JPS6149289B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a therapeutic agent for superficial skin infections characterized by containing N-cocoyl arginine lower alkyl ester (including its salt form) as an active ingredient. The present inventor has discovered that the acid salt of N-cocoyl arginine ethyl ester (hereinafter simply referred to as arginine derivative) has a therapeutic effect on superficial skin infections, particularly Pseudomonas aeruginosa infection and Candida The present invention was completed based on the discovery that the present invention has a specific therapeutic effect on the disease. Cocoyl groups are acid groups derived from coconut oil fatty acids. When used as a therapeutic agent of the present invention, the arginine derivative of the present invention may be used in the form of a salt, and in that case, the acid forming the salt may be any pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, etc. , mineral acids such as phosphoric acid and nitric acid, and organic acids such as acetic acid, tartaric acid, 2-pyrrolidone-5-carboxylic acid, glutamic acid, and aspartic acid. In addition, the arginine residue is L-
It can be either body, D-body DL-body,
The L-form is preferable because it is a constituent of living organisms. The arginine derivative used in the present invention may be prepared, for example, by a method for producing N-long chain acylarginine lower alkyl ester. Incidentally, the method for synthesizing the N-long chain acylarginine lower alkyl ester (or its salt) is well known. For example, it can be easily synthesized by reacting arginine and fatty acid chloride in a mixed solvent of acetone and water in the presence of an alkali to form N-long chain acyl arginine, which is then esterified. The superficial skin infections that are the subject of this invention are bacterial or fungal skin infections. There may be a single infection caused by one type of bacteria, or there may be multiple infections caused by several types of bacteria. The main diseases caused by bacteria include impetigo contagiosum, folliculitis, impetigo herpetiformis, impetigo vulgaris,
Pyoderma pyoderma (this is a complex infection involving Pseudomonas aeruginosa), secondary bacterial infections associated with trauma, burns, surgical wounds, etc., and those caused by fungi include:
These include ringworm, ringworm, tinea hidraformis, tinea, superficial candidiasis, superficial cryptochococcosis, and secondary fungal infections caused by trauma, burns, surgical wounds, etc. In recent years, advances in antibiotics and chemotherapeutic agents have led to considerable resolution of diseases caused by bacteria, but on the other hand, two problems have arisen.
One of these is the emergence of resistant bacteria, and the other is the phenomenon of bacterial replacement. As a result, single infections caused by Pseudomonas aeruginosa and fungi, particularly Candida albicans, which are less susceptible to many broad-spectrum antibiotics and chemotherapeutic agents, are on the rise.
As a countermeasure, gentamicin, polymyxin, and colimycin are used internally or externally for Pseudomonas aeruginosa, and homosulfamate ointment is used externally, while amphotericin B, nystatin, and pimaricin are used for the above fungi. However, none of them are satisfactory in terms of side effects (fever, skin irritation, etc.) compared to their medicinal efficacy. On the other hand, apart from these, non-specific disinfectants have also been used to prevent secondary infections, particularly in wounds, burns, and surgical wounds. In the past, mercury agents such as iodine tincture, markyurochrome, and marzonin, or pigment agents such as gentian aviolect, were used, but they cause skin irritation, sensitization, contamination of the skin wound surface, and
It is no longer used due to environmental pollution caused by mercury. Since then, hexachlorophene liquid preparations have been widely used, but side effects such as cross-allergy and neurological disorders with other halogenated phenol disinfectants have been discovered. As mentioned above, the arginine derivative of the present invention is
It is effective in treating superficial skin infections, whether caused by bacteria or fungi, and is particularly effective against Pseudomonas aeruginosa infections and candidiasis. Up until now, many substances with bactericidal properties have been discovered in vitro, but in order to be applied to human diseases, they must go through extensive testing in terms of efficacy, side effects, and safety before they can be put to practical use. I don't get it. It is a well-known fact that it is almost impossible to immediately discuss the usefulness for human diseases based on in vitro results. In view of the above facts, the present inventor has determined that the arginine derivative has acute oral toxicity, acute subcutaneous toxicity, percutaneous primary irritation, percutaneous sensitization, injured skin primary irritation, and ocular mucosal primary irritation (the above). depending on the animal),
We investigated the primary irritation to human skin and confirmed that the above arginine derivative is an extremely safe substance. Table 1 shows the results of acute oral toxicity and acute subcutaneous toxicity tests using various animals.

[Table] In addition, as can be understood from the clinical examples shown below, it can be used safely without side effects even on skin that is sensitive to irritation and sensitization, such as infected skin. I understand. It has also been found that the arginine derivative of the present invention is effective not only for the treatment of human diseases, but also for the treatment of superficial skin infections in domestic animals such as horses, dogs, cats, and other mammals. Therefore, the therapeutic agent of the present invention is suitable not only for humans but also for mammals. The arginine derivatives of the present invention can be used alone or in combination with solid, liquid, or pasty pharmaceutical carriers to form ointments, foams, lotions, creams, etc.
It is administered parenterally in the form of suppositories, aqueous solutions, etc. Examples of carriers used as ointments include petrolatum, blastibase, polyethylene glycol, and oily ointment bases, hydrophilic ointment bases, and water-absorbing ointment bases made of various bases. To obtain a foam, water is used as the carrier, and an appropriate amount of a non-irritating, non-flammable propellant such as carbon dioxide gas, nitrogen gas or Freon gas is charged into a pressure vessel. Just attach a suitable nozzle and spray. This is suitable for treating hair areas and intertriginous areas. Note that the therapeutic agent of the present invention can be used not only for treating superficial skin infections but also for preventing them. For example, to prevent secondary sensitization of wounds, burns, and surgical wounds, they are applied to these wound surfaces before such infections actually occur. Generally, when treating or preventing superficial skin infections, the dosage of the drug of the present invention is adjusted as appropriate depending on the symptoms and the area of the affected area or wound. For example, apply N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate as a 0.2% ointment to the entire affected area daily. Hereinafter, the production examples of the therapeutic agent of the present invention will be explained by Examples, and the therapeutic effect will be explained by clinical examples. Example 1 Method for producing ointment A solution of 2 g of N-cocoyl-L-arginine ethyl ester-DL-pyrrolidone carboxylic acid salt dissolved in 148 g of propylene glycol by heating,
The mixture was added dropwise to 350 g of white petrolatum at 80° C. while stirring. After the addition was completed, the mixture was stirred for another 10 minutes and allowed to cool to produce an ointment. Example 2 Method for producing foam N-cocoyl-L-arginine ethyl ester/DL-pyrrolidone carboxylate 2 g, polyvinylpyrrolidone 10 g and propylene glycol
200g was dissolved in 788g of distilled water. 150g of this solution
was made into an aerosol product using carbon dioxide as a propellant. When sprayed, a foam was obtained. Example 3 Method for producing suppositories 0.2 g of N-cocoyl-L-arginine ethyl ester DL-pyrrolitone carboxylate was dissolved by heating in 2 ml of distilled water, and after cooling, it was mixed with 2 g of cacao butter in a mortar. Furthermore, 96 g of cacao butter was mixed and kneaded little by little to form a uniform soft mass. This was removed with a spatula, shaped into a cylinder on a rolling plate, divided into 50 pieces, and formed into oval suppositories. Example 4 Method for producing antiseptic lotion 35 g of liquid paraffin, 1 part of lanolin alcohol
g, 1 g of cetanol, 2 g of beeswax, 3 g of isopropyl myristate, 10 g of solid paraffin, 2 g of polyoxyethylene monostearate, and 3 g of polyoxyethylene cetyl ether were heated and dissolved at 80°C, and N-cocoyl-L-arginine was dissolved therein. Ethyl ester DL-pyrrolidone carboxylate 1
g was dissolved in 40 g of distilled water, mixed at 80°C with stirring, and slowly cooled to produce a lotion. Clinical Example 1 The ointment prepared in Example 1 was used to treat several patients with superficial skin infections. In each case, the ointment was applied to the entire affected area every day. The results are shown in Table 2. Furthermore, no side effects were observed in any of the patients.

[Table] Clinical case 2 1 year old female. The patient had been suffering from candidiasis that had spread throughout his body and had been intractable since birth, and secondary bacterial infections were also observed. The ointment prepared in Example 1 above was applied to the body every day for closed therapy, and the foam powder prepared by spraying the aerosol product obtained in Example 2 above was applied daily to the head. The patient was completely cured within 10 days of starting treatment. No side effects were observed.

Claims (1)

[Claims] 1. A therapeutic agent for superficial skin infections characterized by containing an acid salt of 1 N-cocoyl arginine ethyl ester as an active ingredient.