US 20090093547A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0093547 A1 Corbitt et al. (43) Pub. Date: Apr. 9, 2009

(54) COMPOSITIONS AND METHODS FOR Publication Classification TREATING PREMATURE EACULATION (51) Int. Cl. (75) Inventors: James M. Corbitt, Tucker, GA st 4. CR (US); Brian Adams, Atlanta, GA ( .01) (US); Larry Dillaha, Atlanta, GA (52) U.S. Cl...... 514/626 (US) Correspondence Address: (57) ABSTRACT Pabst Patent Group LLP 1545 PEACHTREE STREET NE SUTE 32O Compositions and methods for the treatment of premature ATLANTA, GA 30309 (US) 9 ejaculation have been developed. It has been discovered that 9 premature ejaculation can be treated by administering a local (73) Assignee: Sciele Pharma, Inc. anesthetic to the glans penis. The local anesthetic may be formulated as an emulsion, lotion, paste, gel, cream, oint (21) Appl. No.: 11/869,280 ment, shea butter, Suspension, Solution, balm, salve, foam, or in the form of a pump spray to achieve local anesthesia of the (22) Filed: Oct. 9, 2007 dorsal neurons of the penis. US 2009/0093547 A1 Apr. 9, 2009

COMPOSITIONS AND METHODS FOR 0007. There exists a need for improved alternatives for the TREATING PREMATURE EACULATION effective treatment of PE. 0008. Therefore, it is an object of the invention to provide FIELD OF THE INVENTION compositions for the effective treatment of PE and methods of use thereof. 0001 Compositions and methods for treating premature 0009. It is another object of the invention to provide local ejaculation have been developed, which are useful for desen compositions containing an effective amount of one or more sitizing the dorsal nerves of the penis. local anesthetics to cause desensitization of the neurons of the glans penis and methods of making and using thereof. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION 0002 Premature ejaculation (PE) remains the most com 0010 Compositions for the treatment of premature ejacu mon sexual dysfunction in men. Although progress is being lation (i.e. to delay or have control over ejaculation) and made in elucidating its causal mechanisms, the disparate Vari methods of making and using thereof have been developed. ety oftechniques and drugs available for its treatment has met The compositions contain an effective amount of one or more only limited Success. For instance, behavioral interventions anesthetics for local administration to the glans penis. The were reported to be effective with initially satisfactory results compositions may be formulated as an emulsion, lotion, in the vicinity of 90%; unfortunately, the success rates decline paste, gel, cream, ointment, shea butter, Suspension, Solution, markedly to less than 25% after 3 years. Systemic drugs have balm, salve, foam, or pump spray to achieve local anesthesia proven to have varying levels of efficacy, but are plagued by of the dorsal neurons of the penis. side effects that are generally considered unacceptable, in the 0011. The compositions may further contain one or more long term, in otherwise healthy men. Equally discouraging, additional pharmaceutically active agents. Suitable classes of the effect of these medications is temporary since the Symp active agents include, but are not limited to, antimicrobial toms return upon their discontinuation. agents (antibacterial and antifungal agents, and/or antiproto 0003. The early Freudian-based causal hypothesis of PE Zoal agents), anti-inflammatory agents (non-steroidal or Ste has been revised and largely abandoned in favor of physi roidal agents), vasodilator agents, anti-oxidants, vitamins, ological facts. A heightened sensitivity of the glans to tactile and hormones. stimuli is currently believed to be a fundamental initiating factor in PE. Therefore, it is possible that reducing the sensi DETAILED DESCRIPTION OF THE INVENTION tivity of the glans could translate into a delaying effect on intravaginal ejaculation latency time (IVELT) without I. Definitions adversely affecting the sensation of ejaculation. A drastic 0012 “Water soluble' as used herein refers to substances approach to desensitization involves “neurotomy' of the dor that have a solubility of greater than or equal to 5 g/100 ml sal nerves of the penis. This invasive and irreversible measure Water. is reported to be effective but has failed to gain wide support 0013 “Lipid soluble' as used herein refers to substances in the medical community. that have a solubility of greater than or equal to 5 g/100 ml in 0004 Topical formulations for the treatment of PE have a hydrophobic liquid Such as castor oil. also been evaluated. Stud 100R) (available from Pound Inter 0014) “Hydrophilic” as used herein refers to substances national, Ltd, England), an over the counter formulations that have strongly polar groups that readily interact with containing 9.6% w/v lidocaine HCl, is marketed as a treat Water. ment for PE. This product contains an ionized form of 00.15 "Lipophilic” as used herein refers to compounds lidocaine in order to increase the solubility of the lidocaine in having an affinity for lipids. the delivery vehicle at physiological pH. However, lidocaine 0016 Amphiphilic” as used herein refers to a molecule salts do not effectively penetrate keratinized and non-kerati combining hydrophilic and lipophilic (hydrophobic) proper nized skin. Thus, this product is considered to be ineffective ties for the treatment of PE. In fact, no controlled clinical trials 0017 “Hydrophobic' as used herein refers to substances have been conducted showing that this product is effective for that lack an affinity for water; tending to repel and not absorb the treatment of PE. water as well as not dissolve in or mix with water. 0005 Xylocalne(R), a lidocaine spray, is used primarily for 0018. As used herein, an “oil is a liquid or liquefiable the treatment of Sore throats. Xylocalne contains ethanol as a material that is immiscible in water. In one embodiment, an Solvent and dichloroethane and trichloroethane as propel oil is a composition containing at least 95% by weight of a lants. Xylocalne is not ideal for use in topical applications lipophilic Substance. Exemplary lipophilic Substances because the propellants can cause irritation of the mucosal include, but are not limited to, naturally occurring and Syn membranes, such as the glans penis. thetic oils, fats, fatty acids, lecithins, triglycerides and com 0006 EMLA, a cream containing a local anesthetic, may binations thereof. be an alternative treatment for PE. However, the active ingre 0019. As used herein, an "emulsion' is a composition dients of EMLA take a long time to penetrate the glans so that containing a mixture of non-miscible components homog the formulations would need to be applied well in advance of enously blended together. In particular embodiments, the sexual activity, which can limit spontaneity. Further, the non-miscible components include a lipophilic component cream is greasy, difficult to administer, and requires the use of and an aqueous component. An emulsion is a preparation of a condom in order to prevent partner transfer. Finally, as one liquid (e.g., the discrete or discontinuous phase) distrib EMLA penetrates keratinized skin, it numbs the whole of the uted in Small globules throughout the body of a second liquid penis, not just the glans, which can compromise sexual sat (e.g., the continuous phase). When oil is the dispersed liquid isfaction. and an aqueous Solution is the continuous phase, it is known US 2009/0093547 A1 Apr. 9, 2009

as an oil-in-water emulsion. When water or an aqueous solu 0024. As used herein, a “cream' is an emulsion having a tion is the dispersed phase and oil or oleaginous Substance is viscosity of greater than 1000 centistokes, typically in the the continuous phase, it is known as a water-in-oil emulsion. range of 20,000-50,000 centistokes. Either or both of the oil phase and the aqueous phase may 0025. As used herein, a “paste’ is a liquid or emulsion contain one or more surfactants, emulsifiers, emulsion stabi having solid material homogenously suspended therein, typi lizers, buffers, and other excipients. Preferred excipients cally in a lotion cream or gel. include Surfactants, especially non-ionic Surfactants; emulsi 0026. As used herein, a “gel’ is a composition containing fying agents, especially emulsifying waxes; and liquid non a thickening agent or polymeric material dissolved or Sus Volatile non-aqueous materials, particularly glycols such as pended in a liquid. The liquid may include a lipophilic com propylene glycol. The oil phase may contain other oily phar ponent, an aqueous component or both. Some emulsions may maceutically approved excipients. For example, materials be gels or otherwise include a gel component. Some gels, however, are not emulsions because Some do not contain a Such as hydroxylated castor oil or sesame oil may be used in homogenized blend of immiscible components. the oil phase as Surfactants or emulsifiers. 0027 “Penetration enhancers', are used herein, refers to 0020. As used herein, “emollients' are an externally materials or techniques which promote transdermal delivery applied agent that softens or soothes skin. Emollients are of drugs across the skin, in particular across the stratum generally known in the art and listed in compendia, Such as corneum. These can be chemical penetration enhancers or the “Handbook of Pharmaceutical Excipients', 4' Ed., Phar physical penetration enhancers, such as ultrasound. maceutical Press, 2003. These include, without limitation, 0028. As used herein, the term “prodrug” refers to an almond oil, castor oil, ceratonia extract, cetostearoyl alcohol, active drug chemically transformed into an inactive derivative cetyl alcohol, cetyl esters wax, cholesterol, cottonseed oil, which, by virtue of chemicalorenzymatic attack, is converted cyclomethicone, ethylene glycol palmitostearate, glycerin, to the parent drug within the body before or after reaching the glycerin monostearate, glyceryl monooleate, isopropyl site of action. Prodrugs are frequently (though not necessar myristate, isopropyl palmitate, lanolin, lecithin, light mineral ily) pharmacologically inactive until converted to the parent oil, medium-chain triglycerides, mineral oil and lanolin alco drug. A prodrug may be converted into the parent drug by hols, petrolatum, petrolatum and lanolin alcohols, soybean various mechanisms, including enzymatic processes and oil, starch, Stearyl alcohol, Sunflower oil, Xylitol and combi metabolic hydrolysis. Examples of prodrugs include, but are nations thereof. In one embodiment, the emollients are eth not limited to, ester and amide prodrugs; polyethylene glycol ylhexylstearate and ethylhexyl palmitate. prodrugs (with and without a linker); N-acylamine prodrugs, 0021. As used herein, “surfactants' are surface-active dihydropyridine prodrugs, 2-hydroxybenzamide prodrgus: agents that lower Surface tension and thereby increase the carbamate prodrugs; peptide prodrugs; Mannich bases, and emulsifying, foaming, dispersing, spreading and wetting Schiffbases. properties of a product. Suitable non-ionic Surfactants 0029. As used herein, the term “analogue' refers to a include emulsifying wax, glyceryl monooleate, polyoxyeth chemical compound with a structure similar to that of another ylene alkyl ethers, polyoxyethylene castor oil derivatives, (reference compound) but differing from it in respect to a polysorbate, Sorbitan esters, benzyl alcohol, benzylbenzoate, particular component, functional group, atom, etc. cyclodextrins, glycerin monostearate, poloxamer, povidone 0030. As used herein, the term "derivative' refers to com and combinations thereof. In one embodiment, the non-ionic pounds which are formed from a parent compound by chemi Surfactant is stearyl alcohol. cal reaction(s). 0022. As used herein, "emulsifiers' are surface active sub stances which promote the Suspension of one liquid in II. Formulations another and promote the formation of a stable mixture, or 0031. The formulations are designed for local treatment of emulsion, of oil and water. Common emulsifiers are: metallic the glans penis to produce local anesthesia of the dorsal Soaps, certain animal and vegetable oils, and various polar nerves of the glans penis. The formulations can consist of one compounds. Suitable emulsifiers include acacia, anionic or more local anesthetics combined with one or more phar emulsifying wax, calcium Stearate, carbomers, cetostearyl maceutically acceptable excipients. The formulation can also alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene further include other constituents such as penetration enhanc glycol palmitostearate, glycerin monostearate, glyceryl ers or other active agents. The formulations can containactive monooleate, hydroxpropyl cellulose, hypromellose, lanolin, agents in the form of micro or nanoparticles, which may be hydrous, lanolin alcohols, lecithin, medium-chain triglycer formed of active agent alone or in combination with an excipi ides, methylcellulose, mineral oil and lanolin alcohols, ent or carrier. The drug formulation may be administered as monobasic sodium phosphate, monoethanolamine, nonionic an emulsion, lotion, paste, gel, cream, ointment, shea butter, emulsifying wax, oleic acid, poloxamer, poloxamers, poly Suspension, Solution, balm, salve, or foam. The active agent oxyethylene alkyl ethers, polyoxyethylene castor oil deriva formulation may also be administered as a pump spray. tives, polyoxyethylene Sorbitan fatty acid esters, polyoxyeth 0032 A. Local Anesthetics ylene Stearates, propylene glycol alginate, self-emulsifying 0033. The compositions described herein contain one or glyceryl monostearate, sodium citrate dehydrate, Sodium lau more local anesthetics. Suitable local anesthetics include, but ryl Sulfate, Sorbitan esters, Stearic acid, Sunflower oil, traga are not limited to, prilocalne, lidocaine, bupivacaine, chlorp canth, triethanolamine, Xanthan gum and combinations rocaine, dibucaine, etidocaine, mepivacaine, tetracaine, thereof. In one embodiment, the emulsifier is glycerol stear dyclonine, hexylcaine, procaine, ketamine, pramoxine, phe ate. nol, and combinations thereof. 0023. As used herein, a “lotion' is a suspension of an 0034. In one embodiment, the composition contains insoluble powder in a liquid or an emulsion having a viscosity lidocaine, prilocalne, or a mixture thereof. Prilocalne is a of between 100 and 1000 centistokes. local anesthetic drug which has the chemical formula: US 2009/0093547 A1 Apr. 9, 2009

sive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio. 0042. In one embodiment, the local anesthetic is a mixture 1N1 of lidocaine and prilocalne. Separately, lidocaine and prilo H calne are solid bases. When mixed togetherinequal quanitites O by weight, however, they form a eutectic mixture. A “eutetic mixture' is defined herein as a mixture in which the melting point of the mixture is lower than the melting points of the 0035. Prilocalne is described in British Patent 839,943 individual components. The lidocaine/prilocalne eutectic (1960 to Astra), and takes the form of crystalline needles mixture is an oil with a melting point of 16°C., which is lipid having a melting point of 37°C.-38°C. soluble. This property allows this anesthetic drug mixture to 0036. The hydrochloride salt, having the formula be formulated into preparations without the use of a non CHCINO, is crystallized from ethanol and isopropyl aqueous solvent. This allows higher concentrations of anaes ether, and is readily soluble in water. thetic to be formulated into the preparation and maintained 0037 Lidocaine is a local anesthetic drug which has the during application. Further, liquid forms of the drug are desir chemical formula: able in clinical applications as they are less likely to clog the metered dose valve of the administration device, unlike dry powders. 0043 Lidocaine and prilocalne can be mixed together in any ratio. In one embodiment, lidocaine and prilocalne are mixed together in equal (50:50) ratios. In other embodiments, lidocaine and prilocalne are mixed together in 5:95, 10:90, 15:8520:80, 25:75,30:70,35:65,40:60,45:65,55:45, 60:40, r 65:35, 70:30, 75:25, 80:20, 85:15, 90:10 and 95:5 ratios. 0044) The concentration of the anesthetic drug in the for 0038 Lidocaine has the chemical formula CHNO. mulation can vary up to 90% by weight, about 70% by weight, 0039. The local anesthetic can be administered as the free about 50% by weight, about 30% by weight, about 20% by acid or free base or as a pharmaceutically acceptable salt. As weight, about 10% by weight, about 8% by weight, about 6% used herein, “pharmaceutically acceptable salts' refer to by weight, about 5% by weight, about 4% by weight, about derivatives of the disclosed compounds wherein the parent 2% by weight, or about 1% by weight, of the formulation. compound is modified by making acid-addition or base-ad 0045 B. Other Active Agents dition salts thereof. Examples of pharmaceutically acceptable 0046. The compositions optionally contain one or more salts include, but are not limited to, mineral or organic acid additional pharmaceutically active agents. Suitable classes of salts of basic residues such as amines; alkali or organic salts active agents include, but are not limited to, antimicrobial of acidic residues such as carboxylic acids. The pharmaceu agents (antibacterial and antifungal agents, and/or antiproto tically acceptable salts include the conventional non-toxic Zoal agents), anti-inflammatory agents (non-steroidal or Ste salts or the quaternary ammonium salts of the parent com roidal agents), vasodilator agents, anti-oxidants, vitamins, pound formed, for example, from non-toxic inorganic or and hormones. organic acids. For example. Such conventional non-toxic salts 0047. Additional agents include benzoyl peroxide, zinc, include those derived from inorganic acids such as hydro aZelaic acid and its derivatives, phenoxyethanol and phenoxy chloric, hydrobromic, Sulfuric, Sulfamic, phosphoric, nitric proponol, ethylacetate, sebostats Such as flavinoids; alpha and the like; and the salts prepared from organic acids such as and beta hydroxy acids; and bile salts such as Scymnol Sulfate acetic, propionic, Succinic, glycolic, Stearic, lactic, malic, and its derivatives, deoxycholate and cholate. The antibiotic tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe can be an antifungal agent. Suitable antifungal agents nylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxy include, but are not limited to, clotrimazole, econazole, keto benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane conazole, itraconazole, miconazole, oxiconazole, Sulcona disulfonic, oxalic, and isethionic. Zole, butenafine, naftifine, terbinafine, undecylinic acid, 0040. The pharmaceutically acceptable salts of the com tolnaftate, and nystatin. pounds can be synthesized from the parent compound, which 0048 Suitable antimicrobial agents include, but are not contains a basic or acidic moiety, by conventional chemical limited to, antibacterial, antifungal, antiprotozoal and antivi methods. Generally, such salts can be prepared by reacting the ral agents, such as beta-lactam drugs, quinolone drugs, cipro free acid or base forms of these compounds with a stoichio floxacin, norfloxacin, a tetracycline, erythromycin, amikacin, metric amount of the appropriate base or acid in water or in an triclosan, doxycycline, capreomycin, chlorhexidine, such as organic solvent, or in a mixture of the two: generally, non chlortetracycline, methacycline, oxytetracycline, clindamy aqueous media like ether, ethyl acetate, ethanol, isopropanol, cin, ethambutol, metronidazole, pentamidine, gentamicin, oracetonitrile are preferred. Lists of suitable salts are found in kanamycin, lineomycin, methacycline, methenamine, Remington's Pharmaceutical Sciences, 20th ed., Lippincott minocycline, neomycin, netilmicin, Streptomycin, tobramy Williams & Wilkins, Baltimore, Md., 2000, p. 704. cin, and miconazole. Also included are tetracycline hydro 0041. The phrase “pharmaceutically acceptable' is chloride, famesol, erythromycineStolate, erythromycin Stear employed herein to refer to those compounds, materials, ate (salt), amikacin Sulfate, doxycycline hydrochloride, compositions, and/or dosage forms which are, within the chlorhexidine gluconate, chlorhexidine hydrochloride, chlo Scope of sound medical judgment, Suitable for use in contact rtetracycline hydrochloride, oxytetracycline hydrochloride, with the tissues of human beings and animals without exces clindamycin hydrochloride, ethambutol hydrochloride, met US 2009/0093547 A1 Apr. 9, 2009 ronidazole hydrochloride, pentamidine hydrochloride, gen (ABS), beta-adrenoceptor agonists (B-agonists), calcium tamicin Sulfate, kanamycin Sulfate, lineomycin hydrochlo channel blockers, endothelin receptor antagonists, nitrodila ride, methacycline hydrochloride, methenamine hippurate, tors, phosphodiesterase (PDE) inhibitors and potassium methenamine mandelate, minocycline hydrochloride, neo channel openers. mycin Sulfate, netilmicin Sulfate, paromomycin Sulfate, Strep 0.052 Representative examples of alpha-blockers include, tomycin Sulfate, tobramycin Sulfate, miconazole hydrochlo without limitation, prazosin, teraZosin, doxazosin, trima ride, amanfadine hydrochloride, amanfadine Sulfate, Zosin, phentolamine and phenoxybenzamine. triclosan, octopirox, nystatin, tolnaftate, clotrimazole, anidu 0053 Representative examples of ACE inhibitors include, lafungin, micafungin, Voriconazole, lanoconazole, ciclo without limitation, benazepril, captopril, enalapril, fosino pirox, econazole, and mixtures thereof. pril, lisinopril, moexipril, quinapril and ramipril. 0049 Representative examples of non-steroidal anti-in 0054 Representative examples of ARBs include, without flammatory agents include, without limitation, oxicams. Such as piroxicam, isoxicam, tenoxicam, Sudoxicam, Salicylates, limitation, candesartan, eprosartan, irbesartan, losartan, olm Such as aspirin, disalcid, benorylate, trilisate, Safapryn, Sol esartan, telmisartan and Valsartan. prin, diflunisal, and fendosal; acetic acid derivatives, such as 0055 Representative examples of B-agonists include, diclofenac, fenclofenac, indomethacin, Sulindac, tolmetin, without limitation, epinephrine, norepinephrine, dopamine, isoxepac, furofenac, tiopinac, Zidometacin, acematacin, fen doputamine and isoproterenol. tiazac, Zomepirac, clindanac, oxepinac, felbinac, and ketoro 0056 Representative examples of calcium-channel lac, fenamates, such as mefenamic, meclofenamic, flufe inhibitors include, without limitation, dihydropyridines such namic, niflumic, and tolfenamic acids; propionic acid as amlodipine, felodipine, isradipine, nicardipine, nifedipine, derivatives, such as ibuprofen, naproxen, benoxaprofen, flur nimodipine and nitrendipine, and non-dihydropyridines, biprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pir Such as Verapamil and diltiazem. profen, carprofen, oxaprozin, pranoprofen, miroprofen, tioX 0057 Representative examples of endothelin receptor aprofen, Suprofen, alminoprofen, and tiaprofenic; pyrazoles, antagonists include, without limitation, ambrisentan, sitax Such as phenylbutaZone, oxyphenbutaZone, feprazone, aza sentan and bosentan. propaZone, and trimethaZone. Mixtures of these non-steroidal 0.058 Representative examples of nitrodilators include, anti-inflammatory agents may also be employed, as well as without limitation, nitric oxide, isosorbide dinitrate, isosor the dennatologically acceptable salts and esters of these bide mononitrate, nitroglycerin, erythrityl tetranitrate, pen agents. For example, etofenamate, a flufenamic acid deriva taerythritol tetranitrate and sodium nitroprusside. tive, is particularly useful for local application. 0059 Representative examples of phosphodiesterase 0050 Representative examples of steroidal anti-inflam inhibitors include, without limitation, milrinone, amrinone, matory drugs include, without limitation, corticosteroids sildenafil and tadalafil. Such as hydrocortisone and hydrocortisone butyrate, 0060 Representative examples of potassium channel hydroxyl-triamcinolone, alpha-methyl dexamethasone, openers include, without limitation, mioxidil, levosimendan amcinafel, amcinafide, beclomethasone dipropionates, and levcromakalim. Additional vasodilator agents, include, betamethasone and the balance of its esters, chloropred but are not limited to, papaverine, prostaglandin E-1, dioyline nisone, chlorprednisone acetate, clescinolone, clobetasol val and ethaverine. erate, clocortelone, cortisone, cortodoxone, dexamethasone phosphate, desonide, desoxymethasone, 0061 C Carriers, Excipients, Solvents and Additives desoxycorticosterone acetate, dexamethasone, dichlorisone, 0062. The one or more local anesthetics are administered diflorasone diacetate, diflucortolone Valerate, fluclorolone in a carrier or a pharmaceutically acceptable carrier for local acetonide, fludrocortisone, flumethasone pivalate, fluosi administration. Suitable carriers or excipients include, but are nolone acetonide, fluocinonide, flucortine butylesters, fluo not limited to, emulsifiers, diluents, Surfactants, Solubility cortolone, fluprednidene (fluprednylidene) acetate, fluran enhancers, Suspending agents, anti-oxidants, chelating drenolone, halcinonide, hydrocortisone acetate, agents, emollients, humectants, pH modifying agents, lipid methylprednisolone, triamcinolone acetonide, flucetonide, bilayer disrupting agents, preservatives, thickening agents, fludrocortisone, fluradrenolone, fludrocortisone, difluo Viscosity modifying agents, vitamins and other skin nutrients, rosone diacetate, fluradrenolone acetonide, medrysone, and combinations thereof. Other additives and excipients diflurprednate, flucloronide, flunisolide, fluoromethalone, include, without limitation, Viscosifiers, additional occluding fluperolone, fluprednisolone, hydrocortisone Valerate, hydro agents, fragrances, deodorants, colorants, preservatives, Vita cortisone cyclopentylpropionate, hydrocortamate, mepred mins and other skin nutrients, antioxidants, solubility enhanc nisone, paramethasone, prednisolone, prednisone, beclom ers, and other stabilizing agents. The various components ethasone dipropionate, triamcinolone, and mixtures thereof. described above can be collected and provided as a kit. Addi 0051 One or more vasodilators may also be added to the tionally, the one or more local anesthetics may be dissolved in formulations. Vasodilators are known to produce and main saline solution (e.g., 0.9% saline or physiological saline solu tain penile erection whether given alone or in combination tion), water or an alcohol Solution. with other vasodilators. Typically, vasodilator agents are 0063 i. Diluents injected into the erectile tissue, however this method of 0064 Diluents may be included in the formulations to administration is painful and puts the patient at risk of nerve dissolve, disperse or otherwise incorporate the drug into the damage and/or excessive bleeding. See, for example, U.S. carrier. Examples of diluents include, but are not limited to, Pat. Nos. 6,007,836 and 5,256,652. Suitable vasodilator water, buffered aqueous Solutions, organic hydrophilic dilu agents include, but are not limited to alpha-adrenoceptor ents, such as monovalent alcohols, and low molecular weight antagonists (alpha-blockers), angiotensin converting enzyme glycols and polyols (e.g. propylene glycol, polypropylene inhibitors (ACE inhibitors), angiotensin receptor blockers glycol, glycerol, butylene glycol). US 2009/0093547 A1 Apr. 9, 2009

0065 ii. Emollients cocamido propyl dimethyl amine oxide, coconut fatty acid 0066 Suitable emollients include petrolatum, high-melt diethanolamide, coconut fatty acid monoethanolamide, dig ing fatty acids and esters, high-melting triglycerides, lanolin, lyceryl diisoStearate, diglyceryl monoisoStearate, diglyceryl hydrogenated castor oil, hydroxyethylated castor oil, and monolaurate, diglyceryl monooleate, ethylene glycol distear hydrogenated hydroxyethylated castor oil, in each case when ate, ethylene glycol monostearate, ethoxylated castor oil, their melting point is above about 38°C. Additional emol glyceryl monoisoStearate, glyceryl monolaurate, glyceryl lients are well known, and listings can be found can be found monomyristate, glyceryl monooleate, glyceryl monostearate, in reference books, for example under "Skin Conditioning glyceryl tricaprylate/caprate, glyceryl trisoStearate, glyceryl Agents—Emollient' and "Skin Conditioning Agents—Oc trioleate, glycol distearate, glycol monostearate, isooctyl clusive' in the “CFTA Cosmetic Ingredient Handbook', copyright 1988 by the Cosmetics, Toiletries and Fragrance Stearate, lauramide DEA, lauric acid diethanol amide, lauric Association of Washington, D.C. Any of the known approved acid monoethanol amide, lauric/myristic acid diethanol emollients is potentially suitable for use in the composition if amide, lauryl dimethyl amine oxide, lauryl/myristyl amide it melts above body temperature. Mixtures of emollients can DEA, lauryl/myristyl dimethylamine oxide, methylgluceth, be used, Concentration ranges of between 1 and 15 weight methyl glucose sesquistearate, oleamide DEA, PEG-distear percent are possible with a range of between 2.5 to 11 weight ate, polyoxyethylene butyl ether, polyoxyethylene cetyl percent preferred. Other USP-grade oils can be used if they ether, polyoxyethylene lauryl amine, polyoxyethylene lauryl are liquid at or near body temperature, preferably at room ester, polyoxyethylene lauryl ether, polyoxyethylene non temperature. These materials may be conventional vegetable ylphenyl ether, polyoxyethylene octyl ether, polyoxyethylene oils, such as corn, canola, peanut, Soy, olive, or other plant octylphenyl ether, polyoxyethylene oleyl amine, polyoxy extracts. Other types of oil include silicone oils and mineral ethyelenoleyl cetyl ether, polyoxyethylene oleyl ester, poly (hydrocarbon) oils. Combinations of oils with each other can oxyethylene oleyl ether, polyoxyethylene Stearyl amine, also be used. polyoxyethylene Stearyl ester, polyoxyethylene Stearyl ether, 0067 iii. Emulsifiers polyoxyethylene tallow amine, polyoxyethylene tridecyl 0068 An emulsifier is desirable to help promote efficient ether, propylene glycol monostearate, Sorbitan monolaurate, release of the actives from the formulation. Suitable surfac Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan tants include, but are not limited to, anionic Surfactants, non monostearate, Sorbitan sesquioleate, Sorbitan trioleate, ionic Surfactants, cationic Surfactants, and amphoteric Surfac Stearamide DEA, Stearic acid diethanol amide, Stearic acid tants. Other Suitable emulsifiers include, but are not limited monoethanol amide, laureth-4, Oleth-10 (polyoxyethylene to, straight chain or branched fatty acids, polyoxyethylene (10) oleyl ether) and combinations thereof. Sorbitan fatty acid esters, Sorbitan fatty acid esters, propylene 0072 Examples of amphoteric surfactants include, but are glycol Stearate, glyceryl Stearate, polyethylene glycol, fatty not limited to, sodium N-dodecyl-y-alanine, sodium N-lau alcohols, polymeric ethylene oxide-propylene oxide block ryl-y-iminodipropionate, myristoamphoacetate, lauryl copolymers, and combinations thereof. betaine, lauryl Sulfobetaine, sodium 3-dodecyl-aminopropi 0069 iv. Surfactants onate, Sodium 3-dodecylaminopropane Sulfonate, Sodium 0070. Examples of anionic surfactants include, but are not lauroamphoacetate, cocodimethyl carboxymethyl betaine, limited to, ammonium lauryl Sulfate, sodium lauryl Sulfate, cocoamidopropyl betaine, cocobetaine, lauryl amidopropyl ammonium laureth Sulfate, Sodium laureth Sulfate, alkylglyc betaine, oleyl betaine, lauryl dimethyl carboxymethyl eryl ether sulfonate, triethylamine lauryl sulfate, triethy betaine, lauryl dimethyl alphacarboxyethyl betaine, cetyl lamine laureth sulfate, triethanolamine lauryl sulfate, trietha dimethyl carboxymethyl betaine, lauryl bis-(2-hydroxyethyl) nolamine laureth Sulfate, monoethanolamine lauryl Sulfate, carboxymethyl betaine, Stearyl bis-(2-hydroxypropyl)car monoethanolamine laureth Sulfate, diethanolamine lauryl boxymethyl betaine, oleyl dimethyl gamma-carboxypropyl Sulfate, diethanolamine laureth Sulfate, lauric monoglyceride betaine, lauryl bis-(2-hydroxypropyl)alpha-carboxyethyl Sodium Sulfate, potassium lauryl Sulfate, potassium laureth betaine, oleamidopropyl betaine, coco dimethyl sulfopropyl Sulfate, Sodium lauryl sarcosinate, sodium lauroyl sarcosi betaine, stearyl dimethylsulfopropyl betaine, lauryl dimethyl nate, lauryl sarcosine, cocoyl sarcosine, ammonium cocoyl sulfoethyl betaine, lauryl bis-(2-hydroxyethyl)sulfopropyl Sulfate, ammonium lauroyl sulfate, sodium cocoyl Sulfate, betaine, and combinations thereof. Sodium lauroyl Sulfate, potassium cocoyl Sulfate, potassium 0073. Examples of cationic surfactants include, but are not lauryl sulfate, triethanolamine laurylsulfate, triethanolamine limited to, behenyl trimethyl ammonium chloride, bis(acy lauryl Sulfate, monoethanolamine cocoyl sulfate, monoetha loxyethyl)hydroxyethyl methyl ammonium methosulfate, nolamine lauryl Sulfate, sodium tridecyl benzene Sulfonate, cetrimonium bromide, cetrimonium chloride, cetyl trimethyl Sodium dodecyl benzene Sulfonate, sodium and ammonium ammonium chloride, cocamido propylamine oxide, distearyl salts of coconut alkyl triethylene glycol ether sulfate; tallow dimethyl ammonium chloride, ditallowdimonium chloride, alkyl triethylene glycol ether sulfate, tallow alkyl hexaoxy guar hydroxypropyltrimonium chloride, lauralkonium chlo ethylene Sulfate, disodium N-octadecylsulfo Succinnate, diso ride, lauryl dimethylamine oxide, lauryl dimethylbenzyl dium lauryl SulfoSuccinate, diammonium lauryl Sulfo Succi ammonium chloride, lauryl polyoxyethylene dimethylamine nate, tetrasodium N-(1,2-dicarhoxyethyl)-N-octadecylsulf oxide, lauryl trimethyl ammonium chloride, lautrimonium oSuccinnate, diamyl ester of Sodium sulfoSuccinic acid, chloride, methyl-1-oleyl amide ethyl-2-oleyl imidazolinium dihexyl ester of sodium sulfosuccinic acid, dioctyl esters of methyl Sulfate, picolin benzyl ammonium chloride, Sodium sulfoSuccinic acid, docusate sodium, and combina polyduaternium, Stearalkonium chloride, Sterayl dimethyl tions thereof. benzyl ammonium chloride, Stearyl trimethyl ammonium 0071 Examples of nonionic surfactants include, but are chloride, trimethylglycine, and combinations thereof. Those not limited to, polyoxyethylene fatty acid esters, Sorbitan skilled in the art would be able to test other surfactants, esters, cetyl octanoate, cocamide DEA, cocamide MEA, beginning with those having similar HLB, in order to arrive to US 2009/0093547 A1 Apr. 9, 2009

stable formulations. Mixtures of surfactants can be used to N',N'-tetrakis(methylenephosphonic acid), O,O'-bis(2- optimize the properties of the formulation. aminoethyl)ethyleneglycol-N.N.N',N'-tetraacetic acid, N.N- 0074 v. Solubility Enhancers bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid, 0075 Suitable solubility enhancing agents include sol 1,6-hexamethylenediamine-N,N,N',N'-tetraacetic acid, vents such as water, diols, such as propylene glycol and N-(2-hydroxyethyl)iminodiacetic acid, iminodiacetic acid, glycerol; mono-alcohols, such as ethanol, propanol, and 1,2-diaminopropane-N,N,N',N'-tetraacetic acid, nitrilotri higher alcohols; DMSO; dimethylformamide: N,N-dimethy acetic acid, nitrilotripropionic acid, nitrilotris(methylene lacetamide: 2-pyrrolidone; N-(2-hydroxyethyl)pyrrolidone, phosphoric acid), 7, 19.30-trioxa-1,4,10,13,16.22,27.33-oc N-methylpyrrolidone, 1-dodecylazacycloheptan-2-one and taaZabicyclo 11, 11.11 pentatriacontane hexahydrobromide, other n-substituted-alkyl-azacycloalkyl-2-ones and other triethylenetetramine-N,N,N',N',N',N'-hexaacetic acid, and n-substituted-alkyl-azacycloalkyl-2-ones (aZones). combinations thereof. 0076 vi. Penetration Enhancers 0084. X. Humectants 0077 Penetration enhancers are frequently used to pro 0085 Suitable humectants include, but are not limited to, mote transdermal delivery of drugs across the skin, in par glycerin, butylene glycol, propylene glycol, Sorbitol, triace ticular across the stratum corneum. Some penetration tin, and combinations thereof. enhancers cause dermal irritation, dermal toxicity and dermal I0086 xi. pH Modifying Agents allergies. Suitable penetration enhancers include, but are not I0087. The compositions described herein may further con limited to, urea, (carbonyldiamide), imidurea, A. N-diethyl tain a pH modifying agent including, but are not limited to, formamide, N-methyl-2-pyrrolidine, 1-dodecal-azacyclo Sodium hydroxide, citric acid, hydrochloric acid, acetic acid, pheptane-2-one, calcium thioglycate, 2-pyyrolidine, N,N-di phosphoric acid, Succinic acid, Sodium hydroxide, potassium ethyl-m-toluamide, oleic acid and its esterderivatives, such as hydroxide, ammonium hydroxide, magnesium oxide, cal methyl, ethyl, propyl, isopropyl, butyl, vinyl and glycerylmo cium carbonate, magnesium carbonate, magnesium alumi nooleate, Sorbitan esters, such as Sorbitan monolaurate and num silicates, malic acid, potassium citrate, Sodium citrate, Sorbitan monooleate, other fatty acid esters such as isopropyl Sodium phosphate, lactic acid, gluconic acid, tartaric acid, laurate, isopropyl myristate, isopropyl palmitate, diisopropyl 1,2,3,4-butane tetracarboxylic acid, fumaric acid, diethano adipate, propylene glycol monolaurate, propylene glycol lamine, monoethanolamine, sodium carbonate, Sodium bicar monooleate and non-ionic detergents such as BRIJ(R) 76 bonate, triethanolamine, and combinations thereof. (stearyl poly(10 oxyethylene ether), BRIJR 78 (stearyl poly 0088 xii. Preservatives. (20)oxyethylene ether), BRIJR 96 (oleyl poly(10)oxyethyl I0089. Preservatives can be used to prevent the growth of ene ether), and BRIJR 721 (stearyl poly (21) oxyethylene fungi and other microorganisms. Suitable preservatives ether) (ICI Americas Inc. Corp.). Fatty acids such as linoleic include, but are not limited to, benzoic acid, butylparaben, acid, capric acid, lauric acid, and neodecanoic acid, which ethyl paraben, methyl paraben, propylparaben, Sodium ben can be in a solvent Such as ethanol or propylene glycol, can be Zoate, sodium propionate, benzalkonium chloride, benzetho used as lipid bilayer disrupting agents. nium chloride, benzyl alcohol, cetypyridinium chloride, 0078 vii. Suspending Agents chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and 0079 Suitable suspending agents include, but are not lim combinations thereof. ited to, alginic acid, bentonite, carbomer, carboxymethylcel (0090 D. Dosage Forms lulose and salts thereof, hydroxyethylcellulose, hydroxypro 0091. The local anesthetic can be formulated as an emul pylcellulose, microcrystalline cellulose, colloidal silicon Sion, lotion, paste, gel, cream, ointment, shea butter, balm, dioxide, dextrin, gelatin, guar gum, Xanthan gum, kaolin, salve or foam using techniques well known in the art. Ansel et magnesium aluminum silicate, maltitol, triglycerides, meth al, Pharmaceutical Dosage Forms and Drug Delivery Sys ylcellulose, polyoxyethylene fatty acid esters, polyvinylpyr tems, 6" Ed. Williams and Williams (1995) describes the rolidone, propylene glycolalginate, sodium alginate, Sorbitan preparation of a variety of dosage forms for topical and trans fatty acid esters, tragacanth, and combinations thereof. dermal administration of one or more active agents. 0080 viii. Antioxidants 0092] 1. Solutions, Dispersions, Suspensions, Emulsions, 0081 Suitable antioxidants include, but are not limited to, Butters butylated hydroxytoluene, alpha tocopherol, ascorbic acid, 0093 Methods for making topical carriers are well known, fumaric acid, malic acid, butylated hydroxyanisole, propyl Many different carriers can be utilized. Suitable excipient gallate, Sodium ascorbate, sodium metabisulfite, ascorbyl bases can be purchased from formulators, to which an effec palmitate, ascorbyl acetate, ascorbyl phosphate, Vitamin A, tive amount of active agent is added. These may be excipients folic acid, flavons or flavonoids, histidine, glycine, tyrosine, for forming a solution, dispersion or Suspension of drug or tryptophan, carotenoids, carotenes, alpha-Carotene, beta drug particles, emulsifiers and Surfactants for making an Carotene, uric acid, pharmaceutically acceptable salts emulsion, or lipids and Surfactants for making shea butters thereof, derivatives thereof, and combinations thereof. and other similar products. 0082 ix. Chelating Agents 0094 2. Gels, Pastes 0083) Suitable chelating agents include, but are not limited 0.095 An emulsifier is desirable to help promote efficient to, EDTA, disodium edetate, trans-1,2-diaminocyclohexane release of the active agents from the formulation. A wide N.N>N',N'-tetraacetic acid monohydrate, N,N-bis(2-hy variety of surfactants are potentially useful. Useful nonionic droxyethyl)glycine, 1,3-diamino-2-hydroxypropane-N,N. surfactants include Oleth-10 (polyoxyethylene (10) oleyl N',N'-tetraacetic acid, 1,3-diaminopropane-N,N,N',N'- ether) in a range from about 1% to about 15%. Those skilled tetraacetic acid, ethylenediamine-N,N'-diacetic acid, in the art would be able to test other surfactants, beginning ethylenediainine-N,N'-dipropionic acid, ethylenediamine-N, with those having similar HLB, in order to arrive to stable N'-bis(methylenephosphonic acid), N-(2-hydroxyethyl)eth formulations. Mixtures of surfactants can be used to optimize ylenediamine-N,N',N'-triacetic acid, ethylenediamine-N,N. the properties of the formulation. US 2009/0093547 A1 Apr. 9, 2009

0096. Any pharmaceutically or cosmetically acceptable Surrounding tissue or the partner. In one embodiment, the thickener, for example, those Suitable for thickening hydro amount ofprilocalne in the formulation can range from about carbon, silicone or vegetable oils may be used in the formu 2 percent to about 8 percent by weight. In another embodi lations. The thickeners modify the rheology of the formula ment, the amount ofprilocalne may range from about 3 per tions in order to establish the properbalance between activity cent to about 6% by weight, or from about 4 percent to about and, application and post application physical behavior. 5% by weight. The amount of lidocaine may range from about Examples of thickeners include colloidal silicas and starches. 6 percent to about 24 percent by weight, or from about 8 An example of a preferred thickener is colloidal silica. The percent to about 18 percent, or from about 10 percent to about thickener is used in a concentration range of between 1.0% to 14 percent, by weight. about 5.0%, more preferably in a range of between 1.0% and (0103. In one embodiment, the formulation includes about 2.5%. Those skilled in the art would be able to test other 7.5 mg of prilocalne and about 22.5 mg of lidocaine applied thickeners in order to prepare stable formulations. Mixtures prior to intercourse. This dose may be divided for easier and of thickeners can be used to optimize the properties of the more effective application. For example, a pump spray appli formulation. The gel or pastes may further contain a penetra cator may be tuned or metered to administer about 2.5 milli tion enhancer. grams of prilocalne and about 7.5 mg of lidocaine perspray. 0097. 4. Pump spray This would allow the user to cover the entire glans in three 0098. The formulation can also be in the form of a propel SprayS. lant-free aerosol preparation Such as a pump spray. In one embodiment, the formulation contains active agents dis III. Methods of Administration solved in 0.9% saline solution, or alternatively, a physiologic 0104. The formulations are administered locally, prefer saline solution. See Hoar and Hickman, A Companion for ably onto the glans penis. The local formulation may be left General and Comparative Physiology, 1975. In another on the glans penis or may be removed after an anesthetic embodiment, the formulation contains active agents dis effect is achieved. The formulation may be administered prior solved in water. to or at the time of intercourse, but preferably prior to and any 0099. In another embodiment, the formulation contains a remainder removed or covered by a prophylactic. liquid phase composed of aliphatic C-C alcohols and a 0105. The combination anesthetic formulation may be vehicle. In a preferred embodiment, the C-C alcohol is ethyl administered at a total dose of between about 20 mg to about alcohol and the carrier is a neutral oil. In one embodiment, the 40 mg, preferably between about 25 mg to about 35 mg, more liquid phase includes 10 to 40% by weight of ethyl alcohol preferably from about 25 to about 30 mg. of anesthetic. This and 90 to 60% by weight of an oil. A pump spray of this dose is effective to induce desensitization of the dorsal nerves composition produces a uniform mistanda Sufficient quantity of the penis. Several actuations of a pump spray device con of the preparation or active substance is still available after a taining active agents, including local anesthetics, dissolved in relatively long storage time. Even if, after 7 days storage, a saline, water, or an alcohol is a suitable method of delivery. quantity loss of maximum 10%, based on the active Substance 0106 Unless defined otherwise, all technical and scien Solution present in the metering chamber, is recorded in the tific terms used herein have the same meanings as commonly first squirt, the loss of active Substance is Smaller because the understood by one of skill in the art to which the disclosed latter remains dissolved in the less readily evaporable neutral invention belongs. Publications cited herein and the materials oil. for which they are cited are specifically incorporated by ref 0100. The active agent or agents may be provided in an CCC. approximately 5% oily solution and then mixed with the other 0107 Those skilled in the art will recognize, or be able to requisite quantities of neutral oil and optionally with other ascertain using no more than routine experimentation, many additives and transferred to the pump spray bottles with the equivalents to the specific embodiments of the invention addition of ethyl alcohol. described herein. Such equivalents are intended to be encom 0101. In one embodiment, the fatty oils are neutral oils passed by the following claims. Such as synthetic triglycerides whose fatty acid proportion is composed of saturated Cs to C fatty acids. These triglycer We claim: ides are also known as Miglyol types. Various types of Mig 1. A formulation for treating premature ejaculation com lyol are distinguished according to the caprylic acid (Cs:0) prising a pharmaceutically acceptable carrier for topical and capric acid (Co.: 0) content. In another embodiment, natu administration to the glans comprising at least one local anes ral oils are used. Preferred natural oils include those oils that thetic in an amount effective to achieve desensitization of the contain as few unsaturated fatty acids as possible. This can be dorsal nerves of the penis. achieved by hydrogenation in the case of oils which contain a 2. The formulation of claim 1 in a dosage form selected large quantity of unsaturated fatty acids. The proportion of the from the group consisting of an emulsion, lotion, paste, gel. neutral oil in the pump spray can be 90 to 60% by weight, but cream, ointment, shea butter, Suspension, Solution, balm, is usually 85 to 70% by weight. Neutral oil quantities of about salve, foam, or pump spray. 80% by weight are preferred. In another embodiment, the 3. The formulation of claim 1 wherein the at least one local formulation contains a mixture of lidocaine and prilocalne anesthetic is selected from the group consisting of lidocaine, dissolved in an aqueous saline solution. The pump spray can prilocalne, bupivacaine, chlorprocaine, dibucaine, eti contain other additives. docaine, mepivacaine, tetracaine, dyclonine, hexylcaine, 0102 The proportion of active agent in the formulation procaine, ketamine, pramoxine and phenol, a derivative or can vary but is usually between 0.1 and 32% by weight. For prodrug thereof, and combinations thereof. example, approximately a 1:3 ratio of prilocalne to lidocaine 4. The formulation of claim 1 wherein the at least one local is Suitable for maintaining both anesthetics in liquid form and anesthetic is a combination of prilocalne and lidocaine, or providing the desired desensitization without affecting the derivatives or prodrugs thereof. US 2009/0093547 A1 Apr. 9, 2009

5. The formulation of claim 4 wherein the pharmaceuti 14. The method of claim 13 wherein the formulation is cally acceptable carrier comprises Saline solution or water. applied in an amount of about 30 mg. 6. The formulation of claim 4 wherein the pharmaceuti 15. The method of claim 14 wherein the at least one anes cally acceptable carrier comprises an alcohol Solution. thetic comprises prilocalne and lidocaine in about a 1:3 ratio. 7. The formulation of claim 4 wherein the are present in 16. The method of claim 12 wherein the pharmaceutically about a 1:3 ratio of prilocalne to lidocaine. acceptable carrier comprises saline Solution or water. 8. The formulation of claim 1 in the form of a pump spray 17. The method of claim 12 wherein the pharmaceutically comprising from about 8 percent to about 32 percent by acceptable carrier comprises an alcohol solution. weight of the at least one anesthetic active agent, a liquid 18. The method of claim 12 wherein the step of adminis phase comprising from about 10 to about 40 percent by tering the formulation comprises spraying the formulation weight of ethyl alcohol and from about 60 to about 90 percent using a pump spray applicator. by weight of synthetic or natural fatty oils. 19. A method for treating premature ejaculation compris 9. The formulation of claim 1 further comprising a vasodi 1ng: lator agent. topically administering to the glans penis of a male human 10. The formulation of claim 9 wherein the vasodilator in need thereof a formulation comprising from about 2 agent comprises papaverine, phentolamine, prostaglandin mg to about 8 mg of prilocalne and from about 6 mg to E-1, dioxyline, ethaverine, or combinations thereof. about 24 mg of lidocaine, 11. The formulation of claim 9 wherein the vasodilator wherein the prilocalne and lidocaine are dissolved or Sus agent is present in an amount of from about 1 percent to about pended in a solvent selected from the group consisting of 10 percent by weight of the composition. Saline Solution, water, alcohol, or combinations thereof 12. A method for treating premature ejaculation compris and 1ng: wherein the step of topically administering the formulation administering to a male human in need thereof a formula comprises spraying the formulation using a metered tion comprising an effective amount of at least one local pump spray applicator. anesthetic, derivative or prodrug thereof in a pharmaceu 20. The method of claim 19 wherein the formulation fur tically acceptable carrier for topical application as ther comprises a vasodilator agent selected from the group defined by any of claims 1-11 to the glans penis to consisting of papaverine, phentolamine, prostaglandin E-1, achieve desensitization of the dorsal nerves of the penis. dioxyline, ethaverine, or combinations thereof. 13. The method of claim 12 wherein the at least one anes thetic is applied in amount ranging from 20 mg to 40 mg. c c c c c