JPS58164516A - Remedy for eczematoid skin disease and drug rash - Google Patents

Abstract

PURPOSE:The titled remedy containing L-carnosine or its salt as an active ingredient. CONSTITUTION:A remedy for eczematoid skin disease and drug rash containing L-carnosine melting point: 250 deg.C(decomposition), alpha <20>D=+20.0 deg. (H2O), tasteless, odorless, easily water-soluble, white crystalline powder, aqueous solution has 8.0-8.5pH or its salt as an active ingredient. Powder of L-carnosine, solid composition such as ointment comprising L-carnosine as an active ingredient, solution for injection, etc. may be used as the dosage form. In its dose and administration, in case of powder, 20mg/cm<2> remedy is uniformly applied the whole affected part. (Once a day). In case of injection, 30-50mg remedy is applied by hypodermic injection once a day by 3wt% solution, and, in case of ointment, 5wt%-10wt% remedy is uniformly applied to the whole affected part (once a day). A large amount of L-carnosine occurs mainly in livers and muscles of various kinds of animals.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to eczematous skin diseases and pharmaceutical treatment agents, and specifically relates to eczematous skin disease and pharmaceutical treatment characterized by the use of carnosine or its salt as an active ingredient. Regarding therapeutic agents.

Eczema is 4. It is a skin disease that occurs most frequently in humans, and it is said that approximately 1.5 million people who have recovered from skin tremors are eczema patients, and that the majority of patients are young children. acute.

It is broadly classified as chronic, and other types include childhood eczema and seborrheic eczema. Symptoms of keratinosis first appear as clusters with indistinct boundaries, and then small papules or dusty lesions forming a port-like shape within the area.
Small water marks appear on the top of each hill. Small water remains as it is, or the suppuration becomes infected and dies, and then it ruptures and creates an erosive surface, which manifests itself or becomes insidious. The secretion eventually solidifies and forms a scab. When the dead skin flakes peel off and grow thick, the area underneath is dry, and after a period of desquamation, the skin returns to normal skin and heals.

It is thought that the internal cause of eczema is eczema preparation, and the addition of eczema stimulation as an external cause causes the onset of the disease.

Possible causes of eczema preparatory factors included a first generation constitutional disorder, impaired S function in the liver and kidneys, and vitamin and hormonal abnormalities, but later a theory was proposed that it was caused by an allergy to sebum. However, in reality, it cannot be said that all the causes of eczema due to allergy have been discovered, and there are still many points that are unclear about the detailed causes.

When eczema is repeated for a long time, it turns into chronic eczema, but it can also occur without going through acute eczema. The sebum thickens and hardens, with fine folds of sebum clearly visible.
Or, small papule-like protuberances grow densely or in the form of claws, causing pigmentation on the skin. In this type of chronic eczema, the affected skin has mild moisture,
Erosion surface: Often erosive, and acute eczema sometimes appears during the remission. Chronic eczema may occur over a wide skin surface with indistinct boundaries, or may be localized in some places to take the form of so-called circumferential eczema or nummular eczema.

Pediatric eczema is a type of eczema that occurs in children aged 7 to 6 years old, and consists of reddened areas and serous papules on the nipples, which are intensely itchy and cause sores and scabs to form when scratched. When the eggs become young, lichens develop on the bent joints of the neck, elbows, and knees, the face, and limbs, the skin becomes extremely itchy, the skin all over the body becomes dry, and the hair follicles become keratinized.

Genetic, similar to bronchial asthma, hay fever, and nasal allergies.
Since it occurs in families, it is believed that specific confinement is the cause of the disease. This is also called atopic dermatitis or atopic eczema (atopic dermatitis includes adult atopic dermatitis, which occurs following the childhood type described above or after several years of recovery). ). Atopic dermatitis shows hypersensitivity to various substances; infants are hypersensitive to dietary substances such as egg white, milk, and wheat, and adults are hypersensitive to environmental substances such as indoor dust, wool, and feathers. has been proven.

Sebum (ks 11-1): It is characterized by hemorrhoids, excessive seborrhea, red discolored areas on the face, armpits, vulva, etc., seborrheic keratin flakes peeling off, and no itching.

Treatment methods for eczema include ointment therapy, radiation therapy, and systemic therapy. Apply static lead flower oil to the pipe and apply a poultice over it. Apply zinc ointment and car 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 septal thickening in chronic eczema. As systemic therapy, intravenous injection of physiological saline - 〇θ~300x, calcium preparations, injections and oral administration of sodium thiosulfate, various vitamins, antihistamines, cortiscin, etc. are recommended, and for chronic eczema, oral administration and injection of arsenic drugs are recommended. It is done. Pediatric atopic dermatitis has relatively little tendency to moisturize, so ointments containing tar and steroid hormones are used.

Medication is a rash caused by a small amount of a drug that does not exhibit an addictive effect reaching sebum or viscosity due to blood clots, and can be caused by internal administration, injection, or inhalation 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 there are many fixed rashes that always appear in the same area, erythema of various sizes all over the body, and toxic erythema that resembles measles or raccoon fever. The cause of the outbreak is difficult to explain by drug effects and is thought to be mostly due to allergy, but the details are still unclear. Treatment methods include systemic drug therapy and local Nf therapy θ. As for systemic drug therapy, anti-plasmin therapy is mainly used to treat inflammation, and vitamins and 1 are used in combination to strengthen the effect of 4fS, and antidote therapy is also added as appropriate. Adrenal cortex hormones are used for severe acute symptoms. As local therapy, an ointment containing #11 renal skin hormone agent or an ointment containing an antibiotic '44A'hi is used, but no definitive treatment has been developed yet.

-IH: As stated in ゛, there are many unknowns regarding the detailed causes of eczematous skin disease and drug fatigue, and regarding drug treatment, there are no therapeutic agents that are reliably effective in a short period of time. , the appearance of such a therapeutic agent is strongly desired.

The present inventor has focused on the unique physiological activity of L-carnosine, which is an in vivo oligobetetide, and has spent many years researching its physiological significance and pharmacological usefulness. It has been demonstrated that L-carnosine or its physiologically acceptable components have excellent efficacy as a medicinal treatment for eczematous skin disease.

The power of lunosine is melted, 2sor:<decomposition), [α]2
0=+, 20.0°(H2O)te, me, su,
It is a white crystalline powder that is easily soluble in water, and the pH of the water Me is
is g, θ~g, 3. Mainly the liver of various animals,
It is present in large amounts in the muscles, is ingested as food rather than meat, and is produced from L-histidine and β-alanine. Once ingested, carnosine enters the bloodstream,
It is decomposed into L-histidine and β-alanine by carnosinase, resulting in a nutritional deficiency, and a portion is resynthesized into L-carnosine.

As mentioned above, Lunosine is a substance similar to food M, but after absorption, it is broken down by carnosinase and becomes nutritional amino acids, which is completely different from many pharmaceuticals. Shi-
The skin application of Lunosine is well known (Journal
of Biolngcal Chem
istry,, 10g.

73.3, / 9,? , S), convert carmepenzoxy β-alanine to chloride with Goba rin, convert it to methyl ester with methanol, convert hydroazide to azide with 1, convert with L-histidine methyl ester, i# It was later possible to produce L-carnosine by removing the carbope/zoxy group by catalytic reduction. The present invention also includes a therapeutic agent consisting of a rare carnosine, but the acid addition salt of L-carnosine is a combination of a salt based on a carboxylic acid group and a pharmacologically acceptable acid based on an amino group. There are also salts based on both carboxylic acid and amino groups. The compounds based on carboxylic acid groups include sodium, potassium, calcium, magnesium, zinc and aluminium, ammonium salts and ammonium salts such as trialkylamines such as triethylamine and amines among them. The salt is (le)su.

Bases based on amino groups include hydrochloric acid, #L acid, phosphoric acid, acetic acid, glopionic acid, lactic acid, tartaric acid, citric acid, succinic acid,
Maleic acid, benzenesulfone ff, ) luenesulfone M's with anhydrous acid, organic acid, etc. are used, but these are calculated stoichiometrically from free carnosine using methods known per se. can be prepared by reacting with a selected amount of an acid or a selected acid.

Next, the negative toxicity of L-lunosine will be described.

Various doses of L-carnosine were administered intraperitoneally and orally to dynamically toxic mice, and acute toxic symptoms were observed for 3 hours after administration. L Dso was determined by Van der Waerden f from the number of deaths after 7.2 hours. For carnosine, the dosage amount is 0. /~0.3d//
It was dissolved in physiological saline to give θ9Vc.

Symptoms of toxicity with L-carnosine include: 0 OOV' to intraperitoneal administration (LD, . . .) After about 30 minutes of vk, spontaneous movement decreases, the patient assumes a supine position, and the respiratory rate decreases and becomes irregular;
No loss of one-way reflex or withdrawal reflex was observed, and half of the patients showed occasional euphoric reactions and intercalary convulsions. As the symptoms further progressed, the patient repeatedly rolled over, became hyperreflexic to contact, and developed convulsions, leading to tonic convulsions and death. / Half of the time is 30 minutes, λ time? -Ml/30%, the gold side died after 3 hours.

After oral administration of 5,000 µ/kg, almost no effect was observed, but death was observed in 72 hours later in 72 hours.

Table 1 LDs of carnosine.

The acute toxicity (7-hour value) to dd Ito mice is as shown in the table, and it can be said that L-carnosine is a compound with extremely low toxicity.

Forms of the therapeutic agents for skin diseases and skin diseases of the present invention.

Examples of the form include L-carnosine powder, solid compositions such as ointments containing L-carnosine as an active ingredient, and injection solutions. When L-lunosine is made into a preparation for injection or infusion, it is usually provided in a unit dose angle or a cartridge for a painless syringe.

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 carnosine previously placed in an ampoule may be dissolved with li + distilled water immediately before injection and used for injection immediately. Also, add K to adjust the pH of the aqueous solution.

It is also possible to prepare a mixed solution of carnosine and its hydrochloride, for example.

To prepare an ointment, according to techniques well known in the pharmaceutical industry, a fine powder of carnosine, such as a 3% or 10% concentration ointment, is added to the ointment base, such as beeswax, whale wax, Dehydrated lanolin, white petrolatum, higher alcohols, macrogol or plastipase (hydrocarbon emollients manufactured by Taisho Pharmaceutical Co., Ltd.), hydrophilic ointments listed in the Japanese Pharmacopoeia, water-absorbing ointments* - these Mix with the mixture, add 24% of necessary Kl, oils such as sesame oil, peanut oil, and olive oil, resins, glycerin, propylene glycol, surfactants, bactericides, fungicides, and antioxidants, Stir thoroughly and knead until homogeneous. To make a powder, synthesize the lunosine and put it into a glass container as a fine powder of about 100 mesh/J.
Heat-extinguish the eaves for several hours at the OU temperature.

Lunosine is available as a powder for topical application and as an ointment for topical application.
Hikofu Aiike is given by one method such as intravenous injection or local subcutaneous injection, and it goes without saying that the dosage when used for adult diseases varies greatly depending on the route of administration, number of administrations, symptoms, etc. Typical dosage forms, dosages, and administration methods of the therapeutic agent of the present invention are illustrated below.

Dosage form Dosage and method of administration Powder side Spray evenly over the entire affected area based on approximately 20 w'aA (once every 7 days) Spray liquid 3% subcutaneously 781 times 30-30 ointment 3% or over the entire affected area 10% applied evenly
(7 days / Shin ()) The usage and dosage described here are only a guideline, and L-
As mentioned above, carnosine is an extremely safe substance, so there is no problem in increasing or decreasing the amount as appropriate depending on the symptoms of the affected area. It is also preferable to use antihistamines and integrated vitamins in combination.

Next, we will discuss formulation examples of the therapeutic agent of the present invention.

Formulation example/(powder) Synthesized L-carnosine is electric! It was made into a fine powder using an f/J pot and sifted through a Japanese Pharmacopoeia-〇〇 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 (injection) Under aseptic operation, an equivalent mixture of powders of L-carnosine and L-carnosine hydrochloride was prepared at 3%, 3% or 70%.
% (both as carnosine) in water and filled into an angle under a stream of inert gas.

Example 3 (Ointment) A 70% ointment was prepared with the following formulation using Carnosine, Plastipase as base 11 and Taplastipase 909.

Next, clinical examples using the therapeutic agent of the present invention will be shown.

Claims (1)

[Claims] A pharmaceutical treatment agent for eczematous skin disease containing carnosine or a salt thereof as an active ingredient.