WO2011057386A1

WO2011057386A1 - Composition and prophylactic device for enhancing sexual performance or pleasure

Info

Publication number: WO2011057386A1
Application number: PCT/CA2010/001725
Authority: WO
Inventors: Michael Farber
Original assignee: Oral Delivery Technology Ltd.
Priority date: 2009-11-13
Filing date: 2010-10-28
Publication date: 2011-05-19

Abstract

There is provided a novel topical composition, a novel prophylactic device, and a method of using them for stimulating and maintaining an erection of a sexual organ in a subject in need thereof. The topical composition, prophylactic device and method comprise an amino acid ester compound with at least one nitric oxide releasing group, or a pharmaceutical salt thereof.

Description

Title: Composition and prophylactic device for enhancing sexual performance or pleasure

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from US Provisional patent applications No. 61/260,883 and 61/261 ,171 , both filed November 13, 2009.

BACKGROUND

(a) Field

[0002] The subject matter disclosed generally relates to compositions, devices and methods for enhancing sexual performance or pleasure, and more particularly to compositions and methods for treating sexual dysfunction in a male; and methods of surface stimulation of the sexual organs of female or male to promote enhanced sexual performance or pleasure.

(b) Related Prior Art

[0003] Loss of erectile capacity in men is an event which adversely affects the physical, emotional and social sphere of the sufferer. When this sexual dysfunction arises, men come to expect yet another "failure" whenever they have sexual intercourse, thus generating a particular state of mind which is both cause and effect of a problem that was originally only physical.

[0004] As sexuality is an important means of communication between a couple, deterioration of erectile potency leads to a build-up of emotional tension between the two partners and a consequent deterioration in their relationship. Loss or absence of erectile capacity and lubrication to various extents also constitutes a serious problem in women, with adverse consequences on the couple's relationship. A variety of mediators and receptors are involved in the tumescence of the male and female genital organs. Acetylcholine (Ach), for example, is the best-known parasympathetic neurotransmitter. In vitro, it causes relaxation of smooth muscle striations previously contracted by noradrenaline, and contraction of smooth muscle cell isolates. This suggests that the main action of Ach is to contract the smooth muscles and determine the release of a substance which causes cavernous relaxation. In addition to Ach, the parasympathetic nerves also release other neurotransmitters, including nitric oxide (NO), VIP and CGRP (calcitonin gene-related peptide).

[0005] The inability of some males to reach an erectile condition may be due to psychological and physiological factors or a combination of both. This invention deals in part with the problems of impotency wherein the afflicted individual is physically capable of having a penile erection but has difficulty reaching and/or maintaining a penile erection for purposes of sexual intercourse.

[0006] Nitric oxide (NO) is synthesized from L-Arginine through the action of the enzyme NOs (nitric oxide synthetase). The two sources of NO in the penis and clitoris are represented by the parasympathetic nerve endings and the endothelium, synthesized by different NOs enzymes: nNOs (neuronal NOs), which is present in the cytoplasm of the parasympathetic nerves, and eNOs (endothelial NOs), found in the endothelium of the blood vessels and trabecular tissue, which mainly seems to bond to the cell membranes. Numerous experiments have demonstrated that stimulation of the parasympathetic nerves leads to the release of NO as a result of direct action by the nerve endings (reaction catalyzed by nNOs) and indirect action resulting from the effect of Ach, released by the parasympathetic nerves, on the vascular endothelium, with stimulation of eNos. There is also evidence in support of a tonic release of NO by the endothelium and the involvement of partial oxygen pressure. In fact, periods when partial oxygen tension is low, as in conditions of flaccidity, are associated with reduced NOs activity. Finally, various studies have confirmed the ability of other substances, whose physiological significance has not yet been established, to determine the release of NO by the endothelium. The clinical evidence that NO plays a part in the erection of the penis includes the observation that intracaverous injection of NO-releasing substances can produce an erection in impotent men as well as men with normal sexual potency. [0007] U.S. Pat. No. 4,127,1 18 discloses devices which addresses the problem of male impotency, and includes a specially designed syringe for injecting a vasodilator into the penis. The use of this device can be somewhat uncomfortable or painful, as well as frightening to some, and occasionally difficult to manipulate. U.S. Pat. No. 3,363,624 discloses a method for prolonging an erectile condition by use of a desensitizing agent applied to the closed end of a condom. This patent deals with the problem of premature ejaculation and maintaining the duration of an erection but does not address the problem of producing an erection for those individuals who have difficulty reaching the erectile state. U.S. Pat. No. 4,849,991 discloses a method of stimulating an erection by using a prophylactic device containing the vasodilator nitroglycerin coated therein. This patent deals with the problem of producing an erection for those individuals having a difficulty to reach an erectile state, but does not address the problem of responsiveness to nitroglycerin that is exhibited by some individuals. Moreover, it does not deal with the drawbacks to the manufacture, storage and use of nitroglycerin. Nitroglycerin is an explosive compound that is difficult to produce and stabilize. It is inherently unstable over the long term resulting in a maximum shelf life of a product containing it of about six months.

[0008] It is thus desirable to provide a composition and method for stimulating and maintaining the erection of a sexual organ which contains an alternative compound than nitroglycerin, and does not require any special operational procedures other than the application of a composition onto the sexual organs.

[0009] It is thus desirable to provide a method and device for stimulating and maintaining a penile erection which contains an alternative compound than nitroglycerin, and does not require any special operational procedures other than the use of a topical composition or a condom. SUMMARY

[0010] In a first embodiment there is disclosed a topical composition comprising:

• water, and

• an effective amount of a compound of formula (I):

wherein n = 1 to 10;

wherein R₁ is chosen an amino acid side chain group (D or L configuration),

wherein R₂ is a hydrogen atom, or an amino acid (D or L configuration) forming a peptide bond, or any pharmaceutically acceptable salts thereof;

• in association with a pharmaceutically acceptable topical carrier.

[0011] The compound of formula (I) may be (2-nitrooxy)-2-ethylamino- 3-methylbutanoate:

[00 2] or any pharmaceutically acceptable salts thereof. [0013] The compound of formula (I) may be valine butylene glycol nitrate:

[0014] or any pharmaceutically acceptable salts thereof.

[0015] The compound of formula (I) may be 2'-nitrooxyethyl 2- pentanoate:

[0016]

[0017] or any pharmaceutically acceptable salts thereof.

[0018] The compound of formula (I) may be 4'-nitrooxybutyl 2-amino- pentanoate:

[0019]

[0020] or any pharmaceutically acceptable salts thereof.

[0021] The compound of formula (I) may be :

[0022]

[0023] or any pharmaceutically acceptable salts thereof.

[0024] The R₂ may be a hydrogen atom. [0025] The R₁ may be chosen from: H,

proline side chain,

hydroxyproline side chain,

and

[0026] The R₂ may be an amino acid of formula (II) (D or L configuration) forming a peptide bond:

wherein R_x is chosen from

proline side chain,

hydroxyproline side chain,

and

[0027] The pharmaceutically acceptable topical carrier may be chosen from a gel and a lotion.

[0028] The composition may further comprise a lubricant.

[0029] The lubricant may be chosen from glycerol, sorbitol, a water soluble cellulose, a polysorbate, a carbomer, a polyethylene glycol (PEG), a polyethylene, and a thickening agent.

[0030] The water soluble cellulose may be chosen from modified starch, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methocel® MC, carboxymethyl cellulose, ethyl cellulose, hydroxyl ethyl cellulose, and any combination thereof.

[0031] The polysorbate may be chosen from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorban 60), polyoxyethylene (20) sorbitan tristrearate (polysorban 65), and polyoxyethylene (20) sorbitan monooleate (polysorban 80), and any combination thereof.

[0032] The carbomer may be a carbopol® polymer chosen from carbopol® polymer 71 G NF, carbopol® polymer 971 P NF, carbopol® polymer 974P NF, carbopol® polymer 980 NF, carbopol® polymer 981 NF, carbopol® polymer 5984 EP and carbopol® polymer Ultrez 10 NF, and any combination thereof.

[0033] The polyethylene glycol (PEG) may be chosen from PEG 200, PEG 200E, PEG 300, PEG 300E, PEG 400, PEG 400E, PEG 600 and PEG 600E, and any combination thereof.

[0034] The thickening agent may be chosen from alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, agar, carrageenan, locust bean gum, xanthan gum, pectin, and gelatin, and any combination thereof.

[0035] The composition may further comprise at least one vasoactive dilator compound.

[0036] The vasoactive dilator compound may be chosen from niacin, nicotinic acid, visnadine, an icarin compound, amentoflavone, and forskolin.

[0037] The icarin may be chosen from 7-hydroxyethyl-icarin, 7- aminoethyl-icarin, 7-hydroxyethyl-3-0-ramnosyl-icarin, 7-aminoethyl-7- desgluco-3-ramnosyl-icarin, 8-dihydro-icarin and its glucosides in 7 and 3, and 7-hydroxyethyl-7-desgluco-icarin.

[0038] The composition may further comprise at least one antiseptic agent.

[0039] The antiseptic agent may be selected from chlorhexidine gluconate, glucono delta-lactone, a paraben compound, benzoic acid, imidazolidinyl urea, a quaternary ammonium compound, and Octenidine dihydrochloride.

[0040] The composition may further comprise a preservative agent.

[0041] The preservative agent may be chosen from EDTA, EGTA, hydroxytoluene butoxide, hydroxyanisol butoxide, sodium hydroxide, calcium propionate, sodium nitrate, sodium nitrite, sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite.

[0042] The composition may further comprise an absorption enhancer, a warming agent or a combination of both.

[0043] The absorption enhancer may be chosen from triglycerides of coconut oil, isopropyl palmitate, isopropyl myristate, laurocapram, glycerol and propylene glycol and derivatives thereof.

[0044] The warming agent may be chosen from niacin, lactic acid menthol, and eucalyptol. [0045] In another embodiment there is disclosed a method of treating male sexual dysfunction comprising:

(a) contacting a penile tissue with the composition of the present invention to help stimulate tumescene to produce an erection.

[0046] In another embodiment there is disclosed enhancing sexual performance or pleasure comprising:

(a) contacting a sexual organ with the composition of the present invention to help stimulate tumescence.

[0047] In another embodiment, there is disclosed the use of a composition according to the present invention for the preparation of a medicament for the treatment of erectile dysfunction.

[0048] In another embodiment, there is disclosed the use of a composition according to the present invention for the treatment of erectile dysfunction.

[0049] In another embodiment, there is disclosed the use of a composition according to the present invention for enhancing sexual performance or pleasure.

[0050] In another embodiment, there is disclosed a device for stimulating and maintaining a penile erection comprising an elastic sleeve-like member adapted to fit onto a penis, said sleeve-like member having an interior surface, and a vasoactive dilator coating on said interior surface adapted to contact penile tissue and stimulate tumescence, the vasoactive dilator coating comprising an effective amount of a compound of formula (I):

[0051] wherein n = 1 to 10; [0052] wherein is chosen an amino acid side chain group (D or L configuration),

[0053] wherein R₂ is a hydrogen atom, or an amino acid (D or L configuration) forming a peptide bond,

[0054] or any pharmaceutically acceptable salts thereof;

[0055] in association with a pharmaceutically acceptable carrier.

[0056] The compound of formula (I) may be (2-nitrooxy)-2-ethylamino- 3-methylbutanoate:

[0057]

[0058] or any pharmaceutically acceptable salts thereof.

[0059] The compound of formula (I) may be valine butylene glycol nitrate:

[0060]

[0061] or any pharmaceutically acceptable salts thereof.

[0062] The compound of formula (I) may be 2'-nitrooxyethyl 2- pentanoate:

[0063]

NH, [0064] or any pharmaceutically acceptable salts thereof.

[0065] The compound of formula (I) may be 4'-nitrooxybutyl 2-amino- pentanoate: [0066]

[0067] or any pharmaceutically acceptable salts thereof.

[0068] The compound of formula (I) may be:

[0069]

[0070] or any pharmaceutically acceptable salts thereof.

[0071] The

may be chosen from:

[0073] H

[0074] The R₂ may be an amino acid of formula (II) (D configuration) forming a peptide bond:

[0075]

[0076] wherein R_x is chosen from

[0077]

, proline side chain,

hydroxyproline side chain,

[0078] The sleeve-like member may comprise a condom.

[0079] The condom may have a closed end portion and an open end portion and the vasoactive dilator coating terminates approximately 1/2 to 1 inch before the open end portion and terminates before the closed end portion.

[0080] The vasoactive dilator coating may be a transdermal^ absorbed coating.

[0081] The transdermal^ absorbed coating may be applied in patches.

[0082] In yet another embodiment, there is disclosed a method of stimulating and maintaining a penile erection comprising:

[0083] (a) fitting onto a penis a sleeve-like elastic member adapted to fit onto a penis having a vasoactive dilator coating on the interior surface, said vasoactive dilator coating contacting the penile tissue to stimulate tumescence and produce a penile erection,

[0084] wherein said vasoactive dilator coating comprises an effective amount of a compound of formula (I): o

CH O (CH₂)_n ON0

NH

[0085] ^R2

[0086] wherein n = 1 to 10;

[0087] wherein R₁ is chosen an amino acid side chain group (D or L configuration),

[0088] wherein R₂ is a hydrogen atom, or an amino acid (D or L configuration) forming a peptide bond,

[0089] or any pharmaceutically acceptable salts thereof;

[0090] in association with a pharmaceutically acceptable carrier.

[0091] The compound of formula (I) may be (2-nitrooxy)-2-ethylamino- 3-methylbutanoate:

[0092]

[0093] or any pharmaceutically acceptable salts thereof.

[0094] The compound of formula (I) may be valine butylene glycol nitrate:

NH₂

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be 2'-nitrooxyethyl 2- [0098]

[0099] or any pharmaceutically acceptable salts thereof.

[00100] The compound of formula (I) may be 4'-nitrooxybutyl 2- pentanoate:

[00101]

[00102] or any pharmaceutically acceptable salts thereof.

[00103] The compound of formula (I) may be:

[00104]

[00105] or any pharmaceutically acceptable salts thereof.

[00106] The R₂ may be a hydrogen atom.

[00107] The R₁ may be chosen from:

[00108] H

[00109] The R₂ may be an amino acid of formula (II) (D or L configuration) and derivatives thereof, forming a peptide bond:

[00110]

[00111] wherein R_x is chosen from [00112]

, _i

and

[00113] The elastic sleeve-like member may be a condom.

[00114] The vasoactive coating may be applied intermediate the closed end of the condom and the open end of the condom.

[00115] The vasoactive coating may be sporadically applied to the inner surface of the condom. [00116] The vasoactive coating may be uniformly applied to the interior surface of the condom.

[00117] The following terms are defined below.

[00118] The term "Amino acid ester compound" is intended to mean the condensation product of an amino acid with mononitrated alkane ou alkene diol. As will be evident to those familiar to the art, the condensation reaction could also involve, but not limited to, dipeptides or tripeptides, nitrated alcohols containing aliphatic, alkyl or aromatic moieties, as well as other nitric oxide groups attached to the alkane or alkene diols. Amino acid or dipeptide reactions are preferred as well as the condensation reaction with short chain mononitrated alkane diols such as 1 ,3 propanediol or 1 ,4 butanediol.

[00119] The term "Therapeutically effective amount" is intended to mean the amount of the compound and/or composition that is effective to achieve its intended purpose.

[00120] "Transdermally absorbed" is intended to mean the delivery of a compound by passage through the skin and into the blood stream.

[00121] "Transmucosal" is intended to mean the delivery of a compound by passage of the compound through the mucosal tissue and into the blood stream.

[00122] "Carriers" or "vehicles" are intended to mean carrier materials suitable for compound administration and include any such material known in the art such as, for example, any liquid, lotion, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner.

[00123] "Nitric oxide adduct" or "NO adduct" is intended to mean compounds and functional groups which, under physiological conditions, can donate, release and/or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO⁺, NO^", NO^'), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action. [00124] "Nitric oxide releasing" or "nitric oxide donating" is intended to mean methods of donating, releasing and/or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO+, NO-, NO^*), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.

[00125] The term "Nitric oxide donor" or "NO donor" is intended to mean compounds that donate, release and/or directly or indirectly transfer a nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo and/or are oxidized to produce nitric oxide and/or are substrates for nitric oxide synthase and/or cytochrome P450. "NO donor" also includes compounds that are precursors of L-arginine, inhibitors of the enzyme arginase and nitric oxide mediators.

[00126] The term "pharmaceutical acceptable carrier" is intended to mean a preservative solution, a saline solution, an isotonic (about 0.9%) saline solution, or about a 5% albumin solution, suspension, sterile water, phosphate buffered saline, and the like. Other buffering agents, dispersing agents, and inert non-toxic substances suitable for delivery to a patient may be included in the compositions of the present invention. The compositions may be solutions, suspensions or any appropriate formulation suitable for administration, and are typically sterile and free of undesirable particulate matter. The compositions may be sterilized by conventional sterilization techniques.

[00127] The term "impotency" is intended to mean the inability to reach and/or maintain an erectile condition by individuals who are otherwise physically capable of having an erection.

[00128] The term "lubricant" is intended to mean a substance (often a liquid) introduced between two moving surfaces to reduce the friction between them, improving efficiency and reducing wear during sexual acts (such as intercourse and masturbation), to reduce friction with the penis, vagina, anus or other body parts. [00129] Features and advantages of the subject matter hereof will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying figures. As will be realized, the subject matter disclosed and claimed is capable of modifications in various respects, all without departing from the scope of the claims. Accordingly, the drawings and the description are to be regarded as illustrative in nature, and not as restrictive and the full scope of the subject matter is set forth in the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[00130] Fig. 1 illustrates a simplified perspective view of one embodiment of the prophylactic device used for stimulating and maintaining a penile erection;

[00131] Fig. 2 illustrates a sectional view taken on the line 2-2 of FIG. 1 ;

[00132] Fig. 3 illustrates a sectional view taken on the line 3-3 of FIG. 2;

[00133] Fig. 4 illustrates a sectional view of another embodiment of the invention; and,

[00134] Fig. 5 illustrates a sectional view taken on the line 5-5 of FIG. 4.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[00135] In a first embodiment there is disclosed a topical composition containing water and a nitric oxide amino acid ester compound in association with a pharmaceutically acceptable carrier chosen from a gel or a lotion.

[00136] In another embodiment there is disclosed a topical composition containing water, a nitric oxide amino acid ester compound and either an absorption enhancer, a warming agent or a combination of both, in association with a pharmaceutically acceptable carrier chosen from a gel or a lotion.

[00137] In another embodiment there is disclosed a method of treating male sexual dysfunction by contacting a penile tissue with a composition containing a nitric oxide amino acid ester compound in association with a pharmaceutically acceptable carrier that is a gel or a lotion.

[00138] In yet another embodiment, there is disclosed a method of enhancing sexual performance or pleasure by contacting a sexual organ with a composition containing a nitric oxide amino acid ester compound in association with a pharmaceutically acceptable carrier that is a gel or a lotion.

[00139] In accordance with yet another embodiment there is disclosed a prophylactic device for stimulating and maintaining a penile erection in a subject in need thereof, the prophylactic device having therein a vasoactive dilator coating containing a nitric oxide amino acid ester compound in association with a pharmaceutically acceptable carrier.

[00140] In another embodiment there is disclosed a method of stimulating and maintaining a penile erection by using a topical vasoactive dilator composition or a prophylactic device coated therein with a vasoactive dilator , wherein said vasoactive dilator containing a nitric oxide amino acid ester compound in association with a pharmaceutically acceptable carrier.

[00141] A prophylactic device incorporating one embodiment of the invention is generally indicated by the reference number 10 of FIG. 1.

[00142] The prophylactic device 10 comprises a condom 12, which can be formed of latex in any suitable known manner. The condom 12 includes an open end 14 having a rim portion 16 and an opposite closed end 18. The condom 12 has an interior surface 20 which extends from the open end 14 to the closed end 18.

[00143] A portion of the interior surface 20 is coated with a transdermal^ absorbed coating 22. The transdermal^ absorbed coating 22 extends from approximately one-half to one inch from the rim 16 to a point just before the curved closed end portion 18 of the condom 12 so as to avoid contact of the nitroglycerin with the urethral meatus. The uncoated portions of the interior surface 20 can be masked or otherwise covered before the transdermal^ absorbed coating 22 is applied. The transdermal^ absorbed coating 22 can be applied by spraying, brushing or use of a coated mandril (not shown).

[00144] The transdermal^ absorbed coating 22 applied to the inside surface of the prophylactic device contains vasoactive amino acid ester compounds according to the present invention.

[00145] The compositions and coatings of the present invention contains vasoactive amino acid ester compounds. The nitric oxide amino acid ester compounds of the present invention possess many of the required characteristics necessary to fulfill the role of a primary boosting of NO levels that help produce an effective and durable penile erection, or in female, produce vasodilation of the female organs to produce enhanced sexual performance and pleasure. The compounds easily dissociate in water into the amino acid derivative and associated ion forming the pharmaceutical salt. The compounds of the present invention are extremely stable in the form of the salts, and thus possess long shelf lives and stability.

[00146] The nitric oxide releasing groups of the compounds of the present invention are preferably nitro groups (i.e. N0₂), nitroso groups (i.e. NO) and/or heterocyclic nitric oxide donor groups that are linked to the amino acid ester compounds through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen. The heterocyclic nitric oxide donor groups are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.

[00147] The preferred compound of the present invention are the valine and norvaline derivatives of the nitric oxide amino acid ester of the present invention. The most preferred compounds are known as valine nitrooxy ethyl ester (or valine ethylene glycol nitrate), valine nitrooxy butyl ester (or valine butylene glycol nitrate), or any pharmaceutically acceptable salts thereof, and the norvaline derivatives 2'-nitrooxyethyl 2-amino-pentanoate and 4'- nitrooxybutyl 2-amino-pentanoate, or any pharmaceutically acceptable salts thereof, which possess many of the required characteristics necessary to fulfill the role of boosting NO levels. The compound easily dissociates in water into the valine derivative valine ethylene or butylene glycol nitrate and the salt forming acid. The compounds are extremely stable in the form of the salt and thus possesses a long shelf life It has been observed that the preferred compounds of the present invention do not cause hypotension in normotensive or hypotensive individuals. Therefore, upon administration of the preferred compounds of the present invention, an hypertensive individual will experience the vasodilatory effect caused by the preferred compounds, which will result in a decrease in blood pressure. The decrease in blood pressure may be up to a normotensive blood pressure. Individuals with normal blood pressure will not experience the vasodilatory effect caused by the preferred compounds, and their blood pressure will remain stable (unchanged). Individuals with lower than normal blood pressure (hypotensive) will not experience a further drop in blood pressure and their blood pressure will remain stable (unchanged). Furthermore, the preferred compounds of the present invention have half-life of approximately 5 hours. Preferably, a therapeutically effective amount of the compounds of the present invention are administered. Therapeutically effective amounts include but are not limited to 0.5 to 30 mg of the compound of the present invention. Preferably, therapeutically effective amounts include 1 to 15 mg, 0.5 to 5 mg, 1 to 5 mg, 5 to 10 mg, 10 to 15 mg, 1 to 15 mg, 1 to 30 mg, 5 to 20 mg, 5 to 15 mg, 5 to 30 mg, 10 to 20 mg, 10 to 30 mg and 15 to 30 mg.

[00148] The compounds and compositions of the invention can be formulated as pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include, for example, alkali metal salts and addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically- acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriate organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as, for example, formic, acetic, propionic, succinic, giycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2- hydroxyethanesulfonic, sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic, galactaric and galacturonic acid and the like. Suitable pharmaceutically-acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesiurn, potassium, sodium and zinc or organic salts made from primary, secondary and tertiary amines, cyclic amines, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine and the like. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. In one embodiment, the pharmaceutically acceptable salts of the compounds of the invention include the nitrate salts. In another embodiment, the pharmaceutically acceptable salts of the compounds of the invention are heterocyclic compounds such as, furoxan, a sydnonimine, an oxatriazole-5- one and/or an oxatriazole-5-imine.

[00149] The compounds of the present invention, because of the small size of the molecule, can be other choices of linkages and/or amino acids or their derivatives. For example, as alternatives to the above choices, propyl, butyl, or longer chains may be linked to any amino acid. Salts such as chloride or hydrochloride salts may be used. Other amino acid derivatives may also be chosen. Derivatives of the base amino acids whether they are in the L or D configuration of these amino acids can be chosen. Non standard amino acids, or synthetic derivative of standard and non-standard amino acids may be elected, such as those containing acetyl groups attached to the amide of the molecule or nor derivatives of the amino acids, when such derivatives can be achieved. File No. P1322PC00

[00150] The amino acid esters compounds may be based on natural, non-standard or even modified amino acids, with the basic structure as depicted below, where the R_x represents the side chain of the amino acid (wherein R_x may be R₁, R₂ or R₃, as applicable to the specific molecule described herein):

Basic amino acid structure

[00151] Natural Amino Acids

essential amino acids

[00153] The nitric oxide amino acid ester compounds of the present invention are not limited to a single amino acid molecule. The compounds of the present invention may be dipeptide or even tripeptide molecules, with the general formula depicted below and where R_x and R_y independently are any of the amino acid side chains described herein.

[00154] The composition containing a compound as defined present invention may include a wide variety of additional components, including, for example, gaseous precursors, liquids, oils, stabilizing materials, pharmaceutical acceptable carriers, photoactive agents.

[00155] The invention provides methods for boosting NO levels prior to or during sexual activity to stimulate smooth muscle relaxation in blood vessels supplying the corpus cavernosum (or the corpus cavernosum clitoridis in females), resulting in increased blood flow and erection of the sexual organ by administering locally in the penile tissue to the patient in need thereof, or to the female sexual organs (e.g. the vaginal and clitoral tissues) an effective amount of the compounds and/or compositions described herein. For example, the patient can be administered locally to penile tissue an effective amount of at least one amino acid ester compound of the present invention comprising a nitric oxide releasing group, In another embodiment, the patient can be administered locally in the penile tissue a therapeutically effective amount of at least one amino acid ester compound comprising a nitric oxide releasing group, and at least one nitric oxide donor compound.

[00156] As the penile, vaginal or clitoral tissues contact the composition of the present invention, prior to or during sexual activity, the flow of blood through the organ increases and a gradual build-up of the tumescent condition results.

[00157] According to one embodiment of the present invention, a vasoactive coating composition that may be transdermally absorbed, as described herein, may be applied inside a prophylactic device. Once the transdermally absorbed coating 22 is applied, the condom 12 is packaged in a suitable known airtight foil wrapper or plastic container (not shown). Preferably the rim 16 of the condom 12 is not rolled toward the end portion 18. Rather, the condom 12 can be folded upon itself in accordion fashion, with one of the fold lines being represented by an end portion 24 of the transdermally absorbed coating 22 and an end portion 26 of the transdermally absorbed coating 22 (FIG. 2).

[00158] In using the prophylactic device 10, the condom 12 is fitted onto the penis (not shown) by grasping the rim 16 and inserting the penis into the interior space of the condom in a manner similar to that used with a conventional condom.

[00159] As the penile tissue contacts the transdermally absorbed coating 22, the flow of blood through the corpus cavernosum increases and a gradual buildup of the tumescent condition results.

[00160] If desired, a light coating of a lubricant such as vaseline petroleum jelly can be applied to the urethral meatus before the condom is applied to minimize contact of the transdermally absorbed coating 22 with the urethral meatus.

[00161] Another embodiment of the prophylactic device is generally indicated by the reference number 30 in FIG. 4. The prophylactic device 30 includes a condom 12 of the type previously described. However, the interior surface 20 is coated sporadically with a transdermally absorbed coating 32 in small areas. Although the small areas are shown as circular, they can be of any shape or form. Uncoated portions of the interior surface 20 are also present in the prophylactic device 30 at the closed end 18 and the open end 14. Use of the prophylactic device 30 is similar to that described for the prophylactic device 10.

[00162] Some advantages of the present invention evident from the foregoing description include a device for stimulating and maintaining a penile erection which requires no special skills or procedures to use. The novel device is painless, with a transient effect, and can be used without apprehension, since no pain is associated with the device.

[00163] The device presents a novel method for producing and maintaining a penile erection, by providing a vasodilator coating to the inner surface of a condom, which contains an amino acid ester compound thereby stimulating a penile erection as the condom is applied to the penis.

[00164] Compositions according to the present invention are preferably prepared in the form of a gel or a lotion, which contains lubricants, such as glycerol, water soluble celluloses, polysorbates, carbomers, polyethylene glycols (PEG), polyethylene, and thickening agent. Therefore, according to an embodiment of the present invention, the composition may act as a personnal lubricating agent as well as stimulate and maintain the erection of a sexual organ prior to or during sexual activity.

[00165] The coating composition that is used to coat the prophylactic device according to the present invention may also be in the form or a gel or a lotion, and it may also be a simple dilution of the compounds of the present invention in a suitable carrier that stays on the surface of the prophylactic device after spraying.

[00166] Water soluble celluloses

[00167] Celluloses are organic compounds with the general formula (C6H₁₀O₅)_n, a polysaccharide consisting of a linear chain of several hundred to over ten thousands β(1→4) linked D-glucose units. Preferred celluloses include water-soluble celluloses, and modified water-soluble celluloses such as those known in the art and have properties similar to cellulose. Examples are methylcellulose of different viscosity, ethylcellulose, hydroxypropyl cellulose, hydroxymethylcellulose, and hydroxyethylcellulose, hydroxypropyl methylcellulose, methocel® MC, and carboxymethylcellulose. These cellulose compounds, like cellulose itself, are not digestible by humans, and they are not toxic, and not allergenic. [00168] Polysorbates

[00169] Polysorbates are a class of emulsifiers used in some pharmaceuticals and food preparation. Polysorbates are oily liquids derived from PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Polysorbates include but are not limited to polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorban 60), polyoxyethylene (20) sorbitan tristrearate (polysorban 65), and polyoxyethylene (20) sorbitan monooleate (polysorban 80).

[00170] Carbomers

[00171] Carbomer is a generic name for synthetic polymers of acrylic acid used as emulsion stabilizers or thickening agents in pharmaceuticals and cosmetic products. They may be homopolymers of acrylic acid, crosslinked with an allyl ether pentaerythritol, allyl ether of sucrose, or allyl ether of propylene. Carbomers include but are not limited to carbopol® polymer 71 G NF, carbopol® polymer 971 P NF, carbopol® polymer 974P NF, carbopol® polymer 980 NF, carbopol® polymer 981 NF, carbopol® polymer 5984 EP and carbopol® polymer Ultrez 10 NF.

[00172] Polyethylene glycol (PEG)

[00173] PEG refers to an oligomer or polymer of ethylene oxide and are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 300 g/mol to 10,000,000 g/mol. The preferred PEG to be used in the present invention are liquid PEGs including but not limited to PEG 200, PEG 200E, PEG 300, PEG 300E, PEG 400, PEG 400E, PEG 600 and PEG 600E.

[00174] Thickening agents

[00175] Thickening agents are often used in cosmetics and personal hygiene products. They include but are not limited to alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, agar, carrageenan, locust bean gum, xanthan gum, pectin, and gelatin. [00176] Other components

[00177] The composition of the present invention may also be prepared by the addition of a vasoactive dilator compound, which include but are not limited to niacin, nicotinic acid, visnadine, an icarin compound, amentoflavone, and forskolin. The icarin compound may be chosen from 7- hydroxyethyl-icarin, 7-aminoethyl-icarin, 7-hydroxyethyl-3-0-ramnosyl-icarin, 7-aminoethyl-7-desgluco-3-ramnosyl-icarin, 8-dihydro-icarin and its glucosides in 7 and 3, and 7-hydroxyethyl-7-desgluco-icarin.

[00178] The composition of the present invention may also be prepared by the addition of an antiseptic agent in order to keep the composition sterile and disinfect the surfaces onto which it is applied during use. The preferred antiseptic agents include but are not limited to chlorhexidine gluconate, glucono delta-lactone, a paraben compound, benzoic acid, imidazolidinyl urea, a quaternary ammonium compound, and Octenidine dihydrochloride.

[00179] The composition of the present invention may also be prepared by the addition of an absorption enhancer. The preferred absorption enhancers include but are not limited to from triglycerides of coconut oil, isopropyl palmitate, isopropyl myristate, laurocapram, glycerol, propylene glycol and derivatives thereof.

[00180] The composition of the present invention may also be prepared by the addition of a warming agent. The preferred warming agents include but are not limited to niacin, lactic acid, menthol, and eucalyptol.

[00181] Furthermore, in order to stabilize and keep the composition for extended periods of time, preservative agents may be added to the composition. The preferred preservative agents include but are not limited to EDTA, EGTA, hydroxytoluene butoxide, hydroxyanisol butoxide, sodium hydroxide, calcium propionate, sodium nitrate, sodium nitrite, sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite.

[00182] The composition of the present invention may also be additioned with a small quantity of fragrance or perfume. Alternative embodiments

[00183] EXAMPLE I

[00184] The compound of the present invention may be added to pharmaceutical compositions in approximately 0.25% to 0.75%, to a maximum of 1 %.

EXAMPLE II

[00185] EXAMPLE III

[00186] The embodiments and examples presented herein are illustrative of the general nature of the subject matter claimed and are not limiting. It will be understood by those skilled in the art how these embodiments can be readily modified and/or adapted for various applications and in various ways without departing from the spirit and scope of the subject matter disclosed claimed. The claims hereof are to be understood to include without limitation all alternative embodiments and equivalents of the subject matter hereof. Phrases, words and terms employed herein are illustrative and are not limiting. Where permissible by law, all references cited herein are incorporated by reference in their entirety. It will be appreciated that any aspects of the different embodiments disclosed herein may be combined in a range of possible alternative embodiments, and alternative combinations of features, all of which varied combinations of features are to be understood to form a part of the subject matter claimed.

Claims

CLAIMS:

1. A topical composition comprising:

• water, and

• an effective amount of a compound of formula (I):

wherein n = 1 to 10;

wherein R₁ is chosen an amino acid side chain group (D or L configuration),

wherein R₂ is a hydrogen atom, or an amino acid (D or L configuration) forming a peptide bond,

or any pharmaceutically acceptable salts thereof; in association with a pharmaceutically acceptable topical carrier.

2. The composition as claimed in claim 1 , wherein said compound of formula (I) is (2-nitrooxy)-2-ethylamino-3-methylbutanoate:

or any pharmaceutically acceptable salts thereof.

3. The composition as claimed in claim 1 , wherein said compound of formula (I) is valine butylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.

4. The composition as claimed in claim 1 , wherein said compound of formula (I) is 2'-nitrooxyethyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

5. The composition as claimed in claim 1 , wherein said compound of formula (I) is 4'-nitrooxybutyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

6. The composition as claimed in claim 1 , wherein said compound of formula (I) is :

or any pharmaceutically acceptable salts thereof.

7. The composition as claimed in claim 1 , wherein said R₂ is a hydrogen atom.

8. The composition as claimed in claim 1 , wherein R₁ is chosen from:

,

hydroxyproline side chain,

and

9. The composition as claimed in claim 1 , wherein said R₂ is an amino acid of formula (II) (D or L configuration) forming a peptide bond:

wherein R_x is chosen from:

proline side chain,

hydroxyproline side chain,

10. The composition as claimed in claim 1 , wherein said pharmaceutically acceptable topical carrier is chosen from a gel and a lotion.

1 1. The composition as claimed in claim 1 , wherein said composition comprises a lubricant.

12. The composition as claimed in claim 11 , wherein said lubricant is chosen from glycerol, sorbitol, a water soluble cellulose, a polysorbate, a carbomer, a polyethylene glycol (PEG), a polyethylene, and a thickening agent.

13. The composition as claimed in claim 12, wherein said water soluble cellulose is chosen from modified starch, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methocel® MC, carboxymethyl cellulose, ethyl cellulose, hydroxyl ethyl cellulose, and any combination thereof.

14. The combination as claimed in claim 13, wherein said polysorbate is chosen from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorban 60), polyoxyethylene (20) sorbitan tristrearate (polysorban 65), and polyoxyethylene (20) sorbitan monooleate (polysorban 80), and any combination thereof.

15. The composition as claimed in claim 13, wherein said carbomer is a carbopol® polymer chosen from carbopol® polymer 71 G NF, carbopol® polymer 971 P NF, carbopol® polymer 974P NF, carbopol® polymer 980 NF, carbopol® polymer 981 NF, carbopol® polymer 5984 EP and carbopol® polymer Ultrez 10 NF, and any combination thereof.

16. The composition as claimed in claim 13, wherein said polyethylene glycol (PEG) is chosen from PEG 200, PEG 200E, PEG 300, PEG 300E, PEG 400, PEG 400E, PEG 600 and PEG 600E, and any combination thereof.

17. The composition as claimed in claim 13, wherein said thickening agent is chosen from alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, agar, carrageenan, locust bean gum, xanthan gum, pectin, and gelatin, and any combination thereof.

18. The composition as claimed in claim 1 , further comprising at least one vasoactive dilator compound.

19. The composition as claimed in claim 18, wherein said at least one vasoactive dilator compound is chosen from niacin, nicotinic acid, visnadine, an icarin compound, amentoflavone, and forskolin.

20. The composition as claimed in claim 19, wherein said icarin is chosen from 7-hydroxyethyl-icarin, 7-aminoethyl-icarin, 7-hydroxyethyl-3-0-ramnosyl- icarin, 7-aminoethyl-7-desgluco-3-ramnosyl-icarin, 8-dihydro-icarin and its glucosides in 7 and 3, and 7-hydroxyethyl-7-desgluco-icarin.

21. The composition as claimed in claim 1 , further comprising at least one antiseptic agent.

22. The composition as claimed in claim 21 , wherein said antiseptic agent is selected from chlorhexidine gluconate, glucono delta-lactone, a paraben compound, benzoic acid, imidazolidinyl urea, a quaternary ammonium compound, and Octenidine dihydrochloride.

23. The composition as claimed in claim 1 , further comprising a preservative agent.

24. The composition as claimed in claim 23, wherein said preservative agent is chosen from EDTA, EGTA, hydroxytoluene butoxide, hydroxyanisol butoxide, sodium hydroxide, calcium propionate, sodium nitrate, sodium nitrite, sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite.

25. The composition as claimed in claim 1 , further comprising an absorption enhancer, a warming agent or a combination of both.

26. The composition as claimed in claim 25, wherein said absorption enhancer is chosen from triglycerides of coconut oil, isopropyl palmitate, isopropyl myristate, laurocapram, glycerol, propylene glycol and derivatives thereof.

27. The composition as claimed in claim 25, wherein said warming agent is chosen from niacin, lactic acid, menthol, and eucalyptol.

28. A method of treating male sexual dysfunction comprising:

(a) contacting a penile tissue with the composition as claimed in claims 1 - 27 to help stimulate tumescene to produce an erection.

29. A method of enhancing sexual performance or pleasure comprising:

(a) contacting a sexual organ with the composition as claimed in claims 1 - 27 to help stimulate tumescence.

30. Use of a composition as claimed in any one of claims 1 - 27 for the preparation of a medicament for the treatment of erectile dysfunction.

31. Use of a composition as claimed in any one of claims 1 - 27 for the treatment of erectile dysfunction.

32. Use of a composition as claimed in any one of claims 1 - 27 for enhancing sexual performance or pleasure.

33. A device for stimulating and maintaining a penile erection comprising an elastic sleeve-like member adapted to fit onto a penis, said sleeve-like member having

an interior surface, and

a vasoactive dilator coating on said interior surface adapted to contact penile tissue and stimulate tumescence, said vasoactive dilator coating comprising an effective amount of a compound of formula (I):

wherein n = 1 to 10;

wherein R₁ is chosen an amino acid side chain group (D or L configuration),

or any pharmaceutically acceptable salts thereof; in association with a pharmaceutically acceptable carrier.

34. The device as claimed in claim 33, wherein said compound of formula (I) is (2-nitrooxy)-2-ethylamino-3-methylbutanoate:

or any pharmaceutically acceptable salts thereof.

35. The device as claimed in claim 33, wherein said compound of formula (I) is valine butylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.

36. The device as claimed in claim 33, wherein said compound of formula (I) is 2'-nitrooxyethyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

37. The device as claimed in claim 33, wherein said compound of formula (I) is 4'-nitrooxybutyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

38. The device as claimed in claim 33, wherein said compound of formula (I) is :

or any pharmaceutically acceptable salts thereof.

39. The device as claimed in claim 33, wherein said R₂ is a hydrogen atom.

The device as claimed in claim 33, wherein is chosen from

hydroxyproline side chain,

and

41. The device as claimed in claim 33, wherein said R₂ is an amino acid of formula (II) (D or L configuration) forming a peptide bond:

wherein R_x is chosen from

proline side cha

hydroxyproline side chain,

and

42. The device as claimed in claim 33, wherein said sleeve-like member comprises a condom.

43. The device as claimed in claim 33, wherein said condom has a closed end portion and an open end portion and said vasoactive dilator coating terminates approximately 1/2 to 1 inch before said open end portion and terminates before said closed end portion.

44. The device as claimed in claim 33, wherein said vasoactive dilator coating is a transdermal^ absorbed coating.

45. The device as claimed in claim 33, wherein said transdermal^ absorbed coating is applied in patches.

46. A method of stimulating and maintaining a penile erection comprising:

(a) fitting onto a penis a sleeve-like elastic member adapted to fit onto a penis having a vasoactive dilator coating on the interior surface, said vasoactive dilator coating contacting the penile tissue to stimulate tumescene and produce a penile erection, wherein said vasoactive dilator coating comprises an effective amount of a compound of formula (I):

wherein n = 1 to 10;

wherein R₁ is chosen an amino acid side chain group (D or L configuration),

47. The method as claimed in claim 46, wherein said compound of formula (I) is (2-nitrooxy)-2-ethylamino-3-methylbutanoate:

or any pharmaceutically acceptable salts thereof.

The method as claimed in claim 46, wherein said compound of formula valine butylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.

49. The method as claimed in claim 46, wherein said compound of formula (I) is 2'-nitrooxyethyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

50. The method as claimed in claim 46, wherein said compound of formula (I) is 4'-nitrooxybutyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

The method as claimed in claim 46, wherein said compound of formula

or any pharmaceutically acceptable salts thereof.

52. The method as claimed in claim 46, wherein said R₂ is a hydrogen atom.

The method as claimed in claim 46, wherein R₁ is chosen from

w

proline side chain,

,

and

54. The method as claimed in claim 46, wherein said R₂ is an amino acid of formula (II) (D or L configuration) and derivatives thereof, forming a peptide bond:

wherein R_x is chosen from: , ,

and

55. The method as claimed in claim 46 wherein said elastic sleeve-like member is a condom.

56. The method as claimed in claim 55, wherein the vasoactive coating is applied intermediate the closed end of the condom and the open end of the condom.

57. The method as claimed in claim 55, wherein the vasoactive coating is sporadically applied to the inner surface of the condom.

58. The method as claimed in claim 55, wherein the vasoactive coating is uniformly applied to the interior surface of the condom.