JP4182008B2 - External preparation for the treatment of sexual dysfunction - Google Patents

Description

  The present invention relates to an external preparation useful for preventing or treating penile erection dysfunction and female sexual dysfunction.

  As the middle-aged and elderly population increases, the erectile dysfunction population also naturally increases. In addition, erectile dysfunction in youth is increasing due to social factors. In addition, an increasing number of women complain of sexual dysfunction symptoms such as lack of sexual feeling, clitoral sensation, vaginal dryness, and sexual pain. Therefore, finding an effective means for preventing and treating such sexual dysfunction and improving sexual life are extremely important for improving QOL.

  Erectile dysfunction in Japanese is 42% at the age of 55-59 and 65% at the age of 65-69 (see, for example, Non-Patent Document 1), and 75% (for example, see Non-Patent Document 2) in diabetic patients. It is around 68% in patients (for example, see Non-Patent Document 3), and occurs at a high rate even in prostate surgery (for example, see Non-Patent Document 4). The main causes of erectile dysfunction are various factors such as mental factors, peripheral neuropathy, endocrine disorders, peripheral circulatory disorders, side effects due to drugs, etc., but the mechanism common to erectile dysfunction is the internal pressure of the corpus cavernosum regardless of the cause. It is a climbing disorder. Penile intracavernous pressure increases when arterial blood flow exceeds venous blood flow, resulting in an erection. Therefore, treatment that increases arterial blood flow is most important.

Conventionally, prostaglandin E1 (PGE ₁ ) and papaverine hydrochloride, which are vasodilators, have been injected into the corpus cavernosum for the purpose of increasing corpus cavernoplast blood flow. It is dangerous because bleeding, local neuropathy, etc. may occur, and the action duration is short and inconvenient (see, for example, Non-Patent Document 5). On the other hand, oral administration of various vasodilators has little effect. Recently, oral administration of sildenafil, which increases NO and increases blood flow by phosphodiesterase type 5 inhibitory action, has been effective, but it is ineffective in 30% of patients (see, for example, Non-Patent Document 6) and has 6 side effects. -54%, sudden cardiac death occurs occasionally (see Non-Patent Document 7). Also, it is contraindicated for nitrate users, and its use is naturally limited.
Therefore, it is hoped to develop a highly safe topical drug that is efficiently absorbed by application to the penis and intraurethral administration, has a sustained increase in cavernosal blood flow, and has no effect on the whole body. It is rare.

Prostaglandin I ₂ (PGI ₂ ) derivatives have a potent platelet aggregation inhibitory action and vasodilatory action, and are used as therapeutic agents for peripheral circulation disorders and the like. In addition, sustained-release preparations containing a prostaglandin I ₂ derivative and a hydrogel base have been reported (see, for example, Patent Documents 1 and 2). However, the topical administration of prostaglandin I ₂ derivatives to the penis and the induction of erection have never been known.

On the other hand, with regard to formulation of saccharides in a locally administered preparation, it has been reported that when saccharides are added to granulocyte colony stimulating factor (G-CSF), absorption of G-CSF from the nasal mucosa is promoted (for example, And Patent Document 3). However, a preparation containing a prostaglandin I ₂ derivative and a saccharide has never been known so far regardless of the dosage form.
International Publication No. 98/41210 Pamphlet International Publication No. 99/33491 Pamphlet JP-A-8-198772 See Non-Patent Document 1: Shirai M: Impotence 2: 67-93, 1987 See Non-Patent Document 2: Soh J Int J Urol 7 (Suppl 88): 110, 2000 Burchardt M: J Urol 164: 1188, 2000 Walsh PC: J Urol 128: 492-497, 1982 Nobuhisa Ishii: Modern Physician 19: 1135-1137, 1999 Goldenstein J: N Engl J Med 338: 1397-1404, 1998 McMahonCG: J Urol 164: 1192-1196, 2000

  An object of the present invention is to provide an external preparation for the treatment of sexual dysfunction that is efficiently absorbed by application to the penis or intraurethral administration, has no effect on the whole body, and is highly effective and safe. And

The present inventors have found that the aim of solving the above circumstances, by direct administration to the penis and urethra, were searching for a drug that exert an effect on sexual function disorders such as erectile dysfunction, prostaglandin I ₂ such that, alone penis Although it is almost ineffective when administered externally, etc., it is absorbed very well from the penis surface or urethra by blending saccharides, has a remarkable blood flow increasing action, such as erectile dysfunction It has been found that it can be an external preparation for the prevention and treatment of sexual dysfunction.

That is, the present invention provides an external preparation for treating sexual dysfunction containing prostaglandin I ₂ and saccharides.

  The topical preparation for the treatment of sexual dysfunction according to the present invention is a topical preparation for external administration to the penis, female genitals, urethra, etc., which is well absorbed from the skin or mucous membrane of the glans, penis, etc., and increases the blood flow volume. Caulking and inducing penile erection. Therefore, by using this preparation, male penile erectile dysfunction and female sexual dysfunction can be prevented or treated with minimal invasiveness and safety, and the sexual life of patients with sexual dysfunction including the elderly Can be normalized to improve the QOL.

The prostaglandin I ₂ class in the present invention includes prostaglandin I ₂ (prostacyclin), prostaglandin I ₂ sodium (prostacyclin sodium), and various prostaglandin I ₂ derivatives. As the prostaglandin I ₂ derivatives, in particular, 4,8-inter-m-phenylene prostaglandin I ₂ derivatives (for example, JP-B-2-12226, JP-B-2-57548, JP-B-1-53672) Gazettes, etc.) are preferred, and specific examples include beraprost, limaprost, iloproslot, clinprost, attaprost, cyprostin, naxaprosten, taprosten, cicaprost, pimiprost, CH-169 and SM-10902, and salts thereof. Among these, in view of the effect of increasing penile blood flow and the effect of inducing penile erection, beraprost sodium ((+)-(1R *, 2R *, 3aS *, 8bS *)-2,3,3a, 8b-tetrahydro-2- Hydroxy-1-[(E)-(3S *)-3-hydroxy-4-methyl-1-octene-6-ynyl] -1H-cyclopenta [b] sodium benzofuran-5-butanoate) is particularly preferred.

Such a prostaglandin I ₂ derivative may be synthesized by a known method (Japanese Patent Laid-Open No. 58-124778, Japanese Patent Publication No. 6-62594, etc.), and may be obtained by extraction and purification from a commercial preparation. But you can.

Examples of the saccharide in the present invention include monosaccharides such as glucose, dextrose, galactose, fructose, mannose, xylose, maltose, lactose, saccharose (including sucrose and syrup), disaccharides such as trehalose, trisaccharides such as raffinose, starch , Dextrin, α-cyclodextrin, dextran, pullulan, cellulose, gum arabic, tragacanth, agar, etc., among which glucose, fructose (particularly, in terms of penile blood flow increasing effect, penile erection inducing effect D (-) fructose), saccharose and cellulose are preferred.
Such saccharides may be used alone or in admixture of two or more.

In the external preparation for treatment of sexual dysfunction according to the present invention, it is preferable from the viewpoint of the effect that 1 to 1000 mg, preferably 20 to 1000 mg of saccharide is added to 1 to 5000 μg of prostaglandin I ₂ species.

Preparations obtained by adding saccharides to prostaglandin I ₂ have almost no effect when the drug is applied alone on the penis or administered into the urethra, as shown in Examples below. It exerts an increasing effect and a penile erection-inducing effect. Therefore, such a preparation is useful as an external preparation for the prevention or treatment of penile erectile dysfunction in males, and also has female sexual dysfunction such as lack of sexual feeling (excited state) (tactile dysfunction, clitoral sensation). Deficiency, vaginal dryness, urinary incontinence or sexual intercourse pain).

The external preparation for treatment of sexual dysfunction according to the present invention contains a gelling agent, that is, a polymer that swells upon contact with water and swells to form gel particles, such as polysaccharides, proteins, and synthetic polymers. Can do. Thereby, the penis blood flow increasing effect and the penis erection inducing effect can be further improved, and at the same time, a friction reducing effect and a moisturizing effect can be imparted.
Examples of such a gelling agent include seaweed extracts such as alginate (eg, sodium salt), kelp extract, fucoidan, and uronic acid that is a component thereof; plant seed sticky substances such as guar gum and locust bean gum; chondroitin Mucopolysaccharides such as sulfuric acid, hyaluronic acid or salts thereof, dermatan sulfate; animal proteins such as gelatin, albumin, casein, and atelocollagen; celluloses such as carboxymethylcellulose, methylcellulose, and microcrystalline cellulose; and derivatives thereof; polyvinyl alcohol, polyacrylate Synthetic polymers such as sodium acrylate) and polyethylene oxide are used, and these are preferably used in combination of one or more.

  The amount of such a gelling agent is preferably about 0.1 to 50% by weight, more preferably about 0.1% by weight, based on the total weight of the preparation, in consideration of penile erection inducing effect, moisturizing effect, frictional resistance reducing effect, etc. 5 to 20% by weight.

  In order to improve the stability of the composition, for example, a lactic acid-based, phosphoric acid-based, citric acid-based, or tartaric acid-based buffer can be blended with the external preparation of the present invention, and these buffers are used appropriately. It is desirable to adjust the pH to 5.5 to 7.5, preferably 7.0.

  In addition, the external preparation of the present invention includes medicinal ingredients having an effect of increasing blood flow, enhancing sexual function, etc., such as hormone agents, aphrodisiacs, sperm production promoters, nitric oxide production agents, phosphodiesterase type 5 inhibitors and the like. It can be blended within a range that does not impair safety. Examples of such components include testosterone propionate (male hormone agent), yohimbine hydrochloride (aphrodisiac), amino acids (lysine (promoters for sperm production), arginine (nitrogen monoxide producer), etc.), ornithine sodium (ATP producer) , Sildenafil (phosphodiesterase type 5 inhibitor) and the like.

  The external preparation of the present invention is an external preparation mainly applied to female genitals such as penis glans, foreskin, penis neck, penis stem, scrotum, urethra, vagina, etc., and contains a known pharmaceutical carrier, According to a known method, any shape suitable for application to the affected area of the skin or mucous membrane, that is, a solution, powder, ointment, paste, cream, gel, emulsion, spray, suppository or the like can be obtained.

  Formulation carriers include fats and oils (lanolin, petrolatum, polyethylene glycols, etc.), emulsifiers (various surfactants, etc.), thickeners (acrylic acid copolymer, fructose, carnauba wax, agar powder, glycerin, aluminum magnesium silicate, Purified gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, propylene glycol, sodium polyacrylate, etc.), adhesive (sodium alginate, xanthan gum, aluminum magnesium silicate, etc.), dispersant (gum arabic, propylene glycol alginate, carboxyvinyl polymer, hydroxy) Ethyl cellulose, methyl cellulose, propylene glycol, polysorbate, macrogol, etc.), solubilizer (tartaric acid, citric acid, lactic acid, L-aspartic acid, sorbitan) Fatty acid esters, hydroxypropyl cellulose, polyoxyethylene hydrogenated castor oil, liquid paraffin, etc., stabilizers (amino acids or salts, etc.), absorption accelerators (sodium glycolate, sodium edetate, etc.), solubilizers (polyoxyethylene hardened) Castor oil, polysorbate 80, polyethylene glycol, etc.), disintegrants (corn starch, carboxymethyl cellulose, etc.), excipients (eg lactose, sucrose, mannitol, crystalline cellulose, silicic acid), binders (crystalline cellulose, saccharides, Dextrin), lubricants (magnesium stearate, calcium stearate, talc), preservatives, isotonic agents, pH adjusters, antioxidants, buffers, preservatives, fragrances, colorants, flavors, etc. Can be mentioned.

  A urethral suppository for intraurethral administration is usually in the shape of an elongated pencil and has a shape suitable for urethral insertion, and has a length of 7 to 14 cm for men and 5 to 7 cm for women. The solid or semi-solid preparation for intraurethral administration may be prepared to an appropriate size for administration into the urethra, for example, 1 cm or less in length. Further, in the case of a liquid urethral preparation, it is injected and administered directly or when necessary by a device that can be inserted into the urethra such as a flexible tube (FIG. 1).

  The dosage of the external preparation for treatment of sexual dysfunction of the present invention is 0.1 to 5 g, preferably 0.5 to 1.0 g per administration in the case of application administration, and in the case of intraurethral administration. The dose is 0.1 to 5.0 g, preferably 0.25 to 0.5 g per dose.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 Preparation of Solution A product 1 of the present invention was prepared by adding 10 mL of physiological saline to a powder of 25 μg of beraprost sodium and 2 g of D (−) fructose and mixing well.
In the same manner, liquid products shown in the present invention products 2 to 12 and comparative products 1 to 3 shown in Tables 1 and 2 below were prepared.
Beraprost sodium was extracted from “Dorner Tablets” (Toray / Yamanouchi).

Example 2 Preparation of Powder (Powder) The present invention product 14 was prepared by adding 2 g of D (-) fructose to 200 μg of beraprost sodium and adding 0.5 g of sodium L (+) alginate and mixing well. In the same manner, powder agents shown in the present invention products 13 and 15 shown in Table 3 below were prepared.

Example 3 Clinical Examination (1) Subjects Five subjects who were 60-69 years old medical professionals who did not have an early morning erection were targeted. After obtaining oral informed consent, the following examination was conducted from May 2003 to December 2015.
After resting at room temperature of 25C and humidity of 60% for 5 minutes in the lower body undressing condition, penis temperature, penile cavernous oxygen saturation, and penis hardness were measured. The measurement was performed at 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, and 36 hours after the administration, with the pre-formulation administration as a control value, and the change values were expressed as (change value + average deviation). If there was no change after 3 hours, it was considered that there was no effect and was discontinued.

(2) Drug administration method 1) Application method: 0.5 mL of each preparation was uniformly applied to the glans and penis.
2) Urethral injection method: An injector having a soft silicone tube at the tip shown in FIG. 1 was devised, the injector was inserted into the urethra, and the cylinder was rotated to inject 1 mL of the preparation.

(3) Measurement method 1) Penis temperature change measurement method The temperature rise reflects the increase in blood flow. Therefore, penis temperature was measured by thermograph (Fukuda Electronics). In this apparatus, the site can be displayed on the screen, and the temperature of the site can be displayed as a numerical value. Therefore, the same site was quantified and compared with before administration.

2) Penis hardness measurement method Erection occurs when penis hardness increases. Therefore, a hardness tester (Hardness tester SD6-11, Mitsutoyo) probe was pressed against the left back of the penis, the hardness was measured, displayed in mm, and compared before and after administration.

(4) Grade 1. Effect of penis glans application a) Change in penis temperature Figure 2 shows comparative product 1 (25 μg beraprost sodium and physiological saline), comparative product 2 (50 μg beraprost sodium and physiological saline), product 1 of the present invention (25 μg beraprost sodium and 2 g fructose) And physiological saline), the increase in penis surface temperature accompanying the application of the product 2 of the present invention (50 g of beraprost sodium and 2 g of fructose and physiological saline) to the penis and glans, and the time course thereof.
In Comparative Product 1, no temperature change was observed, but in Comparative Product 3, the temperature increased and lasted for 48 hours or more. In the comparative product 2, only a slight temperature increase was observed, but in the product 2 of the present invention, the temperature rose significantly and lasted for 48 hours or more. The penis hardness also continued to increase as shown in Table 4. That is, it shows that absorption of beraprost sodium was promoted by fructose.

  For other preparations, as shown in Table 4, the action of beraprost sodium was enhanced by fructose and glucose as monosaccharides and saccharose as disaccharides. The gels sodium alginate and sodium polyacrylate themselves did not show any potentiating action, but the potentiating action was also observed in the preparations containing monosaccharides, disaccharides and gels. Similar results were obtained with the powder formulation.

b) Change in penis hardness Table 4 shows the increase in penis hardness with application of each formulation. In comparative products 1 and 2, the hardness hardly increased, but in inventive products 1 and 2 to which fructose was added, the hardness increased significantly. That is, the erection action by beraprost sodium was enhanced. It was similarly enhanced in preparations containing other monosaccharides and preparations added with gels. The same was true for powder formulations.

2. Effect of intraurethral injection FIG. 3 shows the degree of change in temperature and the time course of the comparison products 1 and 2 and the inventive products 1 and 2 accompanying the intraurethral injection. In the products 1 and 2 of the present invention, the temperature increased and the hardness increased, and it was shown that the saccharide promoted the absorption of verapro sodium from the urethral mucosa. As shown in Table 5, the absorption promotion effect by saccharides was also observed for other preparations.

Example 3 Study on Early Morning Erection (1) Method Early morning erection is a good index indicating that there is erection ability. Therefore, in 4 cases in which early morning erection was not observed, the products of the present invention shown in Table 6 were applied to the penis glans to examine whether early morning erection occurred.

(2) Results Table 6 shows the results. In the comparative products 1 to 3 of beraprost sodium and physiological saline, erection was not induced in the early morning or the frequency was low, but erection was induced at a high rate in the product of the present invention.

Example 4 Stability of Formulation The products of the present invention shown in Table 7 were stored in a cold place at 4 ° C. and applied to the head of the penis after 1, 2, and 4 weeks at 2 weeks, and the effects were compared. As shown in Table 7, the product of the present invention was stable even after long-term storage, and the pharmacological effect was maintained.

It is a schematic diagram (A: syringe type, B: cap type cylinder type) of the drug injector used for intraurethral administration. It is a graph which shows the time transition of the surface temperature accompanying penis turtle head application. It is a graph which shows the time transition of the surface temperature accompanying injection | pouring in a urethra.

Explanation of symbols

1: Grooved cylinder of syringe 2: Internal organ barrel of syringe 3: Tube for insertion 4: Cap 5: Scale indicating dosage

Claims (5)

An external preparation for treating sexual dysfunction comprising beraprost or a salt thereof and a saccharide selected from glucose, fructose, saccharose and cellulose . Salts of beraprost is 1 Symbol placement sexual dysfunction therapeutic agent for external use according to claim is beraprost sodium. The external preparation for treatment of sexual dysfunction according to claim 1 or 2 , further comprising a gelling agent. The external preparation for treatment of sexual dysfunction according to any one of claims 1 to 3 , which is administered into a penis, female genitals or urethra. The external preparation for treatment of sexual dysfunction according to any one of claims 1 to 4 , which is a preventive or therapeutic agent for penile erection dysfunction or female sexual dysfunction.