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., “, 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', , 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 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, , 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 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

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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 . 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 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 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. More recently, studies have reported that New Zealand White BRIEF DESCRIPTION OF THE DRAWINGS female rabbits are also Suitable, relatively inexpensive ani mal models for Studying the vascular pathology in female 50 In the drawings, Sexual dysfunction and have shown that vaginal engorge ment and clitoral erection depend on blood inflow. See, for FIG. 1 is a bar graph depicting the effect of apomorphine example, Park et al., “Vasculogenic female Sexual dysfunc on female rabbit clitoral blood flow in milliliters per minute tion: the hemodynamic basis for vaginal engorgement insuf per 100 grams tissue before and after nerve stimulation for ficiency and clitoral erectile insufficiency,” International 55 placebo and intravenous apomorphine amounts of 0.05, 0.1, Journal of Impotence Research, 9, (1), 27-37 (March 1997). 0.2,0.3 and 0.4 milligrams per kilogram body weight; In medically managing vasculogenic Sexual dysfunction, FIG. 2 is a bar graph depicting the effect of apomorphine a female patient needs to have her discomfort or dysfunction reduced for Sexual functioning. For psychogenic Sexual on female rabbit vaginal wall blood flow, in milliliters per dysfunction management, psychological can 60 minute per 100 grams tissue before and after nerve Stimu also be employed to help the patient. lation for placebo and intravenous apomorphine amounts of 0.05, 0.1, 0.2, 0.3 and 0.4 milligrams per kilogram body Apomorphine previously was shown to have very poor weight; and oral bioavailability. See, for example, BaldeSSarini et al., in Gessa et al., (eds.), Apomorphine and Other 65 FIG. 3 is a graph depicting the effect of intravenous Dopaminomimetics, Basic Pharmacology, 1, 219–228, apomorphine on female rabbit Systemic (diastolic and Raven Press, N.Y. (1981). Systolic) arterial pressure. 5,945,117 3 4 DETAILED DESCRIPTION OF PREFERRED Sublingually over this time period preferably is in the range EMBODIMENTS of about 25 ug/kg of body weight to about 80 ug/kg of body Apomorphine can be represented by the following for weight. mula Illustrative preferred Sublingual dosage forms are set forth 5 in Table I, below.

OH TABLE I HO 150 Milligram Apomorphine Hydrochloride Sublingual Tablets 1O 3-mg Tablet N Apomorphine Hydrochloride 2.00 wt % H Mannito 66.67 wt % CH Ascorbic Acid 3.33 wt % Citric Acid 2.00 wt % 15 Avice PH102 15.OO wt % and exists in a free base form or as an acid addition Salt. For Methocel E4M 10.00 wt % the purposes of the present invention apomorphine hydro Aspartame O.67 wt % Magnesiurn Stearate O.33 wt % chloride is preferred; however, other pharmacologically 4-mg Tablet acceptable moieties thereof can be utilized as well. The term “apomorphine” as used herein includes the free base form of Apomorphine Hydrochloride 2.66 wt % this compound as well as the pharmacologically acceptable Mannito 66.00 wt % Ascorbic Acid 3.33 wt % acid addition salts thereof. In addition to the hydrochloride Citric Acid 2.00 wt % Salt, other acceptable acid addition Salts are the Avice PH102 15.OO wt % hydrobromide, the hydroiodide, the bisulfate, the phosphate, Methocel E4M 10.00 wt % 25 Aspartame O.67 wt % the acid phosphate, the lactate, the citrate, the tartrate, the Magnesium Stearate O.33 wt % Salicylate, the Succinate, the maleate, the gluconate, and the 5-mg Tablet like. Apomorphine is a dopamine receptor agonist that has a Apomorphine Hydrochloride 3.33 wt % Mannito 65.34 wt % recognized use as an emetic when administered Subcutane Ascorbic Acid 3.33 wt % ously in about a 5-milligram dose. For the purposes of the Citric Acid 2.00 wt % present invention, apomorphine or a similarly acting dopam Avice PH102 15.OO wt % ine receptor agonist is administered in an amount Sufficient Methocel E4M 10.00 wt % to excite cells in the mid-brain region of the patient but with Aspartame O.67 wt % minimal side effects. This cell excitation is believed to be Magnesium Stearate O.33 wt % part of a cascade of Stimulation that is likely to include 35 neurotransmission with Serotonin and oxytocin. If desired, and in order to facilitate absorption and thus It is known from studies with males that the dopamine bioavailability, the presently contemplated dosage forms can receptors in the mid-brain region of a male patient can be also contain, in addition to tabletting excipients, Stimulated to a degree Sufficient to cause an erection by the B-cyclodextrin or a B-cyclodextrin derivative Such as Sublingual administration of apomorphine So as to maintain 40 hydroxypropyl-B-cyclodextrin (HPBCD). Illustrative dos a plasma concentration of apomorphine of no more than age forms containing HPBCD are shown in Tables II and III, about 5.5 nanograms per milliliter (5.5 ng/ml). below. The pharmacokinetics of apomorphine are the same for both female and males, based on apomorphine hydrochlo TABLE II ride Studies with humans (Parkinson's disease) and animals 45 reported in the literature. Thus, the onset and duration of Apomorphine Hydrochloride Sublingual Tablets effect from a given dose of apomorphine in men compared With HydroxVDropyl-B-Cyclodextrin to animals applies to females as well. mg/Tab It was found that an intravenous dosage of apomorphine of about 100 micrograms per kilogram (ug/kg) of body 50 Apomorphine Hydrochloride 4.0 HPBCD 5.0 weight was optimum for producing a vasculogenic effect on Ascorbic Acid 1O.O nerve stimulated vaginal and clitoral blood flow in female PEG8OOO 39.5 rabbit Studies. For human females, this dosage correlates to Mannitol 39.5 an optimum dosage of about 1/10 or 10 ug/kg of body Aspartame 2.O weight. In Sublingual tablet forms, the bioavailability of 55 apomorphine is about 13% compared to Subcutaneously TOTAL 1OO.O administered apomorphine hydrochloride. ASSuming an average female body weight of about 70 kilograms, a Significant Sexual readineSS dose of apomorphine would be TABLE III about 76 ug/kg or about a 5.3 milligram (mg) tablet. A 60 Apomorphine Hydrochloride Sublingual dosage range of about 2 mg to about 12 mg, therefore, would Tablets With B-Cyclodextrin produce Sexual readiness (i.e., clitoral erectogenesis and vaginal engorgement on ) in women. mg/Tab Sublingual administration preferably takes place over a Apomorphine Hydrochloride 5.0 time period in the range of about 2 to about 10 minutes, or 65 B-Cyclodextrin 2O.O longer, more preferably about 15 to about 20 minutes prior Ascorbic Acid 5.0 to Sexual activity. The amount of apomorphine administered 5,945,117 S 6 centration of apomorphine can be maintained. More TABLE III-continued preferably, the dissolution time in water for the presently contemplated dosage forms is about 3 minutes to about 5 Apomorphine Hydrochloride Sublingual minutes. Tablets With B-Cyclodextrin The following examples further illustrate the vasculo mg/Tab genic effect of apomorphine on vaginal and clitoral blood flow in females, employing an appropriate female animal Mannitol 68.9 Magnesium Stearate 1.O model. D&C Yellow 10 Aluminum Lake O1 Methods TOTAL 1OO.O New Zealand White female rabbits (n=6, about 3.5-4 kg) were anesthetized with intravenous administration of pen The onset of nausea can be obviated or delayed by tobarbital. A 20 gauge angiocatheter was placed into the delivering apomorphine at a controlled dissolution rate So as right carotid artery for measurement of Systemic arterial to provide circulating Serum levels and mid-brain tissue 15 levels of apomorphine Sufficient for vaginal and clitoral preSSure. A midline abdominal incision was made and the engorgement without inducing nausea. When apomorphine pelvic nerve branch to the vagina and was dissected. is administered at or near the relatively higher amounts of Nerve stimulation was performed with a Harvard Submin the aforementioned dosage range, the likelihood of nausea iature electrode placed around the pelvic nerve branch to the onset can be reduced by concurrent administration of a vagina and clitoris and connected to a Grass SD-9 Stimula ganglionic agent (inhibitor of ganglionic response) Such as tor. Clitoral intracavernosal and vaginal wall blood flow nicotine or lobeline Sulfate. For this purpose, the weight were measured with a laser Doppler flow probe placed ratio of apomorphine to ganglionic agent is in the range of directly into the clitoral cavernoSal tissue or into the vaginal about 10 to about 1. wall and connected to a laser Doppler flowmeter. Other antiemetic agents that can be used in conjunction 25 Basal arterial blood pressure and clitoral and vaginal with apomorphine are antidopaminergic agents Such as blood flow were each recorded before and then after stimu me to clopramide, and the phenothia Zines, e.g., lation of the pelvic nerve branch to the clitoris and vagina. chlorpromazine, prochlorpe razine, pip amazine, After this, apomorphine was administered through the ear thiethylperazine, oxypendyl hydrochloride, and the like. vein in a dose response manner (0.05 mg/kg, 0.1 mg/kg, 0.2 Also Suitable are the Serotonin (5-hydroxytryptamine or mg/kg, 0.3 mg/kg and 0.4 mg/kg). The effect of apomor 5-HT) antagonists Such as domperidone, odansetron phine administration on arterial blood pressure and clitoral (commercially available as the hydrochloride salt under the and vaginal blood flow were each recorded before and then designation ZofrancE), and the like, the histamine antago after nerve Stimulation. nists such as buclizine hydrochloride, cyclizine hydrochloride, dimenhydrinate (Dramamine), and the like, Results the parasympathetic depressants Such as Scopolamine, and 35 the like, as well as other anti-emetics Such as metopimazine, 1. Effect of apomorphine on clitoral intracavernosal blood trimethobenzamide, benzcuinamine hydrochloride, dipheni flow. dol hydrochloride, and the like. Stimulation of the pelvic nerve branch to the vagina and Nicotine-containing dosage forms and domperidone clitoris caused a significant increase in clitoral intracavern containing dosage forms are illustrated in Table IV, below. 40 osal blood flow. Intravenous administration of apomorphine did not affect baseline clitoral intracavernosal blood flow. TABLE IV Intravenous administration of apomorphine at concentra tions of 0.05 mg/kg to 0.2 mg/kg caused a concentration Apomorphine Hydrochloride Sublingual Tablets dependent increase in nerve Stimulation-induced peak clito Containing an Anti-Emetic Agent 45 ral intracavernosal blood flow, as depicted graphically in mg/Tab FIG. 1. In particular, apomorphine at 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg caused a Statistically significant increase in Apomorphine Hydrochloride 5.0 Ascorbic Acid 5.0 nerve Stimulation-induced peak clitoral intracavernosal Mannitol 67.9 blood flow compared to that observed before apomorphine Magnesium Stearate 1.O 50 administration (FIG. 1). Nicotine 1.O 2. Effect of apomorphine on vaginal wall blood flow. p-Cyclodextrin 2O.O D&C Yellow 10 Aluminum Lake O1 Intravenous administration of apomorphine did not affect basal vaginal wall blood flow. Apomorphine at concentra TOTAL 1OO.O Apomorphine Hydrochloride 5.0 55 tions of 0.05 and 0.2 mg/kg caused a concentration depen Ascorbic Acid 5.0 dent increase in nerve Stimulation-induced peak vaginal wall Mannitol 58.9 blood flow, as graphically depicted in FIG. 2. Intravenous Magnesium Stearate 1.O administration of 0.1 and 0.2 mg/kg apomorphine caused a Domperidone 1O.O Statistically significant increase in nerve Stimulation-induced B-Cyclodextrin 2O.O peak vaginal wall blood flow compared to that observed D&C Yellow 1.0 Aluminum Lake O1 60 before apomorphine administration (FIG. 2). TOTAL 1OO.O Apomorphine at concentration of 0.4 mg/kg produced an adverse effect on nerve Stimulation-induced increase in The preferred Sublingual dosage forms dissolve within a vaginal wall blood flow. time period of at least about 2 minutes but preferably less 65 3. Effect of apomorphine on Systemic arterial preSSure. than about 10 minutes. The dissolution time can be longer, The effect of increasing doses of apomorphine on dias however, if desired as long as the necessary plasma con tolic arterial pressure is shown in FIG. 3. Intravenous 5,945,117 7 8 administration of apomorphine caused a concentration 2. The method in accordance with claim 1 wherein the dependent moderate decrease in diastolic arterial pressure Sublingual dosage form contains about 2 milligrams to about while having minimal effect on Systolic arterial preSSure. 12 milligrams of apomorphine. 3. The method in accordance with claim 1 wherein the Conclusion amount of apomorphine administered is in the range of Intravenous administration of apomorphine at a concen about 25 to about 80 micrograms per kilogram of body tration of 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg caused a weight. Significant increase in nerve Stimulation-induced peak cli 4. The method in accordance with claim 1 wherein the toral intracavernoSal blood flow. Intravenous administration apomorphine is administered as the hydrochloride Salt. of apomorphine at a concentration of 0.1 mg/kg and 0.2 5. The method in accordance with claim 1 wherein the mg/kg caused a significant increase in vaginal wall blood apomorphine is administered together with a B-cyclodextrin. flow. The main side effect of intravenous administration of 6. The method in accordance with claim 1 wherein the apomorphine noted was a moderate decrease in diastolic B-cyclodextrin is hydroxypropyl-3-cyclodextrin. blood pressure. A dose of about 0.1 mg/kg was judged 15 7. A method of Stimulating dopamine receptors in the optimal. mid-brain region of a human female to cause clitoral erec Studies with this female rabbit model showed that the togenesis and vaginal engorgement which comprises admin hemodynamic mechanisms of clitoral erection and vaginal istering to the human female apomorphine in a Sublingual engorgement depend on the relaxation of clitoral cavernoSal dose containing about 25 to about 80 micrograms of apo and vaginal wall Smooth muscle. It is also known that in the morphine per kilogram of body weight and at a rate So as to female human, of the vagina entails lubri maintain a plasma concentration of apomorphine of no more cation of the vagina and Swelling of the external genitalia than about 5.5 nanograms per milliliter during Sexual activ during Sexual excitation. Thus, the enhancement of clitoral ity. blood flow by apomorphine in the female rabbit was judged 8. The method in accordance with claim 7 wherein the indicative of improving clitoral erection and the enhance ment of vaginal blood flow by apomorphine was judged 25 plasma concentration of apomorphine is maintained in the indicative of increasing vaginal lubrication and augmenting range of about 0.3 to about 4 nanograms per milliliter during vaginal engorgement in human females. Sexual activity. It is known that dosage ranges with apomorphine hydro 9. The method in accordance with claim 7 wherein the chloride are species dependent. In humans, the effective plasma concentration of apomorphine is maintained in the dosage compared to animals is about 1/10. Thus, an opti range of about 1 to about 2 nanograms per milliliter during mum dose of about 0.1 mg/kg given intravenously, based on Sexual activity. the female rabbit study would correlate to an effective dose 10. A method of ameliorating Sexual dysfunction in a of about 0.01 mg/kg in a human female. Since Sublingual human female which comprises administering to Said human administration of apomorphine is known to provide about 35 female apomorphine or a pharmaceutically acceptable acid 13% bioavailability compared to subcutaneous administered addition Salt thereof Sublingually prior to Sexual activity, and apomorphine, a dosage of about 76 micrograms/kg or about in an amount Sufficient to Stimulation induce clitoral erec 5.3 mg tablet for a 70 kg weight woman would produce a togenesis and vaginal engorgement and to maintain a plasma Significant Sexual readiness (clitoral erectogenesis and vagi concentration of apomorphine at a level of no more than nal engorgement on Sexual stimulation). Thus, a dosage 40 about 5.5 nanograms per milliliter. range of about 2 to about 12 mg, preferably about 2 to about 11. The method in accordance with claim 10 wherein the 8 mg., more preferably about 4 to about 6 mg. is Sufficient plasma concentration of apomorphine is maintained at a for producing Sexual readineSS in women without inducing level of about 0.3 to about 4 nanograms per milliliter. Substantial nausea. 12. The method in accordance with claim 10 wherein the The foregoing discussion and the reported Studies are 45 plasma concentration of apomorphine is maintained at a intended as illustrative of the present invention and are not level of about 1 to about 2 nanograms per milliliter. to be taken as limiting. Still other variants within the spirit 13. The method in accordance with claim 10 wherein the and Scope of this invention are possible and will readily amount of apomorphine administered is in the range of present themselves to those skilled in the art. about 2 milligrams to about 12 milligrams. We claim: 50 14. The method in accordance with claim 10 wherein the 1. A method of ameliorating Sexual dysfunction in a amount of apomorphine administered is in the range of human female which comprises administering to Said human about 25 to about 80 micrograms per kilogram of body female apomorphine or a pharmaceutically acceptable acid weight. addition Salt thereof as a Sublingual dosage form and in an 15. The method in accordance with claim 10 wherein amount Sufficient to increase intraclitoral blood flow and 55 apomorphine is administered as the hydrochloride Salt. vaginal wall blood flow on stimulation of said human female but leSS than the amount that induces Substantial nausea.