JPH0145451B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a therapeutic agent for eczematous skin disease and drug eruption, and more particularly to a therapeutic agent for eczematous skin disease and drug eruption characterized by containing L-carnosine or a salt thereof as an active ingredient. Eczema is a common skin disease, and it is said that approximately 1/3 of skin disease patients are eczema patients, and another 1/3 of these patients are young children. It is broadly classified into acute and chronic, and includes childhood eczema and seborrheic eczema. Symptoms of acute eczema initially include erythema with indistinct borders, then small papules appearing in the form of dots within the area, and then small blisters forming on the top of each papule. The vesicles remain as they are, or become infected with Pseudomonas and turn into pustules, which rupture to form an erosive surface that becomes moist. The secretion eventually solidifies and forms a scab, and when the dead skin flakes fall off, the area underneath is dry, and after a period of desquamation, the skin returns to healthy skin and heals. It is thought that eczema preparation is an internal cause of eczema, and that the disease develops when eczema stimulation is added as an external cause. Preparations for eczema include physical constitution, metabolic disorders, liver and visceral dysfunction, and vitamin and hormonal abnormalities, but later a theory was proposed that it was caused by skin allergies. However, in reality, it cannot be said that all causes of eczema due to allergies have been elucidated, and the detailed causes are still unclear. When eczema lasts for a long time or recurs, it becomes chronic eczema, but it can also occur without acute eczema. The skin becomes thickened and hardened, causing fine skin folds to become visible, or dense papule-like bumps or warts to form, causing pigmentation over the entire skin area. In such chronic eczema, the moist and erosive surfaces of acute eczema are often seen here and there on the affected skin, and the state of acute eczema occasionally appears during the course of the disease. Chronic eczema may occur over a wide area of the skin with a clear sub-circumscribed area, or it may be localized in some areas, causing so-called plaque eczema.
It may also take the form of nummular eczema. Pediatric eczema is eczema that appears in children between the ages of 1 and 6 and is often treated separately from eczema in adults. Symptoms include reddened areas and serous papules on infants' cheeks, which are extremely itchy and cause sores and scabs to form when scratched. In young children, lichenification occurs on the bent joints of the neck, elbows, and knees, as well as on the face and limbs, causing severe itching, dry skin all over the body, and keratinization of the hair follicles. Like bronchial asthma, hay fever, and nasal allergies, it occurs genetically and familially, so specific predispositions are thought to be the cause of the disease. This is also called atopic dermatitis or atopic eczema.
or adult atopic dermatitis that occurs several years after it has been cured). Atopic dermatitis shows hypersensitivity to various substances, with infants showing hypersensitivity to dietary substances such as egg white, milk, and wheat, and adults to environmental substances such as indoor dust, wool, and feathers. ing. Seborrheic eczema is a type of eczema that affects the head, face, armpits, and
It is characterized by a reddened area on the vulva, peeling off of seborrheic keratin, and no itching. Treatments for eczema include ointment therapy, radiation therapy,
Examples include whole body therapy. Apply zinc flower oil to the affected area and apply a compress over it. Apply zinc borate ointment and carbo wax. In many cases, it is common to add anti-inflammatory and anti-itch agents such as picylol, ichthiol, glitter, and tumenol to these. As radiation therapy, infrared rays are said to be effective for acute eczema, and X-rays are effective for skin thickening caused by chronic eczema. As systemic therapy, intravenous injections of 200 to 300 c.c. of physiological saline, injections and oral administration of calcium preparations, sodium thiosulfate, etc., various vitamins, antihistamines, cortisone, etc. are recommended, and for chronic eczema, oral administration and injection of arsenic drugs are recommended. will be carried out.
Pediatric atopic dermatitis has relatively little tendency to moisturize, so ointments containing tar and steroid hormones are used. Drug eruption is a rash caused by a small amount of a non-toxic drug reaching the skin or mucous membrane through the bloodstream, and can be caused by oral administration, injection, inhalation, etc. of the drug. It often occurs within a few minutes to more than 10 hours after administration. There are a wide variety of rashes, but the most common are fixed erythema, in which erythema always appears in the same area, and toxic erythema, in which erythema appears in various sizes all over the body, resembling measles or scarlet fever. The cause of the outbreak is difficult to explain by pharmacological effects and is thought to be mostly due to allergies, but the details are still unclear. Treatment includes systemic drug therapy and local therapy. As for systemic drug therapy, anti-plasmin drug therapy is mainly used for inflammation, and vitamin _K1 is used in combination to enhance its effect, and antidote therapy is also added as appropriate. Adrenal corticosteroids are used for severe acute symptoms. As local therapy, ointments containing corticosteroids or ointments further containing antibiotics are used, but no definitive therapeutic agent has yet appeared. As mentioned above, there are many unknowns about the detailed causes of eczematous skin disease and drug eruption, and there are no drug treatments that are reliably effective in a short period of time. At present, there is a strong demand for the emergence of The present inventor has discovered that L-
Focusing on the unique physiological activity of carnosine, we have spent many years researching its physiological significance and pharmacological usefulness. was found to be highly effective as a therapeutic agent for eczematous skin diseases and drug eruptions. L-carnosine has a melting point of 250℃ (decomposition), [α ²⁰ _D = +
20.0° (H ₂ O), it is a tasteless, odorless, white crystalline powder that is easily soluble in water, and the pH of its aqueous solution is 8.0 to 8.5.
It is. It is a substance that exists in large amounts mainly in the liver and muscles of various animals, is ingested as food from daily meat, and is biosynthesized from L-histidine and β-alanine. Ingested L-carnosine enters the blood and is decomposed by carnosinase into L-histidine and β-alanine, which serve as a nutritional source, and a portion is resynthesized into L-carnosine. As mentioned above, L-carnosine is a food-like substance, and after absorption, it is broken down by carnosinase in the blood and becomes a nutritional amino acid, which is completely different from the fact that many pharmaceuticals are metabolized in the liver and place a burden on liver function. different. The synthesis method for L-carnosine is known (Journal of Biological Chemistry, 108,
753, 1935), carbobenzoxy β-alanine was converted to chloride with phosphorus pentachloride, converted to methyl ester with methanol, converted to azide via hydroazide, coupled with L-histidine methyl ester, and finally catalytically reduced. By removing the carbobenzoxy group, L-carnosine can be obtained. The present invention also includes therapeutic agents consisting of salts of L-carnosine, and the salts of L-carnosine include salts based on carboxylic acid groups;
There are acid addition salts with pharmacologically acceptable acids based on amino groups, and there are salts based on both carboxylic acid groups and amino groups. Salts based on carboxylic acid groups include salts with metals such as sodium, potassium, calcium, magnesium, zinc and aluminum, ammonium salts and substituted ammonium salts, salts with trialkylamines and other amines such as triethylamine; Salts based on amino groups include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid,
These include salts with inorganic acids and organic acids such as propionic acid, lactic acid, tartaric acid, citric acid, succinic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, etc. - a stoichiometrically calculated amount of carnosine,
It can be produced by reacting with a selected acid or base. Next, the acute toxicity of L-carnosine will be described. Acute Toxicity Various doses of L-carnosine were administered intraperitoneally and orally to groups of 10 mice, and symptoms of acute toxicity were observed 5 hours after administration. LD ₅₀ is based on the number of deaths after 72 hours.
Waerden) method. L-carnosine was dissolved in physiological saline so that the amount of administration was 0.1 to 0.3 ml/10 g. The symptoms of L-carnosine toxicity are 15000mg/
Approximately 30 minutes after intraperitoneal administration of Kg (LD ₁₀₀ ), locomotor activity decreases, the patient takes a prone position, and the respiratory rate decreases and becomes irregular, but no loss of righting reflex or withdrawal reflex is observed, and occasionally the tail is raised. Half of the patients showed a reaction or developed clonic convulsions. As the symptoms progressed further, the patient repeatedly rolled over, hyperreflexia to contact stimulation, and seizures were induced, which progressed to tonic seizures and led to death. Half of the cases died after 1 hour and 30 minutes, 80% died after 2 hours, and all cases died after 5 hours. 15000
After oral administration of mg/Kg, there was almost no effect, but death was observed in 1 out of 10 patients 12 hours later.

[Table] Acute toxicity to DD male mice (72 hour value)
As shown in the table, it can be said that L-carnosine is a compound with extremely low toxicity. Examples of the form of the therapeutic agent for eczematous skin disease and drug eruption of the present invention include a powder of L-carnosine, a solid composition such as an ointment containing L-carnosine as an active ingredient, and a solution for injection. When L-carnosine is made into a preparation for injection or infusion, it is usually provided in a unit dose ampoule or a painless syringe cartridge. Since L-carnosine is easily soluble in water, an aqueous solution of L-carnosine can be easily prepared under aseptic operation.
A certain amount of L-carnosine previously placed in an ampoule may be dissolved in sterile distilled water immediately before injection and used immediately for injection. Further, in order to adjust the pH of the aqueous solution, a mixed solution of L-carnosine and its salt, such as its hydrochloride, may be prepared. To prepare the ointment, an amount of finely powdered L-carnosine is added to an ointment base such as beeswax, spermaceti wax, or dehydrated lanolin, such as to give an ointment of 5% or 10% concentration, according to techniques known in the pharmaceutical industry. , white petrolatum, higher alcohols, macrogols or Plastibase (hydrocarbon gel ointment base manufactured by Taisho Pharmaceutical KK), hydrophilic ointments listed in the Japanese Pharmacopoeia, water-absorbing ointments, or mixtures thereof, and as necessary. Add oils such as sesame oil, peanut oil, and olive oil, resins, glycerin, propylene glycol, surfactants, bactericides, fungicides, antioxidants, etc., and thoroughly stir and knead until homogeneous. To make a powder, synthesized L-
Carnosine is put into a glass container as a fine powder of about 200 mesh, and sterilized by dry heat at a temperature of about 120°C for several hours. L-carnosine is administered by methods such as topical dispersion of a powder, topical application of an ointment, intravenous injection, or local subcutaneous injection, and when used for adult patients, the dosage depends on the administration route, number of administrations, Typical dosage forms, dosages, and administration methods of the therapeutic agent of the present invention are exemplified as follows, although they naturally vary greatly depending on the symptoms and the like. Dosage form Dosage and method of administration Powder Spread evenly over the entire affected area at approximately 20 mg/cm ² (once a day) Injection 3% subcutaneously 30-50 mg once a day Ointment 5% or 10% on the affected area Apply evenly to the entire surface (once a day) The dosage described here is just a guideline, and as L-carnosine is an extremely safe substance as mentioned above, the amount may be increased or decreased as appropriate depending on the patient's symptoms. There is no difference in what you do. It is also preferable to use antihistamines and integrated vitamins in combination. Next, examples of formulations of the therapeutic agent of the present invention will be given. Formulation Example 1 (Powder) The synthesized L-carnosine was made into a fine powder using an electric mortar and sifted through a 200-mesh sieve.
This fine powder was placed in a glass container and sterilized by dry heat using a conventional method to obtain a powder. Formulation Example 2 (Injection) L-carnosine and L-
3% equivalent mixture of carnosine hydrochloride powder;
A 5% or 10% (both as L-carnosine) aqueous solution was filled into an ampoule under an inert gas flow. Formulation Example 3 (Ointment) Using the synthesized L-carnosine and Plastibase as a base, a 10% ointment was prepared using the following formulation: L-carnosine 10g and Plastibase 90g. Next, clinical examples using the therapeutic agent of the present invention will be shown.

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Claims (1)

[Claims] 1. A therapeutic agent for eczematous skin disease and drug eruption containing L-carnosine or its salt as an active ingredient.