KR20030041433A - Transdermal preparation containing L-arginine for treatment of erectile dysfunction and sexual frigidity - Google Patents

Abstract

PURPOSE: A composition for transdermal administration comprising L-arginine which has excellent therapeutic effect and presents no adverse effects even when administered in excess as a main drug is provided. The composition is an external application which overcomes the defects of conventional injections or oral therapeutic agents and effective in treatment of erectile dysfunction and frigidity. CONSTITUTION: A preparation for transdermal administration contains 1 to 20% by weight of L-arginine, 1 to 30% by weight of a skin permeation enhancer, a pharmaceutically acceptable carrier and additionally 1 to 80% by weight of one or more additives selected from a solubilizing aid, a softening agent, a surfactant, a thickening agent and a pH controller. The preparation is applied to the peripheral surface of the penis and the clitoris in a single dose of about 0.1 to 2g.

Description

Transdermal preparation containing L-arginine for treatment of erectile dysfunction and sexual frigidity

The present invention relates to a transdermal formulation for treating erectile dysfunction and sexual insensitivity, comprising L-arginine, a permeation accelerator, and a pharmaceutically acceptable carrier, and having a pH of 9 or more.

Male erectile response is maintained by the complex interaction between vascular and neurological effects with vascular effects initiated by neurological action. Parasympathetic nerve stimulation relaxes the trabecular smooth muscles and causes erections by expanding the spiral arteries of the penis. This expands the lacunar space and collects blood into the penis by pressing the sclera against the tunica albuginea.

Erectile dysfunction or sexual impotence is a term used to describe the sexual inability of a man who does not have an erection enough to have successful sexual intercourse. These erectile dysfunctions are caused by psychological disorders (psychopathic), physiological abnormalities (stromal), or a combination of both. Typically, many factors contribute to erectile dysfunction.

The causes of organic erectile dysfunction, which are the main cause of erectile dysfunction, include vascular abnormalities, neurologic deficiencies and drug treatment side effects. Primary vascular causes of erectile dysfunction are arterial insufficiency that prevents the penis from filling up with blood and venous dysfunction that prevents blood from remaining in the penis during erection. Arterial insufficiency is primarily due to atherosclerosis and has been found to worsen due to smoking. In rare cases, somewhat undesirable vascular causes of erectile dysfunction are painful priapism, which causes hypoxia and necrosis of penile tissue.

Insensitivity can be said to be mainly for women, and generally refers to a state in which there is sexual desire or sexual excitement but not orgasm. It is also called sexual insensitivity and loss of sexuality, but it is difficult to distinguish strictly, but a slightly different concept is called cold feeling or sexual desire insufficiency. In normal women, a series of physiological stages of sexual response include congestion and increased saturation and subsequent rapid release of vasculature and myotonia as a result of orgasm. If the clitoris is not congested with blood, it will not reach normal orgasm. Women who complain of these problems are diagnosed with sexual irritation. This condition is more precisely defined as a continual failure or failure to regain or maintain a lubrication-swelling response of sexual excitement until the end of sexual excitement, which is strong and persistent. And occurs despite appropriate sexual stimulation.

The causes of insensitivity include mental and psychological causes and physical causes. First, the physical causes include local diseases such as endometriosis, cystitis and vaginitis, systemic diseases such as hypothyroidism, diabetes, and central nervous system such as multiple sclerosis. (CNS) peripheral diseases, muscular diseases such as muscular dystrophy, oral contraceptives, drugs such as antihypertensives and antipsychotics, and surgical resections.The psychological causes include psychological oppression or fear, fear of pregnancy or sexually transmitted diseases, Guilt, masculine hatred, and ignorance of sexual intercourse are the main factors.

Erectile dysfunction treatment includes vacuum compressor, vascular surgery, penile prosthesis, sexual psychotherapy, hormone therapy and vasodilator. Among them, the main drugs for improving and enhancing erection are male hormones such as testosterone, and prostaglandin E1 derivatives such as aldosterone, nitroglycerin, and L-arginine (L-). NO donors such as arginine, phosphodiesterase inhibitors such as sildenafil, alpha-adrenergic antagonists such as yohimbin, and many others. Vasoactive agents are being used.

As an example of the prior art, US Pat. No. 4,127,118 describes a method for treating male erectile dysfunction by injecting into the penis an appropriate vasodilator, in particular an adrenaline blocker or muscle relaxant, which affects and promotes erection. 4,801,587 describes a method for treating erectile dysfunction using ointments. The ointment consists of papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine or phentolamine, as a vasodilator, and a carrier that helps the skin absorb the main agent.

In particular, US Pat. No. 5,910,316 describes a method for administering a nitric oxide donor agent (NO releasing agent) for urethral dysfunction treatment, such as a transurethral application, a penile implant, a patch, and the like. In addition, US Pat. No. 5,994,294 describes a variety of NO donor drugs of various structures for treating erectile dysfunction.

However, these erectile dysfunction and sexual insensitivity therapeutics have the following problems depending on the dosage form of the formulation.

First, when administered as an external preparation, since it is difficult to absorb a sufficient amount of the drug through the local route, it is difficult to exert an effective drug, or a disadvantage arises in that a large amount of drug must be administered. In addition, direct injection into the cavernous body is excellent in terms of effectiveness, but may cause undesirable side effects such as pain, erectile dysfunction, and tissue fibrosis, and in the case of oral administration, the drug into the tissue to be effective after the drug is absorbed. There is a problem that it is difficult to expect the desired effect because the implementation rate is very low.

In relation to sexual insensitivity treatment of women, psychological therapy is widely used based on psychological causes among women who do not reach orgasm. It is not attainable.

Therefore, various cause-based approaches are required for the treatment of sexual insensitivity in women.The drug acts directly on the female clitoris and causes congestion, based on the medical content that the clitoris responds during the first phase of the sexual response cycle, the excitatory phase. Therefore, there is also an urgent need for the development of external preparations to have a useful effect in the treatment of women who complain of insensitivity.

Of the drugs known to have erectile dysfunction and sexual insensitivity, L-arginine is an excellent amino acid and has a therapeutic effect. As a result of selecting the transdermal administration formulations that have only skin irritation problems, and devoting all efforts to developing transdermal administration formulations for the treatment of erectile dysfunction and sexual sensitization, these formulations not only improve skin absorption rate but also improve skin irritation problems. It was found that this did not occur to complete the present invention.

Accordingly, an object of the present invention is to provide a transdermal preparation for treating erectile dysfunction and sexual insensitivity, which has little side effects and can obtain a sufficient effect even in a small amount.

The present invention relates to a transdermal formulation for treating erectile dysfunction and sexual insensitivity, comprising L-arginine, a permeation accelerator, and a pharmaceutically acceptable carrier, and having a pH of 9 or more.

The composition of the present invention has a low skin permeability of L-arginine when the pH is less than 9. In consideration of skin irritation, the pH of the composition is more preferably 9-11.

The composition of the present invention preferably comprises 1 to 20% by weight of L-arginine and 1 to 30% by weight of a permeation accelerator based on the total weight of the composition.

L-arginine, a drug used in the present invention, is converted to nitric oxide (NO) and L-citrulline (N-citrulline) by nitric oxide synthase when sexual stimulation occurs. The produced nitric oxide (NO) is a physiological messenger of smooth muscle relaxation and serves as a major mediator of penile erection and clitoris hyperemia, treating erectile dysfunction and sexual insensitivity. In addition, the drug is an amino acid, so even if the excess is absorbed by the skin, there are almost no side effects.

In the present invention, as the permeation accelerator, higher fatty acids such as oleic acid; Higher alcohols such as lauryl alcohol; Higher fatty acid esters such as isopropyl myristate; Fatty acid esters of glycerin, such as glycerol monolaurate; Fatty acid ethers of polyethylene glycol, such as polyethylene glycol lauryl ether; Fatty acid esters of polyethylene glycol, such as polyethylene glycol laurate; Fatty acid ethers of propylene glycol, such as propylene glycol lauryl ether; Propylene glycol fatty acid esters such as propylene glycol laurate; Sorbitan fatty acid esters such as sorbitan monolaurate; Polyethylene glycol sorbitan fatty acid esters such as polyethylene glycol sorbitan monostearate; Terpenes such as menthol, menthol derivatives and limonene; Sulfoxides such as dimethyl sulfoxide and dodecyl sulfoxide; Pyrrolidones such as N-methyl-2-pyrrolidone; Amides such as lauryl diethanolamide; N-hydroxy methyl lactide, sorbitol, urea, squalene, olive oil, mineral oil and derivatives thereof and the like can be used.

The composition of the present invention is lauric acid, oleic acid, lauryl alcohol, oleyl alcohol, isopropyl myristate, glycerol monolaurate, polyethylene glycol lauryl ether, polyethylene glycol laurate, propylene glycol laurate, sorbitan monolaurate Permeation accelerator of at least one component selected from the group consisting of polyethylene glycol sorbitan monostearate, menthol derivatives, limonene, dimethyl sulfoxide, dodecyl sulfoxide, N-methyl-2-pyrrolidone, and lauryl diethanolamide It is preferable to include as.

The composition of the present invention may be prepared by including additives such as dissolution aids, softeners, surfactants, thickeners, pH adjusters, if necessary. In addition, the additive is preferably included in 1 to 80% by weight based on the total weight of the composition.

Among the additives that may be additionally included in the composition of the present invention, as a dissolution aid, purified water, ethanol, isopropanol, propylene glycol, glycerin, polyethylene glycol, ethoxydiglycol, and the like may be used. As a softener, hydrocarbon polymers, silicones, Synthetic and natural esters may be used, and as the surfactant, nonionic surfactants such as sorbitan fatty acid esters (Spans, Arlacels) and polyoxyethylene sorbitan fatty acid esters (Tweens) are preferable. In addition, an appropriate amount of polysaccharide-based (e.g. Keltrol F) or polyacrylamide-based (e.g. Sepigel 305) thickener may be added to improve the usability and formulation stability of the composition. To this end, organic acids such as citric acid (citric acid) or a suitable pH adjuster such as alkalizing agent can be added. In addition, in order to prevent the growth of potentially harmful microorganisms in the composition according to the present invention can be used in an effective amount of preservatives, it can also be prepared by the addition of perfume.

In general, nonionic drugs have a higher skin permeability than ionic drugs, and positive ion and zwitterion drugs that can carry both positive and negative ions at the same time have negative net ions at zero net charge. Alternatively, since skin permeability is relatively lower than that of plus ions, in order to increase the skin permeability of these drugs, it is necessary to adjust the pH so as not to have negative ions, and to prevent side effects on the skin to which the preparation is applied. PH should also be taken into account. Therefore, the external preparations according to the prior art have generally been prepared by adjusting the pH to slightly acidic to neutral, that is, similar to the pH of human skin, that is 5-7.

However, in the present invention, when the pH of the external preparation is adjusted to 9 or more unlike the prior art, when the charge of the main drug L-arginine has a negative ion, the skin permeability is excellent and the skin side effects are also minimized. This was confirmed and applied to the present invention.

The present invention is also very effective in the treatment of insensitivity because it is designed to act directly on the clitoris and cause hyperemia, based on the medical content that the clitoris responds during the first phase of the sexual response cycle, the clitoris.

The composition of the present invention may be prepared in transdermal dosage forms such as creams, gels, ointments, and lotions, and the composition may be administered by applying the composition at a dose of about 0.1 to 2 g at once around the penis and clitoris.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the Examples.

Example 1. Preparation of transdermal formulation for the treatment of erectile dysfunction and sexual insensitivity (cream formulation: pH about 10.5)

Furtherance

L-arginine 10% by weight

Dimethicone 5 〃

Cyclomethicone 5 〃

Cetylethyl hexanoate 5 〃

Cetanol 2

Stearic acid 2 〃

Glycerol Monostearate 2 〃

Polyoxyethylene sorbitan monostearate 5 〃

Ethanol 5 〃

Propylene Glycol 5 〃

Citric acid 0.3 〃

Keltrol F. 0.2 〃

Methyl paraben 0.2 〃

Floral Musk flavor 0.1 0.1

Purified water level

quite

(1) Dimethicone, cyclomethicone, cetylethyl hexanoate, cetanol, stearic acid, glycerol monostearate, polyoxyethylene sorbitan monostearate, and methyl paraben are dissolved by heating to 75 ° C.

(2) Dissolve L-arginine, propylene glycol, citric acid, ketrol f, and purified water by heating to 75 ℃.

(3) Put (1) into (2) and emulsify while mixing and stirring.

(4) Add ethanol and floral musk flavor during emulsification.

(5) A cream is prepared by cooling to 30 ° C or lower.

(6) The pH of the prepared cream is about 10.5.

Comparative Example 1-1. Preparation of transdermal formulation for the treatment of erectile dysfunction and sexual insensitivity (cream formulation: pH about 8.5)

Furtherance

L-arginine 10% by weight

Dimethicone 5 〃

Cyclomethicone 5 〃

Cetylethyl hexanoate 5 〃

Cetanol 2

1 stearic acid

Glycerol Monostearate 2 〃

Sorbitan sesquioleate 5 〃

Ethanol 5 〃

Propylene Glycol 5 〃

Citric acid 3 〃

Keltrol F. 0.2 〃

Methyl paraben 0.2 〃

Floral Musk 0.1

Purified water remaining

quite

Prepared in the same manner as in Example 1, the pH of the prepared cream is about 8.5.

Comparative Example 1-2. Preparation of transdermal formulation for the treatment of erectile dysfunction and sexual insensitivity (cream formulation: pH about 6.5)

Furtherance

L-arginine 10% by weight

Dimethicone 5 〃

Cyclomethicone 5 〃

Cetylethyl hexanoate 2 〃

1 stearic acid

Glycerol Monostearate 2 〃

Sorbitan monooleate 5 〃

Ethanol 5 〃

Propylene Glycol 5 〃

Citric acid 6 〃

Keltrol F. 0.2 〃

Methyl paraben 0.2 〃

Floral Musk flavor 0.1 0.1

Purified water level

quite

Prepared in the same manner as in Example 1, the pH of the prepared cream is about 6.5.

Example 2. Preparation of transdermal formulation for the treatment of erectile dysfunction and sexual insensitivity (gel formulation: pH about 10.4)

Furtherance

L-arginine 10% by weight

Carbopol 2 〃

Cetylethyl hexanoate 10 〃

Isostearic acid 2 〃

Polyoxyethylene sorbitan monostearate 5 〃

Ethanol 5 〃

Citric acid 0.3 〃

Sepigel 305 0.5 〃

Propylene Paraben 0.2 〃

Floral Musk flavor 0.1 0.1

Purified water level

quite

(1) Dissolve Carbopol sufficiently in purified water.

(2) Dissolve L-arginine, cetylethyl hexanoate, isostearic acid, polyoxyethylene sorbitan monostearate, ethanol, citric acid, propyl paraben, and floral musk in (1) above.

(3) Put the Sepigel 305 in the above (2) and mix and stir with a stirrer.

(4) A gel is prepared.

Example 3 Preparation of Transdermal Dosage Formulation for Treatment of Erectile Dysfunction and Sex Insensitivity (Ointment: pH about 10.2)

Furtherance

L-arginine 10% by weight

White Vaseline 25 〃

Stearyl alcohol 20 〃

Propylene Glycol 10 〃

Polyoxyethylene Cured Castor Oil 4 〃

1 g of monostearic acid glycerin

Citric acid 0.3 〃

Propyl paraben 0.2 〃

Floral Musk flavor 0.1 0.1

Purified water remaining

quite

(1) White Vaseline, stearyl alcohol, polyoxyethylene hardened castor oil, and glycerin monostearate are heated and dissolved in a water bath to about 75 ° C.

(2) Dissolve propylene glycol, citric acid, propyl paraben and purified water by heating to 75 ℃.

(3) Put the above (1) into (2) and mix and stir to prepare a hydrophilic ointment base.

(4) After dissolving L-arginine in an appropriate amount of water, it is mixed uniformly with the hydrophilic ointment base with a floral musk flavor.

(5) Prepare ointment.

Example 4 Preparation of Transdermal Dosage Formulation for Treatment of Erectile Dysfunction and Sex Insensitivity (Lotion Formulation: pH 9.8)

Furtherance

L-arginine 10% by weight

Isopropyl myristate 7 〃

Cetanol 2

Olive oil 2 〃

1 stearic acid

Sorbitan sesquioleate 3 〃

Propylene Glycol 6 〃

Citric acid 0.3 〃

Sepigel 305 0.1 〃

Propyl paraben 0.1 〃

Floral Musk flavor 0.1 0.1

Purified water level

quite

(1) Isopropyl myristate, cetanol, olive oil, stearic acid, sorbitan sesquioleate and propyl parabens are dissolved by heating to 75 ° C.

(2) Dissolve L-arginine, propylene glycol, citric acid and purified water by heating to 75 ℃.

(3) Put (1) into (2) and emulsify while mixing and stirring.

(4) During the emulsification, add Cepigel 305 and floral musk flavor.

(5) A lotion is manufactured by cooling to 30 degrees C or less.

Experimental Example 1 transdermal absorption test

The abdominal hair of a male guinea pig, weighing about 350 g, is shaved with an electric hair clipper, and then completely shaved with an electric shaver, followed by cutting the entire skin of a certain abdomen and freezing it (freezing below 20 ° C). After storage, it was used after melting when necessary for the test.

Cut the melted skin to 2 × 2cm ^{2, cover the} skin with Franz-type diffusion cell well, put on the cap and fix it. The temperature of the diffuser was maintained at 37 ° C. 250 μl of the external preparations prepared in Comparative Examples and Examples were applied to the stratum corneum layer of the skin, and then the receptor solution (buffer solution) was stirred at a constant speed (600 rpm). After a predetermined time elapsed, an appropriate amount of the solution in the receptor portion was collected, and a new buffer solution was added as much as the collected amount. The collected samples were measured by high performance liquid chromatography (HPLC) and the test results are shown in Table 1.

Percutaneous administration of guinea pig skin L-arginine skin dosage in external preparations division pH 6 hours skin penetration (μg / ㎠) Example 1 10.5 2667.8 ± 330.8 Comparative Example 1-1 8.5 563.2 ± 64.4 Comparative Example 1-2 6.5 353.6 ± 45.8 Example 2 10.4 2419.6 ± 267.1 Example 3 10.2 1985.5 ± 228.3 Example 4 9.8 1688.3 ± 120.9

As can be seen in Table 1 above, in Example 1, Comparative Example 1-1 and Comparative Example 1-2, experiments with the same formulation (cream) prepared by varying the pH of the composition with the same components, the pH of the composition The composition permeation amount of Example 1, wherein is basic of 9 or more, was significantly different from that of Comparative Examples. In addition, in the case of Examples 2, 3, and 4, each prepared with a gel, ointment, and lotion formulation having a pH of 9 or more, it was confirmed that the skin permeation of the composition was superior to the comparative examples.

Experimental Example 2 Animal Skin Primary Stimulation Test

Using six healthy male rabbits, each animal's back is about 2.5 × 2.5 cm in size, with two parts of the scaly, two skins and two parts of the skin and skin. Examples 1, 2, 3 and 4) were applied in 0.5 g increments. 24 hours and 72 hours after application of the test substance, irritation such as erythema, crust formation, and edema formation was observed. The skin response was evaluated using the "toxicity test standard of drug". In addition, the determination of the degree of irritation to the results is generally performed by P.I.I. According to the calculation method of (Primary Irritation Index), the results are shown in Table 2.

Skin primary stimulation test results of L-arginine external preparations Test substance P.I.I Judgment Example 1 0.375 Non-irritating Example 2 0.345 Non-irritating Example 3 0.375 Non-irritating Example 4 0.350 Non-irritating

As shown in Table 2 above, the transdermal formulation of the present invention can be confirmed that there is no skin irritation.

The composition of the present invention is an external preparation that can overcome the disadvantages of conventional injections or oral therapeutic agents, unlike conventional formulations, even when the drug is transdermal, it can produce a sufficient effect without side effects in a safe and excellent erectile dysfunction and Treatment for sexual insensitivity may be provided.

Claims (8)

A transdermal formulation for treating erectile dysfunction and sexual insensitivity, comprising L-arginine, a permeation accelerator, and a pharmaceutically acceptable carrier, and having a pH of at least 9. The transdermal formulation for treating erectile dysfunction and sexual insensitivity according to claim 1, wherein the pH of the composition is 9-11. The transdermal preparation for treating erectile dysfunction and sexual insensitivity according to claim 1, comprising 1 to 20% by weight of L-arginine and 1 to 30% by weight of a permeation accelerator. The method of claim 1, wherein the permeation accelerator is lauric acid, oleic acid, lauryl alcohol, oleyl alcohol, isopropyl myristate, glycerol monolaurate, polyethylene glycol lauryl ether, polyethylene glycol laurate, propylene glycol laurate, sorbate One containing at least one selected from non-methane monolaurate, polyethylene glycol sorbitan monostearate, menthol derivatives, limonene, dimethyl sulfoxide, dodecyl sulfoxide, N-methyl-2-pyrrolidone, lauryl diethanolamide A transdermal formulation for treating erectile dysfunction and sexual insensitivity, characterized by the above-mentioned. The transdermal preparation for treating erectile dysfunction and sexual insensitivity according to claim 1, further comprising at least one additive selected from the group consisting of dissolution aids, softeners, surfactants, thickeners, and pH adjusting agents. The transdermal preparation for treating erectile dysfunction and sexual insensitivity according to claim 5, wherein the additive comprises 1 to 80% by weight based on the total weight of the composition. 2. The transdermal formulation of claim 1, wherein the formulation is a cream, gel, ointment or lotion. The transdermal preparation for treating erectile dysfunction and sexual insensitivity according to claim 1, wherein the composition is applied at a dose of about 0.1 to 2 g at one time around the penis and clitoris.