US 2003O134861A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0134861A1 Doherty, JR. et al. (43) Pub. Date: Jul. 17, 2003

(54) TRANSMUCOSAL PHOSPHODIESTERASE Publication Classification INHIBITORS FOR THE TREATMENT OF ERECTILE DYSFUNCTION (51) Int. Cl." ...... A61K 31156; A61K 31/5377; A61K 31/497; A61K 31/522; (76) Inventors: Paul C. Doherty JR., Cupertino, CA A61K 31/517; A61K 31/519 (US); Virgil A. Place, Kawaihae, HI (52) U.S. Cl...... 514/252.16; 514/249; 514/263.3; (US); William L. Smith, Mahwah, NJ 514/266.1; 514/267; 514/266.22; (US) 514/269; 514/345; 514/262.1; Correspondence Address: 514/234.5; 514/263.38; 514/308; REED & EBERLE LLP 514/252.17 800 MENLO AVENUE, SUITE 210 MENLO PARK, CA 94025 (US) (21) Appl. No.: 10/351,198 (57) ABSTRACT (22) Filed: Jan. 24, 2003 A pharmaceutical formulation is provided for treating erec Related U.S. Application Data tile dysfunction in a mammalian male individual. The phar maceutical formulation includes a phosphodiesterase inhibi (60) Division of application No. 09/467,094, filed on Dec. tor or a pharmaceutically acceptable Salt, ester, amide or 10, 1999, now Pat. No. 6,548,490, which is a con derivative thereof, that is administered transmucosally tinuation-in-part of application No. 09/181,070, filed within the context of an effective dosing regimen. Preferred on Oct. 27, 1998, now Pat. No. 6,037,346, which is a modes of administration include transbuccal, Sublingual and continuation-in-part of application No. 08/958,816, transrectal routes. A kit for the administration of the phar filed on Oct. 28, 1997, now abandoned. maceutical formulation is also provided. US 2003/0134861 A1 Jul. 17, 2003

TRANSMUCOSAL PHOSPHODESTERASE central neuroendocrine control or local neurovascular con INHIBITORS FOR THE TREATMENT OF trol of penile Smooth muscle. Krane et al., New England ERECTILE DYSFUNCTION Journal of Medicine 321:1648 (1989). Penile erection requires (I) dilation of the arteries that regulate blood flow CROSS-REFERENCE TO RELATED to the lacunae of the corpora cavernosum, (2) relaxation of APPLICATIONS trabecular Smooth muscle, which facilitates engorgement of 0001. This application is a divisional application of U.S. the penis with blood, and (3) compression of the venules by Ser. No. 09/467,094, filed Dec. 10, 1999, which is a con the expanding trabecular walls to decrease venous outflow. tinuation-in-part of U.S. Ser. No. 09/181,070, filed Oct. 27, 0006 Trabecular smooth muscle tone is controlled 1998, which is a continuation-in-part of U.S. Ser. No. locally by adrenergic (constrictor), cholinergic (dilator) and 08/958,816, filed Oct. 28, 1997, the disclosures of which are nonadrenergic, noncholinergic (dilator) innervation, and by hereby incorporated by reference. endothelium-derived vasoactive Substances Such as vasoac tive intestinal polypeptide (VIP), prostanoids, endothelin TECHNICAL FIELD and nitric oxide. High Sympathetic tone (noradrenergic) is 0002 This invention relates generally to methods and implicated in erectile dysfunction, and, in Some patients, the pharmaceutical compositions for treating erectile dysfunc disorder can be Successfully treated with noradrenergic tion; more particularly, the invention relates to transmucosal receptor antagonists. See, e.g., Krane et al., Supra. (e.g., buccal, Sublingual and transrectal), phosphodiesterase inhibitors that are used to treat erectile dysfunction. 0007. There is also evidence that dopaminergic mecha nisms are involved in erectile function. For example, phar BACKGROUND macologic agents that elevate the level of brain dopamine or 0.003 Impotence is the consistent inability to achieve or Stimulate brain dopamine receptors increase Sexual activity Sustain an erection of Sufficient rigidity for Sexual inter in animals (see, e.g., Gessa & Tagliamonte, Life Sciences course. It has recently been estimated that approximately 10 14:425 (1974); Da Prada et al., Brain Research 57:383 million American men are impotent (R. Shabsigh et al., (1973)). “Evaluation of Erectile Impotence,” Urology 32:83-90 0008 Administration of L-DOPA, a dopamine precursor, (1988); W. L. Furlow, “Prevalence of Impotence in the enhances sexual activity in male rats. L-DOPA has been used United States,”Med. Aspects Hum. Sex. 19:13-6 (1985)). in the treatment of Parkinsonism and is known to act as an Impotence is recognized to be an age-dependent disorder, aphrodisiac in Some patients (Gessa & Tagliamonte, Supra; with an incidence of 1.9 percent at 40 years of age and 25 Hyppa et al., Acta Neurologic Scand. 46:223 (Supp. 43, percent at 65 years of age (A. C. Kinsey et al., “Age and 1970)). Specific dopamine agonists have been studied for Sexual Outlet,” in Sexual Behavior in the Human Male; A. their effects on erectile function. Apomorphine, (n-propyl C. Kinsey et al., eds., Philadelphia, Pa.; W. B. Saunders, )norapo-morphine, bromocryptine, amantidine, fenflu 218-262 (1948)). In 1985 in the United States, impotence ramine, L-DOPA and various other pharmacological activa accounted for more than Several hundred thousand outpa tors of central dopaminergic receptors have been found to tient visits to physicians (National Center for Health Statis increase episodes of penile erection in male rats (Benassi tics, National Hospital Discharge Survey, 1985, Bethesda, Benelli et al., Arch. int. Pharmacodyn. 242:241 (1979); Md., Department of Health and Human Services, 1989 Poggioli et al., Riv. di Farm. & Terap. 9:213 (1978); Falaschi DHHS publication no. 87-1751). Depending on the nature et al., Apomorphine and Other Dopaminomimetics, 1: 117 and cause of the problem, treatments include psychoSexual 121 (Gessa & Corsini, Eds., Raven Press, N.Y.)). In addition, therapy, hormonal therapy, administration of vasodilators U.S. Pat. No. 4,521,421 to Foreman relates to the oral or Such as nitroglycerin and -adrenergic blocking agents intravenous administration of quinoline compounds to treat ("-blockers”), oral administration of other pharmaceutical Sexual dysfunction in mammals. agents, vascular Surgery, implanted penile prostheses, Vacuum constriction devices and external aids Such as penile 0009. The currently available dopamine agonists, with Splints to Support the penis or penile constricting rings to few exceptions, have found limited use in the treatment of alter the flow of blood through the penis. erectile dysfunction because of their peripheral Side effects. These effects include nausea and vomiting, postural 0004. A number of causes of impotence have been iden hypotension, arrhythmias, tachycardia, dysphoria, psycho tified, including Vasculogenic, neurogenic, endocrinologic sis, hallucinations, drowsiness and dyskinesias (See, e.g., and psychogenic. Vasculogenic impotence, which is caused Martindale The Extra Pharmacopoeia, 31 st Ed., pages by alterations in the flow of blood to and from the penis, is thought to be the most frequent organic cause of impotence. 1151-1168). Common risk factors for vasculogenic impotence include 0010. The invention described herein provides a means to hypertension, diabetes, cigarette Smoking, pelvic trauma, avoid the above-mentioned problems encountered with pre and the like. Neurogenic impotence is associated with Spi viously known methods for treating erectile dysfunction. nal-cord injury, multiple Sclerosis, peripheral neuropathy Specifically, the invention relates to methods and formula caused by diabetes or alcoholism and Severance of the tions for effectively treating erectile dysfunction by trans autonomic nerve Supply to the penis consequent to prostate mucosally, e.g., buccally, Sublingually or transrectally, Surgery. Erectile dysfunction is also associated with distur administering a Selected active agent, wherein the active bances in endocrine function resulting in low circulating agent is an inhibitor of a phosphodiesterase. testosterone levels and elevated prolactin levels. 0011 Phosphodiesterases are a class of intracellular 0005 Impotence can also be a side effect of various enzymes involved in the metabolism of the Second messen classes of drugs, in particular, those that interfere with ger nucleotides, cyclic adenosine monophosphate (cAMP), US 2003/0134861 A1 Jul. 17, 2003 and cyclic guanosine monophosphate (cGMP) (see, e.g., 0020. It is yet another object of the invention to provide Doherty, “Oral, Transdermal, and Transurethral Therapies a kit capable of use by an individual for Self-administration for Erectile Dysfunction” in Male Infertility and Dysfunc of a phosphodiesterase inhibitor as provided herein. tion, Hellstrom, ed., Chapter 34 (New York, N.Y.: Springer VerlagHellstrom, 1997)). Numerous phosphodiesterase 0021 Additional objects, advantages and novel features inhibitors have previously been described in the literature of the invention will be set forth in part in the description for a variety of therapeutic uses, including treatment of that follows, and in part will become apparent to those obstructive lung disease, allergies, hypertension, angina, skilled in the art upon examination of the following, or may congestive heart failure and depression (See, e.g., Goodman be learned by practice of the invention. and Gilman's The Pharmacological Basis of Therapeutics 0022. In one aspect of the invention, a method is provided Ninth Edition, Chapter 34). Oral and parenteral administra for treating an individual prone to erectile dysfunction, e.g., tion of phosphodiesterase inhibitors, as alluded to above, vasculogenic erectile dysfunction, the method comprising have also been Suggested for the treatment of erectile transmucosally administering to the individual a pharma dysfunction (Doherty, supra; see also PCT Publication Nos. ceutical formulation containing a phosphodiesterase inhibi WO 96/16644, and WO 94/28902). The phosphodiesterases tor. Administration of the pharmaceutical formulation is have been classified into seven major families, Types I-VII, carried out within the context of a predetermined dosing based on amino acid or DNA sequences. The members of the regimen Such that the agent is effective in the treatment of family vary in their tissue, cellular and Subcellular distribu erectile dysfunction. The method is especially useful in the tion, as well as their links to cAMP and coMP pathways. For treatment of vasculogenic impotence, although other types example, the corpora cavernoSa contains: Type III phos of erectile dysfunction may also be treated using the present phodiesterases, which are cAMP-specific coMP inhibitable; formulations, e.g., neurogenic, endocrinologic and psy Type IV phosphodiesterases, the high affinity, high-speci chogenic impotence. Drug delivery is preferably effected ficity cAMP-specific form; and Type V phosphodiesterases, through the buccal mucosa, Sublingual mucosa or transrectal one of the coMP-specific forms. mucosa but the drug may also be administered through other 0012. The invention, as noted above, is directed to trans mucosal Surfaces of the body. For buccal administration, the mucosal administration of pharmacologically active agents active agent is typically although not necessarily adminis to treat erectile dysfunction. The agents are preferably, tered by affixing a buccal dosage unit to the buccal mucosa although not necessarily, Type III, Type IV or Type V of the individual undergoing treatment, and allowing the phosphodiesterase inhibitors. Surprisingly, it has now been dosage unit to remain in place until drug delivery is com found by the inventors herein that transmucosal and par plete. Alternatively, buccal administration may be effected ticularly buccal, Sublingual or transrectal administration of by the application to the buccal mucosa of a cream, ointment these phosphodiesterase inhibitors as disclosed herein is or paste containing the active agent. For Sublingual admin highly effective in treating erectile dysfunction, including istration, the active agent is typically although not neces vasculogenic impotence. Transmucosal and particularly Sarily administered by placing a Sublingual tablet under the tongue of the individual undergoing treatment, and allowing buccal, Sublingual or transrectal administration of phoS the tablet to remain in place until tablet disintegration and phodiesterase inhibitors to treat erectile dysfunction accord thus drug delivery is complete. For transrectal administra ingly represents an important advance in the treatment of tion, the active agent is typically although not necessarily impotence and other erectile disorders. administered by placing a Suppository within the rectum and SUMMARY OF THE INVENTION allowing the dosage unit to remain in place until melting of 0013. It is a primary object of the invention to provide the carrier and thus drug delivery is complete. Alternatively, pharmaceutical formulations for treating erectile dysfunc transrectal administration may be effected using a cream, tion that have a therapeutically effective amount of a ointment or Solution (e.g., enema) containing the active Selected phosphodiesterase inhibitor and that are adminis agent. tered transmucosally. 0023. In another aspect of the invention, a pharmaceuti 0.014. It is another object of the invention to provide the cal formulation is provided for carrying out the present pharmaceutical formulation for transbuccal administration. method for treating erectile dysfunction. The pharmaceutical 0.015. It is a further object of the invention to provide the formulation comprises an effective amount of a phosphodi pharmaceutical formulation for application to the Sublingual esterase inhibitor, a carrier or vehicle Suited to transmucosal administration and, optionally, a permeation enhancer. The COS. formulation may contain one or more additional active 0016. It is still another object of the invention to provide agents, e.g., dopaminergic drugs, Smooth muscle relaxants, the pharmaceutical formulation for application to the rectal vasoactive drugs, and additives, e.g., excipients, Surfactants, COS. preservatives (e.g., antioxidants), Stabilizers, chelating 0.017. It is another object of the invention to provide the agents, enzyme inhibitors, antibacterial agents, binders, pharmaceutical formulation with a Type III phosphodi diluents, lubricants, and the like, as will be appreciated by esterase inhibitor. those skilled in the art of drug formulation preparation and delivery. Buccal formulations will generally although not 0.018. It is a further object of the invention to provide the necessarily comprise a Solid dosage unit containing the pharmaceutical formulation with a Type IV phosphodi active agent, a hydrolyzable (or “bioerodible”) polymeric esterase inhibitor. carrier, and a means for affixing the dosage unit to the buccal 0019. It is yet another object of the invention to provide mucosa. The latter may represent a separate adhesive com the pharmaceutical formulation with a Type V phosphodi ponent in the formulation, or the polymeric carrier itself may esterase inhibitor. Serve as an adhesive. Sublingual formulations comprise a US 2003/0134861 A1 Jul. 17, 2003 dosage form for application to the Sublingual mucosa and a their underlying cause, and improvement or remediaton of carrier Suitable for Sublingual drug delivery. Thus, Sublin damage. The present method of “treating erectile dysfunc gual formulations will generally although not necessarily tion, as the term is used herein, thus encompasses both comprise a Solid dosage unit containing the active agent and prevention of the disorder in a predisposed individual and one or more vehicles and a lubricant. Transrectal formula treatment of the disorder in a clinically Symptomatic indi tions comprise a dosage form for application to the rectal vidual. mucosa and a carrier Suitable for transrectal drug delivery. 0031. The term “phosphodiesterase inhibitor” as used Thus, transrectal formulations in the form of a Suppository herein is intended to mean an agent that is capable of will generally although not necessarily comprise a Solid inhibiting or Selectively reducing the activity of any one or dosage unit containing the active agent and one or more more phosphodiesterases. Suppository bases. 0032. The terms “active agent,”“drug” and “pharmaco 0024. In another aspect, a kit is provided to assist an logically active agent” are used interchangeably herein to individual in drug administration to carry out the method of refer to a chemical material or compound that induces a the invention. Generally, the kit will include the following desired effect. In the preferred embodiment herein, the terms components: a pharmaceutical formulation comprising the refer to a phosphodiesterase inhibitor which is capable of phosphodiesterase inhibitor to be administered; a container being delivered transmucosally. Included are derivatives and housing the pharmaceutical formulation during Storage and analogs of those compounds or classes of compounds Spe prior to use; and instructions for carrying out drug admin cifically mentioned which also induce the desired effect. istration in a manner effective to treat erectile dysfunction. When the kit is for assisting an individual in buccal drug 0033 “Penetration enhancement” or “permeation administration, Specifically, the kit will include at least the enhancement' as used herein relates to an increase in the following: a buccal dosage unit comprising the active agent permeability of the mucosal tissue to the Selected pharma and a bioerodible polymeric carrier; a container housing the cologically active agent, i.e., So that the rate at which the dosage unit prior to use; and written instructions for carrying drug permeates therethrough is increased. out administration of the active agent for the intended 0034). “Carriers” or “vehicles” as used herein refer to therapeutic purpose. carrier materials Suitable for transmucosal drug administra tion. Carriers and vehicles useful herein include any Such DETAILED DESCRIPTION OF THE materials known in the art which is nontoxic and does not INVENTION interact with other components of the composition in a deleterious manner. 0025 Definitions: 0035. By “transmucosal” drug delivery is meant admin 0026. Before describing the present invention in detail, it istration of a drug to the mucosal Surface of an individual So is to be understood that this invention is not limited to that the drug passes through the mucosal tissue and into the particular drugs or drug delivery Systems, as Such may vary. individual’s blood stream. A preferred form of transmucosal It is also to be understood that the terminology used herein drug delivery herein is “buccal' or “transbuccal” drug is for the purpose of describing particular embodiments only, delivery which refer to delivery of a drug by passage of a and is not intended to be limiting. drug through an individual’s buccal mucosa and into the 0027. It must be noted that, as used in this specification bloodstream. Another preferred from of transmucosal drug and the appended claims, the Singular forms “a,”“an and delivery herein is “sublingual” or “transublingual” drug “the' include plural referents unless the context clearly delivery which refer to delivery of a drug by passage of a dictates otherwise. Thus, for example, reference to “a phos drug through an individual’s Sublingual mucosa and into the phodiesterase inhibitor” includes a mixture of two or more bloodstream. An additional preferred form of transmucosal Such compounds, reference to “a permeation enhancer' drug delivery herein is “rectal' or “transrectal’ drug delivery includes mixtures of two or more enhancers, and the like. which refer to delivery of a drug by passage of a drug through an individual’s rectal mucosa and into the blood 0028. In describing and claiming the present invention, Stream. the following terminology will be used in accordance with the definitions set out below. 0036 By an “effective” amount of a drug or pharmaco 0029. The term "erectile dysfunction” is intended to logically active agent is meant a nontoxic but Sufficient include any and all types of erectile dysfunction, including: amount of the drug or agent to provide the desired effect, i.e., Vasculogenic, neurogenic, endocrinologic and psychogenic treatment of erectile dysfunction. impotence (“impotence” is used here in its broadest sense to 0037 Active Agents for Treatment of Erectile Dysfunc indicate a periodic or consistent inability to achieve or tion: Sustain an erection of Sufficient rigidity for Sexual inter course; see U.S. Pat. No. 5,242,391 to Place et al., cited 0038. In order to carry out the method of the invention, Supra); Peyronie's Syndrome; priapism; premature ejacula a Selected phosphodiesterase inhibitor is administered trans tion; and any other condition, disease or disorder, regardless mucosally to an individual prone to erectile dysfunction. of cause or origin, which interferes with at least one of the 0039 The active agent herein may be any agent which is three phases of human Sexual response, i.e., desire, excite effective to inhibit the activity of a phosphodiesterase. ment and orgasm (see Kaplan, Disorders of Sexual Desire Suitable phosphodiesterase inhibitors include, but are not (New York, N.Y. Brunner Mazel Book Inc., 1979)). limited to, inhibitors of the Type III phosphodiesterases (the 0030) The terms “treating” and “treatment” as used cAMP-specific-cGMP inhibitable form), the Type IV phos herein refer to reduction in Severity and/or frequency of phodiesterase (the high affinity-high specificity cAMP form) Symptoms, elimination of Symptoms and/or underlying and the Type V phosphodiesterases (the coMP specific cause, prevention of the occurrence of Symptoms and/or form). Additional inhibitors that may be used in conjunction US 2003/0134861 A1 Jul. 17, 2003 with the present invention are coMP-specific phosphodi methyl-2-butenyl)pyrido2.3apyrazin-5-one); esterase inhibitors other than Type V inhibitors. quinazolinediones Such as nitraduaZone (3-3'-nitrophenyl 0040 Examples of Type III phosphodiesterase inhibitors N-ethylguinazoline-2,6-dione), CP-77059 (1-(carbomethox that may be administered herein include, but are not limited yphenyl)-3-benzylpyrido 2,3dpyrimidine-2,4(1H,3H)di to, bipyridines Such as milrinone and amrinone; imidazolo one), RS-25344 (1-(3-nitrophenyl)-3-(4-pyridylmethyl)-1,2, neS Such as piroXimone and enoXimone, imidazolines Such 3,4-tetrahydro pyrido(2,3-d) pyrimidine-2,4-dione)) and as imaZodan and 5-methyl-imaZodan; dihydropyridaZinones other nitraduaZone analogs, Xanthine derivatives Such as Such as indolidan and LY181512 denbufylline (1,3-di-n-butyl-7-2'-oxopropylxanthine), XT-44 (1-n-butyl-3-n-propylxanthine), arofylline (LAS 31025; 1-propyl-3-(4-chlorophenyl)-xanthine) and BRL O 61063 1n --- C NH O; vory OPC3911

0041 dihydroquinolinone compounds such as cilosta mide, cilostazol, Vesnarinone and OPC 3911 BRL 61063

0044) phenyl ethyl pyridines such as CDP 840 (4-(1-(3- cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl) pyridine) and compounds disclosed in WO 97/22585 to Guay et al.; tetrahydropyrimidones such as atizoram (CP80633)

LY 181512 s' 0.042 other compounds Such as anagrelide, bemoradan, ibudilast, isomazole, lixazinone, motapizone, olprinone, phthalazinol, pimobendan, quaZinone, SiguaZodan and tre 2-c. quinsin; and mixed Type III and Type IV inhibitors such as CH benafentrine, cis-6-p-acetamidophenyl-1,2,3,4,4a,10b CP80633 hexahydro-8,9-dimethoxy-2-methylbenzo-c1,6-naphthy ridine, EMD 54622 (5-1-(3,4-dimethoxybenzoyl)-4,4-dim ethyl-1,2,3,4-tetrahydrochinolin-6-yl-6-methyl-3,6- dihydro-1,3,4-thiadiazin-2-one), Org 20241 (N-hydroxy-4- 0045 diazepine derivatives such as C11018 3,4-dimethoxyphenyl-thiazole-2-carboxim idamide), Org30029 (N-hydroxy-5,6-dimethoxybenzo-b-thiophene 2-carboximidamide), Saterinone, tolafentrine and Zardaver ine. Preferred Type III PDE inhibitors herein are bipyridines, imidazolones, imidazolines, dihydropyridaZinones and dihydroquinolinone compounds. Of these, the inhibitors that are particularly preferred herein are milrinone, amrinone, piroXimone, enoXimone, imaZodan, 5-methyl-imaZOdan, indolidan, ciloStamide, ciloStaZol and Vesnarinone. The inhibitors may be used alone or in combination; if in combination, they may be administered either Simulta neously or Sequentially. O 0043. Examples of Type IV phosphodiesterase inhibitors C 101.8 that may be administered herein include, but are not limited to: pyrrolidinones Such as rolipram (4-(3-cyclopentyloxy 4'-methoxyphenyl)-2-pyrrolidinone)) and rolipram deriva 0046) and compounds disclosed in WO 97/36905 to tives such as R020-1724 (4-(3-butyloxy-4-methoxyphenyl)- Pascal et al.; oxime carbamates Such as filaminast (PDA imidazolidinone) and RS 33793 (8-(3-nitrophenyl)-6-(3- 641); naphthyridinones such as RS 17597 US 2003/0134861 A1 Jul. 17, 2003

(SB 207499, (c-4-cyano-4-3'-cyclopentyloxy-4-methox yphenyl-r-1-cyclohexanecarboxylic acid)); benzamides O such as piclamilast (RP73401; N-(3,5-dichloro-4-pyridyl)- 3-cyclopentoxy-4-methoxy benzamide); benzothiophenes such as tibenelast (LY 186655); pyridopyridazinones such as 1N7s 2N

NO RS17597

0047 benzofurans such as 2-butyl-7-methoxy-benzofu ran-4-carboxylic acid (3,5-dichloro-pyridin-4-yl)-amide, NO2 2-benzyl-7-methoxy-benzofuran-4-carboxylic acid (3,5- dichloro-pyridin-4-yl)-amide, 7-methoxy-2-phenethyl-ben Zofuran-4-carboxylic acid (3,5-dichloropyridin-4-yl)-amide 0050 substituted phenyl compounds, as disclosed in U.S. and 5-(2-butyl-7-methoxy-benzofuran-4-yl)-tetrahydro-py Pat. No. 5,891,896 to Warrellow et al.; Substituted biphenyl rimidin-2-one, phenyldihydrobenzofurane compounds Such compounds as disclosed in U.S. Pat. No. 5,877,190 to as those disclosed in U.S. Pat. No. 5,902,824, 4-substituted Dhainaut et al.; etazolate; and S-(+)-glaucine (S)-(+)-1,2, benzofurane compounds Such as those disclosed in EP 9,10-tetramethoxyaporphine). 819688AI; Substituted furans as disclosed in Perrier et al. 0051 Examples of Type V phosphodiesterase inhibitors Bioorg. Med. Chem. Lett. 9:323-326 (1999); naphthalene include, but are not limited to, Zaprinast, MY5445, dipy derivatives Such as T440 ridamole, and sildenafil. Other Type V phosphodiesterase inhibitors are disclosed in PCT Publication Nos. WO 94/28902 and WO 96/16644. 0.052 The compounds described in PCT Publication No. WO 94/28902 are pyrazolopyrimidinones. Examples of the inhibitor compounds include 5-(2-ethoxy-5-morpholi noacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H N pyrazolo 4,3-dpyrimidin-7-one, 5-(5-morphol inoacetyl-2- n-propoxyphenyl) 1-methyl-3-n-propyl-1,6-dihydro-7H O pyrazolo 4,3-dipyrimidin-7-one, 5-2-ethoxy-5-(4-methyl 1-piperazinylsulfonyl)-phenyl-1-methyl-3-n-propyl-1,6- OH dihydro-7H-pyrazolo 4,3-dpyrimidin-7-one, 5-2-allyloxy 1n 5-(4-methyl-1-piperazinylsulfonyl)-phenyl-1-methyl-3-n- propyl-1,6-dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one, T-440 5-2-ethoxy-5-4-(2-propyl)-1-piperazinylsulfonyl)-phe nyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo 4,3-d 0048 purine derivatives such as V-12294A pyrimidin-7-one, 5-2-ethoxy-5-4-(2-hydroxyethyl)-1-pip erazinylsulfonyl)phenyl-1-methyl-3-n-propyl-1,6-dihydro 7H-pyrazolo 4,3-dpyrimidin-7-one, 5-5-4-(2- NH hydroxyethyl)-1-piperazinylsulfonyl-2-n-propoxyphenyl N 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo 4,3-d CH pyrimidin-7-one, 5-2-ethoxy-5-(4-methyl-1- piperazinylcarbonyl)phenyl-1-methyl-3-n-propyl-1,6- dihydro-7H-pyrazolo 4,3-dpyrimidin-7-one, and 5-2- ethoxy-5-(1-methyl-2-imidazolyl)phenyl-1-methyl-3-n- propyl-1,6-dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one. 0053) The phosphodiesterase inhibitors described in PCT Publication No. WO96/16644 include griseolic acid deriva HCO tives, 2-phenylpurinone derivatives, phenylpyridone deriva tives, fused and condensed pyrimidines, pyrimidopyrimi dine derivatives, purine compounds, quinazoline V-112294A compounds, phenylpyrimidinone derivative, imidazoqui noxalinone derivatives or aza analogues thereof, phenylpy ridone derivatives, and others. Specific examples of the 0049 imidazolidinones such as 1,3-dimethyl-2-imidazo phosphodiesterase inhibitors disclosed in WO 96/16644 lidinone (DMI); cyclohexane carboxylic acids such as ariflo include 1,3-dimethyl-5-benzylpyrazolo 4,3-dipyrimidine-7- US 2003/0134861 A1 Jul. 17, 2003 one, 2-(2-propoxyphenyl)-6-purinone, 6-(2-propoxyphe and the like, provided the Salt, ester, amide, prodrug or nyl)-1,2-dihydro-2-oxypyridine-3-carboxamide, 2-(2-pro derivative is Suitable pharmacologically, i.e., effective in the poxyphenyl)-pyrido2,3-dipyrimid-4(3H)-one, present method. Salts, esters, amides, prodrugs and other 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-py derivatives of the active agents may be prepared using rimido-4,5-dpyrimidine, 6-hydroxy-2-(2-propoxyphe Standard procedures known to those skilled in the art of nyl)pyrimidine-4-carboxamide, 1-ethyl-3-methylimidazol, Synthetic organic chemistry and described, for example, by 5aquinoxalin-4(5H)-one, 4-phenylmethylamino-6-chloro J. March, Advanced Organic Chemistry: Reactions, Mecha 2-(1-imidazoloyl)guinazoline, 5-ethyl-8-3-(N-cyclohexyl nisms and Structure, 4th Ed. (New York: Wiley-Interscience, N-methylcarbamoyl)-propyloxy-4,5-dihydro-4-oxo-pyrido 1992). For example, acid addition salts are prepared from 3.2-e-pyrrolo1,2-apyrazine, 5'-methyl-3'- the free base using conventional methodology, and involves (phenylmethyl)-spirocyclopentane-1,7(8H)-(3'H)-imidazo reaction with a suitable acid. Generally, the base form of the 2,1-bpurin4(5"H)-one, 1-6-chloro-4-(3,4- drug is dissolved in a polar organic Solvent Such as methanol methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine-4- or ethanol and the acid is added thereto. The resulting Salt carboxylic acid, (6R, 9S)-2-(4-trifluoromethyl either precipitates or may be brought out of Solution by phenyl)methyl-5-methyl-3,4,5,6a,7,8,9,9a addition of a less polar Solvent. Suitable acids for preparing octahydrocyclopent4.5-imidazo2,1-b-purin-4-one, 1-t- acid addition Salts include both organic acids, e.g., acetic butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo 3,4-d- acid, propionic acid, glycolic acid, pyruvic acid, Oxalic acid, pyrimid-4-One, 1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5- malic acid, malonic acid, Succinic acid, maleic acid, fumaric dihydro-1H-pyrazolo 3,4-dpyrimid-4-one, 2-butyl-1-(2- acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, chlorobenzyl)6-ethoxy-carbonylbenzimidazole, and 2-(4- mandelic acid, methaneSulfonic acid, ethaneSulfonic acid, carboxypiperidino)-4-(3.4-methylenedioxy-benzyl)amino p-tolueneSulfonic acid, Salicylic acid, and the like, as well as 6-nitroquinazoline, and 2-phenyl-8- inorganic acids, e.g., hydrochloric acid, hydrobromic acid, ethoxycycloheptimidazole. Sulfuric acid, nitric acid, phosphoric acid, and the like. An 0.054 Still other Type V phosphodiesterase inhibitors acid addition salt may be reconverted to the free base by useful in conjunction with the present invention include: treatment with a suitable base. Particularly preferred acid IC-351 (ICOS), 4-bromo-5-(pyridylmethylamino)-6-3-(4- addition Salts of the active agents herein are halide Salts, chlorophenyl)propoxy-3 (2H)pyridazinone; 1-4-(1,3-ben Such as may be prepared using hydrochloric or hydrobromic Zodioxol-5-ylmethyl)amiono-6-chloro-2-quinazolinyl-4- acids. Conversely, preparation of basic Salts of acid moieties piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a, which may be present on a phosphodiesterase inhibitor 7.9,9.9a-hexahydro-2-4-(trifluoromethyl)-phenylmethyl-5- molecule are prepared in a similar manner using a pharma methyl-cyclopent-4.5imidazo2,1-bpurin-4(3H)one; ceutically acceptable base Such as Sodium hydroxide, potas furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-oc sium hydroxide, ammonium hydroxide, calcium hydroxide, tahydrocyclopent4.5imidazo2,1-bpurin-4-one; 3-acetyl trimethylamine, or the like. Particularly preferred basic salts 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate, 4-bromo herein are alkali metal Salts, e.g., the Sodium Salt, and copper 5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl) propoxy)- Salts. Preparation of esters involves functionalization of 3-(2H)pyridazinone; 1-methyl-5-(5-morpholinoacetyl-2-n- hydroxyl and/or carboxyl groups which may be present propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3- within the molecular structure of the drug. The esters are d)pyrimidin-7-one; 1-4-(1,3-benzodioxol-5- typically acyl-Substituted derivatives of free alcohol groups, ylmethyl)amino-6-chloro-2-quinazolinyl-4- i.e., moieties which are derived from carboxylic acids of the piperidinecarboxylic acid, monosodium salt; pyrrolo1,2-c formula RCOOH where R is alkyl, and preferably is lower imidazolone derivatives (as described in U.S. Pat. No. alkyl. Esters can be reconverted to the free acids, if desired, 4.937,258 to Shaw); 1-phenylmethyl-N-(4-ethyl-2-(2- by using conventional hydrogenolysis or hydrolysis proce ethyl-4-methyl-1H-imidazol-1-yl)pyrimidin-5-yl)-1H-imi dures. Amides and prodrugs may also be prepared using dazol-2-carboxamide; 1-phenylmethyl-N-4-ethyl-2-(1H techniques known to those skilled in the art or described in imidazol-1-yl)pyrimidin-5-yl)-1H-imidazol-2-carboxamide the pertinent literature. For example, amides may be pre (see U.S. Pat. No. 5,318,975 to Lis); 4,9-diethyl-2-(2-ethyl pared from esters, using Suitable amine reactants, or they 4-methyl-1H-imidazol-1-yl)-7-methylimidazo[5,1-hpteri may be prepared from an anhydride or an acid chloride by din-6(5H)-one; and 9-ethyl-2(2-ethyl-4-methyl-1H-imida reaction with ammonia or a lower alkyl amine. Prodrugs are Zol-1-yl)-7-methyl-4-(2-propyl)imidazo,5,1-hpteridin typically prepared by covalent attachment of a moiety which 6(5H)-one (see U.S. Pat. No. 5,602,252 to Davey); results in a compound that is therapeutically inactive until Pharmaprojects No. 4516 (Glaxo Wellcome); Phar modified by an individual's metabolic system. maprojects No. 5051 (Bayer); Pharmaprojects No. 5064 0057 Pharmaceutical Formulations and Modes of (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. Administration: 5069 (Schering Plough); GF-196960 (GlaxoWellcome); and 0058. The active agent is administered transmucosally to Sch-51866. treat erectile dysfunction, and is accordingly administered in 0055. Other phosphodiesterase inhibitors that may be a pharmaceutical formulation Suitable for transmucosal drug co-administered with the Type III PDE inhibitor include administration. nonspecific phosphodiesterase inhibitorS Such as aminophyl line, enprofylline, isbufylline, IBMX, papaverine, pentoxi 0059. The pharmaceutical compositions may be in the form of Solid, Semi-Solid or liquid dosage forms, Such as, for fylline, theobromine and theophylline, and direct vasodila example, buccal tablets, Sublingual tablets, rectal Supposi torS Such as hydralazine. tories, Suspensions, creams, ointments, Solutions, lotions, 0056. The active agents may be administered, if desired, pastes or the like, preferably in unit dosage form Suitable for in the form of Salts, esters, amides, prodrugs, derivatives, Single administration of a precise dosage. The compositions US 2003/0134861 A1 Jul. 17, 2003 comprise an effective amount of the phosphodiesterase 0064 Preferred buccal dosage forms will typically com inhibitor in combination with a pharmaceutically acceptable prise a therapeutically effective amount of the Selected carrier and, in addition, may include other pharmaceutical phosphodiesterase inhibitor and a bioerodible (hydrolyz agents, adjuvants, diluents, buffers, etc. able) polymeric carrier that may also serve to adhere the 0060 For solid compositions, conventional nontoxic dosage form to the buccal mucosa. The buccal dosage unit Solid carriers include, for example, pharmaceutical grades of is fabricated So as to erode gradually over a predetermined mannitol, lactose, Starch, magnesium Stearate, Sodium sac time period, wherein drug delivery is provided essentially charin, talc, cellulose, glucose, Sucrose, magnesium carbon throughout. The time period is typically in the range of ate, and the like. Liquid pharmaceutically administrable approximately 0.5 hours to 24 hours. Buccal drug delivery, compositions can, for example, be prepared by dissolving, as will be appreciated by those skilled in the art, avoids the dispersing, etc., an active compound as described herein and disadvantages encountered with oral drug administration, optional pharmaceutical adjuvants in an excipient, Such as, e.g., Slow absorption, degradation of the active agent by for example, water, Saline, aqueous dextrose, glycerol, etha fluids present in the gastrointestinal tract and/or first-pass nol, and the like, to thereby form a Solution or Suspension. inactivation in the liver. The “therapeutically effective If desired, the pharmaceutical composition to be adminis amount of phosphodiesterase inhibitor in the dosage unit tered may also contain minor amounts of nontoxic auxiliary will of course depend on the potency of the agent and the Substances Such as wetting or emulsifying agents, pH buff intended dosage, which, in turn, is dependent on the par ering agents and the like, for example, Sodium acetate, ticular individual undergoing treatment, the Specific indica Sorbitan monolaurate, triethanolamine Sodium acetate, tri tion, and the like. Suitable doses of Specific phosphodi ethanolamine oleate, etc. Actual methods of preparing Such esterase inhibitors will be known to those skilled in the art, dosage forms are known, or will be apparent, to those skilled or may be deduced from the literature in combination with in this art, for example, See Remington. The Science and the teaching of the present disclosure. By way of example, Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.; Mack a typical daily dosage of Sildenafil citrate for treatment of Publishing Company, 1995). Sexual dysfunction as discussed herein is in the range of about 25 to 100 mg, although more or less may be effective. 0061 Depending on the particular phosphodiesterase The dosage unit will generally contain from approximately inhibitor administered, it may be desirable to incorporate a 1.0 wt.% to about 60 wt.% active agent, preferably on the permeation enhancer in the formulation in order to increase order of 1 wt.% to about 30 wt.% active agent. With regard the rate at which the active agent permeates through the to the bioerodible (hydrolyzable) polymeric carrier, it will be mucosal tissue to which it is applied, e.g., the buccal appreciated that Virtually any Such carrier can be used, So mucosa, Sublingual or rectal mucosa. Examples of Suitable long as the desired drug release profile is not comprised, and permeation enhancers include dimethylsulfoxide the carrier is compatible with the phosphodiesterase inhibi (“DMSO”), dimethyl formamide (“DMF), N,N-dimethy tor to be administered and any other components that may be lacetamide ("DMA"), decylmethylsulfoxide (“DMSO”), present in the buccal dosage unit. Generally, the polymeric polyethylene glycol monolaurate (“PEGML'), glycerol carrier comprises hydrophilic (water-soluble and water monolaurate, lecithin, the 1-Substituted azacycloheptan-2- Swellable) polymers that adhere to the wet surface of the ones, particularly 1-n-dodecylcyclazacycloheptan-2-one buccal mucosa. Examples of polymeric carriers useful (available under the trademark AZone(R) from Nelson herein include acrylic acid polymers and co, e.g., those Research & Development Co., Irvine, Calif.), SEPAGE) known as “carbomers” (Carbopol(R), which may be obtained (available from Macrochem Co., Lexington, Mass.), alco from B. F. Goodrich, is one such polymer). Other suitable hols (e.g., ethanol), Surfactants as discussed above, includ polymers include, but are not limited to: hydrolyzed poly ing, for example, Tergitol(R), Nonoxynol-9(E) and TWEEN vinylalcohol; polyethylene oxides (e.g., Sentry Polyox(R) 800F, and lower alkanols such as ethanol. water soluble resins, available from Union Carbide); poly 0062) The formulations may additionally include one or acrylates (e.g., GantreZE), which may be obtained from more enzyme inhibitors effective to inhibit drug-degrading GAF), vinyl polymers and copolymers; polyvinylpyrroli enzymes which may be present at the Site of administration. done; dextran; guar gum, pectins, Starches, and cellulosic Such enzyme inhibiting compounds may be determined by polymerS Such as hydroxypropyl methylcellulose, (e.g., those skilled in the art by reference to the pertinent literature Methocel(R), which may be obtained from the Dow Chemical and/or using routine experimental methods. Additional Company), hydroxypropyl cellulose (e.g., Klucel(R), which optional components include excipients, binders, fillers, may also be obtained from Dow), hydroxypropyl cellulose lubricants (e.g., Stearates Such as magnesium Stearate), pre ethers (see, e.g., U.S. Pat. No. 4,704,285 to Alderman), Servatives (e.g., antioxidants), chelating agents, Solubilizing hydroxyethyl cellulose, carboxymethyl cellulose, Sodium agents (e.g., Surfactants), and the like, as will be appreciated carboxymethyl cellulose, methyl cellulose, ethyl cellulose, by those skilled in the art of drug formulation preparation cellulose acetate phthalate, cellulose acetate butyrate, and and delivery. the like. 0.063 Transmucosal drug may involve administration of 0065 Other components may also be incorporated into any type of formulation or dosage unit Suitable for applica the buccal dosage forms described herein. The additional tion to the mucosal tissue. For example, the Selected active components include, but are not limited to, disintegrants, agent may be administered in an ointment, cream, paste, or diluents, binders, lubricants, flavoring, colorants, preserva the like, or in a Solid dosage form unit to be placed under the tives, and the like. Examples of disintegrants that may be tongue (Sublingual formulations), affixed to the buccal used include, but are not limited to, croSS-linked polyvi mucosa as an adhesive tablet or patch (buccal formulations), nylpyrrolidones, Such as crospovidone (e.g., Polyplasdone(R) or placed within or near the rectum (transrectal formula XL, which may be obtained from GAF), cross-linked car tions). boxylic methylcelluloses, Such as croScarmelose (e.g., Ac US 2003/0134861 A1 Jul. 17, 2003 di-sol(R), which may be obtained from FMC), alginic acid, agents, antioxidants, preservatives, and the like. Examples and Sodium carboxymethyl Starches (e.g., Explotab(F), which of Stiffening agents that may be used include, for example, may be obtained from Edward Medell Co., Inc.), methyl paraffin, white wax and yellow wax. Preferred antioxidants, cellulose, agar bentonite and alginic acid. Suitable diluents if used, include Sodium bisulfite and Sodium metabisulfite. are those which are generally useful in pharmaceutical 0070 Ointments, as is well known in the art of pharma formulations prepared using compression techniques, e.g., ceutical formulation, are Semisolid preparations that are dicalcium phosphate dihydrate (e.g., Di-TabE), which may typically based on petrolatum or other petroleum deriva be obtained from Stauffer), Sugars that have been processed tives. Creams containing the Selected active agent, are, as by cocrystallization with dextrin (e.g., co-crystallized known in the art, Viscous liquid or Semisolid emulsions, Sucrose and dextrin Such as Di-Pakg, which may be obtained either oil-in-water or water-in-oil. Cream bases are water from Amstar), lactone, calcium phosphate, cellulose, kaolin, washable, and contain an oil phase, an emulsifier and an mannitol, Sodium chloride, dry Starch, powdered Sugar and aqueous phase. The oil phase, also called the “internal’ the like. Binders, if used, are those that enhance adhesion. phase, is generally comprised of petrolatum and a fatty Examples of Such binders include, but are not limited to, alcohol Such as cetyl or Stearyl alcohol. The aqueous phase Starch, gelatin and SugarS Such as Sucrose, dextrose, molas usually, although not necessarily, exceeds the oil phase in Ses, and lactose. Particularly preferred lubricants are Stear Volume, and generally contains a humectant. The emulsifier ates and Stearic acid, and an optimal lubricant is magnesium in a cream formulation is generally a nonionic, anionic, Stearate. cationic or amphoteric Surfactant. The Specific ointment or 0.066 Preferred Sublingual dosage forms include sublin cream base to be used, as will be appreciated by those skilled gual tablets, creams, ointments and pastes. The tablet, in the art, is one that will provide for optimum drug delivery. cream, ointment or paste for Sublingual delivery comprises AS with other carriers or vehicles, an ointment base should a therapeutically effective amount of the Selected phosphodi be inert, Stable, nonirritating and nonsensitizing. The oint esterase inhibitor and one or more conventional nontoxic ment or cream is applied to a Suitable mucosal Surface. carrierS Suitable for Sublingual drug administration. The 0071 Pastes are semisolid dosage forms in which the Sublingual dosage forms of the present invention can be active agent is Suspended in a Suitable base. Depending on manufactured using conventional processes. The Sublingual the nature of the base, pastes are divided between fatty dosage unit is fabricated to disintegrate rapidly. The time pastes or those made from a single-phase aqueous gels. The period for complete disintegration of the dosage unit is base in a fatty paste is generally petrolatum or hydrophilic typically in the range of from about 10 seconds to about 30 petrolatum or the like. The pastes made from Single-phase minutes, and optimally is less than 5 minutes. aqueous gels generally incorporate carboxymethylcellulose 0067. Other components may also be incorporated into or the like as a base. The paste is applied to a Suitable the Sublingual dosage forms described herein. The addi mucosal Surface. tional components include, but are not limited to binders, 0072 Suppositories are solid dosage forms in which the disintegrators, wetting agents, lubricants, and the like. active agent is carried in a Suitable base. Specifically shaped Examples of binders that may be used include water, etha for insertion into body orifices, the Suppository melts, Soft nol, polyvinylpyrrolidone, Starch Solution gelatin Solution, ens or dissolves resulting in effective delivery of the active and the like. Suitable disintegrators include dry Starch, agent. The Suppository base can be an oleaginous base, calcium carbonate, polyoxyethylene Sorbitan fatty acid water-soluble base, or mixture of both. The base must esters, Sodium lauryl Sulfate, Stearic monoglyceride, lactose, remain a Solid at room temperature but melt, Soften or and the like. Wetting agents, if used, include glycerin, dissolve at body temperature. Thus, Suitable Suppository Starches, and the like. Particularly preferred lubricants are bases include, for example, cocoa butter, glyceryl Stearates and polyethylene glycol. Additional components monoStearate and polyethylene glycol. The Suppository is that may be incorporated into Sublingual dosage forms are made using conventional techniques including molding, known, or will be apparent, to those skilled in this art; for compression, or hand rolling. The Suppository is inserted example, see Remington: The Science and Practice of Phar into a body orifice having a Suitable mucosal Surface. macy, 19th edition (Mack Publishing, 1995). 0073 Enemas are liquid dosage forms in which the active 0068 Preferred transrectal dosage forms include rectal agent is Solubilized or Suspended in a Suitable liquid carrier. Suppositories, creams, ointments, and liquid formulations AS will be readily apparent to those skilled in the art, the (enemas). The Suppository, cream, ointment or liquid for Selection of the liquid carrier is dependent upon the Stability mulation for transrectal delivery comprises a therapeutically and chemical reactivity of the active agent. Suitable liquid effective amount of the selected phosphodiesterase inhibitor carriers for enemas include, for example, Sodium chloride and one or more conventional nontoxic carrierS Suitable for Solution. Alternative carriers, additional components and transrectal drug administration. The transrectal dosage methods of preparing enemas are known to those skilled in forms of the present invention can be manufactured using the art or disclosed in Remington. The Science and Practice conventional processes. The transrectal dosage unit can be of Pharmacy, referenced above. fabricated to disintegrate rapidly or over the period of Several hours. The time period for complete disintegration is 0074. Additional pharmacologically active agents may be preferably in the range of from about 10 minutes to about 6 delivered along with the primary active agent, i.e., the hours, and optimally is less than 3 hours. phosphodiesterase inhibitor. Vasoactive agents, particularly vasodilators, are preferred additional agents. Suitable vaso 0069. Other components may also be incorporated into active agents include, but are not limited to, nitrovasodila the transrectal dosage forms described herein. The addi torS Such as: nitroglycerin; linsidomine, particularly linsi tional components include, but are not limited to, Stiffening domine chlorhydrate (“SIN-I”); molsidomine; organic US 2003/0134861 A1 Jul. 17, 2003

nitrates Such as isosorbide dinitrate, erythrityl tetranitrate 0078 Use in Conjunction With Venous Flow Control and amyl nitrate, Sodium nitroprusSide, S-nitroSothiols Such (“VFC”) Device: as S-nitroso-N-acetyl-d.l-penicillamine (“SNAP), S-ni troso-N-cysteine and S-nitroso-N-glutathione (“SNO 0079. In an alternative embodiment of the invention, a GLU”); and diazenium diolates (“NONOates”) such as pharmaceutical formulation containing the Selected phos (Z)-1-(N-methyl-N-6-(N-methyl-ammoniohexyl)amino phodiesterase inhibitor is administered transmucosally in diazen-1-ium-1,2-diolate, (Z)-1-N-(3-ammoniopropyl)-N- combination with use of a venous flow control device Such (n-propyl)aminodiazen-1-ium-1,2-diolate, (Z)-1-(N-3- as that described in U.S. Pat. No. 5,855,548 to Place for aminopropyl-N-4-(3-aminopropylammonio)butyl “Venous Flow Control Element for Maintaining Penile Erec aminodiazen-1-ium-1,2-diolate and sodium (Z)-1-(N.N- tion,” assigned to VIVUS, Inc. (Mountain View, Calif.). diethylamino)-diazen-1-ium-1,2-diolate. Other suitable Preferred devices are formed from a length of flexible tubing vasoactive agents include, for example, long and short having an integral fastening means, So as to provide for acting-blockerS Such as phenoxybenzamine, dibenamine, readily adjustable venous flow control when applied to the doxazosin, teraZosin, phentolamine, tolazoline, praZosin, penis. The device is applied to the base of the penis prior to trimaZoSin, alfuzosin, tamsulosin and indoramin; ergot alka and during Sexual intercourse, Such that it effectively loids Such as ergotamine and ergotamine analogs, e.g., enhances retention of blood within the penis without Sub acetergamine, braZergoline, bromerguride, cianergoline, Stantially obstructing arterial inflow or becoming too con delorgotrile, disulergine, ergonovine maleate, ergotamine Strictive during the erectile process. In this embodiment, a tartrate, etisulergine, lergotrile, lySergide, meSulergine, kit will include the venous flow control device in addition to metergoline, metergotamine, nicergoline, pergolide, propis the components noted above, along with instructions for ergide, proterguride and terguride; antihypertensive agents using the device. Such as diaZOxide, hydralazine and minoxidil; vasodilators 0080. It is to be understood that while the invention has Such as nimodipine, pinacidil, cyclandelate and isoxSuprine; been described in conjunction with the preferred specific chlorpromazine; haloperidol; yohimbine; Rec 15/2739; tra embodiments thereof, that the foregoing description as well Zodone; naturally occurring prostaglandins Such as PGE, as the examples which follow are intended to illustrate and PGE, PGA, PGB, PGF, 19-hydroxy-PGA, 19-hydroxy not limit the Scope of the invention. Other aspects, advan PGB, PGE, PGA, PGB, 19-hydroxy-PGA, 19-hydroxy tages and modifications within the Scope of the invention PGB, PGE, PGF; semisynthetic or synthetic derivatives will be apparent to those skilled in the art to which the of natural prostaglandins, including carboprost invention pertains. All patents, patent applications, and tromethamine, dinoprost tromethamine, dinoprostone, lipo publications mentioned herein are hereby incorporated by prost, gemeprost, metenoprost, Sulprostone and tiaprost; and reference in their entireties. vasoactive intestinal peptide. Prazosin, prostaglandin E, prostaglandin E and prostaglandin E are particularly pre EXAMPLE 1. ferred vasoactive agents to be co-administered with the 0081 Preparation of transmucosal paste: A transinucosal active agent. formulation is prepared containing Zaprinast, a Type V 0075. The amount of active agent administered and the phosphodiesterase inhibitor. 10 g of bulk Zaprinast is placed dosing regimen used, will, of course, be dependent on the in a mortar and a pestle is used to grind the Solid into a fine particular drug Selected, the age and general condition of the powder. About 10g of a previously weighed out quantity of Subject being treated, the Severity of the Subject's condition, 100 g of OPABASE(E) (Colgate-Hoyt Laboratories, Nor and the judgment of the prescribing physician. A typical wood, Mass.) is combined with the Zaprinast powder on an daily dose of an active agent as administered transmucosally, ointment tile. The Zaprinast powder and ORABASE(R) are e.g., buccally, Sublingually, or transrectally, is generally in levigated together using a Spatula. The remaining ORA the range of approximately 0.1 to 500 mg, with 5 mg to 100 BASEOR is added to the ointment tile and levigated with the mg representing an optional dosage range for most active previously mixed components to produce a Smooth, consis agents. Depending on the half-life of the drug and the tent formulation. The resulting formulation is a 10%. Zapri availability via the chosen route of administration, the nast transmucosal formulation. dosing regimen can be modulated in order to achieve 0082) This procedure can be used with various phos Satisfactory therapeutic results. phodiesterase inhibitors, ointment bases and additional com 0076 Kits: ponents, e.g., enhancers or the like. 0077. The invention also encompasses a kit for patients to EXAMPLE 2 carry out the present method of treating premature ejacula 0083 Preparation of transmucosal paste: A transmucosal tion using transmucosal, e.g., buccal, Sublingual, and tran formulation is prepared containing Sildenafil citrate, a Type Srectal drug therapy. The kit contains the pharmaceutical V phosphodiesterase inhibitor. About 5 g of bulk sildenafil formulation to be administered, a container, preferably citrate is placed in a mortar and a pestle is used to grind the Sealed, for housing the formulation during Storage and prior Solid into a fine powder. About 5 g of a previously weighed to use, and instructions for carrying out drug administration out quantity of 100 g of ORABASEOR is combined with the in an effective manner. The formulation may consist of the sildenafil citrate powder on an ointment tile. The sildenafil drug in unit dosage form. The kit may contain multiple citrate powder and ORABASE(E) are levigated together formulations of different dosages of the same agent. The kit using a spatula. The remaining ORABASE(R) is added to the may also contain multiple formulations of different active ointment tile and levigated with the previously mixed com agents. The instructions may be in written or pictograph ponents to produce a Smooth, consistent formulation. The form, or can be on recorded media including audio tape, resulting formulation is a 5% Sildenafil citrate transmucosal Video tape, or the like. formulation. US 2003/0134861 A1 Jul. 17, 2003

EXAMPLE 3 mer melt. The Zaprinast-polyethyleneglycol mixture can then be poured into a mold Suitable to provide a Zaprinast 0084 Preparation of buccal dosage form: 10 g of Zapri rectal Suppository, and allowed to cool. The Suppository So nast and 90 g of gelatin are mixed and pulverized in a mill. provided is a unit dosage form Suitable for transrectal After the mixing is complete, 20g of concentrated glycerin, administration. 10 g of lactose and 20 g of mannitol are added and the components are mixed until uniform. 150 mg aliquot por EXAMPLE 10 tions of the mixture are compression-molded to provide a buccal dosage unit. Each buccal unit contains 10 mg of 0091 Preparation of a rectal suppository: A phannaceu Zaprinast. tical formulation containing an a Type V phosphodiesterase inhibitor for transrectal administration is prepared by mixing EXAMPLE 4 to 100 mg Sildenafil citrate with polyethylene glycol, molecular weight approximately 4000, and heating the mix 0085 Preparation of a buccal dosage form: 10 g of ture to a temperature just high enough to produce a Sildenafil Sildenafil citrate and 90 g of gelatin are mixed and pulver citrate-polymer melt. The Sildenafil citrate-polyethylenegly ized in a mill. After the mixing is complete, 20 g of col mixture can then be poured into a mold Suitable to concentrated glycerin, 10 g of lactose and 20 g of mannitol provide a Sildenafil citrate rectal Suppository, and allowed to are added and the components are mixed until uniform. 150 cool. The Suppository So provided is a unit dosage form mg aliquot portions of the mixture are compression-molded Suitable for transrectal administration. to provide a buccal dosage unit. Each buccal unit contains 10 mg of Sildenafil citrate. EXAMPLE 11 EXAMPLE 5 0092 An effective phosphodiesterase-inhibiting dose may be determined using the following procedures. 0.086 Preparation of a buccal dosage form: 10 g of milrinone (a Type III phosphodiesterase inhibitor) and 90 g 0093 Buccal administration: Patients with penile vascu of gelatin are mixed and pulverized in a mill. After the lar insufficiency are given a Single dose of 0.5 g of a mixing is complete, 20g of concentrated glycerin, 10 g of phosphodiesterase inhibitor (e.g., Zaprinast) transbucally in lactose and 20 g of mannitol are added and the components a buccal dosage form. Prior to and approximately 3 hours are mixed until uniform. 150 mg aliquot portions of the after administering the inhibitor, blood Samples are taken mixture are compression-molded to provide a buccal dosage and assayed for plasma phosphodiesterase activity using, for unit. Each buccal unit contains 10 mg of milrinone. example, high-performance liquid chromatography with fluorimetric detection as described by Lee et al., J. Chroma EXAMPLE 6 tography 421:237-244 (1987). This procedure is repeated at 24 hour intervals with dosage adjusted as necessary. 0.087 Preparation of a buccal dosage form: 10 g of rolipram (a Type IV phosphodiesterase inhibitor) and 90 g of 0094. Sublingual administration: The same procedures gelatin are mixed and pulverized in a mill. After the mixing described for determining an effective phosphodiesterase is complete, 20 g of concentrated glycerin, 10 g of lactose inhibiting dose for buccal administration are followed and 20 g of mannitol are added and the components are except that a Suitable dosage form is administered Sublin mixed until uniform. 150 mg aliquot portions of the mixture gually. are compression-molded to provide a buccal dosage unit. 0095 Transrectal administration: The same procedures Each buccal unit contains 10 mg of rollipram. described for determining an effective phosphodiesterase inhibiting dose for buccal administration are followed EXAMPLE 7 expect that a Suitable dosage form is administered transrec 0088 10074) Preparation of a sublingual tablet: 1.0 g of tally. Zaprinast, 1.0 g of mannitol, 2.0 g of microcrystalline cellulose, and 10 mg of magnesium Stearate are blended in EXAMPLE 12 a Suitable mixer and then compressed into Sublingual tablets. 0096. The pharmaceutical formulations of Examples Each Sublingual tablet contains 10 mg of Zaprinast. 1-10 can be used to treat erectile dysfunction in individuals in which the dysfunction is associated, for example, Vascular EXAMPLE 8 insufficiency. Dosage may be adjusted using the methodol 0089 Preparation of a sublingual tablet: 1.0 g of sildena ogy of Example 11. In all instances, the individuals are fil citrate, 1.0 g of mannitol, 2.0 g of microcrystalline expected to respond positively, although variations in the cellulose, and 10 mg of magnesium Stearate are blended in intensity and duration of erection may be observed depend a Suitable mixer and then compressed into Sublingual tablets. ing on dose, formulation, and environment. Generally, Each Sublingual tablet contains 10 mg of Sildenafil citrate. between approximately 5 and 90 minutes following drug administration, it is expected that an erection may be EXAMPLE 9 achieved. 0090 Preparation of a rectal suppository: A pharmaceu tical formulation containing a Type V phosphodiesterase inhibitor for transrectal administration is prepared by mixing What is claimed is: 10 to 100 mg Zaprinast with polyethylene glycol, molecular 1. A pharmaceutical formulation for treating erectile dyS weight approximately 4000, and heating the mixture to a function in an individual and Suitable for transmucosal drug temperature just high enough to produce a Zaprinast-poly administration, comprising a therapeutically effective US 2003/0134861 A1 Jul. 17, 2003

amount of a phosphodiesterase inhibitor, a carrier Suitable 21. The formulation of claim 20, wherein the dihydro for transmucosal drug administration, and, optionally, a quinolinone is Selected from the group consisting of cilos permeation enhancer. tamide, cilostazol, Vesnarinone and OPC 3911. 2. The formulation of claim 1, wherein the formulation 22. The formulation of claim 1, wherein the phosphodi comprises a Solid dosage form for application to buccal esterase inhibitor is a Type IV phosphodiesterase inhibitor. mucosa, and the carrier is Suitable for transbuccal drug delivery. 23. The formulation of claim 22, wherein the Type IV 3. The formulation of claim 2, wherein the carrier is a phosphodiesterase inhibitor is Selected from the group con hydrolyzable polymer. Sisting of pyrrolidinones, quinazolinediones, Xanthine 4. The formulation of claim 3, wherein the dosage form derivatives, phenyl ethyl pyridines, tetrahydropyrimidones, further comprises an adhesive Suitable for affixing the doS diazepine derivatives, OXime carbamates, naphthyridinones, age form to the buccal mucosa. benzofurans, naphthalene derivatives, purine derivatives, 5. The formulation of claim 2, wherein the phosphodi imidazolidinones, cyclohexane carboxylic acids, benza esterase inhibitor represents approximately 1 wt % to 30 wt mides, benzothiophenes, pyridopyridaZinones, etazolate, % of the buccal Solid dosage form. S-(+)-glaucine, Substituted phenyl compounds, and Substi 6. The formulation of claim 2, wherein the buccal Solid tuted biphenyl compounds. dosage form contains at least one additional component 24. The formulation of claim 23, wherein the Type IV Selected from the group consisting of disintegrants, diluents, phosphodiesterase inhibitor is a pyrrolidinone. binders, lubricants, flavoring, colorants, and preservatives. 25. The formulation of claim 24, wherein the pyrrolidi 7. The formulation of claim 1, wherein the formulation comprises a dosage form for application to Sublingual none is Selected from the group consisting of rolipram, mucosa, and the carrier is Suitable for Sublingual drug RO2O-1724 and RS 33793. delivery. 26. The formulation of claim 25, wherein the pyrrolidi 8. The formulation of claim 7, wherein the Sublingual none is rolipram. dosage form completely disintegrates in less than five min 27. The formulation of claim 1, wherein the phosphodi utes after administration. esterase inhibitor is a Type V phosphodiesterase inhibitor. 9. The formulation of claim 7, wherein the Sublingual 28. The formulation of claim 27, wherein the Type V dosage form contains at least one additional component phosphodiesterase inhibitor is Selected from the group con Selected from the group consisting of binders, disintegrators, Sisting of Zaprinast; MY 544, dipyridamole; Sildenafil; pyra wetting agents, and lubricants. Zolopyrimidinones, griseolic acid derivatives; 2-phenylpu 10. The formulation of claim 1, wherein the formulation rinones, phenylpyridone derivatives, pyrimidines, comprises a dosage form for application to rectal mucosa, pyrimidopyrimidines, purines, quinazolines, phenylpyrimi and the carrier is Suitable for transrectal drug delivery. dinones, imidazoquinoxalinones or aza analogues thereof; 11. The formulation of claim 10, wherein the transrectal phenylpyridones; 1C-351 (ICOS), 4-bromo-5-(pyridylm dosage form completely disintegrates within approximately ethylamino)-6-3-(4-chlorophenyl)propoxy-3 (2H)py 3 hours following administration. ridazinone; 1-4-(1,3-benzodioxol-5-ylmethyl)amiono-6- 12. The formulation of claims 11, wherein the transrectal chloro-2-quinazolinyl-4-piperidine-carboxylic acid, dosage form is a rectal Suppository. monosodium salt; (+)-cis-5,6a,79,9.9a-hexahydro-2-4-(tri 13. The formulation of claim 12, wherein the rectal fluoromethyl)-phenylmethyl-5-methyl-cyclopent-4.5imi Suppository further includes at least one additional compo dazo[2,1-bpurin-4(3H)one; furazlocillin; cis-2-hexyl-5-me nent Selected from the group consisting of Stiffening agents, thyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent 4.5imidazo[2,1- antioxidants, and preservatives. bpurin-4-one; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole 14. The formulation of claim 1, wherein the phosphodi 6-carboxylate, 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4- esterase inhibitor is a Type III phosphodiesterase inhibitor. chlorophenyl) propoxy)-3-(2H)pyridazinone; 1-methyl-5- 15. The formulation of claim 14, wherein the Type III (5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6- phosphodiesterase inhibitor is Selected from the group con dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 1-4-(1,3- Sisting of bipyridines, imidazolones, imidazolines, dihydro benzodioxol-5-ylmethyl)amino-6-chloro-2-quinazolinyl pyridazinones, dihydroquinolones, mixed Type III-Type IV 4-piperidinecarboxylic acid, monosodium salt; pyrrolo1,2- inhibitors, anagrelide, bemoradan, ibudilast, isomazole, lix climidazolone derivatives; 1-phenylmethyl-N-4-ethyl-2- aZinone, motapizone, olprinone, phthalazinol, pimobendan, (2-ethyl-4-methyl-1H-imidazol-1-yl)pyrimidin-5-yl)-1H quaZinone, SiguaZodan and trequinsin. imidazol-2-carboxamide; 1-phenylmethyl-N-4-ethyl-2- 16. The formulation of claim 15, wherein the Type III (1H-imidazol-1-yl)pyrimidin-5-yl-H-imidazol-2- phosphodiesterase inhibitor is a bipyridine. carboxamide; 4.9-diethyl-2-(2-ethyl-4-methyl-1H-imidazol 17. The formulation of claim 16, wherein the bipyridine 1-yl)-7-methylimidazo,5,1-hpteridin-6(5H)-one; and is Selected from the group consisting of amrinone and 9-ethyl-2(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-methyl-4- milrinone. (2-propyl)imidazo5,1-hpteridin-6(5H)-one. 18. The formulation of claim 15, wherein the Type III 29. The formulation of claim 28, wherein the Type V phosphodiesterase inhibitor is an imidazolone. phosphodiesterase inhibitor is Zaprinast. 19. The formulation of claim 18, wherein the imidazolone 30. The formulation of claim 28, wherein the Type V is Selected from the group consisting of piroXimone and phosphodiesterase inhibitor is a pyrazolopyrimidinone. enoXimone. 31. The formulation of claim 28, wherein the Type V 20. The formulation of claim 15, wherein the Type III phosphodiesterase inhibitor is Sildenafil or a pharmaceuti phosphodiesterase inhibitor is a dihydroquinolinone. cally acceptable Salt thereof. US 2003/0134861 A1 Jul. 17, 2003

32. The formulation of claim 1, wherein the phosphodi 38. A kit to assist an individual in administering a drug esterase inhibitor is Selected from the group consisting of used for the treatment of erectile dysfunction comprising: pentoxifylline, papaverine, doxazosin, praZosin, teraZosin, a pharmaceutical formulation comprising a Selected phos trimaZoSin and hydralazine. phodiesterase inhibitor; a container for housing the pharmaceutical formulation 33. The formulation of claim 1, further comprising an during Storage and prior to use; and additional active agent. instructions for carrying out drug administration in a 34. The formulation of claim 33, wherein the additional manner effective to treat erectile dysfunction. active agent is a vasoactive agent. 39. The kit according to claim 38, wherein the pharma ceutical formulation is for buccal administration. 35. The formulation of claim 33, wherein the additional 40. The kit according to claim 39, wherein the phosphodi active agent is a Smooth muscle relaxant. esterase inhibitor is housed in a buccal Storage unit with a bioerodible polymeric carrier. 36. The formulation of claim 1, wherein the daily dose of 41. The kit according to claim 38, further comprising a the formulation is in the range of approximately 5 mg to 100 venous flow control device. mg. 42. The kit according to claim 41, wherein the venous 37. The formulation of claim 36, wherein the phosphodi flow control device comprises a flexible tubing having esterase inhibitor in the daily dose of the formulation is in a integral fastening means. range of approximately 0.1 to 500 mg. k k k k k