JP2006199642A - Preventing and/or treating agent for lichen planus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preventing and/or treating agent for lichen planus containing suplatast tosilate as an active component. <P>SOLUTION: The preventing and/or treating agent for lichen planus contains (±)-[2-ä4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl}ethyl]dimethylsulfonium p-toluenesulfonate expressed by formula (1) as an active component. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a prophylactic and / or therapeutic agent for lichen planus comprising suplatast tosylate as an active ingredient.

  Lichen planus is a skin and mucous membrane disease that causes inflammation, itchiness, and characteristic skin lesions, with a primary eruption of a single inflammatory rash (papules, sometimes blisters) in the skin and mucous membranes. The etiology of lichen planus is known to be viral, autoimmune, or enzyme abnormal, but none is definitive and unknown. A rash similar to this disease may appear in toxic rashes such as photographic developers, antimalarial agents, gold preparations, bismuth agents, etc. It is said that there is a possibility of autoimmune disease (Non-patent Document 1).

  Lichen planus generally begins in or after middle age. The first seizure lasts for weeks to months, may fade, and then recur for years. The clinical picture of lichen planus is characterized by a glossy, flat, cutaneous polygonal, purplish red papule with itching. Individual papules vary in size from punctate to pea size. These papules may be isolated but may be arranged in a line, ring, or strip. Annular papules are also caused by central healing of one large papule of lichen planus. Although it can occur in skin anywhere in the body, the wrist, lumbar region, and surrounding area of the Achilles tendon are particularly common sites, and rarely develop erythroderma. The mucosa, particularly the buccal mucosa and the tongue, are frequently occurring sites, and can also occur in the anus, genital region, larynx, etc. (Non-patent Document 2).

Chemical hypersensitivity is known as a disease that shows skin symptoms similar to lichen planus such as itching and erythema, and the etiology is not clear, but lichen planus is a distinctly different disease. That is, chemical hypersensitivity is (1) a chronic condition, (2) symptoms appear reproducibly, (3) responds to low concentrations of substance exposure, (4) many unrelated types Although it is defined that (5) ameliorates or cures by removal of stimulating substances, (6) the symptoms span multiple organ systems (Non-patent Document 3) Since there is no reproducible identifiable causative substance, it does not fall under (2), (3), (4), (5), and because it is a disease limited to the skin, it does not fall under (6) Therefore, it can be said that both are different diseases.
The symptoms seen in chronic eczema, such as atopic dermatitis and Vidal lichen, show “mossification” of the skin, but lichen planus is also clearly different. That is, “mossification” means that the skin is hard and thick, and the formation of skin grooves and dermis becomes prominent, whereas lichen planus is a red papule that is isolated or linear or cyclic, Or the skin symptom arranged in strip | belt shape is shown, and both disease states differ (nonpatent literature 4). In addition, atopic dermatitis is a type I allergic reaction, that is, a reaction caused by an antigen-specific IgE antibody, whereas in lichen planus, there is no specific antigen and both are heterogeneous diseases. .

  As a method for treating lichen planus, symptomatic treatment is mainly used, and exacerbation is prevented by treatment for sensation, and inflammation is reduced or ameliorated by an anti-inflammatory preparation. Specifically, in addition to corticosteroids, antihistamines, radiation irradiation, surgical treatment, etc., vitamin A oral tablets and local anesthetics are applied to mucosal eruptions. However, development of a prophylactic and / or therapeutic agent for lichen planus is often desired from the medical standpoint because it often exhibits resistance to such drugs and has excellent therapeutic effects and few side effects.

(±)-[2- {4- (3-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-toluenesulfonate (hereinafter referred to as “splatast tosylate”) is an excellent inhibitor of IgE antibody production. Known as a therapeutic agent for bronchial asthma, atopic dermatitis, and allergic rhinitis (see, for example, Patent Document 1), a therapeutic agent for urination disorder, a therapeutic agent for pruritus associated with renal dialysis, type C or non-B It is also known that it is useful as an agent for improving liver function abnormalities caused by non-hepatitis C virus (see, for example, Patent Documents 2 to 4), and further effective for chemical hypersensitivity (see Patent Document 5). ).
However, it is not known at all that suplatast tosylate has an excellent effect as a prophylactic and / or therapeutic agent for lichen planus.
Japanese Patent Publication No. 3-70698 International Patent Publication No. 00/27383 Pamphlet Japanese Patent Laid-Open No. 11-315019 JP 2002-114672 A JP 2004-292407 A Encyclopedia of Medical Science (Kodansha) 43, p.179-181 Latest clinical (Chugai Medical Company) p.24-25 Arch. Environ. Health 54, p.147-149, 1999 STEP Dermatology (Kaiba Shobo) p.32

  An object of the present invention is to provide an excellent prophylactic and / or therapeutic agent for lichen planus.

  As a result of extensive research, the present inventors have found that suplatast tosylate is useful for the prevention and / or treatment of lichen planus and has few side effects.

  That is, the present invention provides the following formula (1):

(±)-[2- {4- (3-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium represented by the formula: Preventive agent and / or treatment of lichen planus It relates to the agent.

  The prophylactic and / or therapeutic agent for lichen planus according to the present invention has an excellent clinical effect, and also exhibits a prophylactic effect on the development of lichen planus by long-term administration, and has few side effects.

  Suplatast tosylate used in the present invention can be produced by a known method, for example, a method described in JP-B-3-70698. Specific examples include a method of reacting (±)-[2- [4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl] ethyl] methyl sulfide with methyl p-toluenesulfonate.

  As shown in Examples below, suplatast tosylate exerts an excellent clinical effect on lichen planus. That is, for cases that were not effective against steroids such as dexamethasone and mometasone furancarboxylate, anti-fungal drugs such as griseofulvin, erythema, brown erythema, brown chromophore, etc. It shows remarkable therapeutic effects such as promotion. In addition, there are almost no side effects even after long-term administration. Therefore, suplatast tosylate is useful as a prophylactic and / or therapeutic agent for lichen planus.

  The dosage form of the prophylactic and / or therapeutic agent for lichen planus of the present invention is not particularly limited, and includes tablets, capsules, powders, granules, fine granules, solutions, pills, emulsions, suspensions and the like. Any of parenteral preparations such as oral preparations, injection preparations, suppositories, ointments, plasters, patches, etc. may be used, and they can be produced by methods commonly used by those skilled in the art.

  When preparing an oral solid preparation, an excipient, a binder, a disintegrating agent, a lubricant, a coloring agent, a corrigent, a flavoring agent and the like are added to the active ingredient of the present invention as necessary. Tablets, capsules, powders, granules, fine granules and the like can be produced by the method. Examples of the excipient include lactose, mannitol, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, glycerin, sodium alginate, gum arabic, and the like. Polyvinyl ether, ethyl cellulose, gum arabic, shellac, sucrose, etc., as a disintegrant, dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, etc. as lubricants May be magnesium stearate, talc and the like, and sucrose, orange peel, citric acid, tartaric acid and the like may be used as a corrigent. In addition, colorants, flavoring agents and the like can be known ones. In addition, when it is set as a tablet, you may coat by a known method.

  When preparing a liquid preparation for oral use, a liquid preparation, syrup, elixir, etc. may be produced by a conventional method by adding a corrigent, a buffer, a stabilizer, a corrigent etc. to the active ingredient of the present invention. it can. In this case, examples of the corrigent include those described above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to the active ingredient of the present invention, and intravenous, intramuscular, subcutaneous, skin, etc. are added by a conventional method. An injection for internal or intraperitoneal injection can be produced. Sodium citrate, sodium acetate, sodium phosphate and the like can be used as the pH adjuster and buffer, and sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid and the like can be used as the stabilizer. Examples of the isotonic agent include sodium chloride and glucose, and examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.

  When preparing a suppository, it can be produced by a conventional method after adding a base usually used for the active ingredient of the present invention and, if necessary, a surfactant and the like. As the base, for example, an oily base such as macrogol, lanolin, cacao oil, fatty acid triglyceride, witepsol (manufactured by Dynamit Nobel) can be used.

  When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are usually used in the active ingredient of the present invention are blended as necessary, and are mixed and manufactured by a conventional method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, and paraffin. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.

  When producing a patch, the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method. Examples of the support include cotton, suf, woven fabrics made of chemical fibers, non-woven fabrics, films of soft vinyl chloride, polyethylene, polyurethane, or foam sheet.

  The amount of suplatast tosylate to be incorporated in each of the above dosage unit forms is not constant depending on the lichen plan symptoms or the dosage form thereof, but generally 5-1000 mg per oral dosage unit dosage form, injection In addition, it is desirable that the dosage is 0.1-500 mg for transdermal administration agents and 5-1000 mg for suppositories. The dosage of the drug having the above dosage form is appropriately selected according to the patient's symptoms, body weight, age, sex, other conditions, etc., but usually 5-1000 mg for an oral dosage per adult, injection In addition, it is preferably administered once to several times a day in the range of 0.1 to 1000 mg for a transdermal administration agent and 5 to 1000 mg for a suppository.

  The prophylactic and / or therapeutic agent for lichen planus according to the present invention includes 1) complementation and / or enhancement of prevention / treatment effect against lichen planus, 2) improvement of kinetics / absorption of suplatast tosylate, reduction of dosage, 3) ) To reduce side effects, etc., it may be administered in combination with irradiation or surgical treatment, or may be administered in combination with other drugs as a concomitant drug.

  The combined use of the prophylactic and / or therapeutic agent for lichen planus of the present invention and other agents may be administered in the form of a combination preparation in which both components are combined in one preparation, or as separate preparations. It may take the form to do. When administered as separate preparations, simultaneous administration and administration by time difference are included. In addition, administration by time difference may be such that suplatast tosylate is administered first, other drugs may be administered later, other drugs may be administered first, and suplatast tosylate may be administered later, The administration method may be the same or different.

  Other agents that supplement and / or enhance the preventive and / or therapeutic effect of suplatast tosylate on lichen planus by the above combination include, for example, corticosteroids, antifungal agents, steroid agents, antihistamines, vitamin A preparations, A local anesthetic is mentioned. Although these specific examples are shown below, it is not limited to these, The same kind of medicine discovered in the future can be used in addition to the existing medicine having the same mechanism.

  Antifungal agents: Examples include amphotericin B, nystatin, flucytosine, miconazole, fluconazole, itraconazole, terbinafine hydrochloride, micafungin sodium, griseofulvin and the like.

  Steroid agents: for example, prednisolone, methylprednisolone, methylprednisolone acetate, prednisolone acetate valerate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, flutamethasone piprate, triamcinolone, triamcinolone acetonide, dexamethasone acetate dexamethasone acetate , Dexamethasone propionate, fluocinolone, fluocinolone acetonide, betamethasone, betamethasone valerate, betamethasone dipropionate, beclomethasone propionate, clobetasone butyrate, fludroxycortide, fluocinonidoharsinonide, amsinonide, difluprednate, valeric acid Diflucortron, diflorazone acetate, clobetasol propionate Mometasone furoate, and the like.

  Antihistamines: for example, diphenhydramine hydrochloride, diphenylpyraline hydrochloride, diphenylpyraline teocrate, clemastine fumarate, chlorpheniramine maleate, triprolidine hydrochloride, alimemazine tartrate, promethazine hydrochloride, homochlorcyclidine hydrochloride, hydroxyzine, cyproheptadine hydrochloride, fumaric acid Examples include ketotifen, azelastine hydrochloride, oxatomide, mequitazine, fexofenadine hydrochloride, emedastine fumarate, epinastine hydrochloride, ebastine, cetirizine hydrochloride, bepotastine besylate, levocabastine hydrochloride, olopatadine hydrochloride, and rotalazine.

  Vitamin A preparation: for example, retinol palmitate and the like.

  Local anesthetics: for example, ropivacaine hydrochloride hydrate, lidocaine, lidocaine hydrochloride, procaine hydrochloride, propitocaine hydrochloride, bupivacaine hydrochloride, mepivacaine hydrochloride, dibucaine hydrochloride, dibucaine hydrochloride / parabutylaminobenzoic acid ethylaminoethyl, tetracaine hydrochloride, Examples thereof include oxybuprocaine hydrochloride. Non-steroidal anti-inflammatory drugs include, for example, sodium salicylate, aspirin (acetylsalicylic acid), salicylamide, flufenamic acid, mefenamic acid, tolfenamic acid, diclofenac sodium, sulindac, fenbufen, ampenac sodium, indomethacin, indomethacin farnesyl, malein Acid Gourmet Tacin, Acemetacin, Nabumetone, Etodolac, Mofezolac, Ibuprofen, Ketoprofen, Flurbiprofen, Flurbiprofen Axetil, Oxaprozin, Fenoprofen Calcium, Tiaprofenic Acid, Naproxen, Pranoprofen, Loxoprofen Sodium, Aluminoprofen , Zaltoprofen, bucolome, piroxicam, ampiroxicam, tenoki Examples include siccam, meloxicam, lornoxicam, epirizole (mepyrizole), thiaramide hydrochloride, emorphazone and the like.

  The weight ratio between suplatast tosylate and the other drug is not particularly limited, and other drugs may be used in combination of two or more.

  Next, the present invention will be further described with reference to formulation examples and test examples, but the present invention is not limited to these examples.

Formulation Example 1 Tablet

Formulation Example 2 Capsule

Formulation Example 3 Granules

Formulation Example 4 Fine granules

Formulation Example 5 Syrup

Formulation Example 6 Injection

Formulation Example 7 Suppository

Example 1 Case 1
Patient: 65-year-old male Medical history: A rash on the lower lip appeared 2 years before the first visit and was diagnosed as lichen planus. Although dexartin ointment (dexamethasone: Nippon Kayaku) was externally administered and chocola A (vitamin A: Eisai) was orally administered, it did not improve.
Symptoms: At the first visit, white cornified desquamation and redness were seen in the central half of the lower lip, and the central part was eroded. Both buccal mucosa in the oral cavity had a mild slate color.
Treatment: Because there was pain when dried, oral administration of glycobin FP (griseofulvin: Sankyo) 375mg / day, dexartin ointment was applied, and subjective symptoms were relieved and keratinization was reduced in 1 to 2 weeks. And the tingling feeling was repeated. For this reason, when the dose of Glysobin FP was increased to 750 mg / day, improvement in subjective symptoms and improvement in skin eruption were observed, but the situation was going on and off.
Glysobin FP administration was discontinued 3 years and 2 months after the first visit and changed to 300 mg / day IPD (splatast tosilate: Taiho Pharmaceutical). On the 4th day, epithelialization occurred, and the tingling subjective symptoms were alleviated. Since there was no relapse even after taking 3 months, the dose was changed to 200 mg / day and observed for 3 months.

Example 2 Case 2
Patient: 46-year-old male Medical history: From 2 years before the first visit, I had noticed that there was a rash without subjective symptoms on the glans. At the first visit, senile pigment spots were suspected and the patient was followed up. Thereafter, the patient visited again 3 years and 10 months later.
Symptoms: At the re-examination, the slightly elevated erythema of mild keratosis up to the grain size was scattered on the glans head, and lichen planus was diagnosed.
Treatment: Glysobin FP (gluceofulvin: Sankyo) 500 mg / day was administered from the time of revisiting. After 8 months, Glysobin FP administration was discontinued and changed to IPD (Suplatast Tosilate: Taiho Pharmaceutical) 300 mg / day. When revisited 1 month later, erythema was relieved, and medication was administered for 4 months 20 days. Observation revealed that there was no relapse and it was judged to be cured. In addition, the concomitant drug in the IPD administration period was only cereal (vitamin C: Yoshishi Shiono) 3.0 g / day.

Example 3 Case 3
Patient: A 68-year-old woman Medical history: The lower lip became white tone several months before the first visit, and lichen planus was diagnosed.
Treatment: IPD (Suplatast Tosylate: Taiho Pharmaceutical) was prescribed at 300 mg / day, but it started to improve on the 10th day after administration, and became almost cured after 2 months.

Example 4 Case 4
Patient: 54-year-old male Medical history; I noticed pruritic plaques on the glans one month before the first visit.
Treatment: From the time of the first visit, 5 g of full meta ointment (mometasone furoate: Yoshishi Shiono) was administered but remained unchanged. One month later, when IPD (Suplatast Tosylate: Taiho Pharmaceutical) was administered at a dose of 300 mg / day for 14 days, itching disappeared and erythema improved. Thereafter, the patient was cured by sequential administration of IPD 300 mg / day 14 days, IPD 300 mg / day 21 days, IPD 300 mg / day 28 days. Around 1 week after oral administration of IPD 300 mg / day, subjective symptoms (pruritus) disappeared and erythema improved. Thereafter, brown erythema and brown erythema were gradually improved.

Claims (1)

Following formula (1):

(±)-[2- {4- (3-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium represented by the formula: Preventive agent and / or treatment of lichen planus Agent.