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United States Patent 19 11 Patent Number: 5,945,117 El-Rashidy Et Al

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United States Patent 19 11 Patent Number: 5,945,117 El-Rashidy Et Al USOO5945117A United States Patent 19 11 Patent Number: 5,945,117 El-Rashidy et al. (45) Date of Patent: Aug. 31, 1999 54) TREATMENT OF FEMALE SEXUAL Halvorsen MD J.G. et al., “Sexual Dysfunction, Part I: DYSFUNCTION Classification, Etiology, and Pathogenesis', J Am Board Fam Pract, 5(1), 51–61 (1992). 75 Inventors: Ragab El-Rashidy, Deerfield; Bruce Halvorsen MD J.G. et al., “Sexual Dysfunction, Part II: Ronsen, River Forest, both of Ill. Diagnosis, Management, and Prognosis”, J Am Board Fam 73 Assignee: Pentech Pharmaceuticals, Inc., Buffalo Pract, 5(2), 177-192 (1992). Grove, Ill. Heaton MD J.P.W., et al., “Recovery of Erectile Function by the Oral Administration of Apomorphine', Urology, 45(2), 21 Appl. No.: 09/016,252 200–206, (1995). Heiman PhD J.R., “Issues in the Use of Psychophysiology 22 Filed: Jan. 30, 1998 to Assess Female Sexual Dysfunction”, Journal of Sex & 51 Int. Cl. ................................ A61F 6/06; A61 K9/20; Marital Therapy, 2(3), 197-204 (1976). A61K 47/32 Abstract of Henson D.E. et al., “Analysis of the consistency 52 U.S. Cl. ........................ 424/430; 424/464; 514/772.6 of objective measures of Sexual arousal in Women”, Journal 58 Field of Search ..................................... 424/430, 435, of Applied Behavior Analysis, 12(4), 701-711 (1979) avail 424/464; 514/772.6 able on Medline (http://www.ncbi.nlm.nih.gov/). 56) References Cited Lavoisier MD P. et al., “Clitoral Blood Flow Increases Following Vaginal Pressure Stimulation”, Archives of Sexual U.S. PATENT DOCUMENTS Behavior, 24(1), 37–45 (1995). 5,565,466 10/1996 Gioco et al. ............................ 514/280 Levin R. J., “VIP, Vagina, Clitoral and Periurethral Glans 5,624,677 4/1997 El-Rashidy et al. ..... ... 424/435 An Update on Human Female Genital Arousal, Exp. Clin. 5,770,606 6/1998 El-Rashidy et al. .................... 514/284 Endocrinol, 98(2), 61-69 (1991). OTHER PUBLICATIONS (List continued on next page.) Azadzoi K. et al., “Relationship Between Cavernosal Ischemia and Corporal Veno-Occlusive Dysfunction in an Primary Examiner Thurman K. Page Animal Model”, The Journal of Urology, 157, 1011-1017 ASSistant Examiner S. Howard (1997). Danjou. P. et al., “ASSessment of erectogenic properties of Attorney, Agent, or Firm-Olson & Hierl, Ltd. apomorphine and yohimbine in man', British Journal of 57 ABSTRACT Clinical Pharmacology, 26, 733–739 (1988). Durif F. et al., “Comparison Between Percutaneous and Sexual dysfunction in human females can be ameliorated, Subcutaneous Routes of Administration of Apomorphine in without substantial undesirable side effects, by Sublingual Rabbit", Clinical Neuropharmacology, 17(5), 445-453 administration of apomorphine dosage forms. Administra (1994). tion of apomorphine increases nerve Stimulated clitoral Goodnow C., “An exercise in arousal”, Chicago Tribune, intracavernosal blood flow and vaginal wall blood flow for Sunday, Womanews, Section 13, p. 8 (Dec. 14, 1997). enhanced clitoral erection and vaginal engorgement in a Abstract of Graber B. et al., “A circumvaginal muscle female. A plasma concentration of apomorphine of no more nomogram: a new diagnostic tool for evaluation of female than about 5.5 nanograms per milliliter is preferably main sexual dysfunction”, Journal Clinical Psychiatry, 42(4), tained. 157-161 (1981) as available on Medline (http://ww w.ncbi.nlm.nih.gov/). 15 Claims, 3 Drawing Sheets 20 Before Nerve Stimulation After Nerve Stimulation arx s k P O 15 g 3 : s xt S E 10 - ESE 5 3 & 5 l- 5 - d O O - O. Apomorphine (mg/Kg) 5,945,117 Page 2 OTHER PUBLICATIONS Seagraves R. T. et al., “Effect of Apomorphine on Penile Abstract of Levin R.J., “Increased vaginal blood flow Tumescence in Men with Psychogenic Impotence”, The induced by implant electrical Stimulation of Sacral anterior Journal of Urology, 145, 1174–1175 (1991). roots in the conscious woman: a case Study', Arch Sex Abstract of “New field could open for urologists: female Behav. 22(5), 471-475 (1993) available on Medline (http:// sexual dysfunction', Urology Times, 2, available on What's www.ncbi.nlm.nih.gov/). New in Urology (http://www.modernmedicine.com/ut/). Abstract of Palle C. et al., “Vasoactive intestinal polypeptide and human vaginal blood flow: comparison between trans Abstract of “Effect of atropine and methylatropine on human vaginal and intravenous administration’, Clin Exp. Pharma vaginal blood flow, Sexual arousal and climax', Acta Phar col Physiol, 17(1), 61-68 (1990) available on Medline macol Toxicol (Copenh), 46(5), available on Medline (http:// (http://www.ncbi.nlm.nih.gov/). www.ncbi.nlm.nih.gov/). Park K. et al., “Vasculogenic female sexual dysfunction: The hemodynamic basis for vaginal engorgement insufficiency Wagner G. et al., “Vaginal blood flow during sexual stimu and clitoral erectile insufficiency”, International Journal of lation', ObstetGynecol, 56(5), (1980) available on Medline Impotence Research, 9(1), 27–37 (1997). (http://www.ncbi.nlm.nih.gov). U.S. Patent Aug. 31, 1999 Sheet 1 of 3 5,945,117 DBefore Nerve Stimulation After Nerve Stimulction 125O k 1 O O O O.O5 O. 1 O.2 O.5 Apomorphine (mg/Kg) FIG, U.S. Patent Aug. 31, 1999 Sheet 2 of 3 5,945,117 16 Before Nerve Stimulation After Nerve Stimulation 14 xk 3 -in D 12 O (2 k 3 1 O k ck 9 8 . S e 6 E '5, N S 5 4. O: O O.O5 O. 1 O.2 O.3 O.4 Apomorphine (mg/Kg) FIG, 2 U.S. Patent Aug. 31, 1999 Sheet 3 of 3 5,945,117 12O 11 O 1 OO 9 O 8O 7O 6O 5O 3O 2O A Systolic Pressure (mmHg) 1 A Diastolic Pressure (mm Hg) O.O O. 1 O.2 O.3 O.4 O.5 Apomorphine (mg/Kg) FIG, 3 5,945,117 1 2 TREATMENT OF FEMALE SEXUAL More recently, studies with males show that oral admin DYSFUNCTION istration of apomorphine can be used to induce an erection in a psychogenic male patient, as long as the apomorphine FIELD OF THE INVENTION dose required to achieve a significant erectile response is not This invention relates to dosage forms and methods for accompanied by nausea and vomiting or other Serious unde ameliorating female Sexual dysfunction. More particularly, Sirable side effects Such as arterial hypotension, flushing and this invention relates to the use of apomorphine-containing diaphoresis. See U.S. Pat. No. 5,624,677 to El-Rashidy et al. compositions for amelioration of female Sexual dysfunction. and Heaton et al., Urology, 45,200-206 (1995). The specific mechanisms by which apomorphine acts to produce an BACKGROUND OF THE INVENTION erectile response in a human patient are not yet completely understood but are believed to be centrally acting through Apomorphine is a Selective dopamine receptor agonist dopamine receptor Stimulation in the medial preoptic area of that has been widely utilized as an emetic agent, Sedative, the brain. antiparkinsonian agent and a behavior altering agent. Recent 15 research and clinical Studies have demonstrated that in males It has now been found that certain controlled delivery apomorphine has an erectogenic effect manifested by penile Systems for apomorphine can provide a practical therapeutic erection. The effect of apomorphine on female Sexual func use in ameliorating Sexual dysfunction in human females tionality has not been previously investigated. while reducing the likelihood of undesirable side effects. Females also can have Sexual dysfunction that increases with age and is associated with the presence of vascular risk SUMMARY OF THE INVENTION factors and onset of menopause. Some of the vascular and muscular mechanisms that contribute to penile erection in Administration of apomorphine increases nerve Stimu the male are believed to be similar vasculogenic factors in lated clitoral intracavernoSal blood flow and vaginal wall female genital response. It is known that in Women, Sexual 25 blood flow, each of which is associated respectively with arousal is accompanied by arterial inflow which engorges enhanced clitoral erection and vaginal engorgement in a the vagina and increases vaginal lubrication and that the female. muscles in the perineum assist in achieving clitoral erection. A Sublingual apomorphine dosage form, usually contain In the female, Sexual dysfunction can arise from organic and psychogenic causes or from a combination of the ing about 2 to about 12 milligrams, preferably about 2 to foregoing. Female Sexual dysfunction includes a failure to about 8 milligrams, of apomorphine, is effective for produc attain or maintain vaginal lubrication-Swelling responses of ing Sexual readineSS in human females without inducing Sexual eXcitement until completion of the Sexual activity. Substantial nausea or other undesirable Side effects. Organic female Sexual dysfunction is known to be related in 35 Sublingually, administration is effected preferably about 15 part to vasculogenic impairment resulting in inadequate to about 20 minutes prior to Sexual activity. The plasma blood flow, vaginal engorgement insufficiency and clitoral concentration of apomorphine is maintained at no more than erection insufficiency. about 5.5 nanograms per milliliter, preferably about 0.3 to Female Sexual dysfunction has not been Studied as exten about 4 nanograms per milliliter, and more preferably about Sively as male Sexual dysfunction. This has partly been due 40 1 to about 2 nanograms per milliliter, to maintain a circu to the difficulty of obtaining volunteer female subjects and lating Serum level and mid-brain tissue level of apomorphine to the historical belief that female sexual dysfunction was during the period of Sexual activity Sufficient to maintain orgasmic-related (delayed or non-orgasmic) or libido and vaginal engorgement, its associated lubrication and clitoral hence lacked an appropriate animal model. 45 erection during coitus, but less than the amount that induces The use of New Zealand White male rabbits as animal Substantial nausea. models for impotence has been well established.
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