United States Patent (19) 11 Patent Number: 6,037,346 Doherty, Jr
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US006037346A United States Patent (19) 11 Patent Number: 6,037,346 Doherty, Jr. et al. (45) Date of Patent: Mar. 14, 2000 54) LOCAL ADMINISTRATION OF WO 96/16644 6/1996 WIPO. PHOSPHODESTERASE INHIBITORS FOR THE TREATMENT OF ERECTLE OTHER PUBLICATIONS DYSFUNCTION Bush et al. (1992), “Nitric Oxide is a Potent Relaxant of 75 Inventors: Paul C. Doherty, Jr., Cupertino, Calif.; Human and Rabbit Corpus Cavernosum.” The Journal of Virgil A. Place, Kawaihae, Hi.; Urology 147(6):1650–1655. William L. Smith, Mahwah, N.J. Doherty (1997), “Oral, Transdermal, and Transurethral Therapies for Erectile Dysfunction,” Male Infertility and 73 Assignee: Vivus, Inc., Mountain View, Calif. Dysfunction, Hellstron, ed., Chapter 33 (New York, New York: Springer-Verlag Hellstrom), pp. 452-467. 21 Appl. No.: 09/181,070 Rajfer et al. (1992), "Nitric Oxide as a Mediator of Relax ation of the Corpus CavernoSum in Response to Nonadren 22 Filed: Oct. 27, 1998 ergic, Noncholinergic Neurotransmission.” The New England Journal of Medicine 326(2):90-94. Related U.S. Application Data Taher et al. (1992), “Cyclic nucleotide phosphodiesterase 63 Continuation-in-part of application No. 08/958,816, Oct. 28, activity in human cavernous Smooth muscle and the effect of 1997, abandoned. various selective inhibitors,” International Journal of Impo tence Research (Supplement 2) 4:11. 51 Int. Cl." - A61K 31/50 Trigo-Rocha et al. (1993), “The Role of Cyclic Adenosine 52 U.S. Cl. .............................................................. 514/258 Monophosphate, Cyclic Guanosine Monophosphate, Endot 58 Field of Search ............................................... 514/258 helium and Nonadrenergic, Noncholinergic Neurotransmis sion in Canine Penile Erection.” The Journal of Urology 56) References Cited 149(4):872-877. U.S. PATENT DOCUMENTS 3,819,631 6/1974 Broughton et al. ............... 260/256.4 F Primary Examiner James H. Reamer 3,933,822 1/1976 Broughton et al. .............. 260/256.5 R Attorney, Agent, or Firm-Dianne E. Reed; Reed & 4,039,544 8/1977 Broughton et al... 260/256.4 F ASSociates 4,666,908 5/1987 Hamilton ................................ 514/229 57 ABSTRACT 4,801,587 1/1989 Voss et al. ... ..., 514/248 5,145,852 9/1992 Virag ....................................... 514/253 A method is provided for treating erectile dysfunction in a 5,242,391 9/1993 Place et al. ............................... 604/60 mammalian male individual. The method involves the local 5,250,534 10/1993 Bell et al. ... 514/258 administration of a phosphodiesterase inhibitor or a phar 5,272,147 12/1993 Bell et al. 514/234.2 maceutically acceptable Salt, ester, amide or derivative 5,346,901 9/1994 Bell et al. ... 514/258 5,426,107 6/1995 Bell et al. 514/234.2 thereof within the context of an effective dosing regimen. A 5,506,347 4/1996 Erion et al. .............................. 536/4.1 preferred mode of administration is transurethral. Pharma ceutical formulations and kits are provided as well. FOREIGN PATENT DOCUMENTS WO 94/28902 12/1994 WIPO. 94 Claims, 1 Drawing Sheet U.S. Patent Mar. 14, 2000 6,037,346 6,037,346 1 2 LOCAL ADMINISTRATION OF Smooth muscle, which facilitates engorgement of the penis PHOSPHODESTERASE INHIBITORS FOR with blood, and (3) compression of the venules by the THE TREATMENT OF ERECTLE expanding trabecular walls to decrease venous outflow. DYSFUNCTION Trabecular smooth muscle tone is controlled locally by adrenergic (constrictor), cholinergic (dilator) and CROSS-REFERENCE TO RELATED nonadrenergic, noncholinergic (dilator) innervation, and by APPLICATIONS endothelium-derived vasoactive Substances Such as vasoac tive intestinal polypeptide (VIP), prostanoids, endothelin This application is a continuation-in-part of U.S. Ser. No. and nitric oxide. High Sympathetic tone (noradrenergic) is 08/958,816, filed Oct. 28, 1997, now abandoned the disclo implicated in erectile dysfunction, and, in Some patients, the Sure of which is hereby incorporated by reference. disorder can be Successfully treated with noradrenergic TECHNICAL FIELD receptor antagonists. See, e.g., Krane et al., Supra. There is also evidence that dopaminergic mechanisms are This invention relates generally to methods and pharma involved in erectile function. For example, pharmacologic ceutical compositions for treating erectile dysfunction; more 15 agents that elevate the level of brain dopamine or Stimulate particularly, the invention relates to local administration of brain dopamine receptors increase Sexual activity in animals phosphodiesterase inhibitors to treat erectile dysfunction. (see, e.g., Gessa & Tagliamonte, Life Sciences 14:425 (1974); Da Prada et al., Brain Research 57:383 (1973)). BACKGROUND Administration of L-DOPA, a dopamine precursor, Impotence is the consistent inability to achieve or Sustain enhances sexual activity in male rats. L-DOPA has been used an erection of Sufficient rigidity for Sexual intercourse. It has in the treatment of Parkinsonism and is known to act as an recently been estimated that approximately 10 million aphrodisiac in Some patients (Gessa & Tagliamonte, Supra; American men are impotent (R. Shabsigh et al., “Evaluation Hyppa et al., Acta Neurologic Scand. 46:223 (Supp. 43, of Erectile Impotence,” Urology 32:83–90 (1988); W. L. 1970)). Specific dopamine agonists have been studied for Furlow, “Prevalence of Impotence in the United States.” 25 their effects on erectile function. Apomorphine, (n-propyl) Med Aspects Hum. Sex. 19:13-6 (1985)). Impotence is norapo-morphine, bromocryptine, amantidine, fenfluramine, recognized to be an age-dependent disorder, with an inci L-DOPA and various other pharmacological activators of dence of 1.9 percent at 40 years of age and 25 percent at 65 central dopaminergic receptorS have been found to increase years of age (A. C. Kinsey et al., “Age and Sexual Outlet,” episodes of penile erection in male rats (Benassi-Benelli et in Sexual Behavior in the Human Male; A. C. Kinsey et al., al., Arch. int. Pharmacodyn. 242:241 (1979); Poggioliet al., eds., Philadelphia, Pa.; W. B. Saunders, 218–262 (1948)). In Riv. di Farm. & Terap. 9:213 (1978); Falaschi et al., Apo 1985 in the United States, impotence accounted for more morphine and Other Dopaminominetics, 1:117-121 (Gessa than Several hundred thousand outpatient visits to physicians & Corsini, Eds., Raven Press, N.Y.)). In addition, U.S. Pat. Rational Center for Health Statistics, National Hospital No. 4,521,421 to Foreman relates to the oral or intravenous Discharge Survey, 1985, Bethesda, Md., Department of 35 administration of quinoline compounds to treat Sexual dyS Health and Human Services, 1989 D-ES publication no. function in mammals. 87-1751). Depending on the nature and cause of the The currently available dopamine agonists, with few problem, treatments include psychosexual therapy, hor exceptions, have found limited use in the treatment of monal therapy, administration of vasodilatorS Such as nitro erectile dysfunction because of their peripheral Side effects. glycerin and C.-adrenergic blocking agents (“C.-blockers-”), 40 These effects include nausea and vomiting, postural oral administration of other pharmaceutical agents, Vascular hypotension, arrhythmias, tachycardia, dysphoria, Surgery, implanted penile prostheses, vacuum constriction psychosis, hallucinations, drowsiness and dySidnesias (See, devices and external aids Such as penile Splints to Support the e.g., Martindale The Extra Pharmacopoeia, 31st Ed., pages penis or penile constricting rings to alter the flow of blood 45 1151–1168). through the penis. Other pharmaceutical methods for treating erectile dyS A number of causes of impotence have been identified, function have also proved to be problematic. For example, including Vasculogenic, neurogenic, endocrinologic and with Viagraf), the most recently introduced oral drug psychogenic. Vasculogenic impotence, which is caused by therapy, not only have significant Side effects been alterations in the flow of blood to and from the penis, is 50 encountered, but interaction with other Systemically admin thought to be the most frequent organic cause of impotence. istered medications has posed enormous risks and numerous Common risk factors for vasculogenic impotence include fatalities have in fact been reported. hypertension, diabetes, cigarette Smoking, pelvic trauma, The invention described herein provides a means to avoid and the like. Neurogenic impotence is associated with the above-mentioned problems encountered with the Sys Spinal-cord injury, multiple Sclerosis, peripheral neuropathy 55 temic administration of pharmacologically active agents to caused by diabetes or alcoholism and Severance of the treat erectile dysfunction. Specifically, the invention relates autonomic nerve Supply to the penis consequent to prostate to methods and formulations for effectively treating erectile Surgery. Erectile dysfunction is also associated with distur dysfunction by locally administering a Selected active agent, bances in endocrine function resulting in low circulating wherein the active agent is an inhibitor of a phosphodi testosterone levels and elevated prolactin levels. 60 eSterase. Impotence can also be a side effect of various classes of Phosphodiesterases are a class of intracellular enzymes drugs, in particular, those that interfere with central neu involved in the metabolism of the Second messenger roendocrine control or local neurovascular control of penile nucleotides, cyclic adenosine monophosphate (cAMP), and smooth muscle. Krane et al., New England Journal of