SA99200430B1 - NORMALIZATION OF SEXUAL RESPONSE GENITAL TISSUE - Google Patents

Abstract

Abstract: According to one embodiment, the present invention relates to a method for normalizing the timing of sexual response in mammals involving administration of an amount of an initiator of the central nervous system sexual response in an amount sufficient to cause genital vasodilation, but in an amount less than required To induce effective vasocongestive arousal congestion. The method is not applied to adjust or calibrate the timing of sexual response in humans only, but it can be applied in the breeding of animals of commercial value such as horses, cattle, sheep, swine and the like and domesticated pets such as dogs and cats. An alternative embodiment, the present invention relates to a method for the prophylactic treatment of long-term tissue degeneration of the genital organs comprising administration to breasts to initiate a central nervous system sexual response in an amount sufficient to induce genital vasodilation but less than the amount required to induce effective vasocongestion. The preferred initiator of the CNS sexual response is apomorphine or its salt plus a pharmaceutically acceptable acid addition salt.

Description

B Methods for calibrating the normalization of sexual response and improving genital tissue degradation in the long term Full description Technical field The current demand relates to pharmaceutical formulations and medical methods of treatment for 0. More specifically, the present invention focuses on the use of a compound that acts as a central nervous system sexual response initiator to calibrate 8 the timing of the sexual response in humans and 0 and for prophylaxis or long-term treatment of damage to genital organs . Background of the invention Proper sexual functioning in men and women depends on a set of steps including 1 (10) induction of an appropriate anticipation mental set (“desire” (Y) induction of vascular congestion Effective vasocongestive arousal (erection 4 in the male is sufficient for vaginal penetration, and in the female clitoral erection, local engorgement and lubrication 6 and (0) orgasm, and the timing of this occurs Steps between couples having sex 1 by one or more different compounds acting in neurological pathways in the midbrain or mid-brain 01 0168606. These pathways include those called eserotonergic, dopaminergic, and dopaminergic pathways. oxytocinergic and nitrous oxide 6p011:0<06.v The timing of different aspects or parameters of the sexual response between couples having sex is important and often or sometimes psychological dysfunction is disproportionate due to psychological deficiency in one spouses or both. And there is a "biogenic dysfunction" or "normal" deficiency in the timing of the response, even in couples who show sexual responses that fall within the normal situation.

The orgasm in the male includes the sensation of emission, followed by ejaculation, and the sensation of emission is considered one of the throbbing matters that cannot be called (Lelia). By the contractions of the muscles that line the wall of the outer third of the vagina Ve 8. In both sexes, generalized muscular tension usually occurs, perincal contractions and involuntary pelvic movement 8. The orgasm is followed by a return to the normal state, cresolution, a feeling of general relaxation, well-being, and muscular relaxation. During this stage, men do not respond physiologically to another erection and orgasm for a varying period of time.

ve otherwise; Women may respond to another stimulus almost soon. The sexual response occurs by a balanced interaction between the sympathetic nervous system and the parasympathetic nervous system, and vascular congestion or erectile tumescence is largely induced by parasympathetic outflow (cholinergic action). Ue Y is cholinergic while orgasm is sympathetic. Ue Y is adrenergic. Ejaculation is almost entirely sympathetic while Y involves

Emission is a more nicely balanced blend of friendly spurt and friendly nadir. A normal biological response in humans usually results in ejaculation within about two minutes or more after vaginal penetration. The majority of women are not able to reach an orgasm within this short period of time; One reason for this problem is the inappropriate timing of ve sexual response between couples; Even when the sexual responses to each are within the responses

¢ Physiological normal. In the case of sexual deficiency in males known as premature ejaculation, the problem is severe as well. The cause of premature ejaculation in males may be psychological or related to the biogenesis of a particular person; Various treatment methods have been suggested. These include therapeutic counseling, techniques for learning to control ejaculation, and the use of Ja serotonin re-uptake inhibitors, fluoxetine hydrochloride (Prozac®) and sertraline hydrochloride (Zoloft). Registered trademark (Zoloft®) to delay the onset of feeling triggered. The problem of inappropriate timing of the sexual response is not limited to ddl but also occurs in 0 inferior cubs for example JB in the offspring of animals of commercial value Jie the mustang cattle, sheep, swine, etc. and domestic pets such as dogs and cats.US Patent No. 5,775,705 (Serial No. 47,4948 (CAO) describes a method for improving erectile dysfunction in a male patient by administering apomorphine or a salt thereof in an amount sufficient to produce an erection adequate for vaginal penetration However, less than the amount that causes nausea Vo, there remains the need to develop an effective method for calibrating the timing of the sexual response in mammals, including humans, and in particular in those cases involving premature ejaculation in human males. In addition; There is a need for agents for the prophylactic treatment and treatment of the effects of long-term degeneration or deterioration of genital tissues in mammals. x The general description of the invention and it has been found; Tg One embodiment of the present invention is the administration of acute a Sal 0 of an agent acting in midbrain dopaminergic pathways; serotonergic oxytocin or nitroxidation of the action to initiate a sexual response in mammals in an amount insufficient to cause effective le-engagement induction; But in an amount sufficient to cause an increased dilatation of the genital vessels

It calibrates the timing of sexual response among couples who have sex. In another embodiment; The present invention relates to a method for improving long-term genital tissue damage comprising chronic administration of a CNS sexual initiator in mammals in an amount less than required to cause vasocongestion in said mammal but in an amount sufficient to induce vasodilation in the genital organs. Brief explanation of the graphics Figure 1: represents a Glad graph of average apomorphine concentrations in plasma after administration of apomorphine subcutaneous 1 and sublingual. Detailed description: In the first embodiment of the invention; A breast CNS sexual response initiator given in an intense dose to one or both spouses in the period prior to sexual intercourse preferably in a dose insufficient to induce effective vascular congestion; But 1 - at a dose sufficient to increase genital vasodilation to help calibrate the timing of sexual response among couples having sex. The drug is given during the time period ranging from about two minutes to about one hundred and twenty minutes before sexual relations; Preferably in the time period ranging from about two to sixty minutes before sexual relations. And in the case in which the male suffers from sexual insufficiency called sexual arousal disorder (pac) sexual arousal disorder Y. the ability to experience psychological desire (psychic readiness) and / or maintain an erection satisfactory for normal intercourse) or the condition known as premature ejaculation, the drug is given to the husband The remembrance. and when the female suffers from a sexual stimulation disorder (permanent or recurrent failure to achieve psychological desire and/or maintain the lubrication and swelling response on 0N11H “8”); The property is given to the female husband. And in the case where both the male and female spouses suffer from

+ the aforementioned disorder; The drug may also be given in combination with a low dose of androgen 0 to make the effect of the mediator drug effective in the mesencephalic pathways. Androgen means ALD testosterone cdihydrotestosterone and dehydroepiandrostenedione either in free base forms or in the form of salt or pro-drug. The term de ya “acute dose” or “acute administration” of a drug means administration of the drug to the Bg patient for a specific program as needed. The term “central nervous system sexual response initiator” refers to a compound that acts in Any of the midbrain dopaminergic, serotonergic, oxytocinergic or nitroxidative pathways of mammals ye to initiate a sexual response Dopaminergic pathway precursors include apomorphine capomorohine <bromocriptine lysiurid 11901106 cmethergoline pergolide 011:06p6:8pm; piribidil and quinpirole. Serotonergic pathway primers include serotonin receptor agonists such as f=nS she EO CY(1-iodophenyl)-1-aminopropane-1 ( 2,5-dimethoxy-4-iodophenyl)-1-aminopropane 8-methoxytryptamine 5¢methoxytryptamine alpha-methyl -* -hydroxytryptamine —=Y <a-methyl-5-hydroxytryptamine methyl-H < hydroxy 11 “2-methyl-5-hydroxytryptamine - acetyl-5-<hydroxytryptamine N-acetyl-S-hydroxytryptamine buspirone and sumatriptin 7. The precursors of the oxytocin pathways include the oxytocin analogues Isotocin < isotocin cr pitocin ccarbetocin Lys “Lys-conoprossin Cris 5 93 6S deaminooxytocin ¢ deaminooxytocin myotocin 0168010010 antocin cantocin columitocin columitocin aspargitocin caspargitocin valtocin cvaltocin asvatos yin casvatocin phasvatocin and seritocin

The preferred central nervous system sexual response initiator for use in the methods of the present invention is apomorphine or asl or its salt forms or prodrugs. The “6=(R)” apomorphine is T-Cl 1-tetrahydro-1-methyl-(4 11)-di-mbenzo [fg ede] quin and lin-10” 111 diol (R)-5 ,6,6a-T-tetrahydro-6-methyl-(4H)- cdibenzo[de,g]quinoline is a derivative of morphine obtained by treating morphine with concentrated hydrochloric acid (see What was reported by L. Small, A.A., and his collaborators, in Org Chem magazine, vol. 0 p.: FYE) 194 AD, or by heating morphine with zine chloride (see what came about Mayer - 0 in Ber magazine, volume of p: (AVY) IVY, and the compound has the following chemical structure: Ham Of on A A 0 !Apomorphine dl Tag center chiral center DY at site 1a. JL. yo Teomere described JL.

Neumeryer and collaborators, total synthesis “of the racemic mixture” in the journal of Pharm.

Sci vol 0d p: av. ) YAO 1 um' and described in. j. Ram .7.1 good. the. Neumeryer, 1.1 Synthesis of separate enantiomers in Org Chem Journal, Vol. 87 p.: 7870 AMY) 1 pm. The compound possesses a basic nitrogen atom at position 1 and thus is able to exist in the form of a free base in addition to the forms of salts in addition to the acid. And he has

A

The compound is given in the form of a free base or in the form of one of its pharmaceutically acceptable salts or derivatives of prodrugs thereof. LS is used in this statement; The term “pharmaceutically acceptable salt” refers to those salts that are considered appropriate within the scope of sound medical judgment sound > 6 0601681 for use in contact with tissues of humans and lower animals without a toxic response ctoxicity irritative irritation allergic Allergic, etc. Considered as commensurate with a reasonable benefit/risk Pharmacologically acceptable salts are defined as Tus in the technique For example, SM Berge and collaborators described the salts Pharmaceutically accepted in detail in the Journal of Pharmaceutical Sciences Volume A p.: (pV 577) YAY 0 The salts are prepared at the reaction site during the final isolation and purification of the compounds of the invention; or separately by the reaction of the functional group In the free base with a suitable organic acid 0 Examples of salts include addition with a non-toxic acid; pharmaceutically acceptable salts of the amino group sire formed with inorganic acids such as chydrochloric acid hydrobromic acid chydrobromic acid vo aes phosphoric acid sulfuric acid and perchloric acid or with organic acids jie acetic acid cacetic acid oxalic acid maleic acid tartaric acid, acid 16: kanah, citric acid, succinic acid, malonic acid, using other methods used in the technique such as ion exchange, jon exchange, and other pharmaceutically acceptable salts include cadipate Ye salts Alginate alginate ascorbate aspartate caspartate benzene sulfate cbenzenesulfonate benzoate benzoate disulfate cbisulfate borate cborate butyrate cbutyrate camphorat ccamphorate camphor sulfate ccamphorsulfonate citrate ccitrate pentane cyclopentane propionate digluconate dodecyl sulfate dodecylsulfate ethane sulfate cethanesulfonate cformarate fumarate 7 glucoheptonate 1106maglycerophosphate p1d:1om6©:00105Ra; gluconate 101.0 chexanoate hexanoate cheptanoate heptanoate chemisulfate hemisulfate gluconate 2 hydrony- nathi-iscordium-1 sulfate hydroiodide ios! daurate sulfate lactate lactate clactobionate lactobionate cethanesulfonate methane sulfate amalonate malonate maleate emalate malate laurylsulfate cnicotinate nicotinate ¢2-naphthalenesulfonate 7-taphthalenesulfonate 061180510756 ° cpalmoate palmitate cpalmitate palmitate oxalate oxalate coleate oleate enitrate nitrate 3-phenyl enylpropionate persulfate cpectinate pectinate cpropionate propionate cpivalate pivalate cpicrate rollers cphosphate phosphate propionate schiosinate ctartrate tartrate csulfate sulfate ¢succinate succinate stearate stearate and valerate undecanaoate para-toluene sulfate 15600316 no 06 about 1 m-m undecanoate thiocyanate Ve

valerate and the like. The term 'prodrug' presupposes compounds that are rapidly transformed in vivo (tl parent compound, for example) by hydrolysis in blood 510600. A comprehensive description of the concept of a prodrug is given in what was reported by T. Higuchi T.

Higuchi and in. Veo Stella 17. Stella in a book entitled “Pro-drugs as Novel Oily System” vol. 104 of the American Chemical Society Symposium Series (ACS) American Chemical Society (99751). Examples may be found of esters that are useful as prodrugs for compounds containing On carboxyl groups, on pages 14-71 of a book entitled “Bioreversible Carries in Design” published by EB.

Roche Pergamon Press Pergamon

(p) AAV) Press v.

The term "pro-drug ester group" refers to any of several ester-forming groups that are hydrolyzed under physiological conditions 5M. dtl includes the ester wd groups of a prodrug Ssh sin methyl ¢pivoyloxymethyl cacetoxymethyl phthalidel enric 1 indelindanyl

0 in addition to other such combinations known in methoxymethyl technically. Pharmaceutically As used in this statement; The term "pharmaceutically acceptable hydrolyzed in vivo ester" includes those that readily hydrolyze into esters to appropriate "acceptable ester"; ester in the human body to remain the base compound or its salt. Ester groups include 0 aliphatic carboxylic acids, for example; Those derived from aliphatic carboxylic acids calkenoic cycloalkanoic acids, especially diay alkanoic acids (Waa) are acceptable alkyl moieties where each moiety contains a calkanedioic and a cycloalkanoic alkane and includes the umbrella of carbon esters 1 carbon atoms usefully not more than alkenyl butyrate propionates propionate acetate acetate formates especially formate compounds 01 esters ethylsuccentaes and ethylsuccinate acrylates acrylates cbutyrates and the term “titration” means The timing of the sexual response in human beings Adjust the onset time, the duration of survival, and the phenomena of the sexual response so that these parameters tend towards the normal response to humans under the calibration of the sexual response. The term “premature ejaculation” in the male means sexual insufficiency that is characterized by continuous or intermittent ejaculation before, at, or shortly after vaginal penetration. More generally, the term may be defined as ejaculation that occurred prior to personal desires. a swollen penis erection; But change Ye

Jdabia is sufficient for vaginal penetration; and in the female; Clitoral erection, engorgement and swelling of the vagina and labia, an erection sufficient for vaginal penetration. “SAN” in “led” means “induction of vasodilation” and is an example of a drug from the apomorphine class. The following study illustrates the use of apomorphine, the compounds it includes the present invention; To calibrate the timing of the sexual response by administering the drug to males to prolong erection duration. Yo 'Yeo

A

A three-stage, double-blind, randomized, drug-controlled multicenter study was conducted in patients diagnosed with male erectile dysfunction without the use of the TV component on Jie in one of the main organic Jie treatment periods. And in every series; Patients received medication at intervals of apomorphine (mg) of apomorphine 1 and doses of (?mg; mg or saa doses) of the other treatment. This arrangement resulted in approximately one-third of the patients receiving 0.3 apomorphine for the study; Patients and their sexual partners were given Gig instructions and during the treatment periods of the study; Gay completed trying to have intercourse at least twice a week. Each time the drug was taken, a questionnaire was taken by the patient and his wife and sent by mail to the person conducting the study. The questionnaire recorded the date and time the study drug was taken; erection for erection; If sexual intercourse > 0 occurred or did not occur; And the degree of satisfaction associated with each attempt. The patient also completed the erection and erection associated with the use of the drug, according to the study, a latency diary in which the latency period, the use of concomitant drugs, and any adverse effects were recorded. If an antiemetic (all) erection occurs after administering the drug according to the study to the patient, the duration of the erection and the time to erection are recorded in .4 to 1 in the patient's diary. Data from these studies are recorded in the tables of 0s mg; Y) the mean duration of erection in minutes for patients who received a dose of 1 vs. placebo in each case for all apomorphine; mg or 76 mg) of apomorphine trials. If the attempt to produce an erection fails; A value of 0 min is used in to significant differences of 1 and the data in the table statistical analysis indicates the dose-dependent statistical significance of the mean duration of erection between drug and drug - © placebo; With the decrease in the mean values, by consensus, by including data with a value of zero, from attempts that did not lead to an erection, to an erection only. The data is indicated in ag, and the table * shows the data for those attempts that did not. There was also a statistically significant dose-dependent difference in survival time of 1.5

1 amount of 7 mg and those de ja erection»; With a difference of approximately 0 minutes between patients who took a drug and those who received a placebo. The table shows ? Mean time to erection for patients included in the study, showing data for all 10 minutes of trials; and in those cases that did not achieve an erection; A value for erection was used in the statistical analysis. The data in Table 7 show differences in latency periods between the 0 and those who received a placebo; However, the differences reflect apomorphine for patients who received apomorphine min for those cases in which 01 did not potentially achieve values in the data of an erection. Table £ shows data for patients whose attempt to achieve an erection was successful only. The data is shown in the table; There was no statistically significant difference in the mean time to erection between 10 patients who received the drug and those who received a placebo; with an average erection time of about 1 minute to ; 1 One of the findings from the data in the tables is that at the doses tested apomorphine did not shorten or lengthen the time to onset of erection, administration of apomorphine despite effects on duration of erection maintenance compared to placebo; But it led to a significant increase in the duration of the erection. And taking into account the generally long time usually required for females to reach orgasm in the sexual response cycle; Giving the drug to the male spouse calibrates the timing of the sexual response between sexual intercourse pairs. The data in the two tables are considered? And another useful clarification. The median time for erection was in, however; Evaluation Lo HE 11 minutes for the study at all doses tested Gy patients received the drug © shown in the graphic capomorphine for pharmacokinetic apomorphine according to the pharmacokinetics graph shown in Figure 1- shows that the time required to reach the maximum Subcutaneous subcutaneous apomorphine levels after administration of apomorphine reached the blood serum level of pharmacokinetics at Ty as indicated by curves of approx. Change Vo to maximum after giving plasma concentration 1 plasma concentrations did not reach Fig. ye

VY

(The formulation used in the studies shown sublingual sublingual apomorphine apomorphine min. 01 to ?); Except after about 1 in the tables from 1 Table - ee Duration of erection survival Results of the statistical analysis of the average duration of survival on the basis of all trials Branch of the study Treatment Number of mean time Difference in standard error coefficient Probability dawg Patients (minutes) Average (minutes) . In 34 mg of apomorphine, the drug AY ay AR

Loa CAAT oN TA ¥.,Yoo 111 Placebo apomorphine 1,4.7 75 mg apomorphine +4 . : m / m Yoav EY apomorphine drug Jie < 4 m ¥ mg of apomorphine drug P Love 3,471 . The apomorphine drug YAS 115 Jie 'is considered statistically significant at a probability factor = 1 2.5. Notes: The 'attempt' is defined by taking the drug (Ey) for the study and its completion by the patient who has adequate efficacy in the patient questionnaire. The analysis was conducted on the average duration of erection for each patient during each period. For attempts that did not lead to an erection; A survival time of zero minutes in the statistical analysis All time averages, standard errors, and probability coefficients are considered from the CANOVA model with effects of treatment regimen, period, sequence, and patient within sequence.

a table? AA SACLE (PY) Survival of erection The results of the statistical analysis of the average duration of survival based on all attempts that achieved an erection, branch of the study, number system, mean time difference in mean. Standard Error in Treatment Patients (minutes) (minutes) Treatment ale 1 nalavir pile of apomorphine 0 77 m7" L404 apomorphine dua & Ye Ve Jie b 4 po. ¢ 0 mg of apomorphine AT 714 mm ATA apomorphine Drug Jae lm yr YA 5 a A | .. 7 mg of apomorphine AY drug VAY tam apomorphine placebo AY 7 Notes: An “attempt” is defined as study drug Gy completion and completion by a patient with adequate efficacy in a patient questionnaire. The analysis was conducted on the mean duration of erection retention for each patient during each period. Attempts were not used Did not result in an erection in the statistical analysis.All time averages and standard errors are from a CANOVA model with effects for treatment regimen, period, sequence, and patient within sequence.\Y.o

Table 1? Time to erection Mean Kaplan-Maier Kaplan-Maier assessment Time to erection based on all trials Branch of study System Number of patients mean CI 6/9 0 { treatment (min gr Yi ale 1 Nate 0 YT 11 from apomorphine A drug pile apomorphine oY, A1-§¥,Vo No 111 A placebo drug? VY £V, YA 1 placebo drug Y no offense EY AY vo LEIS drug apomorphine once EAT Suen placebo drug: Notes for the study And completed by the patient who has adequate activity in the Gay questionnaire defines "attempt" by taking the drug patients. lead to an erection; use a time to erection of \Y.o

V1 £ Table Time to Erection for Mean Kaplan-Maier Kaplan-Maier Evaluation of Time to Erection Based on the Attempts at which an Erection Occurred Branch of Study Patient Number System | Mean treatment time Confidence interval % q0 Treatment VLAN mg of apomorphine Drug 4% Mn 1 apomorphine

VE em de VY, 1v AY a placebo

VOY by YY, 0 ? mm of apomorphine

Yo, oN oe 101 Dla q¢ Jae medicine what im righteous Vy ry vad? mg of apomorphine

Yo, Placebo 7 7 PCH Notes: A “attempt” is defined as taking the drug according to the study and completing it by the patient who has an appropriate efficacy in the patient questionnaire. The analysis was conducted on the average time to erection for each patient during each period 2 The analysis is based on the first eight attempts. And the; The median time to erection is about buccal, which is one-fifth of the time required to reach the maximum plasma concentration after buccal administration. Erections were observed in patients who had difficulty achieving lays. 0

VY begins after therapeutic effect Ladle erection when not taking the drug. The data show an exact effect of oral administration. As shown by the examination according to Figure 1; At this point in time the drug “achieves approximately one-fifth to a quarter of the maximum blood serum levels,” indicating that it achieves the desired effect at lower doses than initially thought necessary.

Fa and in the time period between administration of apomorphine and about 0? minutes after administration; Plasma concentration curves for all three doses tested (7 mg; The production of apomorphine concentrations in plasma generally in the range from about 107 ng/ml to 5 0.7 ng/ml is considered preferable to the method of this embodiment according to the invention. Thus giving a dose of apomorphine is less than the dose required for effective congestive induction; But it is enough to increase blood flow in the genitals, effective in prolonging the duration of the erection and helping in calibrating the timing of sexual responses between spouses in intercourse. Preferably, the dose administered to the patient in this embodiment according to the invention is generally sufficient to produce mean plasma levels of less than about YO ng/mL; The best is in the range from about 1.07 ng/mL to about 1.75 ng/mL. These serum levels result from doses typically in the range from about 0.7 mg to about 4 mg per dose given; Ve based on the formulation delivery system and in this embodiment according to the invention; The drug is disposed of by tacute administration, ie; In a dose given as needed immediately in the period of time prior to sexual intercourse. It is preferable to administer the drug in a rapidly acting formulation to the device, and any method known to a person practicing pharmaceutical formulation techniques that achieves this purpose may be used. for example; The drug may be dispensed into the device quickly through a liquid formulation given under the tongue »Tablet 80166 a round lozenge tablet or a sucking tablet 101100 kept in a pill and sucked by the cheek or by using a suppository given intravaginally or intravaginally rectally or by using powder, gel, cgel, suspension, spray combination inside the nose, intranasal spray for

VA sterile The drug may also be given in the form of a sterile non-intestinal formulation or subcutaneous intramuscular injection parenteral formulation via sublingual cheek although dntramuscular formulations are preferable to use suppository For ease of administration and greater efficacy intranasal cbuccal resulting from patient acceptance. 5 For efficacy for a particular formulation; The drug is given directly in the Typ period, depending on the maximum time prior to sexual intercourse; usually during the period between about two and 11 minutes before sexual relations; Preferably during the period between about two and 10 minutes before sexual relations. In cases where the male sex partner suffers from sexual stimulation disorder; or ejaculate co- the drug is given to the male; and optionally with contributory cpremature ejaculation early 01 and in those cases of low androgen deal administration the female sex partner suffers from sexual induction disorder; The drug is given to the female; and optionally with low androgen de jal co-administration androgen 0 in the form of (1) “co-administration” meaning “co-administration” taking into account “apomorphine before apomorphine administration” separate dosage form Separate dose (Y and candrogen Consider pharmacokinetic profile for androgen apomorphine and androgen comitant administration Combined administration in those cases where the pharmacokinetic profile of the two drugs is similar The two drugs, candrogen 23, and the androgen, apomorphine, may be administered in combination with a single apomorphine, or they may be given at the same time in a dosage form in the form of a single dose 7 at apomorphine, and in studies that used female rats. A response to apomorphine was observed and testosterone-treated animals showed low-dose testosterone bending testosterone treatment with a combination of apomorphine 200010001106 and testosterone and gential grooming actions in the forward lumbar vertebrae 5 genital cleaning of the animal Yeo

YY.0

Another case related to Sale is sexual stimulation. The 05 androgens suitable for use in this embodiment according to the invention include testosterone “Ss ctestosterone” and “dehydroepiandrostenedione” and dehydroepiandrostenedione with testosterone being particularly preferred. When a covalent administration of androgen is used in this method the lady of the invention; Androgen is given in sufficient doses to produce plasma concentrations ranging from about 1 nanomol/liter (nmol/L) to 100 nanomol/L. LS will appear to someone familiar with the technology; It is reasonable to use the rat as a model for the affected vascular systems described in this statement; like; The pudendal and pudenal vascular system pudenal cand penile vasculature 01 Such studies should include appropriate doses and treatments Calon A Jie Other primates and humans. As demonstrated by cMordenti in a paper entitled “Man versus Beast: Pharmacokinetic Sealing in Mammals” in J Pharm.Sci' vol.: pp. AAT 0140-0174 (2) and similar articles; Dosage forms for animals such as rats may be used extensively directly to achieve dose levels in therapeutic applications in primate mammals including humans.One of the current inventors contributed to the development of a biological standard for erectile function in the rat model at an early date such as (44 hil) AY what follows on JBW Heaton 1.0 .177. Heaton and collaborators in 1.0:81 vol 058 p. The narrow effective dose range for an oral drug, apomorphine 0001000106, is approximately Soke when appropriately controlled for differences in body weight as described by Mordenti above (see JBW Heaton). 1.0.17 cHeaton and collaborators in Urology vol 46: pp. 715-701 (34680 AD). In an alternative embodiment of the present invention, it is given as the initiator of a sexual response to the central nervous system yo. Chronically at a low maintenance dose to prevent infection

YL

prolonged vasoconstriction cl dl improvement; or reverse the effects of damage to the reproductive organs and in this embodiment; The drug is given in the form of vasoconstriction repeated doses occurring for a long period of time; For example, once daily; once a week; Or, or a stored formula, transdermal patch, in the form of a stored formula, such as a patch on the dermis, biodegradable intramuscular intramuscular, biodegradable, depot formulation 2 -formulation maintenance supportive dc ja" or "chronic administration" and the two terms indicate " Chronic administration of the drug refers to the repeated, regular, systematic administration of the drug to the patient for a long period. “dose, normal clitoris, clitoris, flaccid penis, and contractions of the two vessels in the typical relaxed penis in tissues of oxygen, their non-enlarged bouncy. As a result; Such oxygen concentrations are closer to the oxygen levels of 0 in the veins than to the oxygen levels of the penis and clitoris from periodic vasodilation and increase the periodic vasodilation of the two vessels with the highest oxygen in these tissues. Oxygen levels interrupt oxygen levels supplied to the tissues of the penis and clitoris as well as vasodilation itself metabolic processes and remodeling of the vascular wall that TGF-P produces (Jie adverse metabolic processes Va leads to tissue damage on Long term Thus, under normal conditions, for example, the body's self-regulating i, a man has three to five erections every night in oxygenating and vasodilating tissues to dilate the body's self-regulating mechanism The penis For the purposes of this embodiment, the drug need not be administered in an amount necessary to induce vasoconstriction, ie, in the male a sufficient penetrating erection. Typically, a low dose is sufficient to induce vasodilation and blood flow. Increased penetration to the genitals is satisfactory; daily doses are usually sufficient to produce average concentrations of ng/mL preferably in the range of 1.7 in plasma of less than about apomorphine ng/mL to about 7 ng/mL 0.017 ml approximately vs

Maintaining such low serum concentration levels of the drug results in a tumescence that is not typical for copulation; But enough vasodilation occurs in the reproductive organs to counteract the harmful effects of the limited flow of all into the organs over time. Whereas the objective of this Tay embodiment of the invention is to obtain a stable, low blood serum level of the drug; The composition of the drug does not require that it be in the form of a rapid disposal of the drug to the device; Typical formulations known in the Jie technique can be used as pills; circular disks; syrups, elixirs, celixirs, suspension solutions, and the like; Like those described below. Pharmaceutical Compositions Pharmaceutical compositions suitable for drug administration (Lig of the present invention) include 1. A therapeutically effective amount of the drug formed with one or more pharmaceutically acceptable carriers 0. As used in this statement; 08014 'pharmaceutically acceptable carrier' means a non-toxic filler an inert solid csemi-solid or liquid; a diluent an encapsulating material or a combination thereof Auxiliary of any kind Some examples of substances that can act as acceptable carriers Vo in a pharmacy are sugars such as lactose glucose and sucrose of gall ¢sucrose starches such as cornstarch Li 5 corn starch Potato starch Cellulose cellulose and its derivatives Jie sodium carboxymethyl cellulose Ethyl cellulose tcellulose acetate s—Liludl and powdered lot tragacanth ¢malt gelatin fgelatin talc ttale excipients 7 such as cocoa butter cocoa butter tsuppository waxes oils Jie peanut oil epeanut cottonseed oil cottonseed ofl safflower oil : 50010/0;sesame oil ¢sesame oil olive oil corn oil rum oil; And soybean oil ¢soybean oil Glycols Jie tglycols Propylene glycol ¢propylene glycol Esters such as ethyl oleate, ethyl laurate, and agar 'agar vo' are pH-regulating agents Jie buffering agents (magnesium hydroxide) gael).

YY

hydroxide and aluminum hydroxide talginic acid JA water from a pyrogen ¢pyrogen-free water ¢isotonic saline Ringer's solution cethyl alcohol alcohol and phosphate buffering solutions, in addition to non-toxic compatible lubricants 5 such as sodium lauryl sulfate and cmagnesium stearatre, in addition to coloring agents. releasing agents “releasing agents” coating agents “coating agents” sweetening agents sweetening agents flavoring agents “flavoring agents” and aromatizing agents “perfuming agents” and there may be preservatives and antioxidants 5 in the composition, according to a decision The pharmaceutical compositions according to the invention may be administered to humans and other animals by dll rectally; by non-enteric route; intravaginally; topically (in the form of powders, ointments, or drops). Oral or nasal spray. Vo: Oral liquid dosage forms include comulsions, microemulsions, solutions; Hangings; Pharmacologically acceptable syrups and elixirs. In addition to the active compounds; Liquid dosage forms may contain inert diluents commonly used in the technique (eg water or other solvents, solubilizing agents, emulsifiers, cethyl alcohol, ye isopropyl alcohol cethyl carbonate ethyl acetate benzyl alcohol benzyl benzoate propylene glycol 7101 butylene glycol SL cl 3 -butylene glycol methylformamide edimethylformamide Oils (in particular; oils of cottonseeds, peanuts, maize, cgom, olive, castor, sesame), glycerol 116001 tetrahydrofurfuryl alcohol ctetrahydrofurfuryl alcohol polyglycol Ethene polyethylene glycols YY.o0

YY

Fatty acid esters of csorbitan and mixtures of these materials. In addition to inert diluents; Oral formulations may also contain adjuvants such as cooling agents, jal se emulsifying and suspending agents, sweetening agents; jal se flavour; And factors ° perfuming. ALE injectable preparations may form eg sterile aqueous or oily 5 injectable preparations (885) of the known technique using dispersing or wetting agents and appropriate suspending agents. The sterile injectable preparation may be; a solution or a suspension or sterile injectable emulsion in an acceptable non-toxic non-Ligne diluent or solvent eg (Jia as a solution in Osu Ve) Diol 1.3-5018060101. Among the 0 excipients vehicles and acceptable solvents that may be used are water Ringer's solution ay solutions of USP and Lisotonic sodium chloride In addition sterile fixed oils are usually used as a solvent or suspension medium For this purpose any bland fixed oil may be used Including synthetic mono or diglycerides In addition 1 Jie fatty acids oleic acid are used in the preparation of injectables Injectable formulations can be sterilized, for example; By filtration through a bacteria retaining filter or by combining sterilizing agents in the form of sterile solid formulations that can be dissolved or dispersed in sterile water or in a sterile injectable medium (AT) before use. vo and to prolong the effect of the drug; It is desirable to slow the absorption of the drug when injected subcutaneously or intramuscularly; This can be achieved by using a liquid suspension of a crystalline or amorphous material that has poor solubility in water. Hence, the rate of absorption of the drug depends on the rate of its dissolution, which in turn depends on the size of the crystal and the crystal shape. On the other hand, delaying the absorption of a drug given via Gia) can be achieved by dissolving or suspending the drug in an oily excipient. Injectable stock shapes are made by forming microencapsule \Y.0.

Similar to the drug in hydrolyzed polymers (Jie Lila) polylactide-polylactide-006 above. And depending on the ratio of the drug to the polymer and the nature of the special polymer used; The rate of release of the drug can be controlled. Examples of other Lila-degradable ALE polymers include poly(orthoesters) and poly(anhydride) (070:10865)O0C. It is also possible to prepare the stored injectable compositions by retaining the drug in liposomes or micro-emulsions that are suitable for the body tissues. Or suitable non-irritating carriers such as cocoa butter, polyethylene glycol, or wick wax that are solid at ambient temperature but liquid at body temperature Ve, thus melting in the rectum or cavity cavity and released active compound. Oral solid dosage forms include capsules, tablets; 0 and in such solid dosage forms; The compound mixes granules into powders; and granules of active con with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate fillers or substances i and/or dicalcium phosphate sodium citrate Vo “glucose csucrose Sucrose, lactose, starch and lactose, Jie extenders, carboxy extenders, Jie binders, binders, silicic acid and silicic acid, mannitol, mannitol, polycgelatin, gelatin calginates, alginate compounds, ccarboxymethylcellulose, methyl cellulose C) tacacia and acacia materials sucrose cpolyvinylpyrrolidinone vinyl pyrrolidinone

Je disintegrating friable (Jal so glycerol 01©”Ra; d) Jie humectants moisture absorbent Y. potato calcium carbonate cagar-agar certain agar-agar and carbonates silicates Calginic acid silicate compounds Alginic acid cor tapioca starch solution retarding 01170 AH :؛ e) Factors that hinder the formation of solutions Sodium carbonate Absorption accelerators (Aba "Yl" and paraffin accelerators ¢ Paraffin agents g Wetting agents Tquaternary ammonium compounds such as quaternary ammonium compounds Yo

Yo

Jie wetting agents e.g. cetyl alcohol ¢glycerol monostearate h) Jie absorbents kaolin, bentonite clay and lubricants such as talc Calcium stearate Calcium stearate Magnesium stearate Cmagnesium stearate Glyco OY solid polyethylene glycols ° Sodium lauryl sulfate csodium lauryl sulfate and mixtures thereof In Alls the use of capsules, tablets and pills form may include de jal also contains pH-regulating agents.Solid compositions of a similar type can also be used as fillers in capsules packed in soft and hard gelatin using such excipients as lactose or milk sugar as well as polyethylene glycols. High molecular weight and the like. 0 Solid dosage forms can be prepared from tablets; intoxicating pills 5H:0; (EY pS) pills and granules with outer layers and coatings (fie) enteric coating and other known outer layers In the technology of forming pharmaceutical compositions. Optionally these forms contain opacifying agents and may also be of a formulation to release only the active ingredient(s) or preferably; In a certain part of the intestinal tract 0 and optionally; late style. Examples of embedded structures include:

Which can be used polymeric substances and waxes and solid structures of a similar type may also be used as fillers in capsules packed in soft and hard gelatin using such excipients as lactose or milk sugar in addition to polyglycols High molecular weight polyethylene glycols and the like. The “©”-active compounds may also be in microencapsulated form; With one or more excipients as mentioned above. Solid dosage forms may be prepared from tablets; intoxicating pills; capsules; pills; Granules with outer layers and coatings such as enteric outer layers, release control outer layers, and other outer layers known in formulation technology. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose Yeo or the starch lactose. Dosage forms of this may include Jl as in

i. Regular application; on additives other than ALA diluents for example; tableting lubricants and other tableting aids Jie magnesium stearate microcrystalline cellulose and in Ala capsules; cal BY and cereals; Dosage forms may also include pH-regulating agents. optionally; These forms contain bulking agents and may also be formulated to release the active ingredient(s); only or preferably; in a certain part of the intestinal tract; and optionally in a later style. Examples of embedded compositions that may be used include polymeric and waxy materials. Topical or intradermal dosage forms of compound G5 of the present invention include ointments, pastes, ointments, creams, and ointments; lotions; gels; powders; dallas sprays csprays inhalants or patches active ingredient mixed in sterile envelopes with a pharmaceutically acceptable carrier and any preservative or pH regulator as needed. The scope of the invention also includes ophthalmic formulations, ear drops “5”; ointments; Ophthalmic powders and solutions. Ve ointments may contain; pastes; creams; gels; In addition to the Active Compound Lay of the invention; contains excipients such as animal and vegetable fats; oils; waxy materials; starch paraffins; tragacanth gum; ctragacanth; cellulosic derivatives; Polyglycols Co glycols their enemies Silicones Silicones Bentonites cbentonites Silicic acid Tale or zinc oxide Mixtures thereof. Powders may contain; © > Aerosols as well as compounds of the present invention on excipients such as lactose or talc silicic acid aluminum hydroxide calcium silicate polyamide powder or mixtures thereof . Aerosols may additionally contain conventional propellants Jie chlorofluorohydrocarbons.

Yv dermal patches have the additional advantage of providing controlled administration of a compound to the body and such dosage forms may be made by dissolving or dispersing the compound in the appropriate medium. It may also be used to increase the flow of the compound through the skin. And absorption enhancers can be adjusted by dispersing the compound in a modified controlling membrane template, either by supplying a rate-controlling membrane

oe polymer or gel.

Although preferred embodiments of the present invention have been described and illustrated; Someone familiar with the technology to which the invention relates will realize that various modifications can be made without going out of scope

The invention as defined in the appended claims.

Claims (1)

YA Protection Elements male Premature ejaculation Premature ejaculation Treating Premature ejaculation 1-1 A way to treat “returned” in need of treatment from this mammal that includes giving male breasts mammal Y pharmaceutically Js Ball 4 als or apomorphine such as apomorphine ¥ genital vasodilation de SU in an amount sufficient to cause dilatation acceptable salt thereof ¢ effective but less than the amount necessary to induce effective vascular congestion > mentioned; Where the aforementioned amount produces a vascongestive arousal concentration of 1 mammal. ng/mL Yo is less than about ∼ in plasma apomorphine 7 said apomorphine is a human mammal where the mammal is 1 of protection element Ta method YX 1 -humane ¥ said Or its salt, apomorphine?*- The method according to the protection element ¥, where the mentioned apomorphine 1 is given to a human to a human pharmaceutically acceptable salt thereof 7 during a period of time ranging between and about two minutes, about one hundred and twenty minutes before sexual intercourse r .sexual relations £ The aforementioned or its salt apomorphine Apomorphine cua Y is given to the protective element (as method —¢ 1 aforementioned human to a human pharmaceutically acceptable salt thereof Y sexual during a period period ranging between about two minutes and about sixty minutes before sexual intercourse r .relations § The aforementioned salt or its salt apomorphine The method according to the element of protection? Y Ya 1 in an amount sufficient to produce a concentration of apomorphine in sl 2 plasma from ¢ of about 7 ng/mL to about 0.759 ng/mL. 1 7- The method according to the claim? It also includes giving my co-administration contribution to androgen Y 21101061 -1 1 the method according to claim 7 where the said androgen selects from Y group consisting of testosterone dihydrotestosterone cdihydrotestosterone 1 and epiander dehydroepiandrostenedione ¢ or its acceptable salt pharmaceutically acceptable Ll na .salt thereof 2 —A 1 method according to claim © where said androgen is Y testosterone or a sla pharmaceutically acceptable lu a .acceptable salt thereof v 1 4- The method according to claim 7, where the aforementioned androgen 00 is given in an amount sufficient Y to produce a concentration of androgen 00 in the plasma ranging from about 1 r nmol/ml to about Yoo nmol/mL. -0 1 method according to the claim? Where the said apomorphine or 7 is given its pharmaceutically acceptable salt thereof in an amount not exceeding 6” ¥ mg. 11-1 method lag of claim 1 where the said mammal is given apomorphine B, Y, or its pharmaceutically acceptable salt thereof Wana, in an amount ranging between about 7 mg and about ¢ mg.