

[0053] Exemplary fixed oils or fatty acids include fish oil, fatty acids from algae and phospholipids (e.g. phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidic acid, phosphadtylinositol).

[0054] Exemplary polysaccharides (polymer of simple sugars and their derivatives) as skin penetration enhancers include chitosan, aloe vera gel or aloe vera juice.

[0055] Other skin penetration enhancers can include methyl salicylate, capsaicin (trans-8-which is an alkaloid derived from hot chili peppers, belonging from the genus Capsicum of the Solanaceae family), vitamin E (?-tocopherol and methyl salicylate, oil of wintergreen or wintergreen oil is an organic ester naturally produced by many species of plants, particularly wintergreens).

[0056] Skin penetration enhancers such as terpenes and phospholipids can also be used to prepare vesicles (e.g. liposomes, ivansomes and ethosomes) for transdermal delivery. In other embodiments, essential oils can also be incorporated into patches for transdermal delivery. Exemplary oils can include any of the disclosed essential oils. In some embodiments, the essential oils used in patches include menthol oil, lemon grass oil, clove oil, eucalyptus oil or combinations thereof The transdermal patches used can include matrix, microreservoir, reservoir, adhesive and membrane-matrix hybrid type patches.

[0057] In some embodiments, the disclosed composition is delivered topically to the skin. Unfortunately, dermal and transdermal delivery can be limited by the permeability of the substance or composition. To enhance or improve the absorption or delivery of L-arginine through the skin, skin penetration enhancers may be included. Both chemical and/or physical approaches can be used to enhance the penetration of substances across the skin. A skin penetration enhancer may include compounds that assist in the effective delivery of a desired ingredient (e.g. L-arginine) into the skin. Exemplary skin penetration enhances include volatile oils (e.g. essential oils), fixed oils (e.g. fatty acids) and polysaccharides. Essential oils are volatile, odoriferous substances found in the flowers, fruit, leaves and roots of certain plants. Fatty acids, on the other hand, are composed of aliphatic hydrocarbon chains, which can be either saturated or unsaturated, and include a terminal carboxyl group.

[0058] Like L-arginine, electrostimulation may also facilitate blood vessel dilation. In contrast to electrophoresis which requires actives to be in the ionized state for delivery, L-arginine and electrostimulation may allow non-ionized actives to be absorbed to a greater extent than in their absence. In some embodiments, the topical composition is applied in combination with electro stimulation. In one embodiment this provides a method of enhancing sexual health comprising of topically administering an effective amount of a topical composition consisting essentially of L-arginine ethyl ester and forskolin to a subject in combination with use of a transdermal electrically polarized conductive pad attached to an electro-stimulation power controlled device, wherein the effective amount of L-arginine ethyl ester and forskolin in combination with an electric field (or current) enhancing skin penetration generates nitric oxide for increased blood flow in the subject, or provides a relaxation state for stimulation of the subject, or both increased blood flow and relaxation state of the subject.

EXAMPLES

Formulating/Packaging Procedures and Processes

[0059] An example of a suitable protocol for formulating L-arginine ethyl ester and forskolin in gel-based lubricants for sexual health is provided below in Table 1.

TABLE-US-00002 TABLE 1 Base Ingredients Supplier Function % w/v Propylene glycol USP Fagron Lubricant 75% Polyethylene glycol Gallipot or Lubricant 25% 400 NF Fagron Total 100% L-arginine ethyl ester Sigma 5 g per vial Active ingredient 40% L-arginine ethyl ester Sigma (same as Active ingredients 40% above/below) Forskolin Sigma 50 mg 0.2%

TABLE-US-00003 TABLE 2 Formulation Schemes Formulation Strength Actives 1 Maximum LA-EE 40% 2 Maximum LA-EE 40%; Forskolin 0.2%

Clinical Investigations

[0060] In a clinical investigation, unit dose sachets (3 ml) containing the formulation set out above in Table 1 were distributed randomly to volunteer self-reported healthy males (n=16, ages: 25 to 75 years) to use in their normal sexual activities. A 14 question survey was then completed anonymously using Survey Monkey post-use. 31.2% of men experienced greater firmness than normal and 81.2% of mean experienced greater than or equal to normal erection firmness. The quality of sexual experience was 75% higher than normal. 81% of men were likely to use product if available.

Performance Feedback

[0061]

TABLE-US-00004 Buy it if Available Today - 80% Enhanced Erection Firmness - 81% Sex Quality better than Normal - 75%

[0062] The female partner perspective was captured in four written testimonials. There was a positive effect on the female partner (age 51 and menopausal); Beyond the lubrication it provided a tingling sensation which made the vagina more sensitive. The overall experience was the best sex in a couple years and outstanding.; From the female (premenopausal) perspective it was outstanding. It created a tingling sense of warmth and lubrication which brought on an orgasm much faster and predictable than normal; and Female partner had a noticeably better than average orgasm.

[0063] It will be readily apparent to one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the composition, methods and applications described herein can be made without departing from the scope of any of the embodiments. The following examples are included herewith for purposes of illustration only and are not intended to be limiting.