JP2001187734A - Type 2 helper t cell differentiation inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for allergic asthma or a therapeutic agent for allergic rhinitis having excellent therapeutic effect and having little adverse effect. SOLUTION: This type 2 helper T cell differentiation inhibitor comprises a biotin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a type 2 T helper cell differentiation inhibitor, and more particularly, to a biotin-containing type 2 T helper cell differentiation inhibitor having use as a therapeutic agent for allergic asthma or allergic rhinitis. Agent.

[0002]

2. Description of the Related Art Biotin acts as a coenzyme for four kinds of decarboxylation reactions in living organisms, and produces energy, fatty acid biosynthesis, and the like.
It plays an important role in metabolism and amino acid metabolism. By activating these enzyme reactions, they have been used for the treatment of dermatitis such as psoriasis, diabetes, arthritis and the like.

[0003] On the other hand, steroids have been used for the treatment of allergic asthma and rhinitis so far, but while exhibiting excellent therapeutic effects, serious side effects have been a problem. Also non-steroidal anti-inflammatory drugs, evening primrose oil, EPA
However, its therapeutic effects were not as good as steroids and were not sufficient.

[0004]

An object of the present invention is to provide a therapeutic agent for allergic asthma or allergic rhinitis which has few side effects and has an excellent therapeutic effect.

[0005]

[Means for Solving the Problems] In recent years, the mechanism of cytokine production patterns and pathological conditions has been gradually elucidated due to the development of techniques for measuring cytokines as information transmitters of immune responses (SCIENCE, VOL. 260, 23). APRIL 1
993). Among them, it has been found that allergic diseases such as allergic rhinitis and asthma are caused by differentiation into type 2 T helper cells (Th2).

The present inventors have found that sensitization of small animals with an antigen that promotes Th2 differentiation, such as an extract of Ascaris, to which a certain amount of biotin is administered suppresses Th2 differentiation. Furthermore, when the effect of biotin on allergic asthma was verified, it was confirmed that a remarkable therapeutic effect was exhibited without side effects. The present invention, which has been completed based on such findings, is directed to a type 2 T containing biotin.
Helper cell differentiation inhibitor. Alternatively, it is a type 2 T helper cell differentiation inhibitor containing biotin which is a therapeutic agent for allergic asthma or allergic rhinitis.

The effective dose of biotin in the present invention is 1500 μg to 10 g per adult per day. This is 15
If it is less than 00 μg, the effect of suppressing Th2 differentiation is not sufficient, and if it exceeds 10 g, the effect of suppressing Th2 differentiation is not promoted.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The type 2 T helper cell differentiation inhibitor of the present invention may be any of known additives other than biotin, such as excipients, disintegrants, binders, lubricants, antioxidants, and coatings. Oral preparations such as granules, powders, capsules, tablets, dry syrups, and liquids can be prepared in a conventional manner by adding agents, coloring agents, flavoring agents, surfactants, plasticizers, and the like.

For example, a prescribed amount of biotin is uniformly mixed with excipients such as Avicel, wet granulated, and dried to prepare granules. A lubricant such as magnesium stearate is added to the obtained granules, mixed, and compression-molded to obtain a biotin-containing tablet.

[0010] In the case of a liquid preparation for internal use, palatability can be imparted by blending other physiologically active ingredients, minerals, vitamins, hormones, nutritional ingredients, fragrances and the like as required.

[0011]

Examples Examples, comparative examples and test examples are given below.
The present invention will be described in more detail. [Example 1] Biotin 2000g Lactose 1980g Low-substituted hydroxypropylcellulose 500g Hydroxypropicellulose 500g Light anhydrous silicic acid 5g DL-menthol 15g The above components were weighed, and each component except DL-menthol was mixed. The obtained mixed powder is wet-stirred and granulated, dried,
DL-menthol was added and mixed. The obtained granules are
The package was divided into 1500 mg per package. [Example 2] Biotin 1.5 g Carnitine chloride 50 g Sodium pantothenate 50 g Taurine 1500 g Nicotinamide 30 g Vitamin B1 5 g Vitamin B2 5 g Vitamin B6 5 g Ginseng 600 g Deer mushroom 10 g Royal yellow jelly 100 g Royal yellow jelly 100 g sodium bee Sodium citrate qs (pH 3.5) After weighing the above components, they were mixed with purified water to obtain a total of 50 mL of an oral solution. Example 3 Biotin 500 g DL-carnitine chloride 50 g Pantethine 50 g Sodium ascorbate 50 g D-mannitol 150 g Lactose 100 g Crystalline cellulose 40 g Hydroxypropyl cellulose 50 g Light anhydrous silicic acid 5 g Magnesium stearate 5 g The above components were weighed, and magnesium stearate was weighed. The components except for the components were mixed. The obtained mixed powder was subjected to fluidized bed granulation.
After drying, magnesium stearate was added and mixed.
The obtained granules were tableted to obtain a tablet weighing 250 mg per tablet. [Example 4] Sodium ellagate 50 g Biotin 10 g Glycerin 100 g Ethanol 50 g Xanthan gum 30 g Flavor 0.1 g The above components were weighed and dissolved in purified water to give a total amount of 2 L of medicinal liquid. [Example 5] A: Oil phase part Liquid paraffin (# 70) 5 g Squalane 10 g Cetostearyl alcohol 6 g Beeswax 2 g Glycerin monostearate 1.5 g Sorbitan monolaurate 2 g Propyl paraoxybenzoate 0.1 g B: Water phase part Sodium ellagate 0.5g Biotin 0.2g Sodium hyaluronate 0.3g Paraoxymethyl benzoate 0.2g Purified water 22.2g After mixing and melting oil phase part A and water phase part B at 70 ° C respectively, Part A was added and mixed uniformly with an emulsifier. Further, a fragrance (a trace amount) was added and the mixture was cooled to prepare a cream. [Example 6] Biotin 1000 mg DL-menthol 5 mg Benzalkonium chloride 5 mg Chlorobutanol 280 mg Suitable amount of boric acid (pH 5.5) Sodium chloride 330 mg After weighing the above components, dissolve them in sterile purified water to make a total amount of 100.
mL ophthalmic solution was prepared and filled into a container. [Test Example 1]
Effect of biotin on Th2 cell differentiation An antigen Asc having differentiation promoting effect on type 2 T helper cells (Th2) was given to 3-week-old male ICR mice weighing about 18 g.
The aris extract 1 mg / kg was subcutaneously administered once a week for a total of three times. At the same time, 0.1 mg / kg, 1 mg / kg and 10 mg / kg of biotin were orally administered once daily for a total of 17 days.
Dexamethasone (steroid) 1mg as positive control
/ Kg once a day for 17 consecutive days. Ascaris Concanavalin 3 days after final sensitization
A) Blood was collected after stimulating 10 mg / kg iv, and the amount of IL-5 in serum was determined.
Quantification was performed by ELISA. The body weight was measured before administration and before blood collection, and used as an index of side effects. The results are shown in Table 1.

[0012]

[Table 1] (Test results) In untreated mice, the production amount of IL-5, which is a cytokine produced by Th2 cells, is 83 pg / mL. However, three sensitizations of Ascaris antigen that promotes Th2 differentiation Production increased to 1221 pg / mL. IL-5 production increased the dose of biotin (1 mg / kg, 10 mg / kg).
kg), and the effect was comparable to the case where 1 mg / kg of the positive control drug dexamethasone (steroid drug) was administered. On the other hand, dexamethasone 1
In contrast to the significant dose-inhibition effect observed at the dose of mg / kg, the dose-inhibition effect was not observed even at 10 mg / kg in the biotin-administered group, which was equivalent to that of the control group (Table 1). From the above results, it was found that biotin, at a dose of 1 mg / kg or more, suppressed the bias toward Th2 cell differentiation due to sensitization of the antigen causing allergy and did not have the effect of suppressing weight gain as a side effect. [Test Example 2] Effect of biotin on asthma model 0.1% ovalbumin (OVA) suspended in aluminum salt in a 6-week-old BALB / c mouse weighing about 20 g
Was sensitized by intraperitoneal administration at a rate of 0.5 mL / animal. After standing for 10 days, a second sensitization was carried out by the same operation, and further 10 days later, 1
% OVA was airway sensitized with a nephrizer for 30 minutes.
This operation was performed three times every four days, and 24 hours after the end of the last airway sensitization, the effect on airway hypersensitivity caused by inhaling and inducing three doses of methacholine in the airway was examined. Biotin and control agent dexamethasone are used from initial sensitization to final airway sensitization.
It was orally administered once a day. Weight gain from the first sensitization to the last sensitization was measured as an index of side effects. The results are shown in Table 2.

[0013]

[Table 2] (Test result) Compared with the non-sensitized mice, the airway constriction by methacholine was significantly increased in each dose of methacholine in the OVA-sensitized mice. Oral administration of biotin 1 mg / kg showed no significant effect on airway sensitization by a low dose of methacholine, but showed a significant inhibitory effect on airway constriction at a high dose. The control drug dexamethasone exhibited airway resistance at each dose of methacholine (FIG. 1).

[0014] Weight gain as an index of side effects showed significant weight gain in the asthma group as compared to the non-sensitized group, and administration of biotin had no effect on the weight loss. In the group, no weight gain effect was observed from the time of the first sensitization.

From the above results, it was confirmed that biotin suppresses airway hyperresponsiveness due to allergic asthma, and hardly causes side effects.

[0016]

According to the present invention, it has become possible to provide a therapeutic agent for allergic asthma or allergic rhinitis, which has less side effects and exhibits the same excellent therapeutic effect as steroids.

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between methacholine concentration and airway resistance.

 ────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Kenji Tsunoda 3-24-1, Takada, Toshima-ku, Tokyo Taisho Seiyaku Co., Ltd. F-term (reference) 4C086 AA01 AA02 CB28 MA01 ZA59 ZA61 ZB02 ZB13 ZB21

Claims (3)

[Claims] 1. A type 2 T helper cell differentiation inhibitor containing biotin. 2. The method according to claim 1, which is a therapeutic agent for allergic asthma.
The type 2 T helper cell differentiation inhibitor according to the above. 3. The method according to claim 1, which is a therapeutic agent for allergic rhinitis.
The type 2 T helper cell differentiation inhibitor according to the above.