JP2000086529A - Il-4 production inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an IL-4 production inhibitor useful as a therapeutic agent for atopic dermatitis and allergic diseases by including a steam distillate of eucalypti as an active ingredient. SOLUTION: This inhibitor comprises a fraction obtained by steam-distilling leaves, twigs, flowers or fruits of eucalypti (evergreen abores belonging to the genus Myptus globulus of the family Myrtaceae or the affinitive plants therefor), as an active ingredient. The daily dosage of the inhibitor is pref. ordinarily 0.1 to 2,000 mg per adult when used as a cosmetic, drug or aquasi- drug. By including e.g. the inhibitor, a base material for external use and other medicinal properties, there is obtained an agent composition for external use for skin suitable for preventing or treating atopic dermatitis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an interleukin 4 (IL-4) production inhibitor, an external preparation for the prevention and treatment of atopic dermatitis, and an antiallergic agent containing the IL-4 production inhibitor. .

[0002]

2. Description of the Related Art
4 is a substance produced from T lymphocytes which are human or animal immune response cells,
It is known to enhance the production of antibodies such as E (Clinical Immunity, 27, 45-57, 1995). IgE
Has long been known to be deeply involved in the development of atopic diseases (Dermatology MOOK., Vol. 1, 49-5).
8, 1985). It is also known that IL-4 has an action of promoting infiltration of inflammatory cells into inflammatory sites in allergic diseases (Cell, Vol. 62, 457-467).
Pp. 1990). These facts suggest that IL-4 is strongly involved in the development of allergic diseases.
Therefore, if the production of IL-4 can be suppressed, histamine release inhibitors conventionally used for allergic diseases, compared with therapeutic methods and preventive methods using inhibitors of IgE or histamine action, It is thought that treatment and prevention can be performed more fundamentally.

As the IL-4 production inhibitor, only a group of sulfonium derivatives are known (Japan. J. Pharmaco.
l., 61, 27-30, 1993), and is used in the treatment of allergic diseases such as atopic dermatitis and itching, etc., but its efficacy is not sufficient. In addition, the route of administration was limited due to the low transdermal absorbability due to its structure. Therefore, there has been a need for an IL-4 production inhibitor and an antiallergic agent which are excellent in efficacy and excellent in transdermal absorption, stability and safety.

[0004]

Means for Solving the Problems The present inventors searched for an IL-4 production inhibitor using an experimental system in which mouse-sensitized lymphocytes were antigen-induced in a culture system for various plants or extracts thereof. , The eucalyptus steam distillate IL
-4 production inhibitory effect. Furthermore, animal experiments have found that these IL-4 production inhibitors are useful as therapeutic agents for atopic dermatitis and allergic diseases.

[0005] That is, the present invention provides an IL-4 production inhibitor containing eucalyptus steam distillate as an active ingredient. The present invention also provides a skin external preparation for preventing or treating atopic dermatitis or an antiallergic agent containing the IL-4 production inhibitor.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Eucalyptus in the present invention is Eucalyptus eucalyptus, an evergreen tree belonging to the family Myrtaceae.
lyptus globulus or other closely related plant leaves, twigs, flowers or fruits.

It is known that eucalyptus used in the present invention has an intestinal controlling effect, a carbohydrate absorption suppressing effect, a cholesterol excretion promoting effect (JP-A-06-133732), and the like. Already known as general skin external preparations and cosmetics, eucalyptus steam distillate
It was not known at all that it had an L-4 production inhibitory effect.

[0008] The eucalyptus steam distillate used in the present invention is a fraction obtained by steam distillation of eucalyptus leaves, twigs, flowers or fruits. Also, eucalyptus leaves, twigs,
The extract obtained by extracting flowers or fruits with water, an organic solvent or a mixture thereof may be subjected to steam distillation. Moreover, you may use a commercial item. This steam distillate is
Although it can be used as an active ingredient such as an L-4 production inhibitor, the steam distillate can be further separated into a fraction having high activity by a suitable separation means such as gel filtration, silica gel column chromatography, or high performance liquid chromatography. It can also be used separately.

The IL-4 production inhibitor of the present invention can be administered either externally or internally. IL of the present invention
In addition to the steam distillate, a commonly used external base material, other medicinal ingredients, and the like can be added to the skin external preparation composition containing the -4 production inhibitor. The external base material used herein may be any of those based on an oily base, those based on an oil / water, water / oil type emulsified base, and those based on water. Is also good.

Examples of the oil base include vegetable oils, animal oils, synthetic oil fatty acids, and natural / synthetic glycerides. Further, humectants, ultraviolet absorbers, alcohols, chelates, pH adjusters, preservatives, thickeners, pigments, fragrances, and the like can be added. Further, as the medicinal component, for example, an analgesic anti-inflammatory agent, a germicidal antiseptic, a vitamin, an emollient and the like can be used. Examples of the form of these skin external preparation compositions include ointments, creams, emulsions, lotions, packs, foundations, bath salts, and the like. The compounding amount and dose of the IL-4 production inhibitor are usually 0.1 to 2000 per day for an adult as an active ingredient as cosmetics, pharmaceuticals, and quasi-drugs.
Used in the mg range.

[0011]

[Example] (Production example) 100 dried and ground eucalyptus leaves
g was placed in a distillation apparatus, and steam distillation was performed by introducing steam. By cooling the steam discharged from the apparatus with a cooling pipe, 1 liter of steam distillate was obtained as a liquid.

Test Example 1 Measurement of IL-4 Production Inhibition Ability Balb / c mice were sensitized by subcutaneous injection of 200 μg of a protein antigen (Limpet hemocyanin) together with Freund's complete adjuvant. Seven days later, the lymph nodes were removed,
Phosphate Buffered Saline
(Hereinafter abbreviated as “PBS”) to prepare a lymphocyte suspension. Put the prepared lymphocytes in a 96-well plate
RPM was sprinkled at a concentration of 4 × 10 ⁵ cells per well, and 10% bovine serum-added RPM was added with the eucalyptus steam distillate obtained in the production example to a final concentration of 0.04% or 0.2%.
After culturing at 37 ° C. for about 1 hour using I 1640 medium, a protein antigen (Limpet hemocyanin) was added (final concentration: 10 μg / ml). After three more days of culture,
The culture supernatant was subjected to quantification by the ELISA method.

The quantification by the ELISA method used a mouse cytokine ELISA system (Amersham). The suppression rate of IL-4 relative to the control was calculated, and the cytokine suppression effect was determined. That is, the IL-4 production inhibition rate (%) (in each of the following tables, abbreviated as “IL-4 inhibition rate”) is the IL-4 production when only a medium solution containing no test substance is added. It indicates what percentage to suppress. As a result, as shown in Table 1, the steam distillate of eucalyptus showed a remarkable IL-4 production inhibitory effect as compared with the comparative product. Eucalyptus steam distillate is useful as an external preparation or an antiallergic agent for atopic dermatitis induced by the production of IL-4.

[0014]

[Table 1]

Example 1 1 g of the steam distillate of eucalyptus obtained in the preparation example, 0.5 g of cholesterol, 1 g of cholesteryl isostearate, 1.5 g of polyether-modified silicone, 20 g of cyclic silicone, 2 g of methylphenylpolysiloxane, A mixture of 2 g of methylpolysiloxane, 0.5 g of magnesium sulfate, 5 g of 55% ethanol, 0.5 g of carboxymethylxan and purified water was mixed with cream 10
0 g.

Example 2 50 g of the eucalyptus steam distillate obtained in the preparation example, hydroxypropylcellulose 8
0 g, 20 g of light anhydrous silicic acid, 50 g of lactose, 50 g of crystalline cellulose and 50 g of talc were prepared into tablets having a diameter of 9 mm and a weight of 200 mg by a conventional method.

EXAMPLE 3 1 g of the eucalyptus steam distillate obtained in the preparation example, sodium lauryl ether sulfate 2
0 g, sodium chloride 2 g, and sodium sulfate 77 g were used as bathing agents in a conventional manner.

[0018]

Industrial Applicability The IL-4 production inhibitor of the present invention is excellent in percutaneous absorbability, stability, safety and price, and has strong efficacy. In addition, skin external preparations and antiallergic agents containing such inhibitors have a preventive or therapeutic effect on atopic dermatitis.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Yoshiaki Ichikawa 2606 Kabane-cho Akabane, Haga-gun, Tochigi Prefecture, Japan Kao Co., Ltd. 72) Inventor Kimihiko Hori 2606 Kabane-cho, Akaga-cho, Haga-gun, Tochigi Pref. In the Kao Co., Ltd. research laboratory AB352 AB362 AB372 AB432 AC102 AC782 AD152 AD162 AD172 AD212 AD262 AD282 AD322 AD492 BB51 CC05 CC25 DD15 DD21 DD23 DD27 DD31 EE13 EE42 4C088 AB57 AC03 AC04 AC05 AC06 BA08 BA09 NA14 ZA89 ZB11 ZB13 ZC41

Claims (3)

[Claims] An interleukin-4 production inhibitor comprising a eucalyptus steam distillate as an active ingredient. 2. An external preparation composition for the prevention and treatment of atopic dermatitis, comprising the interleukin-4 production inhibitor according to claim 1. 3. An antiallergic agent comprising the interleukin 4 production inhibitor according to claim 1.