MXPA00011386A - A medicament for prevention and treatment of sexual dysfunction - Google Patents

Abstract

The present invention relates to the medicament for prevention and treatment of sexual dysfunction using potassium channel opener solutions for topical appliance, as a medicament for prevention and treatment of sexual dysfunction. Sexual dysfunction can be treated y increasing blood flow into clitoris or vagina, thereby increasing a secretion from vagina and elevating the sense by means of topically applying a pharmaceutical composition comprising one kind of K ATP channel opener selected from the group consisting of nicorandil, minoxidil, pinacidil and cromakalim to clitoris and vagina immediately before sexual intercourse in female sexual dysfunction patients who have problems in sexual arousal or excitement. Also, since the medicament according to the present invention is directly absorbed to target organ via topical application of the minimum thereof, the effect of the medicament is excellent and the medicament is practically free from systemic or local side effects.

Description

MEDICINE FOR THE PREVENTION AND TREATMENT OF SEXUAL DYSFUNCTION TECHNICAL FIELD The present invention relates to a medicament for the prevention and treatment of sexual dysfunction, and in particular, to a medicament for the prevention and treatment of sexual dysfunction, comprising potassium channel openers and / or papaverine.

DESCRIPTION OF THE PREVIOUS TECHNIQUE Studies regarding female sexual function are very few compared to studies regarding male sexual function, due to social and cultural prejudices in which female sexual expression was traditionally considered a taboo or disgrace. However, sexual dysfunction exists in women, as well as in men. In sexual dysfunction of normal partners, erectile dysfunction and dyspermia (ie, ejaculation disorder) comprise 40% of male sexual dysfunction, and orgasmic and arousal disorders comprise 63% of female sexual dysfunction (see Frank E, Anderson C, Rubinstein D. Frequency of sexual dysfunction in 'normal' couples, New Engl J Med 1978: 299: 111-115). The female sexual response is classified in the following phases: sexual desire, sexual awakening, excitement, plateau, orgasm and resolution. Female sexual dysfunction is classified into the following disorders according to the phases of female sexual response: hypoactive sexual desire disorder, arousal disorder, orgasmic disorder, dyspareunia and vaginismus (see Leiblum SR, Definition and classification of female sexual disorder. Int J Impot Res 1998: 10: 104-6). The blood flow in the clitoris and vagina increases and a vaginal discharge increases in the sexual desire, and the filling of blood in the vagina and the enlargement of the clitoris to sexual stimuli such as the erection of the male penis, occur in the awakening sexual or arousal, although it is difficult to separate the clitoris from the vagina in the female sexual response phase (see Geer JH, Direct measurement of genital responding, Am Psychol 1975: 30: 415-418). This series of responses in women is very similar to penis erection responses in men. In the case of the vagina, vascular smooth muscle relaxation and increased blood flow are also important responses in sexual arousal. The filling of blood in the vagina according to the previous answers, results in an increase in the length and inner diameter of the vagina, and the increased secretion of fluid from the vagina makes the insertion of the penis into the vagina easy (see Park K, Goldstein I, Andry C, Siroky MB, Krane RJ, Azadzoi KM.Vasculogenic female sexual dysfunction: the hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency Int J Impot Res 1997: 9: 27-37) .

In the past, most studies regarding the causes of female sexual dysfunction focused on sexual deviance in terms of psychiatry or temperamental causes due to female hormone deficiency in the post-menopause. The morbidity of female sexual dysfunction increases with age in women as occurs in men, and the increased morbidity of female sexual dysfunction is associated with menopause or increased risk factors of the vascular system. In fact, women with vascular system risk factors or post-menopausal women complained of dysfunction of the vagina or clitoris more frequently than the control group (see Sadeghi-Nejad H, Moreland R, Traish A, Azadzoi K, Nhera A, Abobakr RA et al Impotence is a couple's disease: studies in female sexual dysfunction J. Urol 1996: 155: 677A). Since the decrease in female hormone in the climacteric or post-menopause results in changes in the vascular system, the decrease in the female hormone and female vasculogenic sexual dysfunction interact in complex ways. Practically, the decrease of the female hormone in menopause decreases the amount of vaginal discharge by decreasing the blood flow in the pelvic region. However, female hormone supplementation therapy restores blood flow. Furthermore, while the co-administration of progesterone and female hormone inhibits the effect of estrogen on blood improvement compared to the administration of female hormone alone, the co-administration of male and female hormones increases the sexual instinct of women, in comparison with that of women. administration of female hormone alone (see Simón JA, Double-blind comparision of two doses of estrogen and estrogen-androgen in naturally post-menopausal women: neuroendocrine, psychological and psychosomatic effects, Fertile Steril 1996: 66: 8971-875). Recently, it was found that this is because the decrease of the female hormone acts as risk factors of the vascular system, and the nitric oxide synthetase (NOS) vaginal and cell necrosis such as the smooth muscle of the vaginal wall, vascular endothelium, nerve, vaginal epithelial cell, or the like, are controlled by female hormones. Hemodynamic studies with respect to male erectile dysfunction developed very well, and attempts were made to apply previous studies to concepts and studies of vasculogenic sexual dysfunction of female external genitalia that have embryological and anatomical similarity to male external genitalia. As a result of the study in regard to smooth muscles of the clitoris and vagina, it was found that vaginal filling and enlargement of the clitoris in sexual awakening resulted from an increase in blood flow according to smooth muscle relaxation by neurotransmitters. such as nitric oxide (NO) or vasoactive intestinal peptide (VIP) and not by hormones that had systemic and complex actions in the case of both women and men. Therefore, the decrease in blood flow due to various causes together with the decrease in female hormones at menopause, or the inappropriate response of smooth muscle to neurotransmitters in the clitoris or vagina can cause female vasculogenic sexual dysfunction. To develop a model in laboratory animals for the study of vasculogenic female sexual dysfunction, atherosclerosis was induced in the bone artery of the internal organ of a female rabbit and then the blood flow of the clitoris and the vaginal wall was determined by stimulating the nerves Pelvic As a result, the blood flow of the arteriosclerosis group decreased significantly compared to that of the normal control group. This result is associated with a decrease in the internal pressure of the vaginal wall and the cavernous body of the clitoris and the length of the vagina. Thus, it was suggested that arteriosclerosis acts as an important factor in female sexual dysfunction such as insufficient vaginal filling and erectile failure of the clitoris (see Park k, Goldstein I, Andry C, Siroky MB, Drane RJ, Azadsoi KM. Vasculogenic female sexual dysfunction: the hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency Int J. Impot Res 1997: 9: 27-37). The reason why a specific approach of vasculogenic female sexual dysfunction is proposed, although decreased blood flow in the clitoris or vagina may occur secondarily due to the decrease in female hormones as described above, is that the increase in Vaginal blood flow in sexual desire or sexual arousal causes it to increase the secretion of fluid in the vagina, thus reducing pain in sexual intercourse and increasing orgasm and sexual instinct according to the increased sensitivity in the clitoris. Therefore, just like the male erectile dysfunction treatment, the effectiveness of the treatment of a method that directly relaxes the smooth muscle in the clitoris or in the vaginal wall that is an objective organ may be higher than that of the therapy with female hormones that has indirect and secondary effects. In female sexual awakening, the responses of the female external genitalia can be separated in response to the clitoris and the vagina. Among them, the clitoris has a pair of erectile tissues similar to the cavernous body of the penis. Acetylcholine by the cholinergic nerve system and non-andrenic, non-cholinergic nitric oxide act as neurotransmitters in sexual arousal, and smooth muscle relaxation and increased blood flow due to neurotranslifts that cause clitoral enlargement (See Semmens JP, Semmens EC Sexual function and the menopause Clin Obstet Ginecol 1984: 27: 717-723). Azadzoi et al reported that unlike neurotransmitters in the clitoris, a primary neurotransmitter involved in vaginal smooth muscle relaxation is VIP, rather than nitric oxide (NO) (See Azadzoi KM, Tarcan T, Siroky MB, Krane RJ, Goldstein I., Characterization of elite cavemosal and vaginal smooth muscle contractility in the rabbit Int J Impot Res 1998: 10 Suppl 2: S58). However, Hoyle et al reported that all nerves that use NO (nitric oxide), NPY (neuropeptide Y), VIP, CGRP (peptide related to the calcitonin gene) and substance P as neurotransmitters, can control the blood flow of the human vaginal wall and the permeability of blood capillaries as a result of the study with respect to the neurotransmitters that control the blood vessels of the human vaginal wall (see Hoyle CHV, Stones RW, Robson T, Whitley K, Burnstock G. Innervation of vasculature and microvasculature of the human vagina by NOS and neuropeptide-containing nerves J Anal 1996: 188: 633-644). That is, it is assumed that various neurotransmitters act in complex in accordance with the type and location of the nerve, tissue handled by the nerve or the like. The ionic channels of the cell membrane are involved in the contraction and relaxation of smooth muscle of all organs, and the opening and closing of these ion channels respond in a diverse manner in accordance with the membrane voltage and the ionic concentration in the cells. cells, etc. In general, if the voltage of the cell membrane is depolarized by nerve stimulation, the calcium channel dependent on the voltage of the membrane opens and the increased calcium concentration due to the influx of intracellular Ca contracts the smooth muscle. If the potassium channel is opened by the membrane voltage or the increased intracellular calcium concentration, the intracellular potassium which maintains a concentration higher than that of the cell exterior flows into the cell interior, and the membrane voltage cell becomes polarized again and the calcium channel dependent membrane voltage closes. This causes the concentration of intracellular calcium to decrease and the smooth muscle to relax.

There are several types of potassium channels in the cell membrane. Potassium channels dependent on the voltage of the membrane (Kv) which are opened by the membrane voltage are inhibited by 4-aminopyridine. In addition, there are calcium-dependent potassium channels (Kca) which are opened and closed by the intracellular calcium concentration there are. Most calcium-dependent potassium channels are maxi-K channels that have a large conductance and are inhibited by TEA (tetraethylammonium) or caliotoxin and caribdotoxin. And calcium-dependent potassium channels that have small conductance are inhibited by apamin. In addition, ATP-dependent potassium channels (KATP), which are opened by a decrease in intracellular ATP concentration in metabolic inhibition or severe hypoxia, can be inhibited by tolbutamide or glibenclamide and TEA. However, ATP-dependent potassium channels rarely open under normal conditions. Therefore, there are many different opinions regarding the physiological mechanism of them. (See Leiblum SR, Definition and classification of female sexual disorder, Int. J Impot Res 1998: 10: 104-6). Among the various potassium channels, the KATP and maxi-K channels are considered physiologically as the most appropriate in the smooth muscle of the corpus cavernosum. Maxi-K channels are the most common subtype of potassium channels that exist in the smooth muscle of the corpus cavernosum of the penis. The maxi-K channels comprise approximately 90% of the outward K-current in smooth muscle cells of the corpus cavernosum of the human penis that were cultured in vitro. In addition, the maxi-K channels control the voltage of the membrane. The mechanisms of smooth muscle relaxation through the opening of potassium channels can be classified into three mechanisms. The first mechanism comprises an increase in cGMP production by NO or the like, and consequently, the activation of protein kinase G (PKG). Activated PKG is involved in the opening of the maxi-K channels and acts on the calcium channel to relax the smooth muscle by inhibiting calcium transfer from the channel. Although it is considered that activated PKG is involved in the opening of KATP channels, there are contradictory opinions in relation to the previous theory. The second mechanism comprises the increase of cAMP by PGE1 or the like, and consequently, the activation of protein kinase A (PKA). Activated PKA also causes the opening of maxi-K channels and the closure of calcium channels, thereby inducing smooth muscle relaxation. Most neurotransmitters that cause smooth muscle relaxation induce direct or indirect smooth muscle relaxation through these two mechanisms (ie, the first and second mechanisms). Therefore, the fact that acetylcholine, L-arginine and PGEi make relaxed cuts in proportion to the concentration, can be explained in two aspects, in calcium channels and potassium channels. That is, it is assumed that cGMP accumulates via the path of the NO pathway, and then PKG is activated, and increases the activity of maxi-K channels, and consequently, calcium channels are inhibited and transfer is also inhibited. of calcium atoms, and subsequently decreases the amount of intracellular calcium ions, and therefore the above phenomenon causes the smooth muscle to relax. The last mechanism uses potassium channel openers such as pinacidil that act directly on the potassium channel to cause the smooth muscle to relax. Said method can provide an excellent relaxation effect and decrease systemic side effects because it acts directly on the potassium channel without complex procedures using neurotransmitters. In addition, said method has a clinical value since it can provide a complementary effect to the relaxation effect of other medications. Therefore, the study related to the action of potassium channels in the relaxation of vaginal smooth muscle makes a direct approach possible and is much simpler than the study related to various neurotransmitters. Papaverine was first discovered by Meck in 1948, and it is an alkaloid extract of a poppy similar to opium. Papaverine is a direct relaxant of smooth muscle. First, papaverine increases the concentrations of cAMP and cGMP by inhibiting the actions of cyclic mononucleotide phosphodiesterase. Second, papaverine controls the myosin light chain and inhibits contraction by blocking calcium channels and inhibiting the flow of calcium. When papaverine was injected into the penis of the patient with erectile dysfunction, it is difficult to find which mechanism works mainly. However, papaverine relaxes all the elements of the tissue of the erect penis, this is the artery of the penis, the smooth muscle of the corpus cavernosum and the vein of the penis. Therefore, papaverine is a powerful relaxant of smooth muscle and is known because a complication of continuous erection of the penis was developed very frequently when papaverine was administered to the male patient with erectile dysfunction. Considering the direction of the study in relation to the female sexual dysfunction mentioned in the present, there is a tendency to diagnose vasculogenic female sexual dysfunction, mainly determining the blood flow of the clitoris or vagina using ultrasound waves of color of Doppler and then said patients who presented decreased blood flow were treated with the administration of smooth muscle relaxants. As therapeutic agents for female sexual dysfunction, which have been developed by many pharmaceutical companies, oral administration of viagra, apomorphine, as well as the topical application of PGEi cream and the like are known. In addition, as effective therapeutic agents for erectile dysfunction, the injection therapy of erection inducers in the corpus cavernosum is known. Although injection formulations are more effective in achieving the erector-inducing effect than oral medications such as viagra, injection formulations have defects such as pain, fear of injection, continuous erection of the penis, etc.

BRIEF DESCRIPTION OF THE INVENTION The inventors of the present invention have made extensive investigations and experiments to develop drugs that can effectively prevent and treat sexual dysfunction. The present inventors have developed the medicaments of the present invention by confirming that when a medicament comprising a potassium channel opener (eg, nicorandil, cromakalim, pinacidil and minoxidil) and / or papaverine was used, it had an excellent effect of Relaxation of smooth muscles of the cavernous body of the penis and smooth muscles of the vaginal wall through various experiments in animals and discovering that the drug can increase blood flow in the penis and clitoris, during research and experiments. An object of the present invention is to provide a medicament for the prevention and treatment of female sexual dysfunction comprising a type of potassium channel opener selected from the group consisting of nicorandil, pinacidil and cromakalim and / or papaverine. Another object of the present invention is to provide a medicament for the prevention and treatment of male sexual dysfunction comprising a type of potassium channel opener selected from the group consisting of nicorandil and cromakalim and optionally, papaverine. According to the present invention, a medicament for the prevention and treatment of female sexual dysfunction comprising a type of KATP channel opener selected from the group consisting of nicorandil, pinacidil and cromakalim and / or papaverine is provided. In addition, a medicament for the prevention and treatment of male sexual dysfunction is provided comprising a type of KATP channel opener selected from the group consisting of nicorandil and cromakalim and optionally, papaverine. The present invention has many advantages, including providing a medicament for the prevention and treatment of sexual dysfunction that can treat sexual dysfunction and providing a medicament for the prevention and treatment of sexual dysfunction, which has excellent effects on the treatment of sexual dysfunction and no side effects.

These and other features, aspects and advantages of the present invention will be better understood with reference to the following description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1a is a graph showing the relaxation of clitoid striae precontracted to the administration of minoxidil, nicorandil, papaverine and PGE-i. Each drug induced a dose-dependent increase in relaxation.

Figure 1b is a graph showing the relaxation of vaginal striae precontracted to the administration of minoxidil, nicorandil, papaverine and PGE-i. Each drug induced a dose-dependent increase in relaxation. Figure 2a is a graph showing the relaxation of pre-contracted clitoris striae in response to the administration of papaverine and PGE-i after pretreatment of minoxidil or nicorandil. Each drug mixture induced a dose-dependent increase in relaxation. The pretreatment of minoxidil or nicorandil significantly increased the relaxation induced by papaverine or PGE-i, together, respectively. M: minoxidil; N: nicorandil, PA: papaverine; and PG: prostaglandin Figure 2b is a graph showing the relaxation of pre-contracted vaginal striae in response to the administration of papaverine and PGE-i after pretreatment of minoxidil or nicorandil. Each drug mixture induced a dose-dependent increase in relaxation. The pretreatment of minoxidil or nicorandil significantly increased the relaxation induced by papaverine or PGE-i, together, respectively. M: minoxidil; N: nicorandil, PA: papaverine; and PG: prostaglandin DETAILED DESCRIPTION OF THE INVENTION The present invention provides a medicament for the prevention and treatment of female sexual dysfunction comprising a type of KATP channel opener selected from a group consisting of nicorandil, pinacidil and cromakalim as an active ingredient, and a pharmaceutically acceptable carrier. . The present invention also provides a medicament for the prevention and treatment of female sexual dysfunction comprising papaverine as an active ingredient, and a pharmaceutically acceptable carrier. In addition, the present invention provides a medicament for the prevention and treatment of female sexual dysfunction comprising papaverine and a type of KATP channel opener selected from a group consisting of nicorandil, pinacidil and cromakalim as active ingredients, and a pharmaceutically acceptable vehicle. The present invention provides a medicament for the prevention and treatment of male sexual dysfunction comprising a type of KATP channel opener selected from a group consisting of nicorandil and cromakalim as an active ingredient, and a pharmaceutically acceptable carrier. Also, the present invention provides a medicament for the prevention and treatment of male sexual dysfunction comprising papaverine and a type of KATP channel opener selected from a group consisting of nicorandil and cromakalim as active ingredients, and a vehicle pharmaceutically acceptable. Most of the potassium channel openers known to date are KATP channel openers. For example, nicorandil, cromakalim, pinacidil, minoxidil or the like are known as potassium channel openers, and are used as anti-hypertensive drugs, hair production promoting agents and therapeutic agents for angina pectoris (see patents of US Nos. 4,446,113 and 4,200,640). However, articles that are being studied as agents to prevent and treat sexual dysfunction are very rare. Only, minoxidil was patented as a therapeutic agent for male erectile impotence in the U.S. patent. (See U.S. Patent No. 5,336,678). Although pinacidil has been used frequently for the treatment of male sexual dysfunction, has never been used to treat female sexual dysfunction. Although it was reported that there was a possibility that minoxidil was used to treat female sexual dysfunction, it was not produced as a commercial product. However, among the potassium channel openers, nicorandil and cromakalim have not been used to treat male or female sexual dysfunction. Papaverine, which is used to treat male erectile dysfunction, has not been used to treat female sexual dysfunction. Particularly, it has not been reported that a medicament comprising a potassium channel opener and papaverine in combination has a synergistic effect in the treatment of female sexual dysfunction. In the present invention, the effects of nicorandil and minoxidil which is used as a hair producing-promoting agent for topical application were compared. Both nicorandil and minoxidil, when administered alone, have a more effective relaxing effect than PGEi, but have a less effective relaxing effect than papaverine. This may be because there are differences in the mechanisms of action of the receptors, innervation structure or similar of the smooth muscle of the clitoris or vagina, unlike the smooth muscle of the cavernous body of the penis. Likewise, the relaxing effect when minoxidil or nicorandil was previously treated was greater than the relaxing effect when PGEi or papaverine was administered alone. Based on the results of the present invention, effective drugs to develop therapeutic agents for female sexual dysfunction adequately comprise nicorandil or papaverine as a single drug, and mixed medications of nicorandil and papaverine as mixed medications. This is because these medications have an excellent relaxing effect of smooth muscle when used as a single medication, and they have an excellent relaxing effect even at low concentrations when used as mixed medications. When the effects of potassium channel openers were tested and compared, pinacidil has the shortest duration of action, cromakalim has the strongest effect for relaxing smooth muscle, and nicorandil has the most effective relaxing effect of smooth muscle cuts. than papaverine because nicorandil has an accumulating effect of cGMP. When pinacidil was administered at a high concentration of 10"6 M or more, even the fully depolarized cavernous body was relaxed in experiments using smooth muscle slices from the cavernous body of a rabbit.Also, when acetylcholine, L-arginine and PGE -i were administered in vivo to the cavernous body of the penis of a live cat that was previously treated with pinacidil, 35-115% of the internal pressure of the cavernous body increased additionally depending on the types of drugs that when the erector inductor was administered alone In addition, in vitro experiments using vaginal wall slices from a rabbit showed that pinacidil was effective in relaxing the vaginal smooth wall A medicament comprising a type of potassium channel opener selected from the group consisting of nicorandil, pinacidil and cromakalim, and / or papaverine has been used in the present invention for the prevention and treatment of sexual dysfunction emenin for the first time, and it was confirmed that the drug was effective in the prevention and treatment of female sexual dysfunction. Also, in the present invention, when a medicament comprising a type of potassium channel opener selected from the group consisting of nicorandil and cromakalim, and optional papaverine was applied topically to the penis, it was reported that the effects that induce erection were greater in patients with male sexual dysfunction. In a medicament for prevention and treatment of sexual dysfunction according to the present invention, a medicament comprising a type of KATP channel opener selected from the group consisting of nicorandil, pinacidil and cromakalim, and / or papaverine as active ingredient (s) can be used for prevention and treatment of female sexual dysfunction , and a medicament comprising a type of KATP channel opener selected from the group consisting of nicorandil and cromakalim, and optional papaverine as active ingredient (s) can be used for prevention and treatment of male sexual dysfunction. In the medicament for the prevention and treatment of sexual dysfunctions according to this invention, the active ingredient (s) is (are) contained, preferably, in an amount of 0.1 to 20% by weight, based on the total weights of the drug and, more preferably, in an amount of 1-10% by weight, based on the total weights of the drug. The daily dose of KATP channel opener of this invention for the prevention and treatment of female sexual dysfunction is generally on the scale of approximately 10 to 30 mg / day for the average adult female patient (60 kg. ) and can be administered in single or divided doses. The daily dose of the KATP channel opener of this invention for the prevention and treatment of male sexual dysfunction generally ranges from approximately 20 to 50 mg / day for the average adult male patient (70 kg) and can be administered in single or divided doses. The daily doses of papaverine of this invention for the prevention and treatment of female sexual dysfunction are, generally, on the scale of approximately 10 to 30 mg / day for the average adult female patient (60 kg) and can be administered in doses simple or divided. The daily doses of papaverine and the KATP channel opener in the medicament of this invention as mixed drugs for the prevention and treatment of female sexual dysfunction are generally on the scale of approximately 10-30 mg / day and approximately from 10 to 30 mg / day, respectively, for the average adult female patient (60 kg) and can be administered in single or divided doses. The daily doses of papaverine and the KATP channel opener compound in the medicament of this invention as mixed drugs for the prevention and treatment of male sexual dysfunction range, generally, in the range of approximately 20 to 50 mg / day and approximately 20 to 50 mg / day, respectively, for the average adult male patient (70 kg) and can be administered in single or divided doses.

The specific dose will be determined depending on the age and body weight of the treated individual, response, route of administration, duration of treatment and the like. In practice, the doctor will determine the actual dose that is most suitable for an individual patient and will vary with the age, weight and response of the specific patient. The aforementioned doses are examples of the average case, but there may, of course, be individual cases in which higher or lower dose scales are needed, and all of those doses fall within the scope of this invention. The active compounds of this invention can be administered alone, but will generally be administered in a mixture with a diluent or pharmaceutical carrier selected with respect to the proposed route of administration and normal pharmaceutical practice. The medicament for the prevention and treatment of sexual dysfunctions according to this invention may consist of a pharmaceutically acceptable base, in addition to the active ingredient described above (drug). Bases that can be used in this invention include, for example, alcohols, fatty acid esters, biocompatible fats, fatty oils, wax, lanolin, paraffin, petrolatum, glycerin, starch, cellulose derivatives, polyethylene glycol, silicone oils, bentonite and mixtures thereof. Also a type of KApt channel opener selected from the group consisting of nicrorandil, minoxidil, pinacidil and cromakalin, and / or papaverine, and a pharmaceutically acceptable cutaneous absorption enhancer can be mixed in different amounts and formulas. The cutaneous absorption enhancers were added in order to pass the active ingredient through the clitoris, vaginal or albuginea tissue of the cavernous body surrounding the penis and the skin surrounding the penis to facilitate sexual arousal or the effects that induce the erection when the active ingredient (drug) was applied topically to the clitoris, vagina or penis. The cutaneous absorption enhancers which may be used in the present invention may include, for example, fatty alcohols, fatty acids, fatty acid esters, surface active agents, fatty alcohol ethers, propylene glycol or mixtures thereof. The medicament according to the present invention may contain additives such as pharmaceutically acceptable solvents, propellants, antiseptics, preservatives, aromatics, stabilizers, suspending agents, colorants, emulsifiers, consistency agents or the like, if necessary. The medicament for the prevention and treatment of sexual dysfunction in accordance with the present invention can be used in dosage forms of spray, solution, cream, gel, ointment, lotion, powder, suppository, patch, implant or the like using conventional preparation methods of dosage forms preceding the mixing of opener of the KA T channels described above and / or papaverine, pharmaceutically acceptable base, cutaneous absorption enhancer and additives with specific ratios. The medicament according to the present invention can be administered orally, parenterally or topically. Preferably, the medicament according to the present invention can be a topical application drug. Preferably, the medicament for the prevention and treatment of female sexual dysfunction in accordance with the present invention can be administered directly to the clitoris, vagina or vicinity. Also, the drug for the prevention and treatment of male sexual dysfunction according to the present invention can preferably be administered directly to the penis or its vicinity. A dosage form of the medicament for the prevention and treatment of female sexual dysfunction in accordance with the present invention may be spray, solution, cream, gel, ointment, lotion, powder, suppository, patch or implant. A dosage form of the medicament for the prevention and treatment of male sexual dysfunction in accordance with the present invention may be spray, solution, cream, gel, ointment, lotion, powder, or patch. The medicament according to the present invention can preferably be for the prevention and treatment of male or female vasculogenic sexual dysfunction. Although a correct mechanism for the pharmacological action of the medicament for the treatment of sexual dysfunction in accordance with the present invention has not been established, when the medicament for the treatment of sexual dysfunction in accordance with the present invention was used, the Potassium was opened, blood flow to the clitoris and vagina increased, and both the smooth muscle of the vaginal walls and the smooth muscle of the cavernous body of the penis relaxed. Thus, the medicament according to the present invention makes possible the diagnosis and treatment of male and female patients who present sexual dysfunction. For example, it is effective to directly apply the medicament to the clitoris or vagina in the case of treatment of female sexual dysfunction and it is effective to directly apply the medicament to the penis or its vicinity for the treatment of male sexual dysfunction. The versions of the present invention described above have many advantages, including the provision of a medicament for the prevention and treatment of sexual dysfunction, which can treat sexual dysfunction, and provide a medicament for the prevention and treatment of sexual dysfunction, that has excellent effects in the treatment of sexual dysfunction and no side effects. In case of female patients with sexual dysfunction, those who have problems in arousing the sexual appetite or excitement, sexual dysfunction can be treated by increasing the blood flow in the clitoris or vagina, thereby, increasing a vaginal discharge and elevating the Sensitivity by applying the medicament for the prevention and treatment of sexual dysfunction according to the present invention is applied to the clitoris and vagina immediately before sexual intercourse. In addition, the medicament for the prevention and treatment of sexual dysfunction according to the present invention is applicable to male patients with sexual dysfunction. Moreover, because preferably, the medicament according to the present invention is directly absorbed by the target organ, by local application of a minimum amount thereof, the effect of the medicament according to the present invention is excellent, and the medicament according to the present invention it is practically free of systematic or collateral effects. Because the drugs according to the present invention have prevention effects and the treatment of sexual dysfunction and no side effects, they are considered adequate in maintaining a satisfactory sexual life in the couple. The present invention will now be described in more detail, in relation to the following examples, which should be considered only in illustrative form, and not limiting the present invention.

EXAMPLE 1 To test the medicine for the prevention and treatment of sexual dysfunction according to the present invention, among female patients who attended the outpatient department of urology of the Hospital, 18 voluntary patients, who consented to be evaluated after explanations of objectives and test methods of this study.

The average age of the 18 volunteers was 41.3 years, and they had no history of sexual dysfunction or diseases that caused it. First, the size of the clitoris was measured with a caliper at baseline. The size of the clitoris, the diameter of the clitoral artery and the blood flow in the clitoris of peak systolic velocities (PSV) and final diastolic velocities (EDV) were measured by color Doppler ultrasonography. Then, a 2% solution of minidoxil was applied to the 18 volunteers, and changes in clitoral size, clitoral artery diameter and peak systolic velocity (PSV) clitoris were measured using the same method. and final diastolic velocities (EDV).

After this, the 2% minoxilil solution was rinsed, as a matter of fact. After a long time, a 5% nicorandil solution was applied to the 18 volunteers, and changes in clitoral size, clitoral artery diameter and peak systolic blood clitoris were measured using the same method. (PSV) and final diastolic velocities (EDV). The size of the clitoris and the diameter of the clitoral artery after the application of the drug increased in comparison with its size at baseline. However, there was no significant statistical difference due to personal differences, and to a deficiency in the discriminant capacity of the measuring device and the measurement standard. Mean scores of peak systolic velocities (PSV) and end-diastolic velocities (EDV) of the clitoral artery at baseline were 5.40 ± 0.78 cm / s and 1.76 ± 0.44 cm / s, respectively. After application, both the 2% minoxidil solution and the 5% nicorandil solution significantly increased the clitoral PSV blood stream at 9.88 ± 2.76 cm / s and 16.87 ± 3.53 cm / s, respectively (p < 0.05). Also the clitoral blood flow of EDV after the application of the 2% minoxidil solution and the 5% nicorandil solution was increased to 3.52 ± 1.26 cm / s and 4.69 ± 2.21 cm / s, respectively. Also, it was found that the relaxation effect of the 5% nicorandil solution was much higher than that of the 2% minoxidil solution. Meanwhile, questions were asked regarding changes in feelings to volunteers. However, the answers to the questions were different and inconsistent due to personal differences and difference in test methods. From the mentioned results, it can be known that when the 2% minoxidil solution was applied topically to the clitoris, the blood flow velocity of the clitoral artery increased significantly, and when the 5% nicorandil solution was applied Topically to the clitoris, the blood flow velocities of the clitoral artery increased significantly. Therefore, KATP channel opening solutions can be used to improve the clitoral artery of female patients with sexual dysfunction, and are also expected to be effective in male patients with sexual dysfunction.

EXAMPLE 2 Using slices (0.1 x 1.2 x 3 mm) obtained from the smooth vaginal muscle of New Zealand white rabbits (2.5 ~ 3.5 kg), isometric contraction was measured. The relaxation responses of the contracted sections were compared with the previous treatment with phenylephrine against L-argigin, PEG-i and acetylcholine. In each response, using apamin, Kaliotoxin, glibenclamide, tolbutamide, 4-aminopyridine and TEA that are potassium channel blockers, as well as minoxidil and pinacidil which are KATP channel openers, the effects of the above compounds on the vaginal smooth muscle contraction and relaxation responses were tested. As a result, there was no spontaneous contraction of the cuts in the basal state, the biphasic response was demonstrated, consisting of relaxation and then contraction by stimulation of electric field (Grass SD9 stimulator, frequency: 200 Hz, delay: 1 msec). , duration: 20 msec, 60 volts). Relaxation and then contraction by electrical field stimulation was not inhibited by previous treatment with atropine. However, it was inhibited by bretilio or acetylcholine, as previous treatments. Cuts proportional to the phenylephrine concentration were contracted. The order of magnitude of the cuts contracted with phenylephrine pre-treatment (1-5 μM) was pinacidil >; acetylcholine > minoxidil > PEGí > L-arginine. The relaxation effect of L-argigin (1-100 mM) and PEGi (1-100 mM) even at high concentrations was 5 ~ 10% and 5-20%, respectively. The relaxation effect of acetylcholine (5-50 μM) was approximately 60% and similar to that of minoxidil (10 μM). However, the duration of action of acetylcholine was short and the resistance to the relaxation effect of acetylcholine was weak, and therefore, the cuts were contracted following a temporary relaxation when treated with acetylcholine. Pinacidil (10 μM) caused the sections to relax completely, and some sections relaxed to values below the baseline values. The relaxation response by acetylcholine was inhibited in part by the high concentration of KATP channel blockers or voltage sensitive potassium channel blockers. Also, the relaxation response by acetylcholine was completely inhibited by apamln or kaliotoxin even at a low concentration (1 μM). The relaxation response by vinacidil (10 μM) was completely inhibited by pretreatment of TEA or 4-aminopyridine. However, the relaxation response by pinacidil (10 μM) was not inhibited by pretreatment of apamin or caliotoxin. From the above results, it was discovered that the neurotransmitters involved in the relaxation response of vaginal smooth muscle of a lapin exhibit relaxation effects through potassium channels as in other smooth muscles, and the relaxation response by pinacidil was the larger.

EXAMPLE 3 After enucleation of the clitoris, vagina, urethra, cysts and uterus of a mature New Zealand female rabbit (3.0-4.0 kg), consistent cuts of clitoral smooth muscle (1x1x5 mm) and distal vaginal wall (2x3x8 mm) were prepared. They remove surrounding tissues under a microscope for microsurgery. The tension of the cuts was measured through a polygraph (SD9, Grass Instrument, Quincy, MA, USA) connected to a force displacement transducer. First, tension was applied to each cut using a weight of 1.0 g and each cut was incubated for 30 minutes. Then, after administering 100 μl of phenylephrine (10 ~ 6 M), tension of 1.0 g was added repeatedly until isometric tension appears. The time at which the difference in maximum contraction stresses before and after the contraction curves was below 10% was considered as the state where the isometric tension was achieved by measuring amplitudes of the contraction curve after administering phenylephrine. Relaxation responses of cuts to administered drugs were evaluated as follows. After contracting the cuts by adding 100 μl of phenylephrine (10"4 M) to the sections in which the isometric tension was achieved, the effective concentration, the maximum relaxation tension and the minimum relaxation concentration were measured in a significant manner by administering the drug in from low concentration to high concentration (bath concentration 10 ~ 8 ~ 3 x 10"5 M), respectively in contracted sections.

Regarding the drug, nicorandil, minoxidil, papaverine and PGEi were administered cumulatively in low concentration (10"8 M) at high concentration (3 x 10" 5 M). As a result, the relaxation ratio was increased proportionally to the concentration of the drug, respectively, in both clitoris and vaginal wall sections. The results are shown in figure 1a and 1b. From the above results, it was found that the order of magnitude of the maximal relaxation ratio of clitoral and vaginal smooth muscle corolles by a single drug was as follows: papaverine, nicorandil, minoxidil, and PEG-i. The results are shown in table 1 below.

TABLE 1 Maximum relaxation (%) of each stria Vagina Clitoris Single drug Mi 34.79 ± 10.01 (N = 9, n = 12) 40.83 + 9.89 (N = 8, n = 11) Ni 65.25 ± 18.54 (N = 9, n = 13) 68.01 + 17.12 (N = 7, n = 8) PG 27.05 ± 12.18 (N = 10, n = 10) 27.75 ± 11.95 (N = 8, n = 14) PA 80.81 ± 7.83 (N = 7, n = 9) 75.19 + 10.39 (N = 7, n = eleven ) Mixture double Mi + PG 37.31 ± 15.42 (N = 7, n = 12) 42.49116.05 (N = 9, n = 17) Ni + PG 43.32 ± 16.16 (N = 7, n = 8) 46.61l20.04 (N = 8, n = 15) Mi + PA 87.93 ± 18.83 (N = 7, n = 11) 73.06124.0 (N = 7, n = 16) Ni + PA 103.06 ± 12.75 (N = 7, n = 9) 91.84120 .44 (N = 7, n = 10) Triple mixture Mi + PG + PA 94.31 ± 10.88 (N = 4, n = 8) 93.48115.96 (N = 4, n = 6) Ni + PG + PA 99.01115.31 (N = 4, n = 8) 105,815. 58 (N = 4, n = 5) My; minoxidil, Ni; nicorandil, PG; prostaglandin E1, PA; papaverine, N; number of animals n; number of stretch marks EXAMPLE 4 Following the procedure described in example 3, except that nicorandil and papaverine were used; minoxidil and papaverine; nicorandil and prostaglandin; and minoxidil and prostaglandin as mixed drugs, the relaxation ratio of each cut was measured. After contracting cuts of smooth muscle of cavernous body of the clitoris and vaginal smooth muscle with 100 μl of phenylephrine (10"4 M) and previously treating the cuts contracted with nicorandil (10" 5 M), papaverine was cumulatively administered from low concentration (10"8 M) to high concentration (3 x 10" 5 M). As a result, the relaxation ratio increased proportionally to the concentration of the mixed drugs, respectively, in the two previous cuts. The results are shown in Figures 2a and 2b. In mixed drugs, prior treatment with nicorandil significantly increased the maximal relaxation ratio of the drug that continued rather than the previous treatment with minoxidil. Papaverine exhibited a stronger relaxation effect than prostaglandin. Also, the mixed drugs had a stronger relaxation effect than the drug comprising only one drug. Among the mixed drugs, the mixture of nicorandil and papaverine exhibits the strongest relaxation effect. The results are shown in table 1 below.

TABLE 1 Maximum relaxation (%) of each strip Clitoris Vagina Single drug My 34.791 10.01 (N = 9, n = 12) 40,831 9.89 (N = 8, n = 11) N¡ 62,251 18.54 (N = 9, n = 13) 68,011 17.12 (N = 7, n = 8) PG 27,051 12.18 (N = 10, n = 10) 27.751 11.95 (N = 8, n = 14) PA 80,811 7.83 (N = 7, n = 9) 75,191 10.39 (N = 7, n = 11) Mixture double Mi + PG 37,311 15.42 (N = 7, n = 12) 42,491 16.05 (N = 9, n = 17) Ni + PG 43.321 16.16 (N = 7, n = 8) 46.611 20.04 (N = 8, n = 15) My + PA 87.931 18.83 (N = 7, n = 11) 73.061 24.0 (N = 7, n = 16) Nl + PA 103,061 12.75 (N = 7, n = 9) 91,841 20.44 (N = 7, n = 10) Triple Mi + PG + PA 94,311 10.88 (N = 4, n = 8) 93,481 15.96 (N = 4, n = 6) Ni + PG + PA 99,011 15.31 (N = 4, n = 8) 105.81 5.58 (N = 4, n = 5) Mi: minoxidil, Ni: nicorandil, PG: prostaglandin E1, PA: papaverine, N: number of animals, n: number of strips A drug that included nicorandil or papaverine as a single drug, or a drug that included mixed drugs of nicorandil and papaverine As mixed drugs, they exhibited an excellent relaxation effect of the clitoral and vaginal smooth muscle. Therefore, these drugs can be developed as topical therapeutic agents for female sexual dysfunction. Especially, in the results of Table 1 above, a drug comprising a potassium channel opener and papaverine in combination exhibited a synergistic effect in the treatment of sexual dysfunction. Although the present invention has been described in detail with reference to the foregoing specific embodiments, other embodiments are possible. Therefore, it should be apparent to those skilled in the art that various modifications and changes may be made thereto without departing from the spirit and scope of the invention and that such modifications and changes may be included in the following claims.

Claims (30)

NOVELTY OF THE INVENTION CLAIMS

1. A medicament for the prevention and treatment of female sexual dysfunction comprising a type of KATP channel opener by selecting from the group consisting of nicorandil, pinacidil and cromakalim as the active ingredient, and a pharmaceutically acceptable carrier.

2. The medicine for prevention and treatment of female sexual dysfunction according to claim 1, further characterized in that said active ingredient is contained in an amount of 0.1-20% by weight based on the total weight of the drug.

3. The medicament according to claim 1 for topical application.

4. The medicament for the prevention and treatment of female sexual dysfunction according to claim 1, further characterized in that said medicament is administered directly to the clitoris, vagina or around them.

5. The medicament for the prevention and treatment of female sexual dysfunction according to claim 1 or 4, further characterized in that the dosage form of said medicament is aspersion, solution, cream, gel, ointment, lotion, powder, patch, suppository or implant.

6. The drug according to claim 1, for the prevention and treatment of female vasculogenic sexual dysfunction.

7. A medicine for the prevention and treatment of female sexual dysfunction comprising papaverine as an active ingredient, and a pharmaceutically acceptable vehicle.

8. The medicament for the prevention and treatment of female sexual dysfunction according to claim 7, further characterized in that said active ingredient is contained in an amount of 0.1-20% by weight based on the total weight of the drug.

9. The medicament according to claim 7 for topical application.

10. The medicament for the prevention and treatment of female sexual dysfunction according to claim 7, further characterized in that said medicament is directly administered to the clitoris, vagina or around them.

11. The medicament for the prevention and treatment of female sexual dysfunction according to claim 7 or 10, further characterized in that the dosage form of said medicament is aspersion, solution, cream, gel, ointment, lotion, powder, patch, suppository or implant.

12. The medicament according to claim 7, for the prevention and treatment of female vasculogenic sexual dysfunction.

13. A medicament for the prevention and treatment of female sexual dysfunction comprising papaverine and a type of KATP channel opener selected from the group consisting of nicorandil, pinacidil and cromakalim as active ingredients and a pharmaceutically acceptable carrier.

14. The medicament for the prevention and treatment of female sexual dysfunction according to claim 13, further characterized in that said active ingredients are contained in an amount of 0.1-20% by weight based on the total weight of the medicament.

15. The medicament according to claim 13 for topical application.

16. The medicament for the prevention and treatment of female sexual dysfunction according to claim 13, further characterized in that said medicament is directly administered to the clitoris, vagina or around them.

17. The medicament for the prevention and treatment of female sexual dysfunction according to claim 13 or 16, further characterized in that the dosage form of said medicament is aspersion, solution, cream, gel, ointment, lotion, powder, patch, suppository or implant.

18. The medicament according to claim 13, for the prevention and treatment of female vasculogenic sexual dysfunction.

19. A medicine for the prevention and treatment of male sexual dysfunction comprising a type of KATP channel opener by selecting from the group consisting of nicorandil and cromakalim as an active ingredient, and a pharmaceutically acceptable vehicle.

20. The medicament for the prevention and treatment of male sexual dysfunction according to claim 19, further characterized in that said active ingredient is contained in an amount of 0.1-20% by weight based on the total weight of the medication.

21. The medicament according to claim 19 for topical application.

22. The medicament for the prevention and treatment of male sexual dysfunction according to claim 19, further characterized in that said medicament is administered directly to the penis or around it.

23. The medicament for the prevention and treatment of male sexual dysfunction according to claim 19 or 22, further characterized in that the dosage form of said medicament is aspersion, solution, cream, gel, ointment, lotion, powder or patch.

24. The medicament according to claim 19, for the prevention and treatment of male vasculogenic sexual dysfunction.

25. A medicine for the prevention and treatment of male sexual dysfunction comprising papaverine and a type of KATP channel opener selected from the group consisting of nicorandil and cromakalim as active ingredients and a pharmaceutically acceptable carrier.

26. The medicament for the prevention and treatment of male sexual dysfunction according to claim 25, further characterized in that said total active ingredients are contained in an amount of 0.1-20% by weight based on the total weight of the medication .

27. The medicine according to claim 25 for topical application.

The medication for the prevention and treatment of male sexual dysfunction according to claim 25, further characterized in that said medicament is administered directly to or around the penis.

29. The medicament for the prevention and treatment of male sexual dysfunction according to claim 25 or 28, further characterized in that the dosage form of said medicament is aspersion, solution, cream, gel, ointment, lotion, powder and patch.

30. The medicament according to claim 25, for the prevention and treatment of male vasculogenic sexual dysfunction.