TW200526229A - External preparation for treating sexual dysfunction - Google Patents

Abstract

This invention relates to an external preparation for treating sexual dysfunction. It comprises a PGI2, and a saccharide. The external using agent for treating sexual dysfunction is high-effect and high-safety. It is efficiently absorbable by applying to the penis or administering into the urethra, and without affecting the whole body. This external using agent is treating sexual dysfunction. In the agent, the saccharide is selected from glucose, fructose and saccharose.

Description

200526229 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to an external preparation which can effectively prevent and treat penile erectile dysfunction and female sexual dysfunction. [Previous technology] With the growth of the middle-aged and elderly population, the number of erectile dysfunction naturally also continues to increase. As a result of social factors, erectile dysfunction has also increased in young and middle-aged people. The number of women who report lack of sexual pleasure, lack of clitoral pleasure, vaginal dryness, and pain during sexual intercourse is also increasing. Therefore, discovering the effectiveness of preventing and treating sexual dysfunction and improving sexual life is extremely important for improving the quality of life (QOL). Among erectile dysfunction patients, 42% are 55-59 years old, 65-69 years old are 65% (for example, Shirai M: Imp〇tence 2: 67_93, 1987), and 75% of patients with diabetes. (Such as Soh J Int J Urol 7 (Suppl 88): 110, 2000), about 68% of patients with hypertension (such as BurchardtM: JUr〇1 164: 1188, 2000), due to prostate surgery The incidence is also very high (eg Walsh pc:; Un) 1 128: 492_4% 1982). The main causes of erectile dysfunction include mental causes, peripheral nerve disorders, endocrine disorders, peripheral circulation disorders, side effects caused by drugs, etc., but for any reason, the mechanism of erectile dysfunction is the same, that is, the inner part of the penile cavernous body Barriers to elevated pressure. When the arterial blood flow of the penile cavernous body increases beyond the venous blood flow, the internal pressure rises and an erection occurs. Therefore, finding ways to increase arterial blood flow is most important for treatment. At present, in order to increase the blood flow of the cavernous body, a method of injecting a vasodilator prostaglandin El (PGEl) or papaverine hydrochloride into the cavernous body is used, but the patient has used this method since 92642.doc 200526229, which sometimes causes a decrease in systemic blood pressure. , Bleeding, local neurological disorders, etc., are very dangerous, and the duration of the effect is very short, very inconvenient (eg, Ishii Suspension: Modern Internal Medicine (乇 夕,. ≫ フ γ ク シ ア シ) 19. 1 135-1 137 '1999). When used, various vasodilators are almost ineffective when used orally. Recently, although sildenafil increased blood flow to increase oral effect by increasing NO through phosphodiesterase type 5 blockade, it has no effect on "% of patients (eg, Goldenstein j: n Engl j Med 338: 1397-1404, 1998), the incidence of side effects reached 6_54%, and sometimes heart failure (McMahonCG: J Ur〇1 164: 1192 1196 2000). At the same time, it is forbidden for nitric acid users, and the scope of use is restricted Limitation. Therefore, 'people want to develop a safe external preparation that can be effectively absorbed by applying on the penis or placed in the vagina, can continuously increase the blood flow of the corpora cavernosa, and does not cause systemic effects. Prostaglandins! 2 (PGl2) derivatives have rampant platelets; suspicious inhibitory effects and vasodilation effects are used to treat peripheral circulation disorders, etc. In addition, a sustained-release preparation containing a prostaglandin 12 derivative and a hydrogel matrix There are also reports (eg, International Publication No. 98/41210 and International Publication No. 99/33491). However, the effect of external use of prostaglandin 12 derivatives on erectile dysfunction caused by penile administration has so far been completely unknown. In addition, in the use of carbohydrates in combination with topical preparations, it has been reported that the addition of carbohydrates to granulocyte colony-stimulating factor (G_CSF) can promote the absorption of G-CSF through the nasal Announcement). However, the combination of prostaglandin 12 derivatives and sugars, no matter what agent 92642.doc 200526229 type is still unknown. SUMMARY OF THE INVENTION The object of the present invention is to provide a topical agent for the treatment of sexual dysfunction that can be effectively absorbed without causing systemic effects by being applied on the penis or intraurethral administration. The strict inventors have researched and developed medicines based on the above-mentioned actual conditions to directly treat various sexual dysfunctions such as erectile dysfunction through direct administration of the yin or urethra. It was found that although prostaglandin l2 is basically ineffective when used externally on yin deficiency and other parts, if it is used with the hearing class from the penis surface: it has excellent absorption up to the urethra and has a significant increase in blood flow, which can be used as An external preparation for preventing and treating various sexual dysfunctions such as erectile dysfunction. That is, the present invention provides a topical agent for the treatment of sexual dysfunction containing prostaglandins 12 and vinegars. The topical zibu for the treatment of sexual dysfunction of the present invention is a topical preparation for external application to the penis, female sexual organs, or urethra, etc., which is well absorbed from the skin and mucous membranes of the glans, stalks, etc., which increases blood flow and causes ^ Stem erection. Therefore, the use of this preparation is low invasive and very safe; it is used to treat male penile erectile dysfunction and female sexual dysfunction 'can make the sexual life of patients with sexual dysfunction including the elderly normalized' Thereby improving their quality of life (QOL). [Embodiment] The prostaglandins 12 in the present invention include prostaglandin 12 (prostacyclin), prostaglandin 12 nanometer (prostacyclin sodium), and various other prostaglandin 12 derivatives. As a prostaglandin 12 derivative, particularly preferred is 4,8_endo-m-phenylene 92642.doc 200526229 adenin l2 derivative (for example, special fair 2_12226 announcement, special fair 2 milk M public :, special fair "Assistance announcement, etc.", specifically, for example, pentoprost, lmaprost, iloprost, iloprost, climatoprost, aprost, siprost MM, Nakoprost (10M Shekou only)>, Taraprost, Sikaprost, Pimetoprost, cm69, SM 10902 and its salts. Among them, the effect of increasing blood flow from the penis and the penis The angle of the erectile initiation effect is particularly good for pentoprost sodium (㈩-⑽ 'looking for' 3aS '8bS) -2, 3, 3a, 8b-tetrahydro_2-jingjixiao [⑻_ (3S *) _ 3 • 经4-methyl-octane-6_quickyl] _Cyclopentamidine M: Na-butyrate) The prostaglandin 12 derivatives described herein can be obtained by conventional methods (Japanese Patent Laid-Open No. H24778, Japanese Patent Publication No. XX, etc.) can also be synthesized by extraction and purification from commercially available preparations. _ In the present invention includes glucose, dextrose, galactose, fructose, mannose, Listening classes such as xylose, maltose, lactose, silk (including white sugar and honey, etc.), didomains such as trehalose, trivinegars such as raffinose, house powder, dextrin, α-cyclodextrin, glucose polymer Polysaccharides such as sugar, puUuian, cellulose, gum arabic, tragacanth, and agar. Among them, from the perspective of the effect of increasing yin anemia flow and initiating penile erection, glucose and fructose (particularly It is D (-) fructose), sucrose, and cellulose. The saccharides can be used alone or in combination of two or more. The external agent for the treatment of sexual dysfunction of the present invention has a 'better prostaglandin' from the viewpoint of effects. ^ The auditory test is added to the tester's test call, preferably 20 ~ 1000 mg. Two columns of adenine 12 are added to the preparation of carbohydrates, as shown in the following Example 92642.doc 200526229, and the _ adenin 12 _When the substance is basically ineffective, or when it is used in the urethra and after adding vinegar, the drug preparation will increase the blood flow of the penis. The effect of buckle hair will be _looking system ... and the effect of Yin-erection. It can be seen that Xisiyi is effective as an external agent for the prevention and treatment of 0x sexual vulvar erectile dysfunction, and it can also be used to improve the performance of female horses and horses. This is not as good as sexual pleasure (excited state) = lack ( A topical preparation for symptoms of palpitation, lack of clitoral sensation, vaginal dryness, urinary incontinence, or pain during intercourse. The external preparation for the treatment of sexual dysfunction of the present invention can be used in combination with a polyacrylamide, a protein, a synthetic polymer, etc. in combination with a coagulant, i.e., a polymer substance that absorbs water and swells to form gel particles in contact with water. Thereby, the effect of increasing blood flow in the yin can be increased and the effect of initiating penile erection can be improved. At the same time, the effect of reducing friction and moisturizing can also be achieved. Examples of such gelling agents include alginate (such as sodium salt), kelp extract, rock bath polysaccharide such as seaweed extract or uronic acid of its components; guar gum, locust ugly gum and other plant seed sticks Sexual substances; mucopolysaccharides such as chondroitin sulfate, hyaluronic acid or its salts, dermatan sulfate; animal proteins such as gelatin, albumin, casein, and telomere; carboxymethyl cellulose, methyl cellulose, microcrystalline Cellulose and other cellulose and its derivatives; polyvinyl alcohol, polyacrylates (sodium polyacrylate), synthetic polymers such as cyclopentadiene. It is also preferable to use one or more kinds in combination. The amount of this gelling agent used is preferably about 0.1 to 50% by weight in terms of the total weight of the preparation from the viewpoints of initiating penile erectile effect, moisturizing effect, and reducing frictional resistance effect. /. , More preferably about 5 to 20% by weight. In order to improve the stability of the composition, it is possible to formulate 92642.doc • 10-200526229 buffers for lactic acid, phosphoric acid, citric acid, and tartaric acid in the external preparation of the present invention. It is desirable to use these buffers appropriately to make the pH value. It is adjusted to 5.5 to 7.5, preferably 7.0. In addition, in the external preparation of the present invention, effective ingredients such as hormones, aphrodisiacs, sperm production promoters, nitric oxide generators, and phosphate diphosphates can be added to the range that does not hinder the stability. Esterase type 5 blockers and the like. The ingredients include, for example, testosterone propionate (androgen), yohimbine hydrochloride (aphrodisiac), amino acids (lysine (sperm production promoter), arginine (nitrogen oxide production agent), etc.), birds Sodium glutamate (ATP producing agent), sildenafil (phosphodiesterase type 5 blocker), etc. The external preparation of the present invention is mainly applicable to the glans of the penis, the foreskin, the neck of the penis, the trunk of the penis, the scrotum, and female sexual organs such as the urethra and vagina. This external preparation can be formulated with a conventional preparation carrier and can be made by conventional methods Applicable to any shape of the affected skin and mucous membranes, such as solutions, powders, softness, coatings, creams, gels, emulsions, sprays, suppositories and other forms. Examples of the preparation carrier include oils and fats (lanolin, petroleum jelly, polyethylene glycols, etc.), emulsifiers (such as various surfactants), thickeners (acrylic acid copolymer, fructose, Brazilian palm wax, margarine, Glycerin, magnesium magnesium oxalate, purified gelatin,

Agents (amino acids or their salts, etc.), carbamidine + carbamide, sorbitan fatty acid esters, Greek hardened castor oil, liquid paraffin, etc.), stable absorption promoters (sodium glycolate, sodium edetate 92642) .doc 200526229, etc.), dissolution aids (polyoxyethylene hardened castor oil, polysorbate 80, polyethylene glycol, etc.), disintegrants (corn starch, carboxymethyl cellulose, etc.), excipients ( Such as lactose, sugar, mannitol, crystalline cellulose, silicic acid), binders (crystalline cellulose, sugars, dextrin), lubricants (magnesium stearate, calcium stearate, talc), and preservatives Agents, isotonic agents, pH adjusters, antioxidants, buffering agents, preservatives, fragrances, colorants, flavors, and the like. A urethral suppository for intraurethral administration is generally in the shape of a slender pencil with a shape suitable for insertion into the urethra. The length is 7 to 14 cm for men and 5 to 7 cm for women. The solid or semi-solid urethral administration preparation can be made into a size suitable for administration into the urethra, such as the length is less than or equal to cm. If it is a liquid urine preparation for intramedicinal administration, it may be injected directly if necessary or an instrument such as a flexible tube (Fig. 1) inserted into the urethra may be used for administration. The dosage of the external agent for the treatment of sexual dysfunction according to the present invention is 0.1 to 5 g, preferably 0.5 to 1.0 g per administration if the method of applying the drug is applied; Administered 〇1 ～ 50 ％, preferably 0.25 ～ 0.5. Hereinafter, the embodiments will be described in detail, but the present invention is not limited to these embodiments. EXAMPLES Example 1 Preparation of a liquid preparation Pentolein sodium 25 pg and D-fructose 2 g of powder were added with physiological food water and thoroughly mixed to prepare the product of the invention. ^ The liquid preparations of the products 2 to 12 of the present invention and the reference products 1 to 3 shown in the following Tables 1 to 2 are prepared in the same way. In addition, pencoglitazone sodium was obtained from "DORNER tablets," (extracted from Torayyama's extract. 92642.doc 200526229) Table 1 (liquid preparation) Reference product of the present invention 1 2 3 4 5 6 7 1 2 3 Pentoprost sodium (μg) 25 50 200 25 50 200 50 25 50 200 Sugar D Fructose (g) 2 2 2 2 2 2 Cellulose (g) 2 Sodium polypropionate (mL) 2 2 2 Physiological table salt Water (mL) 10 10 10 8 8 8 10 10 10 10 Table 2 (Liquid preparation) Product of the present invention 8 9 10 11 12 Pentoprost sodium (Kg) 200 200 200 200 200 Cool D-fructose (g) 2 Glucose ( g) 2 2 Sucrose 2 2 L Sodium alginate (g) 150pc 0.5 0.5 0.5 Physiological saline 10 10 10 10 10 Example 2 Preparation of powder (powder) Pentoprost sodium 200 pg Added D (-) fructose 2g Then, 0.5 g of L (+) sodium alginate was added, and then mixed thoroughly to prepare the product of the invention 14. The following method was used to prepare the powder of the product 1 of the present invention shown in Table 3 3-15 92642.doc -13- 200526229 Table 3 The present invention produces 14 15 200 200 1 2-2 1 1 (powder) -------- L (+) Sodium alginate (g) 15 〇gp Example 3 Clinical study ⑴ The subjects were 5 to 60-69-year-olds who were engaged in medical services ~, scholars, and no morning erections. The verbal informed homonym F1 was obtained. ^ After that, he conducted the following research between May, 2015 and December, 2015. At the room temperature of 25 ° C and humidity of 60%, I will take off my clothes and protect my lower body. ; For Zhong Jing'an, then measure the temperature of the penis, # 2, the current degree, the oxygen saturation of the penile cavernous body, and the decrease in hardness. Use the value before the administration as the value ^ and the value as the confrontation value. The values of 3 hours, 6 hours, 12 hours, 24 hours, and the time of material are shown in Table 1. The change values (change value + average deviation). If there is no change 3 hours after administration, the measurement is stopped as soon as possible. (2) Drug administration method 1) Smear method: apply 0.5 ml of each preparation to the glans and penis. 2) Urinary tract injection method: Use an injection device with a _ Table f human officer at the front end as shown in Figure 1, insert this injection 1§ Urinary tract, rotating the cartridge to inject preparations (3) Measurement method 1) Penile temperature change measurement method Temperature rise system blood flow Coupled reaction. Therefore, M 仏 used a calorimeter 92642.doc -14-200526229 (ThermoPhy) (FUKUTA Electronics) to measure the temperature of the penis. With this device, you can mark a part on the screen and use the numerical value to indicate the temperature of the part. Therefore, quantitative analysis is performed on the same part and compared with before administration. 2) Penile hardness measurement An increase in penile hardness results in an erection. Therefore, we measured the hardness by pressing the probe of a hardness tester (Hardness tester SD6-11, Mitsutoyo) on the left back of the penis, expressed in mm, and comparing before and after administration. (4) Result 1 • Penis glans smearing effect a) Change in penile temperature Figure 2 shows the comparison with (pentaprost sodium and physiological saline) and control 2 (pentaprost sodium 50 and normal saline) The product of the present invention is U penzestil sodium 25 and 2 g fructose and physiological saline), produced by the present invention. 2 (Pentaprost 50g and fructose 2g and normal saline) are applied on the penis = head, the temperature of the stem surface is high and the daytime experience. There was no temperature change in the reference product i, and the temperature of the reference product 3 rose and held the reed for more than 48 hours. The control 2 only had a slight increase in temperature, and the mouth 2 of the present invention showed that: the increase was sustained for more than 48 hours. At the same time, the hardness of the penis is as close as possible: there is a persistent increase. This shows that fructose promotes the absorption of pentaprost sodium. As shown in Table 4, fructose and carbohydrates, and carbohydrates of monotonic enhance the effect of carprost sodium. Gelatinizers ::, Polyacrylic acid sodium did not see a strengthening effect by itself, but it was found that the formulations of Zao, Di M and gelling agent showed a strengthening effect. Λ 92642.doc 200526229 4 doses have the same result. b) Changes in penile hardness Table 4 shows the degree of increase in penile hardness after application of each preparation. Controls 1, and 2 had no increase in hardness, but the products 1 and 2 of the present invention to which fructose was added had a significant increase. This shows that it enhances the potency of pentoprost sodium. The formulations used in combination with other monosaccharides and the formulations with added gelling agents also showed the same effect: enhanced effect. In addition, the powder preparation has the same result. Apply to penis Product of the invention (powder) Control product of the invention (liquid preparation)

2. Urinary tract injection, maximum hardness Table 4

Effect of administration

Fig. 3 shows the degree of change in temperature and time duration of the administration loss of the intraurethral injection of the products 1 and 2 of the present invention. The product of the present invention ... increased in temperature and hardness, shows that radon promotes the absorption of pentoprostna from the urethral mucosa. 92642.doc -16- 200526229 As shown in Table 5, other preparations also showed the absorption-promoting effect of sugars. Table 5-Injection 1 Inner urinary product of the invention (liquid preparation)

Example 12 789Τ0ΤΓΪ2

Erection research

(1) Method Morning erection is a good indicator of erection ability. Therefore, we took 4 cases without morning erection, and applied the product of the present invention to the glans of the stem as shown in Table 6 to study whether morning erection occurred. (2) Results Table 6 shows the results of this study. The use of sodium pentoprost and physiological water to make a photo product has not risen in the morning, or even if it has, it is rare. Those who use the product of the present invention produce high frequency erections. 92642.doc -17- 200526229 _ Number of cases of erection in the early morning _ Ben 1 1/4 ~~~ Hair 2 2/4 Ming 3 '4/4 — Produce 7 4/4 ^ Pin 9 ZZ ΙΓ 3/4 ~ 11 1 ~ ~ 3/4 ~ to Π / 7 1 0/4 ~ — mouth σ 2 " 0/4 ~~ ^ 3 ~ " 2/4 * ~ ^ Example 4 Stability of the preparation 2 weeks, 1 After months, compare effects. As shown in Table 7, the effect is stable. The product of the present invention shown in Table 7 is stored refrigerated at 4 ° C, and applied to the glans of the penis after 2 months and 4 months. As shown, the product of the present invention is still

Fig. 1 is a model diagram of a drug injector for intraurethral administration (injector type, B ·· cylinder type). 1. Slotted cartridge of the 1-insertor 2: the inner cylinder of the preparation of the syringe, 3: the inserting member 4: the cap, and 5 ·· indicates the scale of the dosage. Figure 2 shows the change in surface temperature over time after application of the penis glans. Figure 0 shows the change in surface temperature. Figure 3 shows the time course after intraurethral injection. 92642.doc -18-

Claims (1)

200526229 X. Patent Application Fan Yuan: 1. A topical agent for the treatment of sexual dysfunction, which contains prostaglandin i2 and sugars. 2. For example, ask for topical agents for the treatment of sexual dysfunction, where the domains are selected from fe glucose, fructose and sucrose. 3. If you request the topical treatment of sexual dysfunction in item 1 or 2, 1 and τ margin are listed as prostaglandin type 12. 4. As requested! The external preparation for the treatment of sexual dysfunction of any one of items 3 to 3 further contains a gelling agent. Θ 5. The topical agent for the treatment of sexual dysfunction as claimed in any one of the items ⑴, further comprising a nitric oxide generator. 6. If you request an external system for the treatment of sexual dysfunction of any one of 5 to 5, the penis, female sex organs or urethra are administered. Η7. To 6 !: A topical agent for the treatment of sexual dysfunction, which is an erectile dysfunction or female sexual function " agent. The prevention or treatment of king disease