JPH10251137A - Inhibitor against photosensitivity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preparation having an excellent inhibitor activity against photosensitivity especially when administered externally (percutaneously), by including a specific compound having an immunosuppressive activity as the active ingredient. SOLUTION: This preparation for external (precutaneous) use for skin, preferably, is prepared by formulating (A) macrolide(s) or analogue(s)/derivatives thereof, cyclosporine A or analogue(s)/derivative(s) thereof, having an immunosuppressive activity as the active ingredient, and (B) an oil, surfactant, perfume, anti-oxidant, UV light-absorber, coloring matter, alcohol, water, moisturizing agent, and/or thickening agent, if necessary. In gradient A is preferably ascomycin, FK506, and/or cycloporine A. Combination of these ingredients affords and additive or synergistic effect on the inhibition agent photosensitivity. The daily dose of the above preparation is preferably 0.1μg- to 10mg-active ingredient/cm<2> -lesion. It is preferable to administrate the amount divides in 1-4 portions per day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a preparation for controlling photosensitivity used for medical and cosmetic science.

[0002]

2. Description of the Related Art Photosensitivity includes extrinsic and endogenous diseases. The former involves exogenous, for example, a photosensitizer coming into contact with the skin and irradiating a certain area of light to the site or another site. There are phototoxic dermatitis and contact photoallergic dermatitis caused by being performed. Other types of photosensitivity diseases include (intrinsic) continuous photosensitivity, photoreticulitis, chronic photosensitivity eczema, and polymorphic solar rash, which are caused only by irradiation of light, regardless of foreign substances. There are various diseases (eg, “Sensitive Eczema: Principles of Diagnosis and Treatment (Photosensitivity Disease)
ses: Principles of Diagnostics
is and Treatment), Leonard
C. Harber and David R. Bic
kers, B .; C. Decker Inc. , 198
9). These diseases are chronic intractable diseases in severely affected patients, whose symptoms are expressed even by an extremely small amount of light, and which hinder daily life.

[0003] Steroids have been conventionally administered for these treatments. As a preventive measure, a sunscreen agent has been applied to block light rays. However, steroids not only have a weak effect, but also cause side effects due to continuous use.On the other hand, sunscreens need to be applied evenly to sun-exposed areas, and they cannot completely block light. It was physically difficult. Against this background, the present inventors have proposed chalcone glycoside-containing drugs and quasi-drugs that are effective for such diseases (see Japanese Patent Application Laid-Open No. 8-205542). On the other hand, certain skin diseases are caused by abnormalities of the immune system, and there have been attempts to use immunosuppressants in the treatment of specific skin diseases. For example, it has been proposed to use an Ascomycin derivative, which is a typical drug having an immunosuppressive action, for the treatment of dermatitis (see WO 91/13899). According to this pamphlet, it is suggested that the muscommycin derivative is effective against a wide range of dermatitis, for example, contact dermatitis, atopic dermatitis, erythema multiforme, urticaria and the like.

[0004]

As described above, the present inventors have proposed an external preparation containing a chalcone glycoside which has no side effects and is effective in preventing and treating photosensitivity. However, given the diverse etiology of photosensitivity, there will still be a need to obtain additional potent dermatological agents for the treatment of the disease.

Accordingly, an object of the present invention is to provide a preparation for suppressing photosensitivity comprising a compound belonging to a category different from that of the chalcone glycoside as an active ingredient, in particular, a drug for dermis and a drug for quasi-drugs. Is to provide.

[0006]

Means for Solving the Problems The present inventors have utilized the above-described drug efficacy evaluation system (particularly, a photosensitivity model) used in developing the aforementioned chalcone glycoside-containing preparation. We have been screening effective compounds for the evaluation system.
As a result, it has been found that a specific compound having an immunosuppressive effect has a remarkable effect on photosensitivity, especially when the skin (or transdermal) is administered.

[0007] Therefore, according to the present invention, in order to solve the above-mentioned problems, it has been found that macrolides and at least one compound selected from cyclosporin A and related compounds are effective. A photosensitivity-suppressing preparation comprising as an ingredient is provided.

[0008] In a preferred embodiment of the present invention, the preparation is provided as an external (or transdermal) preparation.

[0009] Macrolides, cyclosporin A and related compounds which have an immunosuppressive effect and can be used as an active ingredient in the present invention may be any compound within the defined range as long as it is a compound suitable for the purpose of the present invention. It may be a compound.

More specifically, typical examples of the macrolides include ascomycin produced by actinomycetes (Arai, T. et al., "Ascomycin, ana."
antifungal antibiotic ", JA
ntibiotics, Ser. A, 15, 231, 1
962): For its use as an immunosuppressant, see EP-A-323 865) and FK506 (Goto, T. et al., "FK506: His.
traditional perspectives ", Tra
nsplant. Proc. , 23: 2713, 199.
1), and their analogs and derivatives subsequently discovered or developed.

Another typical type of compound, cyclosporin A, is an immunosuppressant produced by actinomycetes and launched in 1983 as an immunosuppressant that specifically acts on T helper cells. (Shevach,
M. “The effects of Cyclosp
orin A on the immune system
em ", Ann. Rev. Immunol., 3, 39.
7, 1985). In the present invention, analogs and derivatives of cyclosporin A can also be used as an active ingredient.

Specific examples of the above-mentioned analogs or derivatives are not limited, but are described in JP-A-6-51030.
4, International Publication Nos. 91/13899 and 94/21
No. 643, No. 96/13249, No. 95/406
No. 1, EP-A-626385, WO-A-94 / 21642, WO-A-94 / 21635, and WO-A-94 / 21635.
Nos. 4/21634, 93/25533 and 93
/ 14780, and the like.

Of these, ascomycin, FK506 and cyclosporin A, which were first found as products of microorganisms, are preferred, and ascomycin is particularly preferred. Further, according to the present invention, two or more of the above compounds can be used in combination. For example, according to Ascomycin and Cyclosporin A, FK506 and Cyclosporin A, an additive or synergistic effect can be obtained on the inhibitory action against photosensitivity.

The preparation of the present invention containing the above compound as an active ingredient is intended to provide a preparation for dermatological (transdermal) use as a main dosage form. These specific dosage forms may be any of those commonly used in medical or cosmetic science (as cosmetics), for example, liquid,
It can be an emulsion, cream, cartilage, poultice.

[0015] In addition to the active ingredient, the preparation of the present invention comprises
One or more pharmaceutically acceptable oils, surfactants, fragrances, antioxidants, ultraviolet absorbers, dyes, alcohols, water, humectants, thickening agents and the like can be added. These formulations can be provided by methods of preparation well known in the art. The active ingredient contained in the preparation thus provided cannot be specified because the optimum amount varies depending on the dosage form, but specifically, the optimum amount will be determined with reference to the preparation examples described later.

The dosage of the preparation of the present invention depends on age, individual differences,
Although it cannot be clearly limited because it changes depending on the medical condition, etc., the dose of the active ingredient generally administered to a human is determined by the amount of the affected area 1c.
m ² and 1 day 0.1Myuji～10mg, preferably 1Myuji～1mg, this amount daily once or 2
It can be administered in four divided doses.

[0017]

EXAMPLES Next, the present invention will be described more specifically with reference to Examples. Note that the present invention is not limited to this.

Examples of Efficacy Tests The following tests were carried out to clarify the efficacy of the preparations of the present invention for photosensitivity diseases.

Ascomycin, FK50 according to the present invention
6. Cyclosporin A and rapamycin, auranofin, indomethacin, and dexamethasone as comparative examples were dissolved in ethanol by a conventional method to prepare a skin external solution.

As a method for measuring the therapeutic effect of a drug on a photosensitivity disease, a test method using a continuous photosensitivity model (Ichikawa, H. et al., "Adjuvant-
induced persistent photo
Sensitivity models in gui
near pigs ", J. Dermatol. Sc
i. , 9, 1-11, 1995).

First, the immunization is performed using Mycobacterium
Butyricum (Mycobacterium butyr)
(icum) was suspended at 5 mg / ml in incomplete Freund's adjuvant, emulsified with physiological saline, and then injected intradermally into the neck of a guinea pig weighing 380 g to 450 g. Next, 0.1% of a 5% ethanol solution of benzocaine was used as a contact photoallergy-causing substance.
ml, and then apply long-wave ultraviolet light at 10 joules / cm ^2.
Irradiation was performed at an energy amount of The application of benzocaine and the irradiation of ultraviolet rays were continued for 5 consecutive days.
Days and 15 days later were also performed.

24 days after the first day of the immunization induction treatment,
Each of the above ethanol solutions was applied to the shaved back skin, and 30 minutes after application, a long-wavelength ultraviolet ray of 10 Joules / cm ² was irradiated to induce a photosensitivity reaction. The inhibitory effect of the drug on the photosensitivity reaction was determined by calculating the inhibition rate using a site irradiated with ultraviolet light without applying the drug as a positive control.

The skin reaction was determined by measuring the intensity of the skin reaction with a spectrophotometer and examining the inhibitory effect of the test substance on the skin reaction. From the average value of the skin reaction intensity at the site where the test substance was applied (E) to the average value of the skin reaction intensity at the site where the test substance was applied (C) Was subtracted, and the result was divided by the average value (C) of the skin reaction intensity at the positive control site and multiplied by 100 to obtain the inhibition rate (%).

[(CE) / C] × 100 = suppression rate (%) The results are summarized in Table I below.

[0025]

[Table 1]

In the table, the preparations used in Test Examples 1 to 6 are the preparations of the present invention, and the preparations used in Examples 7 to 12 are comparative preparations.

Each example was carried out using 5 guinea pigs per group as test animals, and the test results are average values.

Next, preparation examples according to the present invention will be described below together with preparation methods.

[0029] (1) was kneaded with (2) composed of liquid paraffin (95%) and polyethylene (5%), and deaerated under reduced pressure to obtain an ointment.

Example 2 (Cream) Cetanol 4.0% Vaseline 7.0 Isopropyl myristate 8.0 Squalane 12.0 Dimethyl polysiloxane 3.0 Glycerin monostearate 2.2 POE (20) Sorbitan monostearate 2.8 Glycyrrhetinic acid stearate 0.02 Ethyl paraben 0.1 Butyl paraben 0.1 B. Water phase Ascomycin 0.1 1,3-butylene glycol 7.0 Phenoxyethanol 0.2 Ascorbic acid phosphate magnesium salt 4.0 Purified water Residual total 100.0% Dissolve ascomycin in 1,3-butylene glycol, and mix phenoxyethanol and magnesium ascorbic acid phosphate Was added to Phase B kept at 70 ° C. while stirring, and the mixture was heated and dissolved at 70 ° C. with stirring, and homomixer treatment was performed to make the emulsified particles fine, followed by rapid cooling with stirring to obtain a cream.

Example 3 (Lotion) FK506 0.5% ethanol 7.0 polyoxyethylene (20) oleyl ether 0.5 methyl paraben 0.05 B. Glycerin 4.0 1,3-butylene glycol 4.0 Citric acid 0.01 Sodium citrate 0.1 Purified water Residual total 100.0% Add phase A dissolved in ethanol to phase B dissolved in purified water, solubilize and filter to obtain lotion. Was.

[0032] After dissolving a part of white petrolatum on a water bath, adding cyclosporin A, kneading the sieved zinc oxide and starch, adding the remaining white petrolatum and kneading sufficiently,
Manufactured as uniform quality.

[0033]

According to the present invention, there is provided a novel preparation which is suitable for the treatment of photosensitivity and has almost no side effects, especially for dermis. Since these preparations have a remarkable effect on the prevention and treatment of photosensitivity, they can be used in the field of medicine and quasi-drugs.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07H 7/06 A61K 37/02

Claims (2)

[Claims] 1. A preparation for suppressing photosensitivity, which has an immunosuppressive effect and comprises, as an active ingredient, at least one compound selected from macrolides and cyclosporin A and analogs thereof. 2. The preparation according to claim 1, wherein the macrolide is ascomycin, and for dermatological purposes.