MXPA00000564A - Composition and method for treating penile erectile dysfunction - Google Patents

Abstract

A composition for the topical transdermal administration to the penis is based on prostaglandin E1. The composition is non-irritating and effective for relieving erectile impotence or other penile erectile dysfunction. A penetration enhancing effective amount of a dioxolane, dioxane, or acetal skin penetration enhancing compound in a pharmaceutically acceptable aqueous alcoholic carrier is used to facilitate the penetration of the prostaglandin E1 active ingredient through the skin. Phentolamine or prazosin may be used in combination with or in place of prostaglandin E1.

Description

COMPOSITION AND METHOD FOR TREATING THE ERECTILE DYSFUNCTION OF THE PENIS BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to compositions and methods for treating penile erectile dysfunctions, such as erectile impotence of man, and more particularly, with compositions and methods effective for topical administration to the penis for the treatment of penile erectile dysfunctions.

BACKGROUND OF THE INVENTION Impotence is generally characterized as the inability to develop or sustain an erection sufficient to complete intercourse. Many men are affected by a degree of impotence resulting from psychological and physiological conditions. The causes of impotence are numerous. These include tonics, due to the paralysis of the motor nerves (erector nerves) without any evidence of injury to the central nervous system. On the contrary, it could be paresthesic as a result of a lesion in the central nervous system, particularly the spinal cord. Alternatively, they could be psychic, and dependent on complex or mental instability. The causes may also be symptomatic, due to some other disorder such as damage to the nerves in the perineal region, or by virtue of which the sensory portion of their erection reflects their blockage. (See, for example, U.S. Patent No. 4,801,587). The specific psychological disorders that may be the cause of penile erectile dysfunction or male impotence, and for which the present invention may be used, in addition to the psychological causes, include, for example, pelvic vascular disease, diabetes mellitus, neurodegenerative disorders, effects Lateral medications, pelvic surgery, trauma, and the like. A solution is used to treat impotence involves implants, which, in essence, are internal prostheses. However, implants, which often include surgery, are expensive and are not always effective. The other main solution to treat male impotence is the use of drugs. Since erection necessarily involves the vasodilatation of the penile arteries, the pathophysiological bases of impotence can often be treated by vasodilating agents. Clinical and experimental research efforts are underway to develop new and better drugs and routes of administration of such drugs. Those efforts have been the subject of several literature articles and patents issued including, for example, the following United States Patents: 4,801,587 - Voss, et al; 5,256,652 - El-Rashidy; 5,336,678 - Cavallini; 5,583,144 - Kral; 5,475,535 - Place, et al; 5,482,039 - Place; 5,451,609 -Bellamy, et al; 5,242,391 - Place, et al; 5,145,852 -Virag; 5,399,581 - Laragh; 5,270,323 - Milne, et al; 5,236,904 - Gerstenberg, et al; 4,127,118 - Latorre; 5,565,466 - Gioco, et al; 5,492911 - Stief; 5,594,032 -Gonzalez-Cadavid, et al; 5,488,059 - Buhl; 5,439,938 -Snyder, et al. Although the interested reader should refer directly to the earlier patents and the patents and literature discussed or cited in those patents, as well as the literature discussed below, the following brief discussion is provided. U.S. 5,583,144 is based on the use of piperoxan for the treatment of erectile impotence and includes a description of topical administration. The combination of piperoxan with prostaglandins, particularly PGE2, is described. Compositions for topical administration include gels, (including hydrogels), ointments, creams, etc. But without any details. Generally, however, the patent technique reveals that topical or transdermal application of the treatment agent is not available or preferred: 5,451,609 (intracavernous route injection); 5,242,391 (urethral insert); 5,145,582 (PGE1 with papaverine); 5,399,581 (enteral); 5,270,323; 5,236,904 (intracavernous injection); and 4,127,118 (injection). Patents that describe topical (transdermal) formulations include U.S. 5,256,652 (652) and U.S. 5,336,678 (? 678). The '678 patent is directed to topical administration of 0.1 to 10% minoxidal. The Patents divide the drugs to treat erectile impotence in three classes: 1) oral, for example, yohimbine; 2) intracavernosal injection, for example PGE1; 3) topical, for example, nitroglycerin. The '652 patent discloses a topical composition which includes an absorption enhancer and, optionally, a vasoconstrictor and an alpha receptor blocker. The improver is a cyclodextrin, particularly, hydroxypropyl-beta-cyclodextrin (HPBCD).

The patent "652" refers to the U.S. 4,311,707 (707) which describes the topical administration of prostaglandins, including an alleged use to treat impotence. The U.S. 4,801,857 (? 857) is also discussed in the? 652 patent. This patent describes a topical ointment for treating impotence. Other references which may be of interest include: U.S. 5,587,167 (topical composition with ginseng root extract for the prophylaxis and treatment of premature ejaculation); 5,565,466 (modulation of the human sexual response by oral, mucosal, intranasal or rectal vasodilator administration); 5,492,911 (linsidomine, alone or in combination with, prostaglandins, by injection); 5,447,920 (cosmetic composition, inclusion product of HPBCD); 5,594,032 (Induced Nitric Oxide Synthase (NOS) agents, non-topical module); 5,488,059 (composed of pyridylguanidine by injection into the cavernous or transdermal body); and 5,439,938 (inhibitors for NOS, topical applications). The transdermal release of prostaglandins has been the subject of scientific study. In a titular report "Aspects of the transdermal release of prostaglandins" by A.C. Watkinson, et al, International J. of Pharmaceutics, 74: 229-236, 1991, the authors studied skin penetration in vitro through human skin for prostaglandins Ei, E2, F? And F2a and the influence of the absorption rates using the Azone® and Transcutol (2-ethoxy-ethoxy ethanol) enhancers. It was found that the preapplication of the improver to the skin facilitates the flow of drug. However, the enhancer for PGE-1 was not as significant as for PGE2. The greatest improvement was found after the treatment with a mixture of Azone and Transcutol, approximately 10% after 48 hours. Although topical nitroglycerin, minoxidil, papavarine and prostaglandins Ei (PGE-1) are still being studied, their efficacy, as documented in the scientific literature, has been used. Anderson, et al, "Treatment of Impotence with Topical Nitrate," Ann. Pharmacotherapy, 27: 1203-1205, 1993, provides a review of the first literature and its conclusions that there is insufficient evidence that topical application is effective. Kim and McVary, "Prostaglandin-The Topical for the Treatment of Erectile Dysfunction", J. Urol 158; 1828-1830, 1995a, reported only 20% (2 of 10) of the patients treated with a topical gel containing 0.4% PGE-1 had erections with intermediate stiffness. The carriers of the topical gel were not described. The authors concluded that the PGE-1 gene results in a significant increase in the diameter of the cavernous artery and a peak systolic flow velocity and appears to be well tolerated after genital and preventive application. However, the results of topical absorption were inconclusive. It was further established that, "Prostaglandin-El gel may be promising at higher concentrations, with different skin improvers or in combination with other topical agents". Additional investigations were considered justified. In other studies, a significant increase in erectile response was observed after topical application of 0.5% PGE-1 and 67% of patients achieved a stiffness consistent with penetration. However, the erections did not persist after the end of the stimulation (Montorsi, et al, Drugs 50 (3): 465-479, 1995a, Intern J. Impotence Res. 7:10, 1995b). In none of these reports was there any adverse event attributable to the application of PGE-1. It was suggested that an increase in the penetration of the active agent through the skin and / or into the erectile tissues should be required to have a better response. In the case of papaverine, the topical application to the penis of 133 to 500 milligrams (mg) of an aqueous gel containing papaverine hydrochloride at concentrations of 7, 15 or 20% was studied (Kim, et al, J. Urol 158 : 361-365, 1995b). Formulations with 15% and 20% increased the cavernous arterial diameter (approximately 36%) and the peak systolic blood flow (approximately 26%) in patients with spinal damage. However, although three of the seventeen patients treated had tumescence and erections, they also responded similarly after the application of a placebo gel. However, the erections after the papaverine gel lasted a lot, although this result was not statistically significant. Gomma, et al. (British Med. Journal 312: 1512-5, 1995) report that a topical formula ("cream") containing three active ingredients (3% aminophylline, 0.25% isosorbide dinitrate, and 0.05% codergocrine mesylate) is effective for the treatment of erectile dysfunction. Becher, et al, in a Summary ("A Double-Blind Placebo Controlled Trial of Prostaglandin Topical for Erectile Dysfunction") presented at the Erectile Dysfunction Symposium held in San Francisco, CA, in February 1997, reported that in three pilot studies using three different formulations on 51 impotent patients, 3% (5 of 15) responded to a formulation with 2 mg of PGE-1, compared to 13% that responded to placebo; 61% (11 of 18) responded to the formulation with 4 mg of PGE-1, compared to 39% that responded to placebo; and 66% (12 of 18) responded to a formulation that contained 4 mg of PGE-1 and nitroglycerin compared to 39% that responded to placebo. In those studies, one patient developed a skin rash and had an episode of hypotension. The compositions used in the tests were not described. Linet, et al, The New England J. of Medicine, 334 (14): 873-877 (April 4, 1996) describe a study on the efficacy and safety of alprostadil administered by intracavernous injection for the treatment of erectile dysfunction in men. . Among other side effects 54 of the 235 men (23 percent) experienced penile pain. Alprostadil is a synthetic prostanglandin Ei. In an accompanying editorial (L. Lipshultz, pages 913-14) Linet's study was described as the "probably the largest multi-institutional study of the effects of undergoing a single drug injection." (Footnote omitted). they did not find, unexpectedly, that alprostadil produced significantly better erections than placebo and that the response was not dose dependent. " The editorial explains that of the 577 men studied, 69 percent completed the six-month study; 87 percent reported that the injection resulted in satisfactory sexual activity. Of 31 percent who did not complete the study, the lack of efficiency was a prominent complaint. We evaluated 683 men to determine side effects and 50 per cent reported penile pain. In a different study used alprostadil 17 percent discontinued therapy due to severe pain with an additional 22 percent having medium to moderate pain. Dr. Lipshultz concludes that intracavernous injections are a well-accepted and effective treatment for erectile dysfunction while, "other forms of administration of alprostadil, such as by means of a medicated urethral system (footnote omitted) and a topical gene 10, have not shown similar results. " Footnote 10 went to the previous article by Kim and McVary (1995a). In an even more recent study of the treatment of erectile dysfunction with alprostadil, Padma-Nathan, etal, The New England J. of Medicine, 336 (1) '. 1-1, January 2, 1997, a transurethral release mechanism was used. Nearly 88 percent of the 996 men in the study completed the entire three-month treatment period. It was found that transurethral administration of alprostadil is effective in 69% of men in the alprostadil group. However, penile pain (categorized as a mean) was reported in almost 36% of men during the clinical trial, while more than 2% discontinued the study due to pain. In the treatment phase at home, penile pain was reported after 10.8% of the administrations of alprostadil and almost in 33% of the men. These authors refer, on page 6, to alternative methods of delivery, including an intraurethral cream containing prostaglandin E2 applied to the urethral meatus. Of the 20 men in this study it was reported that complete penile tumescence occurred in 30 percent of the subjects. The authors also refer to the Kim and McVary pilot study of transdermal PGE-1 as failed to induce rigid erections, apparently due to insufficient transfer of the drug through the skin. It is known from the U.S. 4,861,764 by Carlos M.

Samour and Stefanous Daskalakis (and commonly granted with the subject application) that the 1,3-dioxolanes and 1,3-dioxanes, including, for example, 2-n-pentyl-, 2-n-heptyl-, 2-n- nonyl-, 2-n-undecyl-, pentylene-1, 5-bis-l, 3-dioxolanes; 2-n-nonyl-, 2-n-undecyl-, 2- (2 ', 6'-dimethyl-2'-heptadienyl) -1,3-dioxanes; They are useful as enhancers of percutaneous absorption to improve the penetration of therapeutic agents into the skin. As described more recently in the U.S. 5,527,797 commonly assigned partially to Eisenberg and Samour, the 1,3-dioxanes, 1,3-dioxolanes and other alkyl or alkenyl substituted compounds of general formula RX (where R is an alkyl or alkenyl of C5 to C2s; X is 1,3-dioxane, 1,3-dioxolane, lactam numbered as 5, 6, 7 or 8; cycloalkylene carbonate, -COOH, -OH, cycloalkylene carbonate; -COR '(R' is a lower alkyl or lower alkyl unsaturated); (OCH2CH2) n-OH (n is an integer from 1 to about 20); -OC (0) R '; R'OC (O) -; -C (0) N (R') 2; acetals and semiacetals can be used as modifiers of the water-insoluble or substantially water-insoluble corium extract lipids to improve the transport of charged molecules through the skin by iontophoresis US Patent No. 5,620,980 recently issued to C. Samour, also commonly assigned with this application, describes the use of 1, 3-ioxolanos and 1,3-dioxanes in a topical formulation which contains minoxidil to treat the hair loss.

There are no suggestions in the prior art, as described above, that could lead a professional to assume or believe that 1,3-dioxolanes and 1,3-dioxanes or acetals could be effective for an improved penetration of prostaglandins especially, prostaglandin Ei (PGE-1), or any other vasodilating agent or other effective drug for use in the treatment of erectile dysfunction. In fact, the use of these compounds to improve the penetration of the skin in combination with PGE-1, pentolamine, prazosin, etc., can be considered contraindicated by the prior art. For example, although dioxanes and dioxolanes are known as penetration enhancers, the release of elevated levels of drugs via a nonvascular route directly to deep target sites, below the skin, was not expected. It would be expected that the well-vascularized dermis would rapidly remove a drug before it penetrated deeper objective tissues, in this case, the corpus cavernosum and spongy. In addition, the cavernous body is covered by a protective tissue, the tunica albuginea, whose barrier properties are very different from those of the skin. Secondly, the main skin function of the skin, the horn extract, is virtually absent on the glands of the penis, which is the site of greatest probability of maximum absorption due to its communication with the aforementioned bodies. Because 1, 3-dioxanes, 1,3-dioxolanes, and acetals are well known as skin penetration enhancers whose mechanism of action is temporary disruption of the stratum corneum, they are increasing the penetration of therapeutically active amounts. of drug through this non-cornified organ structure would not have been expected. Although not specifically addressed in the aforementioned prior art related to topical formulations for treating erectile dysfunction, PGE-1 is substantially insoluble in water. Attempts to increase solubility by increasing the pH of the system are of limited use since the stability of PGE-1 decreases at pH levels above the pKa of the free acid. Accordingly, an object of the invention is to provide a prostaglandin composition effective for topical delivery of penile erectile dysfunction treatment. A related object is to provide a topical formulation for transdermal delivery that is more effective than known formulations and is easier to use than injectable formulations or implants. Still another object of the invention is to provide a topical composition for the transdermal release of active agent for the treatment of penile erectile dysfunction where the composition can be applied only to the glands of the penis.

BRIEF DESCRIPTION OF THE INVENTION The foregoing and other objects of the invention, which will become more apparent in connection with the following detailed description, are achieved by a composition for topical transdermal administration to the penis of a patient in need thereof, the composition comprising: (a) a pharmacologically effective amount of prostaglandin Ei; (b) an effective amount of a skin penetration enhancing compound selected from the group consisting of 1-3, dioxane, 1,3-dioxolane and acetal substituted with a hydrocarbyl group from Ce to C2o • (C) a carrier pharmaceutically effective comprising (i) a mixture of ethyl alcohol and water effective to solubilize components (a) and (b); (ii) a mixture of isopropyl alcohol and water effective to solubilize components (a) and (b); or (ii) a mixture of propylene glycol with ethanol or isopropyl alcohol or both of those alcohols; and (d) an effective gelling amount of a gelling agent, and, optionally, (e) an effective anti-irritant amount of menthol. In another aspect, the invention provides a method for treating penile erectile dysfunction in a patient in need thereof, which comprises topically administering to the patient's genitalia a composition comprising a pharmacologically effective amount of prostaglandin Ei in the presence of an effective amount for improving the skin penetration of a compound that improves skin penetration selected from the group consisting of 1,3-dioxolane, 1,3-dioxane and acetal substituted with a C6 to C20 hydrocarbyl group; wherein the prostaglandin Ei and the compound that improves skin penetration are solubilized in a pharmacologically acceptable aqueous-alcoholic carrier comprising ethyl alcohol and water, isopropyl alcohol and water; or a non-aqueous carrier comprising ethyl alcohol and / or isopropyl alcohol, and propylene glycol; and a thickening agent in an amount effective to retain the prostaglandin Ei and the compound that increases the penetration of the skin on the penis. According to one embodiment of the process of the invention, the topical composition is applied topically only to the glans.

DETAILED DESCRIPTION AND PREFERRED MODALITIES The compositions and methods of this invention can be used for the treatment of any underlying causes of penile erectile dysfunction or male impotence, including for example, pelvic vascular disease, diabetes mellitus, neurodegenerative disorders, pelvic surgery, effects Side effects of other medications, trauma or psychological problems. The compositions of the invention are intended for topical, non-invasive application to the genital regions, especially the penis, in its entirety, or preferably just at the glans penis. In addition, the composition can be applied to the scrotum and / or perineum.

A particular advantage of this invention is that the composition is effective even when applied only to the glans; Another advantage is the reduction of side effects, such as the sensation of burning or pain. The term "non-invasive" means that the treatment does not require puncturing the skin, surgical removal of tissues, or any other type of surgical intervention, including transnural administration. The active ingredient in the formulation of this invention is prostaglandin Ei (PGE-1) [11,15-dihydroxy-9-oxoprost-13-en-l-oic acid; 3-hydroxy-2- (3-hydroxy-1-octenyl) -5-oxo-cyclopentanheptanoic acid] which is a known vasodilator. However, other prostaglandins, such as prostaglandin E2 (PGE-2), or prostaglandin mimetics, or other drugs useful for the treatment of penile erectile dysfunctions, such as, for example, paverin (1- [3, 4-dimethoxyphenyl) methyl] -6,7-dimethoxyisoquinoline), dioxoline, etaverine (1- [(3,4-diethoxyphenyl) methyl] -6,7-diethoxyisoquinoline), pentolamine (3- [[4,5-dihydro- lH-imidazol-2-yl) methyl] (4-methylphenyl) amino] phenol), prazosin (1- (4-amino-6,7-dimethoxy-3-quinazolinyl) -4- (2-furanyl-carbonyl) piperazine ), minoxidil, nitroglycerin, alpha blockers, nitric oxide donors, peptides (eg, VIP), can be used. Especially, mixtures of PGE-1 with phentolamine or prazosin are preferred; for example at ratios of PGE-1 to phentolamine or prazosin from 1: 200 to 1: 1, preferably from 1: 100 to 1: 5, more preferably from 1:50 to 1:10. Generally, the amount of active ingredient to be applied will depend on factors such as the particular disorder being treated, the severity of the disorder, the age of the patient, the amount and type of improver. Usually, amounts ranging from about 25 μg to about 4 mg of PGE-1 per application, preferably from about 50 μg to about 2.5 mg of PGE-1, more preferably from about 125 μg to about 1.5 mg, per application, will provide acceptable results for most individuals. Accordingly, PGE-1 will usually be included in compositions for topical application in amounts ranging from about 0.001 to 5.0 percent (as used herein, unless noted otherwise, all percentages, percentages, amounts and ratios are on a weight basis) preferably from 0.05 to 1.5 percent, more preferably from 0.05 to 1.0 percent, based on the total composition. Where PGE-1 is used in combination with another active ingredient, such as phentolamine or prazosin, the total amount of the active ingredient can fall within larger amounts. Similarly, when phentolaine or prazosin is used in place of PGE-1 the amount of active ingredient may be within higher amounts. Penetration of the active ingredient through the skin increases to an acceptable level by including in the composition an effective amount to improve the skin penetration of an improving compound of which is a 1,3-dioxolane substituted at the 2-position of the formula (I): or a 1,3-dioxane of the formula (I I): or an acetal (including a semiacetal) of formula III: where R represents an alipc group of C6 to R2R 3f R4, Rdi and Rff each independently represent hydrogen or an alipc group from Ci to C. R'i, R'2, each independently represent an alipc group of Ci to C4. Preferably, R represents an alipc group of C6 to C2; especially an alipc group of C7 to Cio- The alipc group may be a straight or branched chain alkyl or alkenyl group, such as, for example, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl , n-undecyl, n-dodecyl, n-hexadecyl, n-octadecyl, 2-methyl-octyl, 4-ethyl-decyl, 8-methyl-decyl, n-octenyl, n-stearyl, and the like. Linear alkyl groups, such as n-heptyl, n-octyl, n-nonyl and n-decyl, are especially preferred. The alipc group of Ci to C4 can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, ethenyl, and the like. Preferred alipc groups for Ri to R6 and for R '1 and R'2 are alkyl groups, especially alkyl having 1 or 2 carbon atoms, more especially ethyl. Ri to R6 can also be, preferably hydrogen. The amount of enhancer compound will be selected to provide the desired release rate for the active compound but, taking into consideration additional factors such as product stability, side effects, carrier system and the like. Generally, amounts in the range of about 0.5 to 25%, preferably about 2 to 15%, especially about 3 to 10 percent, of the composition will provide stable and effective compositions. The compositions are generally formulated as gels, especially aqueous-alcoholic gels. However, other forms may be used, such as, for example, lotions, creams, foams, sprays, ointments, lubricants, etc., as long as they are applied to the genitals the formulation will remain in place, ie, without running , for a sufficient time to allow an individual to disperse the composition over the entire penis, preferably only on the glans penis. In addition to the different prior forms of the composition, the compositions may also be provided for administration by any known release forms, including, for example, unit dose and multiple dose systems (i.e., multiple unit doses in a single package or container) and bulk forms. As examples of unit dosage forms, mention may be made of, for example, syringes, gelatin capsules, alcohol packaging and the like. The bulk forms can be stored in, for example, tubes, bottles, jars, pumps, aerosol containers and the like, formed of glass, coated metal containers or plastic materials. Again, the formulation and packaging of pharmaceutical products is also within the capabilities in the art. It is also within the scope of the invention, and in some cases to increase the stability (for example, of the appearance of the composition, such as phase separation, chemical stability of the ingredients), to provide the composition in two or more, generally two, parts, with the enhancer compound maintained in a separate container or separated from the same container, of at least the PGE-1 component. A two-part composition, for mixing just before use, is especially convenient when the improver is of formula (III) but also for the 1,3-dioxolanes and 1,3-dioxanes. In this regard, under the preferred acidic pH of the composition, for example, from about 5 to about 6, the acetal and to a lesser extent the dioxolanes and dioxanes, are subjected to hydrolysis. Therefore, keeping the improver separate from the other ingredients exactly before using it will prevent the hydrolysis of the enhancer compound from proceeding to any significant degree., if not everything. When two parts are provided, with the enhancer material separated from the PGE-1, it is preferred to mix the enhancer with PGE-1 and the other components, before application to the genitals. Thus, although it is generally more convenient to store the necessary formulation ingredients as a single composition, in this case there is often a practical limitation with respect to storage, or shelf life. That is to say, that the optimum pH for relatively low PGE-1 is about 5, while percutaneous penetration enhancers of dioxane, dioxolane, or, especially, acetal are more stable at a higher pH, usually from 6 or higher Thus, a single formulation will normally compromise the stability of one or both of the components to a greater or lesser degree, depending on the specific pH of the composition. Therefore, it may be desirable to place the PGE-1 and the improver in separate compositions or compartments in the same container, each with its pH optimized for its respective stability, to be mixed immediately before use. Similarly, when the active ingredient includes prazosin the composition should not be aqueous, that is, alcohol (ethanol and / or isopropanol) and propylene glycol, or prazosin should be stored separately from the aqueous medium exactly until before use. In addition, the stability of PGE-1 can be affected by its physical form, and, specifically, PGE-1 is generally recognized as being more stable as a solid in solution. Thus, a two-part composition can, advantageously, with respect to stability, contain solid PGE-1, ie, crystalline, in a part to be dissolved in the mixture with fluid ingredients in the second part, for Give a single composition easy to use immediately. In this regard, crystalline PGE-1 can be stably maintained under refrigeration for very long periods of up to about 2 years. However, it is also within the scope of the invention to first apply the enhancer to the genitals (e.g., the glans or the body or the penis or the entire penile area, including the scrotum) and then, usually within 30 minutes, of preferably within 15 minutes, apply the PGE-1 (together with any other optional active component) and the rest of the composition. In addition, as will be appreciated by those skilled in the art, the pharmaceutically acceptable carrier may be present, all or in part, with either or both of the enhancer and PGE-1, taking into consideration such factors as solubilities, stability of the products, ease of application, and the like. In this regard, PGE-1 is hardly soluble in water but not soluble in ethanol. In addition, this solubility is not damaged to a practical degree by the incorporation of the water-insoluble builder compound used in this invention. Accordingly, the carrier system for PGE-1 and the enhancer components preferably an aqueous carrier or non-aqueous alcohol containing sufficient alcohol, especially ethanol and / or isopropanol, to solubilize PGE-1 is essentially insoluble in water, and is miscible with the improver. Generally, however, depending on the amounts of the enhancer and PGE-1 in the aqueous alcohol carrier formulations it may contain from about 10% to about 90% ethyl alcohol or isopropyl alcohol, preferably from about 60 to about 80 percent ethanol or from about 45 to about 55 percent isopropanol. Mixtures of ethanol and isopropanol can be used in proportions that provide the desired solubility of PGE-1 and compatibility with the improver. Again, the total amount of aqueous alcoholic or non-aqueous carrier will depend on the amount of PGE-1, another active ingredient, the amount and type of the improver, and the form of the composition, for example, gel, cream, ointment, etc. Usually, amounts of the aqueous or non-aqueous alcohol carrier can be used within the range of about 70% to about 97%. Preferred compositions which are in the form of a gel, a thickening agent, such as hydroxypropyl cellulose, which includes a gelling agent. However, another pharmaceutically acceptable thickening / gelling agent can be used. For example, mention may be made of other cellulosics, polymeric thickening agents, for example, acrylic acid polymers, Carbopol® thickeners, etc., xanthan gum, guar gum, and the like, as well as inorganic thickeners / gelling agents. The amount of thickening agent is not particularly critical and may be selected to provide desired consistency or viscosity to the product to allow easy application to the genitals but may not be too watered down or loose to remain where it was applied. In this regard, an advantage of the composition can be obtained by being applied to the genitals while the person is at rest. Generally depending on their molecular weight, amounts of thickening agent is about 5%, such as, for example, from 0.1 to about 2%, of the composition will provide the desired effect. Although the compositions of this invention generally have little or no side effect, especially on the penile side, a percentage of individuals in the general population may experience some minor discomfort, such as a burning sensation, especially when applied to the body of the penis. When applied to the glans of the penis the tendency to burn sensation decreases further. This is another advantage of the present invention, namely that the compositions are more effective when applied only to the glans of the penis. As noted above the effectiveness of the composition when applied only to the glans (a non-cornified tissue) was not entirely expected in view of the obvious mode of action of the improver, such as dioxolane, dioxane and acetal improvers. In any case, especially when it is intended to apply the composition to the entire penis and / or genital area, it is also within the scope of the invention to include in the compositions a smaller amount, for example, up to about 5%, especially up to about 3% , such as from about 0.1 to 1 or 2%, of a moderate local anesthetic, or an anti-scald agent. Although many such agents are known in the art, satisfactory results have been achieved with menthol. Other moderate local anesthetics may be used, such as, for example, chlorobutanol, camphor, benzyl alcohol, etc. For treatment in erectile dysfunction and with the preferred application on the glans, the amount of formulation to be applied is preferably in the range of from about 0.1 to about 1 milliliter (ml), preferably from about 0.1 to 0.5 ml, more preferably from about 0.2 to 0.3 ml. For those preferred application amounts the active ingredient should be contained in the formulation in the amounts described above, namely from about 0.001 to 5.0%, preferably from 0.05 to 1.5%, more preferably from 0.05 to 1.0%, For a representative, typical gel formulation, according to the invention contains 0.5% PGE-1 and 5% 2-n-nonyl-1,3-dioxolane, the amounts of the appropriate doses, as a function of intended use of the application area, can be from about 0.1 to about 0.5 ml, preferably from about 0.2 to 0.3 ml, such as, for example, 0.25 ml. The gel ratios in representative alcohol (non-aqueous) and alcoholic water gel according to the invention are shown below, with the quantities for the "wide", "intermediate" and "preferred" intervals being in weight.

Ethanol or Isopropanol Wide Preferred Intermediate Gel PGE-1 0.001-5.0 0.05-1.5 0.05-0.5 Improver 0.5-25 2-15 3-12 Carrier: 50-98 70-97 80-94 Ethanol / Water 45 / 55-90 / 10 50 / 50-90 / 10 55 / 45-90 / 10 (o) i- 30 / 70-90 / 10 35 / 65-90 / 10 40 / 60-90 / 10 Propanol / Water Agent 0.1-5.0 0.2-2.0 0.4-1.2 Gellet Ethanol or Isopropanol Gel with Wide Preferred Intermediate Menthol PGE-1 0.001-5.0 0.05-1.5 0.05-0.5 Improver 0.5-25 2-15 3-12 Carrier: 50-98 70-97 80-94 Ethanol / Water 45 / 55-90 / 10 50 / 50-90 / 10 55 / 45-90 / 10 (o) i- 30 / 70-90 / 10 35 / 65-90 / 10 40 / 60-90 / 10 Propanol / Water Agent 0.1-5.0 0.2-2.0 0.4-1.2 Gelificante Menthol 0.1-5.0 0.2-3.0 0.2-1.0 Gel with Propylene Glycol / Preferred Intermediate Wide Alcohol PGE-1 0.05-5.0 0.05-1.5 0.05-0.5 Improver 0.5-25 2-15 3-12 Carrier: 50-98 70-97 80-94 C2 / C4 Alkanol 10-90 20-70 40-50 Propylene 2-80 5-60 10-50 Glycol Water 0-45 0-40 0-40 Gel with Propylene Glycol / Alcohol (continued) Wide Preferred Intermediate Agent 0.1-5.0 0.2-2.0 0.4-1.2 Menthol Gelifier 0-5.0 0-3.0 0-1.0 Although it is difficult to measure the pH of the compositions, the compositions tend to be moderately acidic, due to the acid nature of PGE-1. In general, pH-modifying agents (eg, acids or bases) are not preferred in the compositions of the invention. A particular advantage of the preferred compositions of this invention is that they remain stable against phase separation and degradation of the product with a wide range of storage conditions. For example, the aqueous and non-aqueous alcohol gel formulations as described above remain stable for a temperature range of at least about -18 ° C to about 10 ° C, for periods of several months to years, depending on the storage temperature . The lower the temperature, the greater the stability. Within this temperature range the concentration of PGE-1 remains greater than 80% of the original concentration. At lower temperatures which can, in some cases, cause phase separation of PGE-1, the composition can be stored in its original condition after thawing. Accordingly, it is often preferred that the compositions be refrigerated until exactly before use. Another particular advantage of the present invention is that by virtue of improving the effectiveness of PGE-1 it is possible to use less of the active ingredient, thereby decreasing the likelihood of irritation or other side effects. Although the compositions of the invention are effective without any additional help a better erection may sometimes be achieved, ie, more suitable for sexual contact, especially when the composition is applied directly and only to the glans, combining topical transdermal application to the active ingredient. , as described above, with the aid of the mechanical venous restriction device, such as a rubber band or other "strangulation" device. Such devices are well known in the art. In the context of the present invention it is believed that the aid of a mechanical restraint device, preferably applied close to the base of the cut of the penis, can improve the effectiveness of the active ingredient by more effectively directing the active ingredient to enter the penis. cavernous body.

Reference Example 1 The following aqueous alcoholic gel was prepared according to the invention: Amount (percent) Prostaglandin Ei 0.1 2-n-nonyl-l, 3-dioxolane 5.0 Hydroxypropyl cellulose (HPC) 1.0 Solvent (Ethanol / Water: 70/30) c.b.p.100 The 2-n-nonyl-l, 3-dioxolane was added to the ethanol / water solvent while stirring to form a clear solution. Solid (crystalline) PGE-1 (commercially available from a number of different sources) was added, under stirring, and allowed to dissolve. The HPC (powder) was then added with continuous mixing until uniform gelation was observed. The mixing was carried out under room temperature but can be carried out at colder temperature if desired. Also, mixing, if desired, can be carried out using a roller mill to mix the ingredients under reduced cutting conditions.

Reference Example 2 The following aqueous alcohol gel was prepared according to the invention: Amount (percent) Prostaglandin Ei 0.5 2-n-nonyl-l, 3-dioxolane 5.0 Hydroxypropyl cellulose (HPC) 1.0 Solvent (Ethanol / Water: 70/30) c.b.p.100 Reference Example 3 The following aqueous alcohol gel was prepared according to the invention: Amount (percent) Prostaglandin Ei 0.5 2-n-nonyl-l, 3-dioxolane 5.0 Hydroxypropyl cellulose (HPC) 1.0 Menthol 0.5 Solvent (Ethanol / Water: 70/30) cbp100 Reference Example 4 The following alcoholic gel was prepared aqueous according to the invention: Amount (percent) Prostaglandin Ei 0.1 2-n-nonyl-l, 3-dioxolane 5.0 Hydroxypropyl cellulose (HPC) 1.0 Menthol 0.5 Solvent (Ethanol / Water: 70/30) c.b.p.100 Reference Example 5 The following aqueous alcoholic gel was prepared according to the invention: Amount (percent) Prostaglandin Ei 0.5 2-n-nonyl-l, 3-dioxolane 5.0 Hydroxypropyl cellulose (HPC) 1.0 Menthol 0.5 Solvent (Ethanol / Water: 70/30) c.b.p.100 Example 1 a) a 57-year-old male was applied to the penis glans 0.25 ml of the gel described in Reference Example 4. He experienced tumescence within 30 minutes. b) On another occasion, this same subject was applied to the penis glans 0.25 ml of the gel described in Reference Example 2. He experienced tumescence within 20 minutes. An unstimulated, full erection was experienced within 30 minutes and lasted approximately one hour. c) On another occasion, this subject was applied to the penis glans 0.25 ml of the gel described in Reference Example 3. He experienced tumescence within 30 minutes. After a visual stimulation 45 minutes after the application, he experienced a complete erection. d) On two different occasions, this subject was applied to the penis glans 0.25 ml of placebo gel, ie without prostaglandin Ei. He did not experience tumescence or erection at any time, even after visual stimulation.

Example 2 A 44-year-old male was applied to the penis glans 0.25 ml of the gel described in Example Reference 2. This individual felt that the blood flow, or elongation, of the penis was greater than that normally experienced during sexual contact.

Example 3 a) A 47-year-old male was applied to the penis glans 0.5 ml of the gel described in Reference Example 4. The subject reported the pleasant feeling of always having a partial erection hours after use - even after washing the gel on the surface of the skin. b) On another occasion, that subject was applied to the penis glans 0.25 ml of the gel described in Reference Example 5, with similar positive results.

Example 4 The formula of Reference Examples 1 was studied in placebo-controlled clinical trials and included 34 impotent individuals. The placebo was the formulation described in Reference Examples 1 and 2 but without prostaglandin Ei. The formulation was tested by applying volumes containing 0.5 mg (Dosage A) or 1.0 mg (Dosage B) of PGE-1 to the penis. Erections were observed for 8 to 12 (67%) men tested with Dosage A and for 7 of 10 (70%) of men treated with Dosage B, while only 2 of the 12 men experienced erections when treated with the placebo gel.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (20)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A composition for topical administration to the penis of a patient in need thereof, the composition is characterized in that it comprises: (a) a pharmacologically effective amount of prostaglandin Ei; (b) an effective amount for improving the penetration of a penetration enhancing compound selected from the group consisting of 1-3, dioxane, 1,3-dioxolane and acetal substituted with a C2o hydrocarbyl group. (c) a pharmaceutically effective carrier comprising (i) a mixture of ethyl alcohol and water effective to solubilize components (a) and (b); (ii) a mixture of isopropyl alcohol and water effective to solubilize components (a) and (b); or (iii) a mixture comprising at least one of the ethyl alcohol and isopropyl alcohol and propylene glycol; and (d) an effective thickener amount of a thickening agent, and, optionally, (e) an effective anti-irritant amount of menthol. The composition according to claim 1, characterized in that it comprises (a) from about 0.01 to about 5 weight percent of prostaglandin Ei; (b) from about 0.5 to about 25 weight percent of the compound that improves skin penetration; (c) (i) a mixture of ethyl alcohol and water at a mixing ratio, by weight, of from about 90:10 to about 45:55; or (ii) a mixture of isopropyl alcohol and water at a mixing ratio, by weight from about 90:10 to about 30:70; or (iii) a mixture comprising propylene glycol and at least one alcohol selected from the group consisting of ethanol and isopropanol at a mixing ratio, by weight, of propylene glycol to alcohol of about 2:90 to 80:10; (d) up to about 5 weight percent of the thickening agent; and (e) up to about 5 weight percent menthol. 3. The composition according to claim 1, characterized in that it comprises (a) from about 0.05 to about 1.5 weight percent of prostaglandin Ei; (b) from about 2 to about 15 weight percent of the compound that improves skin penetration; (c) (i) a mixture of ethyl alcohol and water at a mixing ratio, by weight, from about 50:50 to about 90:10, or (ii) a mixture of isopropyl alcohol and water at a mixing ratio, by weight from about 35:65 to about 90:10; or (iii) a mixture comprising propylene glycol and an alcohol selected from the group consisting of ethanol and isopropanol at a mixing ratio, by weight, of about 5:70 to 60:20; (d) up to about 2 weight percent of the thickening agent; and (e) from 0 to about 2 weight percent methanol. The composition according to claim 3, comprising (a) from about 0.05 to about 0.5 weight percent of prostaglandin Ei; (b) from about 3 to about 12 weight percent of compound that improves skin penetration; (c) from about 70 to about 97 weight percent of the pharmaceutically effective carrier; (d) from about 0.2 to about 2 weight percent thickening agent; and (e) from 0 to about 2 weight percent menthol. 5. The composition according to claim 4, characterized in that menthol is present. 6. The composition according to claim 1, characterized in that the component (b) comprises from about 2 to about 15 weight percent of 1,3-dioxolane substituted with alkyl of C to C12 • 7. The composition in accordance with claim 1, characterized in that the component (c) comprises from about 2 to about 15 weight percent of acetal substituted with C7 to Ci2 alkyl. 8. The composition according to claim 1, characterized in that the composition has a pH in a range from about 5 to about 6. 9. The composition according to claim 8, characterized in that the compound that improves skin penetration is acetal and where the acetal is physically separated. of prostaglandin Ex exactly before its use. 10. A composition for topical administration to the penis of a person in need thereof, the composition is characterized in that it comprises (a) a pharmacologically effective amount of active ingredient selected from the group consisting of prostaglandin Ei, phentolamine, prazosin and a mixture of prostaglandin Ei with phentolamine or prazosin; (B) an amount effective to enhance penetration of a compound that enhances skin penetration selected from the group consisting of 1,3-dioxane, 1, 3-dioxolane and acetal substituted with a hydrocarbyl group of C6 to C2o; (c) a pharmaceutically effective carrier comprising (i) a mixture of ethyl alcohol and water effective to solubilize components (a) and (b); or (ii) a mixture of isopropyl alcohol and water effective to solubilize components (a) and (b); or (iii) a mixture comprising at least one of the ethyl alcohol and the isopropyl alcohol and propylene glycol; (d) an effective thickener amount of a thickening agent; and, optionally, (e) an effective anti-irritant amount of menthol. 11. The composition according to claim 10, characterized in that the active ingredient (a) is the mixture. 1

2. The composition according to claim 10, characterized in that the active ingredient (a) is phentolamine. The composition according to claim 10, characterized in that the active ingredient (a) is prazosin. 14. A method for treating penile erectile dysfunction in a person in need thereof, comprising topically administering wherein the genitals of the patient a composition comprising a pharmacologically effective amount of an ingredient selected from the group consisting of prostaglandin Ei, phentolamine, prazosin, and mixture of prostaglandin Ei with phentolamine or prazosin, in the presence of an amount effective to improve skin penetration of a compound that enhances skin penetration selected from the group consisting of 1, 3-dioxolane, 1, 3-dioxane and acetal; substituted with a hydrocarbyl group of C6 to C2o; wherein the prostaglandin Ei and the compound that improves skin penetration are solubilized in a pharmaceutically acceptable alcohol carrier comprising ethyl alcohol and water or isopropyl alcohol and water; and a thickening agent in an amount effective to retain the active ingredient and a compound that improves the penetration of the skin on the genitals. 15. The method according to claim 14, characterized in that it further comprises including an effective anti-irritant amount of the composition. 16. The method according to claim 14, characterized in that it comprises topically administering the composition only to the penis glans. 17. The method according to claim 16, characterized in that it further comprises applying mechanical venous restriction to the body of the penis. 18. The method according to claim 14, characterized in that it also comprises applying mechanical venous restriction to cutting the penis. The method according to claim 14, characterized in that it comprises topically administering the composition to provide from about 25 μg to about 4 mg of prostaglandin Ex to the penis glans. The method according to claim 14, characterized in that it comprises topically administering the composition to provide from about 50 μg to about 2.5 mg of prostaglandin Ex to the penis glans.