US20030207903A1

US20030207903A1 - 1,2,3,6-tetrahydropyrimidine-2-one compositions and therapeutic methods therewith for sexual disfunction

Info

Publication number: US20030207903A1
Application number: US10/191,481
Authority: US
Inventors: Edward Wei
Original assignee: Individual
Current assignee: Individual
Priority date: 2002-05-02
Filing date: 2002-07-08
Publication date: 2003-11-06
Also published as: DE60330333D1; US20030207904A1; US6933301B2; US20030206866A1; ATE450260T1; US20030207851A1; US6743801B2; US20030206873A1; US6919348B2; ZA200408895B

Abstract

A therapeutic composition is provided that comprises a 1-R1-phenyl, 4-R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one sensory nerve receptor agonist in a therapeutically effective amount. The sensory nerve receptor agonist may be represented by the general formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein: R1 is -hydroxy, -chloro, - fluoro, -alkyl, -acetoxy, -trifluoromethyl ; and R2 is -nitro, -chloro, -fluoro, -alkyl, -trifluoromethyl. Therapeutic compositions of the invention elicit soothing, cooling, and stimulatory effects when formulated for topical delivery to human sexual organs and to anorectal areas of the body and are useful to alleviate dysfunction in sexual response and intercourse for both men and women.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 10/139193, filed May 2, 2002, inventor Wei, entitled “Therapeutic 1,2,3,6-Tetrahydropyrimidine-2-One Compositions and Methods Therewith”, incorporated by reference.[0001]

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a class of chemicals that activate receptors on sensory nerve endings of human sexual organs and therapeutic use of these chemicals for sexual dysfunction. This invention more particularly relates to therapeutic compositions preferably formulated for topical delivery to the human sexual organs and the anorectal region. The particularly preferred embodiment compositions are formulated as an ointment or cream and comprise “icilin”, a 1,2,3,6-tetrahydropyrimidine-2-one compound.

2. Description of Related Art

Living organisms reproduce as this process is necessary for the preservation of the species. In humans the delivery of sperm to egg is achieved by sexual intercourse. During coitus, male and female embrace and the male inserts the male genital organ, the penis, into the female genital orifice, the vagina, discharging the semen therein. Coitus is complex, requiring both psychogenic stimuli such as arousal, excitement and passion, and synchronized physiological processes such as blood flow, lubrication, and muscle relaxation. Disruption of this sexual activity by age, organic disease, or other factors may lower the quality of life.

Sexual dysfunction has been defined as impairment during any stage of the sexual response cycle (desire, arousal, orgasm, and resolution) that prevents the individual or couple from experiencing satisfaction as a result of sexual activity. For women, the definition has included those who are indifferent to sexual intercourse, who have no response to sexual advances or stimulation, or who are unable to have an orgasm during sexual intercourse. For men, treatment has focused on “erectile dysfunction”, term used to define the condition of a consistent inability to obtain or maintain an erection for satisfactory sexual relations. This term is more precise than “impotence”, a word that could be vague and pejorative. Estimates suggest that the number of U.S. men with erectile dysfunction may be about 10 to 20 million. The prevalence of erectile dysfunction of any degree may be as high as 39% in 40-year old men, and 67% in those aged 70 years. Ageing women also suffer from erectile disorders in part because after menopause dryness of the vagina and diminished arousal thresholds may cause discomfort during intercourse.

Physiology of Sensory Nerve Endings and Sexual Function. The penis is composed of the head and the shaft. The glans is the smooth conelike head of the penis, and is a sexually sensitive and excitable part of a man's body. The corona and sulcus, the ridge at the back of the glans at the juncture of the glans and penile shaft, is also filled with many sensory nerve endings. When stimulated, the corona is an important source of sexual pleasure and excitement. Another sensitive area is the frenulum, this is the thin tissue on the underside of the glans that is also attached to the skin at the top of the penile shaft. The clitoris is the anatomical equivalent of the penis in females and shares similar morphology and physiology.

The head and surface of the penis and clitoris are densely innervated by free nerve endings linked to sensory neurons of the dorsal division of the pudendal nerve located in the sacral region of the spinal cord. Typical free nerve endings are derived from thin myelinated axons measuring 1 to 3 μm in diameter or from unmyelinated C fibers. These nerve endings when activated convey sensations that initiate, enhance, and perpetuate the sexual response. Other anatomical structures present in the head of the penis are Merkel cells, Meissner, Pacinian, and Ruffini corpuscles, and genital end bulbs, but the exact functions of these structures are not known. I believe that receptors located on the free nerve endings or within the corpuscles, some of which have axons, are likely to be the targets of drugs disclosed in the present invention.

Vasocongestion and erectile tumescence in both male and female sexual organs are triggered by the sensory afferent input from the pudendal nerve, by psychic stimuli, and by associated autonomic nervous system reflexes. The positive sensation from stimulation of the head of the penis during sexual arousal, and consequent erection, is a fact of male experience and does not require further description. In females, clitoral stimulation results in increased clitoral length and diameter, increased blood flow and tumescence of associated structures such as the labia folds. There is also increased vaginal secretion and lubrication, engorgement of the vaginal wall, and increased diameter of the vaginal lumen. Thus, an agent that causes sexual arousal will also relieve conditions of a contracted vagina, such as vaginismus, vaginal dryness, and dyspareunia (difficult or painful coitus). Ultimately, appropriate integration of the sensory inputs from the nerve endings of the penis or clitoris together with other stimuli culminates in orgasm, satisfaction, and termination of coitus.

Drug access to receptors is also influenced by the anatomy of the genitalia. The intact penis is covered by one single continuous skin sheath or skin system. The folded part of the skin sheath is called the foreskin or prepuce. An unusual feature of the skin system is the transition from a keratinized surface on the outer foreskin surface to a mucocutaneous surface on the inner foreskin surface (just behind the glans). An analogous change in surface anatomy is found, for example, on the upper and lowers lips. The absence of keratin on the inner foreskin, corona, frenulum and glans readily permits drug access to sensory nerve targets. The interplay of nerves and sensation during sexual activity is described on the Web by the Circumcision Information Resource Page (www.cirp.org):

“The most important components of the physical erogenous stimulation of the penis during foreplay and intercourse are the sensations from the foreskin, frenulum band, and glans. These structures each have their own feeling, and each contributes in its own way to the man's total experience of lovemaking. It must be emphasized that emotional excitement is an extremely important component of sexual enjoyment, and intensifies the man's perception of any physical sensations from his penis.

The foreskin has an inner and outer layer. The outer foreskin layer contains nerve endings which respond to gentle touching during the early stages of sexual arousal. This helps to trigger an erection. The nerves of the inner and outer foreskin contribute to the experience of penile stimulation, up to and including orgasm. These receptors are stimulated by stretching, or when the foreskin rolls over the surface of the glans during intercourse or masturbation.

The foreskin contains sensory receptors called Meissner corpuscles. We believe that these nerves, similar to nerve endings in the fingertips, are there to provide pleasure, as well as fine sensory perception. This seems to help a man to enjoy sex longer without ejaculating prematurely, because he can more easily tell when he is approaching the threshold of orgasm.

We believe that stimulation of the glans is most significant in the later stages of sexual intercourse, when penetration is deepest and emotions are running at the highest. Sensations from the glans contribute to the quality of the sensual experience. They are also apparently capable of triggering orgasm on their own.”

Nevertheless, the field of the pharmacology of sensory nerve endings is in its infancy, and little is known about the chemical sensitivity of the nerve endings in the glans of the penis or clitoris.

Background on icilin. 1,2,3,6-Tetrahydropyrimidine-2-one compounds were described in U.S. Pat. No. 3,821,221(inventors C. Podesva and J. M. Do Nascimentoet al, Jun. 28, 1974). These compounds were thought to have depressant and/or stimulant effects on the central nervous system. In 1972, an abstract described a compound in this series called AG-3-5 (1[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one). This prototype elicited a syndrome of “wet dog shake behavior” in rats and monkeys accompanied by hyperthermia, hyperactivity and ptosis. Wei (Chemical stimulants of shaking behavior. Journal of Pharmacy and Pharmacology 28: 722-724, 1976) provided the first detailed report of the actions of AG-3-5 in animals and noted that shaking behavior similar to those of a dog when wet could be evoked in various laboratory animals such as the rat, mouse, cat, dog, gerbils, guinea pigs and hamsters.

Subsequently, Wei (Pharmacological aspects of shaking behavior produced by AG-3-5, TRH, and morphine withdrawal. Federation Proceedings 40: 1491-1496, 1981) reported that 0.1 mg of AG-3-5, dissolved in propylene glycol, applied to the dorsum of the tongue elicited prickling sensations of cold and ingestion of 6 mg, on one occasion out of three, produced sensations of coolness on the cheeks and on the inner surfaces of the arms and legs. It was hypothesized that AG-3-5 may produce specific activation of receptors for cold, and that stimulation of these receptors accounted for the shaking seen in laboratory animals. In a subsequent publication (E. T. Wei and D. A. Seid. AG-3-5: A chemical producing sensations of cold. Journal of Pharmacy and Pharmacology 35: 110-112, 1983) the effects of AG-3-5 on shaking behavior in the rat were compared to those of menthol and AG-3-5 was shown to be 400 times more potent than menthol on a molar basis on this behavioral endpoint. AG-3-5 was less toxic than menthol, as measured by the oral median lethal dose in rats. AG-3-5 was named icilin because of its cold-producing properties.

Recently, two independent groups simultaneously cloned a biological macromolecule (called a receptor) from trigeminal sensory neurons of the rat. These receptors belong to the transient receptor potential (TRP) family of ion channels and responded to cold temperature and to menthol. Using a sample provided by Wei, McKemy et al. (Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416: 52-58, 2002) showed that icilin was about 200 times more potent than menthol in eliciting ion channel current changes in the cloned and transfected TRP(M8) receptor. The ion permeability changes elicited in transfected cells were more robust with icilin than those elicited by menthol, and the presence of extracellular calcium was required for activity. Menthol currents did not require extracellular calcium.

The chemical structure of icilin bears little similarity to that of menthol; the former chemical being a pyrimidine-2-one attached to two phenyl rings, and the latter a cyclohexanol derivative. Activation of the TRP(M8) receptor on the neuronal membrane may lead to depolarization of the sensory nerve ending and send action potentials towards the spinal cord and brain that are eventually recognized as psychic signals of skin stimulation.

Background on drugs for sexual therapy. Therapy of sexual dysfunction in men and women has evolved in many directions during the past 30 years—beginning with penile prostheses in the 1970s, intracavemous injection of drugs and a vacuum constriction device in the 1980s, and now the use of transurethral alprostadil (Muse®), topical alprostadil with a enhancer of percutaneous absorption (Topiglan®), and oral sildenafil (Viagra®). The sales of Viagra® in 2001 are estimated to be U.S. $1.5 billion, but Viagra® has little effect on sexual arousal in women. Drugs that affect brain centers of sexual arousal, such as apomorphine and related analogs, have also been examined as prospective therapy but are not products in the market. Research on novel drugs is primarily focused on substances that affect the hemodynamic pathways of penile erection. Thus, drugs that cause arterial dilation, sinusoidal expansion, venous compression and relaxation of the intracorporeal smooth muscles have received the greatest attention.

As noted above, Viagra® has little effect on sexual arousal in women, but other compounds are being sold as female sexual enhancers. In the “Physicians Desk Reference For Nonprescription Drugs” reference is made to Vitara™ as a “Female Sexual Aids/Enhancer.” (www.vitara.com) that is approved by the Food and Drug Administration. The active ingredients are N-methylnicotinate, Wild Yam Plant Extract (Discoreae), and dihyroepiandrostenedione (DHEA). Inactive ingredients are water, propylene glycol, glycerin, polyquatemium-37/propylene glycol dicaprylate, sorbic acid, methyl and propyl paraben, and fragrance.

Vitara™ is sold as a liquid in 1 oz bottles. It is claimed that the drug will cause profound vasodilation to the female genitalia and facilitate orgasm. N-methylnicotinate is a known vasodilator and will cause a flush after application at most sites on the skin. The efficacy of this drug is uncertain.

Other drugs that have been promoted as “sexual enhancers” after topical application include L-arginine, niacin, N-methylnicotinate, menthol, cyclic GMP (guanosine monophosphate), and a topical cream containing aminophylline, isosorbide dinitrate, and co-dergocrine mesylate (Gomaa, A.; Shalaby, M.; Osman, M.; Eissa, M.; Eizat, A.; Mahmoud, M.; Mikhail, N., Topical treatment of erectile dysfunction: randomised double blind placebo controlled trial of cream containing aminophylline, isosorbide dinitrate, and co-dergocrine mesylate. British Medical Journal 312: 1512-1515; 1996).

In manuals on sexual foreplay, ice and ice-cream are occasionally recommended for stimulating arousal. Ice may be applied to the lower back or to the nipple for its “shock value”, according to Dr. Alex Comofort, author of the Joy of Sex, or ice-cream may be licked off the body. But there is no mention of applying ice to the penis or clitoris and it may be expected that such an event would have aversive properties. Application of ice on skin may reduce erectile responses by causing vasoconstriction. In the patient information pamphlet for the prescription drug Muse® (the transurethral application of alprostadil for erectile dysfunction) it is recommended that users of the drug apply ice packs to the thigh if erections are maintained longer than desired (priapism). The ice packs are to be placed on the inner thigh to shorten the duration of the erection, since the cold “ . . . will restrict blood flow to the penis. If used, ice packs are to be applied alternately to each inner thigh for a period not exceeding 10 minutes.”

Menthol, a chemical that activates the cold receptor, and related menthol analogs will also elicit strong cooling sensations when applied to the penis or clitoris. The sensations evoked are, however, intense and do not cause much sexual arousal or interest. Topical application of drugs with 1% alprostadil (Topiglan®) as the principal ingredient has been described by Samour et al., U.S. Pat. No. 5,942,545 “Composition and method for treating erectile dysfunction.” In this formulation, menthol is added for its local anesthetic properties with the intent of countering the irritation produced by the other chemicals present.

BRIEF SUMMARY OF THE INVENTION

In one embodiment of the present invention, a composition is provided that comprises a 1-R1-phenyl, 4-R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one sensory nerve endings receptor agonist dispersed in a vehicle that is therapeutically effective when applied topically to human sexual organs or to anorectal areas of the body. The sensory nerve endings receptor agonist may be represented by the general formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein: R1 is -hydroxy, -chloro, - fluoro, -alkyl (with about 2 to 4 carbons), -acetoxy, -trifluoromethyl; and R2 is -nitro, -chloro, -fluoro, -alkyl, -trifluoromethyl.

A particularly preferred sensory nerve endings receptor agonist embodiment is called “icilin” and a particularly preferred composition has icilin dispersed as an emulsion in a dermatologically acceptable vehicle, such as an ointment or cream. Icilin formulated and administered topically as an ointment or cream offers improved therapeutic benefit for the treatment of sexual dysfunction. Thus, for example, a particularly preferred method of treating sexual dysfunction or enhancing sexual pleasure in a human comprises topically applying a composition comprising 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog to the gentalia or anorectal area, wherein the 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog is preferably in an amount of at least about 0.1 wt. % of the composition, more preferably from about 0.1 wt. % to about 20 wt. % of the composition.

Thus, the present invention describes certain compounds that specifically activate sensory nerve endings located in the genitalia and anorectal area for both men and women. Activation of these nerve endings on the head of the penis or clitoris or anus can cause sexual arousal or enhance sexual response and act as aphrodisiacs. I describe here compositions and methods for the topical application of 1,2,3,6-tetrahydropyrimidine-2-one compounds that have the properties of: 1) eliciting pleasant sensations from the penis and clitoris 2) lowering the threshold for tumescence under the appropriate setting, 3) increasing the mind set of the subject towards sexual intercourse, and 4) increasing the duration of intercourse. Use of these therapeutic compositions is a novel strategy for the treatment of sexual dysfunction.

The advantages and aspects of the present invention will be understood by reading the following detailed description and the accompanying claims.

DETAILED DESCRIPTION OF THE INVENTION

Compositions and therapeutic methods in accordance with this invention utilize a 1-R1-phenyl, 4-R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one sensory nerve endings receptor agonist,

Formula. 1: 1-R1, 4-R2, substituted 1,2,3,6-tetrahydropyridimine-2-one preferably of the general formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one wherein: R1 preferably is -hydroxy, -chloro, -fluoro, -alkyl (with about 2 to about 4 carbon atoms) -acetoxy, -trifluoromethyl; and R2 preferably is -nitro, -chloro, -fluoro, -alkyl (with about 2 to 4 carbons), -trifluoromethyl. I refer to the particularly preferred compound and its analogs as “icilin” and its analogs as “icilin analogs”. Formula 1 illustrates the general formula and icilin is represented by Formula 2.

Formula 2: Icilin, 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one.

Icilin is a lemon yellow crystalline powder with a molecular weight of 311 Daltons and a melting point of 229 to 231° C. The powder is without odor and non-irritating, meaning that it does not elicit any smell or unpleasant sensations upon contact with the surfaces of the human body. The compound is stable at room temperature. Icilin is readily soluble in organic solvents such as dimethylsulfoxide, nitromethane, dimethylacetamide and, after warming, in propanediols; slightly soluble in ethanol and acetone; and virtually insoluble in water. Thus, icilin would be considered as a lipophilic, hydrophobic compound that is not easily miscible with aqueous systems. Analogs of icilin, for example, with acetyoxy, ethyl, fluoro, or trifluoromethyl substitutions, retain similar chemical and physical properties and are included within the scope of this invention.

In the context of this application sexual dysfunction is meant to include conditions of impotence in men, of frigidity in women, of erectile dysfunction in both sexes, and of unfulfilled psychic desire of individuals for a better experience and performance in sexual intercourse (e.g. sexual enhancement).

Sites of Action of Icilin Compounds. In the Examples, I show that icilin and other 1,2,3,6-tetrahydropyrimidine-2-one derivatives have the property of stimulating sexual arousal when applied to the head of the penis, the clitoris, or to the anorectal region. The sensations detected first are a tingling or prickly sensations of the tissues, followed by punctate discharge of cold spots, and, if the applied amount is large, e.g. 1 cc of a 2% icilin ointment, a slight feeling of wetness on the tissue surfaces. These effects are pleasant, reinforcing and, afterwards, accompanied by a desire to repeat the experience. The sensory effects of icilin and 1,2,3,6-tetrahydropyrimidine-2-one derivatives are qualitatively different from ice and menthol.

It has been noted that application of icilin to the mucous membranes, as described in the parent application, produces sensations of cold, but it also produces tingling and prickling sensations. This has suggested to me that other modalities may be activated. The specific types of sensory nerve endings from where sexual arousal is initiated after icilin ointment application to the glans of the penis or clitoris are not known. Both sensations of tingling and of cold are felt.

As noted earlier, little is known about the chemical sensitivity of the nerve endings in the glans of the penis or clitioris. In the parent application I used the phrase “cold receptor agonist” to describe the class of compounds contemplated for use in practicing the invention. In this application, I believe that it is more precise to characterize icilin as a “sensory nerve endings receptor agonist” rather than as a “cold receptor agonist” when describing its action on sexual organs after topical application. However, all sensory phenomenon are detected on nerve endings, so the cold receptor may be viewed as one subset located on a sensory nerve endpoint.

The pudendal nerve, originating from the second to fourth sacral segments, is composed of three main divisions, the dorsal nerve of the penis (or clitoris), the perineal nerve, and the inferior rectal nerve. The skin of the human glans of the penis (or clitoris) is innervated by the dorsal nerve. This nerve is considered essential for spontaneous erectile and ejaculatory function because section of this nerve terminates these activities. Yang and Bradley (Neuroanatomy of penile portion of the human dorsal nerve of the penis. Brit. J. Urol. 82: 109-113; 1999) have shown that as dorsal nerve enters the glans it becomes extensively branched and there is dense innervation of the glans. These authors postulate that the glans to be a sensory organ with transmission of afferent signals through the dorsal nerve to the spinal cord and brain. During arousal, the glans distends during erection and there is a resultant increase in the glanular surface area. Stretching of the glans exposes more sensory nerve endings receptors to stimulation. The afferent signals sent to the central nervous system further propagate the sexual response by maintaining erection or initiating ejaculation. A similar dense innervation is seen in the human clitoris (Baskin, L. S.; Erol, A.; Li, Y. W.; Liu, W. H.; Kurzrock, E.; Cunha, G. R., Anatomical studies of the human clitoris. J. Urol. 162: 1015-1020; 1999).

The terminations of the dorsal nerve of the penis have been examined at higher magnification by Halata and Munger (The neuroanatomical basis for the protopathic sensibility of the human glans penis. Brain Research 371: 205-230, 1986). As expected, they found a dense network of free nerve endings innervating the base of the dermal papillae (the finger-like projections of the dermis) near the surface of the glans (see FIG. 3 in the paper by Halata and Munger). In addition, the glans contains lamellated, onion-skin like, encapsulated sensory corpuscles called genital end bulbs, as well as smaller less complex Pacinian corpuscles, Meissner corpuscles, and Ruffini corpuscles. Halata and Munger (1986) consider the inner core of genital end bulbs to be a tangled skein of free nerve endings. Similar genital end bulb structures are found in the lip, but not in other types of skin. Without being limited to theory, receptors located on the free nerve endings of the head and surface of penis and clitoris are believed to be the targets of drugs described in this invention.

Formulation of Icilin Compounds for Topical Delivery to Targets

Methods suitable for the preparation of the Formula 1 and Formula 2 compounds are described by Podesva and Do Nascimento, U.S. Pat. No. 3,821,221, issued Jun. 28, 1974, incorporated herein by reference, and are exemplified by Example A hereinafter.

Pharmaceutical carriers or vehicles suitable for the topical administration of icilin and combinations provided herein to the penis, clitoris and/or anorectal surfaces include any such carriers known to those skilled in the art to be suitable for the particular mode of administration, which in the preferred mode is topical application. These suitable carriers for composition embodiments of the invention are typically ointments or creams preferably with an oleaginous base (e.g. to include one or more of a wax, petrolatum, mineral oil, lanolin and glycerin). Standard ointment formulations may be used for delivery to the penis, clitoris and anorectal surfaces. Thus, particularly preferred embodiments of this invention are wherein icilin is used in a non-irritating ointment or cream.

The effective concentration of the icilin and/or icilin analog in the carrier or vehicle may be determined empirically by testing the compounds using in vitro and in vivo systems. Methods for preparing solutions, emulsions and suspensions, using standard methods for formulated Medical Topicals are well known to the art (J. G. Nair, Chapt. 39: Solutions, Emulsions, Suspensions and Extracts, pg. 721-752 and L. H Block, Chapt. 44, Medicated Topicals, pg. 836-857, in “Remington, the science and practice of pharmacy,” Alfonso R. Gennaro, Chairman of the editorial board and editor. 20th ed. Baltimore, Md. Lippincott Williams & Wilkins, 2000). The recipes for ointment preparation, for example, are also published on the Internet, such as at the site of the School of Pharmacy, University of North Carolina (www.pharmlabs.unc.edu or www.unc.edu/courses/phar051/ointments). The selected icilin compound of this invention may be dispersed in the various dermatologically acceptable vehicles as an emulsion wherein it is either in a suspension or is solubilized, and is in either the aqueous or the oil phase. The preferred dose per application would be in the range of 0.1 mg to 50 mg per application, depending on the potency of the icilin analog and the area of tissue to be medicated. A more preferred dose is in the range of 1 to 15 mg per application. The individual doses may be repeated as necessary to achieve the desirable sensory effects.

The rate of drug absorption across the skin surface is dependent on drug concentration in the formulation, its solubility and its oil/water partition co-efficient. The physical form of icilin to be delivered to the receptors of the sensory nerve endings is optimized by design for penetration of barriers, receptor activation, and sufficient duration of action. Although icilin may be administered dissolved in a solvent such as propanediol, it is more preferably suspended in this solvent as a solid and admixed as an emulsion in an ointment or cream, preferably with an oleaginous base. Before formulation, icilin may be milled to a fine particle size, modified by re-crystallization to a particle with maximal surface area, incorporated onto nanospheres, or incorporated into nanoparticles or liposomes, to maximize biological activity and duration of action using such methods as are now known in the art.

It is well understood in the art that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.

In Example A, I describe a 2% solution of icilin formulated in an Aquaphor® ointment and used for investigation. The ingredients in the commercially available Aquaphor® ointment are petrolatum, mineral oil, ceresin, lanolin alcohol, pathenol, glycerin and bisabolol. This product is quite similar in consistency to pure petrolatum (Vaseline®), but somewhat less viscous, and is non-irritating. The details for preparation of the ointment are given in Example A.

The U.S. Pharmacopoeia recgonizes four general classes of ointment bases, while the North Carolina Web site (www.unc.edu/courses/phar051/ointments) describes five. The Aquaphor® formulation is in the category of “Absorption Bases (Anhydrous)”. Some further examples are below described.

Thus, another ointment embodiment of the invention in the “Absorption Bases (water in oil type)” would be composed of icilin, preferably from about 1.0 to 5% by weight, and containing emulsifying wax, white petrolatum, purified water and propylene glycol, butylated hydroxyanisole, propyl gallate, citric acid and lactic acid.

A further example of an ointment embodiment is a lotion containing icilin, from about 0.3 to 2% by weight, composed of a smooth, homogeneous, opaque emulsion formed from benzyl alcohol 2% (wt/wt) as preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water, and polyethylene glycol 400.

A yet further example of an inventive embodiment is a more viscous ointment containing these ingredients: a homogeneous melt of 50.0% methyl salicylate, 25.0% white beeswax, 25.0% anhydrous lanolin to which is added 2% by weight of icilin. The mixture is warmed and then allowed to solidify.

Yet another example is where icilin is formulated in Hydrophilic Petrolatum USP, using 30 g cholesterol, 30 g stearyl alcohol, 80 g white wax, 860 g white petrolatum, combined with 20 g icilin in 110 ml propylene glycol. The finely powdered icilin is levigated thoroughly with a small quantity of the base to form a concentrate. The concentrate then is diluted geometrically with the remainder of the base.

The just described examples of the invention are prepared by standard procedures for preparing ointments with petrolatum or oleaginous bases.

The solvent used for suspending or dissolving icilin may be a nonaqueous pharmacologically approved solvent with non-irritating properties. Suitable organic materials useful as the solvent or a part of a carrier system are as follows: propylene glycol, polyethylene glycol (M.W. 200-600), polypropylene glycol (M.W. 425-2025), glycerine, sorbitol esters, butanediol and mixtures thereof. Other examples include ethoxydiglycol, and 1 methyl-2 pyrrolidone, purified water, saline solution, polyethylene glycol, glycerine, glycerine polymethacrylate, propylene glycol, white ointment, petroleum jelly (petrolatum), lanolin, beeswax, and cholesterol; these chemicals being alone or in combination. The preferred vehicle for levigation use in the present invention is a propanediol, preferably containing in the finished product about 0.2 to 5% of Formula 1 compounds by weight.

In certain situations, aqueous suspensions, gels, pastes, foams, aerosols, and sprays may also be considered for topical administration. Compositions of the present invention with icilin and/or icilin analogs may also be formulated as liniments (defined as a preparation that may be liquid or semiliquid intended for external application). Enhancers of percutaneous absorption such as cyclodextrins, dioxane and 2-ethoxy-ethoxy ethanol, may also be added to achieve optimal pharmacological effect.

As noted in the Background section, there are other drugs that have been promoted as “sexual enhancers”, such as transurethral alprostadil (Muse®), topical alprostadil with an enhancer of percutaneous absorption (Topiglan®), L-arginine, niacin, N-methylnicotinate, menthol, cyclic GMP (guanosine monophosphate), and a topical cream containing aminophylline, isosorbide dinitrate, and co-dergocrine mesylate These substances act by physiological mechanisms that are different from icilin compounds, but it is within the scope contemplated for practicing this invention to use such compounds in combination with icilin compounds to potentiate the overall drug effect on sexual dysfunction (including sexual enhancement).

In the below experimental section, Example A describes a preparation and formulation of icilin and analogs, while Examples 1-4 describe therapeutic uses of the invention with human subjects.

EXPERIMENTAL

EXAMPLE A

Chemical Synthesis of Icilin and Analogs. The methods of chemical synthesis are as described by Podesva and Do Nascimento in U.S. Pat. No. 3,821,221, incorporated by reference. Briefly, a substituted acetophenone, e.g. 3-nitroacetophenone or 3-trifluoromethylacetophenone, readily obtainable from commercial sources such as Sigma-Aldrich, Co., was mixed with diethylamine or dimethylamine in formaldehyde and refluxed in acidic solutions. After addition of a second substituent (e.g. ortho-aminophenol), the Mannich reaction produced a β-amino-ketone compound (e.g. [β-ortho-hydroxyanilino]-meta-nitropropiophenone) which was isolated. This reagent was then reacted with potassium cyanate or sodium cyanate to produce an unstable urea intermediate that proceeds to cyclize into the tetrahydropyridimine-2-one ring, with the appropriate groups on position 1 (2-hydroxyphenyl) and 4 (3-nitrophenyl) on the 1,2,3,6-tetrahydropyrimidine-2-one ring. The precipitated product was readily collected by filtration (which may be recrystallized using solvents such as ethyl acetate or purified on silica gel columns). The final products are solids stable at room temperature. [0058]
Preparation of Icilin embodiment compositions: A 2% icilin ointment was prepared by adding 10 grams of icilin (in powder form) to 100 ml of propylene glycol (1,2-propanediol) at room temperature. The propylene glycol was used as “wetting (levigating) agent” to suspend the icilin in a uniform liquid medium. This liquid icilin suspension was then progressively admixed in batches with 400 grams of commercial Aquaphor® ointment (produced by Beiersdorf, Inc. a German Company with U.S. offices in Wilton, Conn.) to obtain the test ointment, which was stored in standard 1 oz. vials. This ointment was prepared by the Drug Product Services Laboratory of the University of California, San Francisco, under the direction of an experienced Ph.D., Pharm. D. investigator. [0059]

EXAMPLE 1

A middle-aged male subject, with a significant decline in sexual energy due to ageing, used a cotton-tipped swab stick to apply about 0.15 to 0.25 cc of the 2% icilin ointment described by Example A to the head of his penis. These trials were conducted on five separate occasions over a period of three days. The dose in each application was about 3 to 5 mg of icilin. This dose was considered relatively risk-free because the median lethal dose of icilin in the albino rat was greater than 1500 mg/kg of body weight when administered intraperitoneally (Wei and Seid, 1983, supra). Within two minutes after application of the ointment to the penis, tingling and prickling sensations were felt in the corona and glans, followed by tumescence. Cooling sensations were also felt on the penis, particularly on the inner foreskin. There was a slight sensation of “wetness” on the organ. The overall sensations were pleasant and sexually arousing and an increased state of libido was maintained for about two to three hours after each application and the subject was keen to proceed to the next experiment. Application of Aquaphor® ointment without icilin did not elicit similar sensations. The individual subsequently felt invigorated by these experiences, he became more robust in his sexual activities, and his self-image improved. [0060]

EXAMPLE 2

A young adult male subject with periodic erectile dysfunction due to work-related stress used a cotton-tipped swab stick to apply 0.2 to 0.5 cc of the 2% icilin ointment to the head of his penis and then proceeded immediately to have sexual intercourse with his partner. It was reported that the penis felt more rigid and that the individual had better control of his sexual rhythm. The duration of intercourse was also extended to twice the expected normal time, the subject felt more satisfied with the experience, and looked forward to the next encounter with his partner. [0061]

EXAMPLE 3

Two male subjects, on separate occasions, used a cotton-tipped swab stick to apply 0.5 to 0.8 cc of the 2% icilin ointment to the anorectal area. Within several minutes, strong cooling sensations were felt in the region around the anal sphincter extending to the scrotum. There were also punctate discharges of cold spots, so the effects were felt as “sparkling” and “provocative.” Both male subjects concluded that some individuals could construe the effects of icilin at this site as an erogenous experience. [0062]

EXAMPLE 4

A female subject used a cotton-tipped swab stick to apply 0.2 to 0.4 cc of the 2% icilin ointment to the upper portion on her labia and on the clitoral surface. Within two to three minutes, tingling and prickling sensations were felt in the clitoris accompanied by tumescence. The subject then proceeded to masturbate and reported that after icilin application orgasm could be achieved more quickly and with less effort. [0063]
These experiments illustrate that topical application of icilin to human sexual organs and the anus is non-irritating and elicits sensations that appear to arouse sexual activity. Under the appropriate environmental setting and the proper mind set I conclude that topical application of 1,2,3,6-tetrahydropyrimidine-2-one derivatives (i.e., icilin and its analogs) in a suitable dermatological vehicle to these erogenous zones will enhance libido and increase the positive reinforcement from sexual intercourse; hence these pharmaceutical formulations are potentially useful in the treatment of sexual dysfunction. [0064]
In summary, I believe that no investigations of icilin on human anogenital area have been reported in the scientific literature other than what is discussed or described here. I point out the unique properties of icilin and describe novel compositions and preferred embodiments for therapeutic methods of use. [0065]
It is to be understood that while the invention has been described above in conjunction with preferred specific embodiments, the description and examples are intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. [0066]

Claims

It is claimed:

1. A composition for the treatment of sexual dysfunction, comprising:

a therapeutically effective amount of a sensory nerve endings receptor agonist having the formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one, wherein R1 is hydroxy, chloro, fluoro, an alkyl of about 2 to about 4 carbon atoms, acetoxy, or trifluoromethyl and R2 is nitro, chloro, fluoro, an alkyl or about 2 to 4 carbon atoms or trifluoromethyl; and

a dermatologically acceptable vehicle in which the a sensory nerve endings receptor agonist is dispersed.

2. The composition for the treatment of sexual dysfunction as in claim 1 wherein the sensory nerve endings receptor agonist is in an amount of from about 0.1% w/w to about 15% w/w and is dispersed as a suspension or an emulsion.

3. An ointment or cream composition comprising:

1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog thereof in an amount of about 0.1 wt. % to about 20 wt. % of the composition; and,

an oleaginous base.

4. A method of treating sexual dysfunction in a human patient comprising: topically administering a therapeutically effective amount of a sensory nerve endings receptor agonist having the formula 1-[R1-phenyl]-4-[R2-phenyl]-1,2,3,6-tetrahydropyrimidine-2-one, wherein R1 is hydroxy, chloro, fluoro, an alkyl of about 2 to about 4 carbon atoms, acetoxy, or trifluoromethyl and R2 is nitro, chloro, fluoro, an alkyl of about 2 to 4 carbon atoms or trifluoromethyl, to a sex organ or an anorectal area of the patient.

5. The method as in claim 4 wherein the sensory nerve endings receptor agonist is administered as an ointment or cream

6. The method as in claim 4 wherein the sensory nerve endings receptor agonist is administered as a lotion, gel, liniment, powder, spray, foam, or in suspension or in emulsified form.

7. The method as in claim 4 wherein the amount of the sensory nerve receptor agonist administered is in an amount of from about 1 mg to about 15 mg per application.

8. A method of treating sexual dysfunction or enhancing sexual pleasure in a man, comprising:

topically applying a composition comprising 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog to the penis or anorectal area.

9. A method of treating sexual dysfunction or enhancing sexual pleasure in a woman, comprising:

topically applying a composition comprising 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog to the gentalia.

10. A method of treating sexual dysfunction or enhancing sexual pleasure in a human, comprising:

topically applying a composition comprising 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog to the gentalia or anorectal area, the 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyridimine-2-one or an analog being in an amount of at least about 0.1 wt % of the composition.