JP2003306429A - Therapeutic agent or drink and food containing coenzyme qs for prophylaxis or treatment of allergic disease as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a prophylactic or a therapeutic agent for allergic diseases, a food and drink and a cosmetic effective for prophylaxis or treatment of the allergic diseases. <P>SOLUTION: The prophylactic or therapeutic agent for the allergic diseases is obtained by formulating a coenzyme Q<SB>n</SB>represented by general formula (I) (wherein, n denotes an integer of 4-12) or a compound convertible into the coenzyme Q<SB>n</SB>in vivo as an active ingredient. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a coenzyme Q _n (n = 4) which exhibits an excellent mast cell histamine release inhibitory action.
To 12) as an active ingredient, prophylactic or therapeutic agent for allergic diseases, and coenzyme Q _n (n = 4 to 12)
The present invention relates to foods and drinks, health foods, and cosmetics that are effective in the prevention or treatment of allergic diseases.

[0002]

2. Description of the Related Art In recent years, the number of patients with allergic diseases such as hay fever, bronchial asthma and atopic dermatitis has been increasing with changes in eating habits, living environment and natural environment. In these allergic diseases, cedar pollen, mites, and specific foods become allergens, which enter the body and bind to IgE bound to the membrane surface of mast cells, and histamine released by the binding causes allergens. It is believed to cause various symptoms. Therefore, antihistamines are used as therapeutic agents for allergic diseases, particularly eye and nose allergies, urticaria and the like. However, classical antihistamines have a central nervous system depressant action, and as a side effect based on them, development of drowsiness and malaise is a major clinical drawback. In other words, drowsiness not only interferes with driving a car and other daily activities, but also may cause a limitation in effectiveness because a high dose cannot be taken. Further, Patent Document 1 describes a plant extract such as Hypericum perforatum, which exhibits a mast cell histamine release-inhibiting action, but the active ingredient is not specified, and a stable quality product is obtained because it is a natural product. There is a problem that it is difficult to obtain. further,
Since the concentration used is as high as 0.1% and it is water-soluble, it is presumed that its absorbability from the skin is not good, and there is no knowledge of skin irritation, and there is a problem in its practical application as an external preparation.

By the way, it is known that coenzyme Q ₁₀ is used as a drug for treating heart diseases under the name of "Ubidecarenone", shows a palliative but certain effect, and is an excellent drug without serious side effects. Coenzyme Q
Researchers from various countries have been studying other usefulness regarding ₁₀ , and the results are based on the results of International Coenzyme Q ₁₀
It is reported at a biennial meeting of the association (Non-patent document 1). In addition, many of them have been studied for other uses and applied for patents in Japan. For example, Patent Document 2 describes a fatigue improving agent. However, it has not been known that the coenzyme Q family including coenzyme Q ₁₀ has a mast cell histamine release inhibitory action.

[0004]

[Patent Document 1] JP-A-6-183991

[Patent Document 2] JP-A-7-330594

[Non-Patent Document 1] BioFactor Vol. 9, No. 2-4, 1999

[0005]

DISCLOSURE OF THE INVENTION From the above points,
In order to prevent or treat allergic diseases, it is required to elucidate substances that have a different mechanism of action from antihistamines and that can be orally or dermally administered, and that have a highly safe antiallergic action based on the histamine release inhibitory action. ing.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to solve the above problems, and as a result, the general formula (I)

[Chemical 2] (In the formula, n represents an integer of 4 to 12) has a compound potent mast cell histamine release inhibitory effect which may be converted to coenzyme Q _n in the coenzyme Q _n or biological represented by excellent no side effects The present invention was completed by discovering that it has an anti-allergic effect.

That is, the present invention has the general formula (I)

[Chemical 3] (In the formula, n represents an integer of 4 to 12) which is a prophylactic or therapeutic agent for allergic diseases coenzyme Q _n or compounds as an active ingredient that can be converted into coenzyme Q _n in vivo represented by. The present invention also relates to the above-mentioned coenzyme Q _n.
Alternatively, it is a histamine release inhibitor containing a compound that can be converted to coenzyme Q _n in vivo as an active ingredient. Further, the present invention is a food or drink effective for the prevention or treatment of allergic diseases, which comprises the above-mentioned coenzyme Q _n or a compound that can be converted into coenzyme Q _n in vivo. Furthermore, the present invention is a health food effective for the prevention or treatment of allergic diseases, which contains the above-mentioned coenzyme Q _n or a compound that can be converted into coenzyme Q _n in vivo. Furthermore, the present invention is a cosmetic effective for the prevention or treatment of allergic diseases containing the above-mentioned coenzyme Q _n or a compound that can be converted into coenzyme Q _n in vivo.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the coenzyme Q _n of the present invention, n represents an integer of 4 to 12. In general, coenzyme Q _n is known to have n (length of side chain) of 1 to 12, but since the short side chain has skin irritation, n is 4 or more. preferable. In the present invention, in particular, coenzyme Q _{n in which} n is 9 or 10
Is preferred. In Japan, coenzyme Q ₁₀ has been used as a drug for nearly 30 years, no serious side effects have been reported, and it has been used overseas as a health food, but no serious adverse events have been reported. . further,
The JP 60-289029 (anti pigmentation agent), coenzyme Q _n has been described that there is no skin irritation, the coenzyme Q _n is an extremely highly safe compounds. Examples of the compound that can be converted into coenzyme Q _n in vivo include ubiquinol and the like.

The dosage form of a prophylactic or therapeutic agent for allergic diseases containing coenzyme Q _n or a compound capable of being converted to coenzyme Q _n in vivo as an active ingredient is tablets, capsules, granules, powders, syrups, and suspensions. Suspensions, suppositories, gels, inhalants, injections and the like can be mentioned. As the dosage form of the external preparation containing coenzyme Q _n , a lotion, an ointment, a cream, an emulsion, a patch, a bath preparation, a gel or the like can be used according to the purpose. These preparations are prepared according to a conventional method.

Various additives may be added to the coenzyme Q _n for formulation, for example, soybean oil, saffler oil, olive oil, germ oil, sunflower oil, beef tallow, sardine oil and other animal and vegetable oils, polyethylene glycol. , Propylene glycol, glycerin, polyhydric alcohols such as sorbitol, sorbitan fatty acid esters, surfactants such as glycerin fatty acid esters, polyglycerin fatty acid esters, excipients such as lactose, starch, crystalline cellulose,
And sweeteners, colorants, flavors and the like. The liquid preparation may be dissolved or suspended in water or other appropriate medium before use. The tablets and granules may be coated by a known method.

When ingesting coenzyme Q _n orally, it is easy to ingest it with a soft capsule, but it is also possible to ingest coenzyme Q _n in various forms in various forms of food. . Examples of food and drink include soft drinks such as carbonated drinks, milk drinks, butter, mayonnaise,
Shortening, margarine, various salad dressings, breads, noodles, pasta, cookies, candy,
All foods to which coenzyme Q _n can be added and blended such as chewing gum and confectionery such as chocolate can be mentioned. Examples of health foods include drinks, tablets, soft capsules, hard capsules, granules or powders, syrups and the like. Further, examples of cosmetics include cream, emulsion,
Lotion, viscous micro emulsion essence, O
/ W type essence, bath salt, etc. can be selected.

The amount of coenzyme Q _n to be ingested daily is preferably 30 to 150 mg for the purpose of preventing pollinosis, and 60 to 300 mg for the prevention of atopic dermatitis. Moreover, coenzyme Q _n amount when formulated as an external preparation or a cosmetic is 0.1 to 10%, preferably 1-5%
Is.

[0013]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 Histamine Release Inhibition Test by Rat Mast Cells Rats were killed by bleeding under ether anesthesia, the skin was excised, a small hole was made in the abdominal wall of the midline, and about 15 mL of 2 mL was intraperitoneally injected. Ty containing% FCS (fetal calf serum, GIBCO)
A rode solution (2% FT solution) was injected, and the abdominal wall was lightly massaged to collect a peritoneal exudate cell suspension. The peritoneal exudate cell suspension thus obtained was treated with 100 xg at 4 ° C.
The cells that precipitated were collected by centrifugation at 10 minutes. Cells were lysed in 2% FT solution to 22.5% (w / v) met
Overlaid with rizamide (Sigma) solution and 350 at room temperature
Centrifuge at xg for 15 minutes. Remove the cells at the interface between the buffer and metrizamide solution, and remove 2% of mast cells in the sediment
Floating in the FT solution, the multi-layer centrifugation was repeated twice. The mast cells thus obtained were suspended in 2% FT solution and
Centrifugation was performed at 100 xg for 10 minutes at 0 ° C and washing was performed twice. Mast cells with a purity of 90 to 95% obtained by this operation were suspended in a 2% FT solution at about 1.0 × 10 ⁵ cells / mL.

The test solution of this example was coenzyme Q ₁₀
(Manufactured by Nisshin Pharma Co., Ltd.) was prepared to a solid content of 0.01% using a 10% DMSO aqueous solution, and a blank was 10% DMS.
Aqueous O was tested using sodium cromoglycate as a control.

25 μl of the test substance was added to 120 μl of the cell suspension and allowed to stand at 37 ° C. for 10 minutes, and then the histamine releasing agent compound 48/80 preheated to 37 ° C.
(Sigma) (final concentration 1 μg / ml) 40 μl added 3
It was left still at 7 ° C. for 15 minutes. The reaction was stopped by cooling with ice and 4
After centrifugation at 100 × g for 10 minutes at 100 ° C., the amount of histamine in the supernatant was measured according to the Shore method. That is, to 25 μl of the supernatant, 100 μl of purified water, 50 μl of 1N NaOH solution, 1% o-phthaldialdehyde-methanol solution 2
After adding 5 μl and standing still for 5 minutes, 25 μl of 3N HCL solution
The reaction was stopped by. 18 minutes at 5 ° C 10 minutes after completion of the reaction
Centrifugation was performed at 00 × g for 5 minutes to obtain a supernatant and a precipitate. The fluorescence of the supernatant has an excitation wavelength of 360 nm and a fluorescence wavelength of 450 nm.
The amount of histamine in the supernatant was determined from the calibration curve of histamine of known concentration. In addition, the amount of histamine remaining in the mast cells was obtained by adding 200 μl of 2% FT solution to the precipitate, sonicating the frozen sample, and further cryopreserving it, and measuring it in the same manner as above to determine the histamine release ratio and inhibition rate. It was

[0017]

[Equation 1] A: Histamine release ratio when a histamine releasing agent is added to a mast cell in the presence of a sample B: Histamine release ratio when a histamine releasing agent is added to a mast cell C: Histamine released naturally from mast cells Free ratio

As a result of this test, the inhibition rate of histamine release of coenzyme Q ₁₀ (solid content: 0.01%) and control sodium cromoglycate (solid content: 0.01%) was 3 each.
It was 8.67% and 4.23%. Coenzyme Q ₁₀ and sodium cromoglycate itself did not affect histamine release.

[Example 2] Effect on hay fever The degree of symptom of hay fever was measured in the morning for 3 hours (9 to 12).
The number of times the nose was blown was evaluated. Five test subjects drank a commercially available soft capsule containing 30 mg of coenzyme Q ₁₀ (Cocure Blon: manufactured by Nisshin Pharma Co., Ltd.), one capsule each in the morning and evening (60 mg / day). The number of times before starting to drink and the number of times to blow the nose 7 days after starting to drink were compared. At the time of measurement, the subject's work environment was set to the same conditions. 2 people who have blown their noses less than half the number of 2 people who have blown their noses less than two-thirds less than 2 people who have blown their noses less than 4/5 less than 1 person All of them showed improvement in their symptoms and did not cause any particularly harmful symptoms at this time.

[Embodiment 3] Effect on hay fever The degree of symptom of hay fever was measured in the morning for 3 hours (9 to 12).
The number of times the nose was blown was evaluated. Five test subjects were given 1 capsule each after each meal (90 mg / day) of a commercially available soft capsule containing 30 mg of coenzyme Q ₁₀ (Cocure Blon: manufactured by Nisshin Pharma Co., Ltd.). The number of times before starting to drink and the number of times to blow the nose 7 days after starting to drink were compared. At the time of measurement, the subject's work environment was set to the same conditions. 3 people who have blown their noses less than half the number of people 3 people who have blown their noses less than 2/3 times 1 person Those who have blown their noses less than 4/5 times more than 1 person All of them showed improvement in their symptoms and did not cause any particularly harmful symptoms at this time.

[Example 4] Effect on hay fever The degree of symptom of hay fever was measured in the morning for 3 hours (9 to 12).
The number of times the nose was blown was evaluated. Five subjects were given consomme soup containing 50 mg of coenzyme Q ₁₀ at the morning and evening meals (100 mg / day). The number of times before starting to drink and the number of times to blow the nose 7 days after starting to drink were compared. At the time of measurement, the subject's work environment was set to the same conditions. 3 people who have blown their noses less than half the number of people 3 people who have blown their noses less than 2/3 times 1 person Those who have blown their noses less than 4/5 times more than 1 person All of them showed improvement in their symptoms and did not cause any particularly harmful symptoms at this time.

Example 5 Effect on Atopic Dermatitis A cream containing Coenzyme Q ₁₀ prepared according to the following formulation was applied daily to the affected areas of 3 patients with mild atopic dermatitis, followed by sunlight. I covered it with clothes to avoid hitting it. The appearance of the affected area after 2 weeks was evaluated. All had an improvement in their symptoms, such as 2 or more people with red patches and thin papules, and almost all of the papules disappeared. Preparation of cream containing coenzyme Q ₁₀ A Squalane 20 parts Olive oil 8 parts Refined beeswax 5 parts Glycerin monostearate 3 parts Cetostearyl alcohol 2 parts Coenzyme Q ₁₀ 2 parts B Polyoxyethylene hydrogenated castor oil 3 parts Glycerin 10 parts Purified water Appropriate amount 100 parts Solution A and solution B are heated to 80 ° C. Add A to solution B while stirring
The liquid was added, and the mixture was emulsified until it became uniform to obtain a cream.
Several days' worth was prepared fresh.

Example 6 Cream containing coenzyme Q ₁₀ A POE (20) sorbitan monostearate 2.0 parts POE (30) sorbitol tetraoleate 0.5 parts Glyceryl monostearate 0.5 parts stearic acid 7.0 parts Cetanol 3.0 parts Palmitic acid Cetyl 3.0 parts Paraffin 3.0 parts Jojoba oil 7.0 parts Coenzyme Q ₁₀ 0.5 parts B 1,3-butylene glycol 5.0 parts Total amount 100.0 parts with purified water A and B are dissolved by heating at 50 ° C, and A and B are added with stirring. Emulsify. The mixture was cooled to around room temperature with stirring to obtain a cream.

Example 7 Emulsion containing coenzyme Q ₁₀ A Squalane 4.0 parts Methylphenylpolysiloxane 4.0 parts Cetostearyl alcohol 1.0 part Isostearic acid 1.0 part Beeswax 0.5 parts Polyoxyethylene (60) sorbitol tetraoleate 0.3 parts Coenzyme Q ₁₀ 0.5 parts B glycerin 5.0 parts 1,3-butylene glycol 5.0 parts Total amount with purified water 100.0 parts Both A and B are dissolved by heating at 80 ° C, and B is added to A while stirring to emulsify. While stirring, the mixture was cooled to around room temperature to obtain an emulsion.

Example 8 Tablet Coenzyme Q ₁₀ 5 g Corn starch 10 g Lactose 40 g Carboxymethylcellulose calcium 8 g Microcrystalline cellulose 27 g Polyvinylpyrrolidone 7 g Magnesium stearate 3 g Total 100 g Coenzyme Q ₁₀ (manufactured by Nisshin Pharma Co., Ltd.) is dissolved in acetone, Then, this was adsorbed on microcrystalline cellulose and then dried. Corn starch, lactose, and carboxymethyl cellulose calcium were mixed with this, and then an aqueous solution of polyvinylpyrrolidone was added as a binder to granulate by a conventional method. Magnesium stearate as a lubricant was added thereto and mixed, and then compressed into tablets of 100 mg each.

[Example 9] Hard capsule Coenzyme Q ₁₀ 5 g Microcrystalline cellulose 60 g Corn starch 30 g Lactose 30 g Polyvinylpyrrolidone 4 g Magnesium stearate 1 g Total 130 g The above ingredients were granulated by a conventional method and then filled into a hard gelatin capsule.

Example 10 Powder Coenzyme Q ₁₀ 50 g Microcrystalline cellulose 600 g Corn starch 300 g Polyvinylpyrrolidone 50 g Total 1,000 g Coenzyme Q ₁₀ (manufactured by Nisshin Pharma Co., Ltd.) was dissolved in acetone, and this was adsorbed on microcrystalline cellulose and then dried. , Crushed. This was mixed with corn starch and polyvinylpyrrolidone and made into a powder by a conventional method.

[Example 11] Granule Coenzyme Q ₁₀ 0.5 g Lactose 130 g Corn starch 87 g Polyvinylpyrrolidone 8 g L-Menthol 15 g Light anhydrous silicic acid 5 g Coenzyme Q ₁₀ (manufactured by Nisshin Pharma Co., Ltd.), lactose, corn starch and polyvinylpyrrolidone The aqueous solutions were mixed, and heated and granulated with stirring with a granulator. After cooling, the particles were separated to a particle size of 500 μm or less, added with L-menthol, added with silicic acid anhydride and mixed (1.
0 g) to obtain granules.

[Example 12] Soft capsule edible oil (wheat germ oil: Nisshin Pharma Co., Ltd.) 250
g, Coenzyme Q ₁₀ (manufactured by Nisshin Pharma Co., Ltd.) 30
g and glycerin fatty acid ester (20 g) were dissolved at about 60 ° C. while blowing nitrogen, and the mixture was homogenized with Ajihomomixer, and then cooled to room temperature around 25 ° C. 30 parts by weight of glycerin was added to 100 parts by weight of gelatin, and the swollen and dissolved gelatin sheet was used to prepare 300 parts of the above oil phase containing coenzyme Q ₁₀ per capsule.
Soft capsules were produced by a punching method so that the content amount was 30 mg (corresponding to 30 mg of coenzyme Q ₁₀ ).

Example 13 Consomme Soup A commercially available consomme soup (about 100 ml) was heated to a temperature suitable for drinking. Coenzyme Q ₁₀ in this one 3
Put 1 capsule of 0 mg containing soft capsule (coke vullon: Nisshin Pharma Co., Ltd.), stir with a spoon,
The encapsulant was dissolved to obtain a consomme soup containing coenzyme Q ₁₀ .

[Example 14] Salad dressing 100 ml of commercially available salad oil was heated to about 60 ° C, and 1.0 g of Coenzyme Q ₁₀ (manufactured by Nisshin Pharma Co., Ltd.) was added thereto.
Was added with stirring to dissolve, and cooled to room temperature. 1 g of salt was dissolved in 50 ml of vinegar, sprinkled with a small amount of pepper, added to the salad oil in which the above-mentioned coenzyme Q ₁₀ was dissolved, and stirred well to obtain a salad dressing.

Example 15 A bathing agent was prepared by blending 5 g of bathing agent, Coenzyme Q ₁₀ (manufactured by Nisshin Pharma Co., Ltd.), 10 g of surfactant, 25 g of glycerin, and 10 g of purified water. Further, Coenzyme Q ₁₀ aqueous solution 10S (manufactured by Nisshin Pharma Co., Ltd.) can be used as a bathing agent. Coenzyme Q ₁₀ formulations of bath agent whereas Yokuyuyaku 200L, coenzyme Q ₁₀ is used by adding to a concentration 0.000001% to 0.001%.

[0033] Put sugar, starch syrup, and water in a pan to boil and dissolve them, and after the boiling temperature reaches 125 ° C, remove from the heat, spice, coenzyme Q ₁₀ (CoQ ₁₀ water-solubilized solution 10S, Nisshin Pharma Co., Ltd.) Manufactured) was added. The mixture was poured into a cooling plate with stirring, cooled to 80 ° C., and then cut into a suitable length to obtain 3.33 g of candy per grain.
This candy is Coenzyme Q ₁₀ 10 per grain
It contained mg.

[0034] Put the gum base in a kneader, dissolve and stir it at about 120 ° C., cool it to 50 ° C., put it in a mixer, and add the reduced maltose, reduced maltose starch syrup, softener, dye, flavor, coenzyme Q _{10 to} the gum base during mixing. (CoQ ₁₀
Water-solubilized powder 5%, manufactured by Nisshin Pharma Co., Ltd.) was added at the above mixing ratio, and this was extruded into a sheet by an injection molding machine and rolled, and 3.3 g per sheet was cut by a cutting machine. I got chewing gum. Each chewing gum contained ₁₀ mg of coenzyme Q ₁₀ .

[Example 18] Chocolate containing coenzyme Q ₁₀ Cocoa bitter 20 g Cocoa butter 16.6 g Sugar 40 g Whole milk powder 20 g CoQ ₁₀ aqueous solution 3.0 g Emulsifier 0.2 g Flavor (vanilla flavor) 0.2 g 100.0 g Chocolate The cocoa mass, cocoa butter, powdered sugar, lecithin, whole milk powder, fragrance, emulsifier and coenzyme Q ₁₀ (CoQ ₁₀ aqueous solution 10S, manufactured by Nisshin Pharma Co., Ltd.) are mixed at the following mixing ratios according to a standard method. And mix it with a mixer,
After finishing refining and conching, tempering was performed. Then, it was cast, subjected to a cooling step and a cutting step to obtain 3.33 g of chocolate per grain. This chocolate contained ₁₀ mg of coenzyme Q ₁₀ per grain.

[0036]

EFFECTS OF THE INVENTION The compound of the present invention has a strong mast cell histamine release inhibitory action and has no drowsiness inducing action or skin stimulating action. Therefore, bronchial asthma, allergic rhinitis, urticaria, atopic dermatitis. , Contact dermatitis, eczema,
It can be used for the prevention or treatment of allergic diseases such as allergic ophthalmitis and hay fever.

[Brief description of drawings]

FIG. 1 is a graph showing the histamine release inhibitory effect, wherein the upper row shows sodium cromoglycate and the lower row shows coenzyme Q.
The results of ₁₀ inhibitory effects are shown.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4B017 LC03 LK23                 4B018 MD90 ME07                 4C206 AA01 AA02 CB27 MA01 MA04                       MA72 NA14 ZB13

Claims (8)

[Claims] 1. A compound represented by the general formula (I): (In the formula, n represents an integer of 4 to 12) a prophylactic or therapeutic agent for allergic diseases coenzyme Q _n or compounds as an active ingredient in vivo be converted to coenzyme Q _n is expressed by. 2. A histamine release inhibitor comprising as an active ingredient a compound in claim 1, wherein the coenzyme Q _n or in vivo may be converted to coenzyme Q _n. 3. A compound capable of converting coenzyme Q _n or within a living body coenzyme Q _n is the prevention of allergic diseases according to claim 1, wherein the compound capable of converting into coenzyme Q ₁₀ in coenzyme Q ₁₀ or in vivo, or Therapeutic agent. 4. A food or drink for preventing or treating according to claim 1, wherein the coenzyme Q _n or allergic diseases which contains a compound in vivo may be converted to coenzyme Q _n. 5. The compound capable of converting into coenzyme Q _n in coenzyme Q _n or in vivo, according to claim 4, wherein the food or drink is a compound capable of converting into coenzyme Q ₁₀ in coenzyme Q ₁₀ or in vivo. 6. A health food for preventing or treating allergic diseases containing a compound in claim 1, wherein the coenzyme Q _n or in vivo may be converted to coenzyme Q _n. 7. A compound capable of converting into coenzyme Q _n in coenzyme Q _n or in vivo, health food according to claim 6, wherein the compound capable of converting into coenzyme Q ₁₀ in coenzyme Q ₁₀ or in vivo. 8. The cosmetic for the prevention or treatment of allergic diseases containing a compound in claim 1, wherein the coenzyme Q _n or in vivo may be converted to coenzyme Q _n.