JPH11147827A - Anti-pruritus agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an anti-pruritus agent having excellent itching-relieving activities against an itching based on an allergy and infectious disease, especially urtiated example of antihistamine by using a macrolide antibiotic as an active ingredient. SOLUTION: This anti-pruritus agent contains a macrolide antibiotic (e.g. roxithromycin, clarithromycin, erythromycin and oleandomycin) as an active ingredient. The administration form of the anti-pruritus agent is, for example, an oral preparation such as a powder and a fine subtilae, a preparation for external use such as an ointment and a plaster, a suppository, a preparation for injection, etc. The oral preparation can be prepared by adding an excipient (e.g. a lactose and a cone starch), and optionally an antioxidant, a binder (e.g. a polyvinyl alcohol and a polyvinyl ether), a disintegrator (e.g. a starch, an agar and a gelatin powder), etc., thereto. The clinical daily dose of the macrolide antibiotic, e.g. that of the roxithromycin is preferably 100-500 mg.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel antipruritic agent which has an excellent antipruritic effect even on itching in general, allergy and infectious diseases, especially against ineffective cases of antihistamines.

[0002]

BACKGROUND OF THE INVENTION Pruritus is classified into physiological and pathological pruritus. Physiological pruritus is temporary with physical irritation or contact with yam, etc., and most do not require treatment. On the other hand, pathological pruritus caused by various diseases such as allergies, skin diseases, primary biliary cirrhosis, and chronic renal failure require long-term or repeated expression, and thus require treatment. Treatment of pathological pruritus is mainly drug treatment, and the treatment of the underlying disease is the principle.However, pruritus is an unbearable subjective symptom. A symptomatic treatment that resolves promptly is also essential.

[0003]

2. Description of the Related Art Heretofore, corticosteroids (steroids), antihistamines and the like have been widely used clinically as antipruritic agents. As a new attempt, Japanese Patent Laid-Open No. 193,286
Nos. 193,290 and JP-A-193,293 also disclose a therapeutic agent for dermatosis, particularly acne, comprising a novel macrolide derivative as an active ingredient.

[0004]

[Problems to be Solved by the Present Invention] However, the mechanism of pruritus expression is still largely unknown, and involves factors such as histamine, serotonin and bradykinin (chemical mediators and mediators). Although it is thought that there are many cases, antihistamines and steroids are ineffective in many cases, and at present, no highly effective antipruritic agents have been developed.

[0005] However, in addition to the problem that corticosteroids cannot be administered for a long period of time, there is also a problem that local side effects such as skin atrophy and steroid flushing tend to occur. In addition, antihistamines tend to cause drowsiness, and there is also a problem in that driving a car or a machine must be avoided while taking the drug. further,
Regarding the novel macrolide derivatives disclosed in JP-A-193,286-193,290 or JP-A-193,293, no experimental results showing pharmacological effects are described, and the true efficacy was not clear. Against this background, anti-pruritic agents with higher efficacy, higher safety, and higher clinical utility have been sought.

[0006]

The inventors of the present invention have made intensive studies for many years to solve the above-mentioned problems and to develop an anti-pruritic agent having high efficacy and safety. As a result, surprisingly, macrolide antibiotics used in the treatment of infectious diseases, especially roxithromycin, clarithromycin, erythromycin, oleandomycin or their ester derivatives, have achieved their intended purpose. The present invention has been completed.
In particular, the present invention has been confirmed to be highly effective and safe in clinical practice as described below, and the value of the present invention is extremely high.

Here, the macrolide antibiotic according to the present invention is not limited as long as it is an antibiotic group having an amino sugar and a giant lactone structure in the molecule, but more specifically, roxithromycin, clarith Lomycin, erythromycin, oleandomycin or ester derivatives thereof can be mentioned, and they are compounds represented by the following chemical names and chemical formulas, respectively. (1) Roxithromycin: Erythromyci
n 9- {O-[(2-methoxyethoxy) methyl] oxime [CAS registry number; 80214-83-1] (2) Clarithromycin: 6-O-Methyl
erythromycin [CAS registration number; 81103-11-9] (3) Erythromycin: [CAS registration number;
114-07-8] (4) Oleandomycin: [CAS registry number: 3922-90-5] Note that macrolide antibiotics include ester derivatives such as phosphoric acid and carboxylic acid. The subject compounds of the invention also include these derivatives.

[0008]

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[0009] Macrolide antibiotics are available as active pharmaceutical ingredients, and roxithromycin is
In U.S. Pat.No. 4,349,545, clarithromycin is disclosed in U.S. Pat.
No. 1,803, erythromycin is disclosed in J. Am. Chem. Soc., 10
3 , 3215 (1981); oleandomycin was used in US-2,757,123.
It can also be manufactured by the methods described in the publications.

Next, the dosage form of the compound of the present invention includes, for example, oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, external preparations such as ointments and patches, suppositories and injections Preparations and the like. At the time of formulation, it can be produced by a conventional method using a usual pharmaceutical carrier.

That is, to prepare an oral preparation, the compound of the present invention and an excipient, and if necessary, an antioxidant, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent and the like are added. Powders, fine granules, granules, tablets, coated tablets, capsules and the like are prepared by a conventional method.

[0012] Examples of the excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like.
For example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol / polyoxyethylene block polymer, meglumine, etc. For example, starch, agar, gelatin powder,
Crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., coloring agents As a flavoring agent, cocoa powder, peppermint brain, aromasan, peppermint oil, dragon brain, cinnamon powder and the like are used as flavoring agents. Of course, these tablets and granules can be sugar-coated and optionally coated as needed.

In preparing an injection preparation, a pH adjusting agent, a solubilizing agent, an isotonic agent and the like, and if necessary, a solubilizing agent, a stabilizing agent, an antioxidant and the like are added to the compound of the present invention. hand,
It is formulated by the usual method.

The method for producing the external preparation is not limited.
It can be manufactured by an ordinary method. In other words, base materials used in the formulation include pharmaceuticals, quasi-drugs,
Various raw materials usually used for cosmetics and the like can be used.

Specific examples of base materials used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, and polyhydric acids. Raw materials such as alcohols, water-soluble polymers, clay minerals, purified water, etc. are added, and if necessary, pH adjusters, antioxidants, chelating agents, antiseptic / antifungal agents, coloring agents, fragrances, etc. are added. However, the base material of the external preparation according to the present invention is not limited to these. If necessary, components such as a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activator, vitamins, amino acids, a humectant, a keratolytic agent, and the like can be added. The amount of the base material to be added is an amount that usually results in a concentration set in the production of an external preparation.

The dosage of the macrolide antibiotic in the present invention varies depending on the symptoms, severity, age, complications and the like, and is not limited.
For example, the clinical dose of roxithromycin or clarithromycin is usually 1 mg to 2000 mg per day, preferably 10 mg to 1000 mg, more preferably 100 mg.
~ 500 mg, given orally, intravenously, intramuscularly, rectally or transdermally.

[0017]

Next, in order to show the usefulness of the compound of the present invention as an antipruritic agent, clinical examples and toxicity test examples are listed below as examples of effects, but the use of the compound of the present invention is not limited to these examples. Needless to say.

Case 1 A 40-year-old female. Initial consultation for psoriasis vulgaris with pruritus Since January 28, 1982, external steroids such as clobetasol propionate ointment and difluprednate ointment and antihistamines such as ketotifen fumarate He continued taking antiallergic drugs. Heisei 8
October 24, 2010: Exacerbation of rash and enhancement of pruritus caused clobetasol propionate ointment and tacalcitol (Tacalitol)
citol) In addition to external use of ointment, roxithromycin (150 mg) 2
Started taking tablets / daily dose. On October 31, the redness decreased slightly,
The spread of the rash was not significantly changed. However, the pruritus almost disappeared. Thereafter, follow-up with the same prescription revealed that on December 9, both rash and pruritus almost disappeared. Thereafter, exacerbation of rash and pruritus was observed due to discontinuation of roxithromycin or change to an antihistamine such as ketotifen fumarate. After that, it was kept in a long-term state by long-term administration of roxithromycin (150 mg) 1 tablet / day and topical clobetasol propionate ointment. The amount of external preparation used was less than 1/2 of that before the start of concomitant use with roxithromycin.

Case 2 A 67-year-old female. First visit to psoriasis vulgaris with pruritus Since October 2, 1978, he had been treated for intractable psoriasis vulgaris mainly on steroid ointments and antihistamines and antiallergic drugs. December 5, 1996 Roxithromycin (150 mg) 2 tablets / oral was started in addition to the external preparation (difluprednate ointment) up to that time. The pruritus gradually decreased and almost disappeared 4 weeks after the start of oral administration. Thereafter, pruritus did not appear during continuous administration of roxithromycin 2 tablets / day. However, the rash did not show any improvement tendency, and she was hospitalized for about 1 week, and changed to topical clobetasol propionate ointment and almost disappeared. After that, the condition was temporarily exacerbated with clarithromycin and clobetasol propionate, and was relieved by changing clarithromycin to roxithromycin. However, it was improved with roxithromycin and clobetasol propionate.

Further, the effects of macrolide antibiotics on pruritus were examined in other cases. The results are shown below.

[0021]

[Table 1]

From the above results, the excellent antipruritic effect of the compound of the present invention is apparent. Subsequently, in order to show the safety of the compound of the present invention, the results of acute toxicity test [LD ₅₀ (mg / Kg)] of roxithromycin are shown below.

───────────────────────── Animal Mouse Rat Beagle Sex ♀ ♀ ♂ ♀ ♂ ♀ ───────────経 口 Oral 665 843 1,059 1,712>2,000> 2,000 毒性 Above toxicity From the test results, the excellent safety of the compound of the present invention is apparent.

Claims (5)

[Claims] An anti-pruritic agent comprising a macrolide antibiotic as an active ingredient. 2. An antipruritic agent for an ineffective case of an antihistamine or antiallergic agent, comprising a macrolide antibiotic as an active ingredient. 3. The pruritus associated with psoriasis vulgaris, palmoplantar pustulosis, atopic dermatitis or prurigo.
Or the antipruritic agent according to 2. 4. A pharmaceutical composition for the purpose of pruritus, comprising a macrolide antibiotic. 5. The anti-pruritus according to claim 1, wherein the macrolide antibiotic is at least one selected from roxithromycin, clarithromycin, erythromycin, oleandomycin or ester derivatives thereof. Or a pharmaceutical composition for the purpose of pruritus.