JP2000319177A - Stress alleviating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a stress alleviating agent capable of alleviating stress, and useful for treating or preventing various psychological diseases attributable to stress by formulating biotin and a specific amino acid. SOLUTION: This stress alleviating agent contains (A) biotin and (B) an amino acid of one or more kinds selected from histidine, arginine, methionine and glutamic acid. The effective dose of the component A for a healthy adult is 10-10,000, preferably 50-1,500 μg/day. The compounding amount of the component B is 1-200 pts.wt. based on 1 pt.wt. of biotin, and for each amino acid, the compounding amount of histidine, arginine, methionine or glutamic acid is preferably 10-80 pts.wt., 5-70 pts.wt., 5-150 pts.wt. or 5-70 pts.wt., respectively, based on 1 pt.wt. of biotin. The agent is preferably formulated into an oral liquid of pH 2-6.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a stress improving agent. More specifically, the present invention relates to a stress ameliorating agent containing biotin and a specific amino acid, relieving stress, and exerting excellent therapeutic and preventive effects on various mental disorders caused by stress.

[0002]

2. Description of the Related Art Modern people are exposed to various stresses in all living environments, such as workplaces, schools and homes, and suffer from mental illness caused by these stresses.

[0003] On the other hand, a large number of nutritional supplements and nutritional tonics have been provided for the purpose of improving physical fatigue, anorexia, nutritional disorders and the like. At present, sufficient therapeutic and preventive effects have not been exerted on neurological disorders, anorexia, nutritional disorders, and the like caused by stress, and there is no other effective treatment.

[0004] Therefore, there is an urgent need for the development of a drug that relieves stress and contributes to the treatment and prevention of mental disorders caused by stress.

[0005]

An object of the present invention is to provide a stress ameliorating agent which is effective in relieving stress and treating and preventing various mental disorders caused by stress.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a composition containing biotin and a specific amino acid can alleviate stress and cause a mental disorder caused by stress. Has a remarkable improvement effect on

[0007] The present invention, which has been completed based on the above findings, comprises a stress ameliorating agent characterized by containing, as an active ingredient, biotin and one or more amino acids selected from the group consisting of histidine, arginine, methionine and glutamic acid. It is.

[0008] Biotin is one type of coenzyme known as vitamin H, and is known to act as an essential coenzyme of four kinds of carboxylases in a living body. In addition, there is a report on a fatigue improving agent containing biotin as an active ingredient (Japanese Patent Application Laid-Open No. Hei 6-305963).
No.), there has been no report that a combination of biotin and an amino acid has a stress relieving effect.

In the present invention, the effective dose of biotin is 10 μg to 10000 μg, preferably 50 μg to 1500 μg per day for a healthy adult.

[0010] The amino acid of the present invention is an amino acid which is effective for treating and preventing psychiatric diseases by relieving stress by being combined with biotin. Such amino acids include histidine, arginine, methionine and glutamic acid. Applicable.

In the present invention, the amount of the amino acid is 1 to 200 parts by weight per 1 part by weight of biotin. The specific amino acids are listed as follows. 1 part by weight of biotin, 10 parts with histidine
-80 parts by weight, 5-70 parts by weight for arginine, 5-150 parts by weight for methionine, 5-70 parts by weight for glutamic acid
It is preferable to mix parts by weight. These amino acids may be used alone or in combination of two or more in the composition.

In the present invention, water-soluble vitamins such as vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, folic acid, carnitine, pantothenic acid and nicotinic acid, vitamins, etc. A,
Fat-soluble vitamins such as vitamin E and vitamin D, xanthine derivatives such as caffeine, crude drugs such as ginseng and ground yellow,
Minerals such as calcium and magnesium can be blended within a range that does not impair the effects of the present invention.

[0013] Here, stress refers to a functional change that occurs in the mind and body when various external stimuli act as a burden, and factors that cause this are physicochemical things such as cold and heat, noise, chemical substances, starvation and infection. -Biological things such as overwork and lack of sleep, and social things such as mental tension, anxiety, fear and excitement.

The stress ameliorating agent of the present invention relieves such stress and treats various psychiatric disorders caused by stress, such as stress-induced neuropathy, anorexia, nutritional disorders, and febrile wasting diseases. It has excellent therapeutic and preventive effects.

The stress improving agent of the present invention can be formulated into various preparations such as liquid preparations and solid preparations by a conventional method.
For example, in the case of a liquid preparation for internal use, the pH is preferably in the range of 2 to 6 in order to stably maintain biotin and maintain the stress relieving effect of the present invention for a long period of time.

The stress improving agent of the present invention may contain, if necessary, other known additives such as excipients, pH adjusting agents, cooling agents, suspending agents, defoaming agents, thickening agents, A dissolution aid, a disintegrant, a binder, a lubricant, an antioxidant, a coating agent, a colorant, a bridge taste odorant, a surfactant, a plasticizer, a fragrance, and the like can be blended.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION

[0018]

The present invention will be described in more detail with reference to the following Examples and Test Examples.

Example 1 Biotin 75 μg L-Histidine hydrochloride 85 mg Vitamin B ₁ (thiamine nitrate) 5 mg Vitamin B ₂ (sodium riboflavin phosphate) 5 mg Vitamin B ₆ (pyridoxine hydrochloride) 5 mg Nicotinamide 20 mg Inositol 50 mg Carnitine chloride 50 mg Potassium aspartate 100 mg Magnesium aspartate 100 mg Calcium aspartate 200 mg Taurine 2000 mg Anhydrous caffeine 50 mg Citric acid 800 mg Sodium citrate Appropriate amount (pH 2.5) Sucrose 10,000 mg The above components are mixed and dissolved in purified water to obtain a total volume of 100 mL. Was.

(Example 2) Biotin 200 μg L-histidine hydrochloride 105 mg Vitamin B ₁ (thiamine nitrate) 10 mg Vitamin B ₂ (riboflavin sodium phosphate) 5 mg Vitamin B ₆ (pyridoxine hydrochloride) 5 mg Nicotinamide 30 mg Carnitine chloride 100 mg Pantothenic acid Calcium 100mg Ginseng extract-M 600mg Deer mushroom tincture 14mg Gummy ginkgo extract 200mg Beef yellow tincture 1mg Royal jelly 200mg Taurine 2000mg Anhydrous caffeine 50mg Citric acid 800mg Sodium chloride 294mg Sodium benzoate 30mg Nichol HCO60 200mg PVP Sugar acid .2) Mix and dissolve each of the above components in purified water. To obtain a liquid formulation of 0mL.

Example 3 Biotin 75 μg L-arginine hydrochloride 200 mg L-methionine 115 mg Vitamin B ₁ (thiamine nitrate) 10 mg Vitamin B ₂ (riboflavin sodium phosphate) 5 mg Vitamin B ₆ (pyridoxine hydrochloride) 5 mg Nicotinamide 20 mg Chloride Carnitine 50 mg Taurine 2000 mg Anhydrous caffeine 50 mg Citric acid 800 mg Sucrose 10,000 mg Sodium citrate Appropriate amount (pH 2.5) Each of the above components was mixed and dissolved in purified water to obtain a 50 mL solution in total.

Example 4 Biotin 200 μg L-histidine 100 mg L-glutamate sodium 30 mg L-arginine hydrochloride 200 mg L-methionine 115 mg Vitamin B ₁ (thiamine nitrate) 8 mg Vitamin B ₂ (riboflavin sodium phosphate) 5 mg Vitamin B ₆ ( Pyridoxine hydrochloride) 5 mg Nicotinamide 20 mg Carnitine chloride 50 mg Inositol 50 mg Taurine 2000 mg Anhydrous caffeine 50 mg Citric acid 800 mg Sucrose 10,000 mg Malic acid Suitable amount (pH 2.8) The above components were mixed and dissolved in purified water to obtain a total volume of 50 mL. Was.

Example 5 Biotin 200 μg L-Histidine Hydrochloride 200 mg L-Arginine Hydrochloride 200 mg L-Methionine 115 mg Carrot Extract-M 90 mg (raw drug equivalent 600 mg) Jiao Extract-A 50 mg (raw drug equivalent 300 mg) Epimedium extract 100 mg (raw material) Citrus extract 1000mg Cistanche extract 91mg (API equivalent 300mg) Licorice extract 25mg (API equivalent 100mg) Bakuryo extract-A 8mg (API equivalent 250mg) Muirapuama extract-A 23mg (API equivalent 450mg) Hampitinki 2mg (Original) Crude drug equivalent 400mg) Rokujo tincture 1.1mg (crude drug equivalent 300mg) Tokyu Ryu extract 0.3mg (crude drug equivalent 300mg) Ougiryu extract 0.3mg (crude drug equivalent 300mg) Eucommia Yuushutsueki 0.3 mg (original crude drug terms 300 mg) Gomishiryuekisu 0.2 mg (original crude drug terms 200 mg) silicate Hiryo extract 0.2 mg (original crude drug terms 200 mg) Cordyceps sinensis liquid extract 0.33 mL (original crude drug terms 330 mg) VB ₂ (riboflavin phosphate Sodium) 5 mg VB ₆ (pyridoxine hydrochloride) 5 mg Taurine 500 mg Anhydrous caffeine 50 mg Sucrose 10,000 mg Sodium benzoate 30 mg Sodium citrate 50 mg Nichol HCO60 200 mg PVP K90 200 mg Citric acid Appropriate amount (pH 4.6) Dissolve the above components in purified water Thus, a total amount of 50 mL of the liquid preparation was obtained.

Example 6 Biotin 200 μg Sodium L-Glutamate 80 mg L-Arginine Hydrochloride 200 mg L-Methionine 115 mg Vitamin B ₁ (Thiamine nitrate) 10 mg Carrot extract-M 90 mg (equivalent to the crude drug 600 mg) Jio extract-A 50 mg (the crude drug) Epimedium extract 100 mg (Natural drug equivalent 1000 mg) Cistanche salsa extract 91 mg (Natural drug equivalent 300 mg) Licorice extract 25 mg (Natural drug equivalent 100 mg) Bakuryo extract-A 8 mg (Natural drug equivalent 250 mg) Muirapuama extract-A 23 mg (Original) Crude drug equivalent 450mg) Hampi tincture 2mg (crude drug equivalent 400mg) Rokujo tincture 1.1mg (crude drug equivalent 300mg) Tokyu Ryu extract 0.3mg (crude drug equivalent 300mg) Ougiryu S 0.3 mg (300 mg of crude drug equivalent) Eucommia persicae 0.3 mg (300 mg of crude drug equivalent) Gomi-silyu extract 0.2 mg (200 mg of crude drug equivalent) Cauliflower extract 0.2 mg (200 mg of crude drug equivalent) (330 mg in terms of crude drug) VB ₂ (sodium riboflavin phosphate) 5 mg VB ₆ (pyridoxine hydrochloride) 5 mg Taurine 500 mg Anhydrous caffeine 50 mg Sucrose 10,000 mg Sodium benzoate 30 mg Sodium citrate 50 mg Nikkor HCO60 200 mg PVP K90 200 mg Citric acid 6.6) The above components were mixed and dissolved in purified water to obtain a 50 mL liquid solution in total.

Test Example 1 It is known that there is a correlation between stress fatigue and blood corticosterone and amino acid concentrations. That is, when stress is applied to a small animal such as a rat or a mouse, the amino acid concentration or the like in the blood of the animal increases. Therefore, a method of evaluating the degree of stress by measuring the amino acid concentration or the like in the blood has been reported. (Japanese Patent Application No. 10-117267).

Therefore, the present inventors applied a psychological stress to rats using a communication box as described below, and administered rats and rats administered with a stress-ameliorating agent containing biotin of the present invention and a specific amino acid. With respect to rats that did not, the changes in blood corticosterone and amino acid concentrations were measured to evaluate the stress improving effect of the present invention.

(Loading of Stress) The present inventors performed psychological stress loading using a communication box according to the method of Ogawa et al. (Biosci. Biotech. Bioche).
m., 59 (4) 731-734, 1995). Here, the communication box is a box divided into 25 sections by a transparent wall, and the floor is made of stainless steel for applying electric shock.
A box made of a steel grid. Rats are placed in each section of the communication box and an electric shock is applied from the floor.The floor of a certain section is covered with a plastic plate. Did not work. Therefore, the rats in this compartment are not directly shocked, but are exposed to emotional reactions such as struggling, squealing, jumping, defecation, etc., and experiencing psychological stress. This situation was originally devised for the purpose of setting anxiety on the basis of emotional communication.Electric shocked rats send emotions and are called senders. Rats exposed to an emotional response are called responders.
By placing the rats in the psychological stress group in the same time zone communication box as the rats in the control group,
Rats in a psychological stress state are in a state of considerable freezing (freezing), and it is considered that emotions close to anxiety and fear are evoked.

The present inventors used SD rats (male, 7 weeks old) and used 0.017 mM biotin + 40 mM L-histidine hydrochloride aqueous solution, 0.017 mM biotin + 40 mM L-arginine hydrochloride aqueous solution, 0.017 mM biotin aqueous solution, 40 mM and 80 mM-hydrochloric acid. A histidine aqueous solution, 40 mM and 80 mM L-arginine hydrochloride aqueous solution and water (6 animals in each group) were orally administered by 2 ml each. Immediately thereafter, psychological stress was applied by the communication box. Immediately after that, blood was collected from the inferior vena cava of the rats in each group, and the concentrations of serum corticosterone and serum amino acids were measured. The load voltage applied to the sender group (N = 12) on the side receiving the electric shock and sending the emotion was 2.5 mA × 5 seconds, and 120 seconds was absent for 3 consecutive hours.

(Measurement of Corticosterone and Amino Acid Concentrations) The corticosterone and amino acid concentrations in the collected blood were measured by the following procedure. First, the collected blood is centrifuged (1,800 × g, 10 minutes),
Prepared to obtain serum. Serum corticosterone was prepared by placing serum in a centrifuge tube with a lid, adding 30 ng / ml dexamethasone internal standard solution using a microsyringe, and mixing well. After standing for 10 minutes, 0.25 M sodium hydroxide was added and mixed well. Further, after standing for 10 minutes, dichloromethane was added, the centrifuge tube was covered, and the mixture was vigorously stirred for 1 minute with a vortex. Then, centrifugation (1,800 × g,
After centrifugation, the upper layer was removed using a Pasteur pipette. The dichloromethane layer was transferred to a vial bin and evaporated to dryness on a centrifugal evaporator. After drying,
58% methanol was added, and the residue was dissolved to prepare a sample for injection. High-performance liquid chromatography (detector: JASCO Corporation UV-970 Intelligent UV /
VIS Detector, pump: JASCO Corporation PU-980 Intell-
igent HPLC Pump, Column: Shim-pack CLC-ODS (6mm × 15
0Mm), (absorbance detector parameters, WAVE: 248nm, RANG
E: 0.1 ~ 0.01, RESPONSE STD) (pump parameters,
FLOW RATE 1.0ml / min, P.MAX200kgf / cm ² P.MIN0kgf / c
m ² )). Serum 3-methylhistidine is
An equivalent amount of 3% sulfosalicylic acid was added to the serum, mixed well, and left overnight at 4 ° C. Then, centrifugation (11,
600 × g, 10 minutes, 4 ° C.), and the obtained supernatant is filtered with a filter (TOYO cellulose acetate 0.45 μm). The concentration of the amino acid was measured using an amino acid analyzer (HITACHI L-8500, Hitachi, Ltd.).
The result is shown in FIG. In addition, serum alanine, taurine, valine and lysine were added with an equal amount of 3% sulfosalicylic acid to the serum, mixed well, and allowed to stand at 4 ° C. overnight. Then, centrifugation (11,600 × g, 10 minutes,
4 ° C) and filter the resulting supernatant (TOYO cellulo
The filtrate is put into an insert tube, a spring and a tube are set in a micro vial, a cap with a hole is closed, and an amino acid analyzer (HITACHI L-8500, manufactured by Hitachi, Ltd.) is used. Amino acid concentrations were measured. The result is shown in FIG.

(Results) When psychological stress was applied to the test rats, the concentrations of corticosterone, 3-methylhistidine, taurine, leucine, isoleucine, valine and alanine in the blood were significantly changed, but 0.017 m
M biotin + 40 mM L-histidine hydrochloride aqueous solution and 0.017 mM
Administration of biotin + 40 mM L-arginine hydrochloride aqueous solution showed no significant change in blood corticosterone, 3-methylhistidine, taurine, leucine, isoleucine, valine and alanine concentrations even when psychological stress was applied. I couldn't.

[0031]

Industrial Applicability According to the present invention, it has become possible to provide a stress ameliorating agent which relieves stress and effectively acts on treatment and prevention of mental disorders caused by stress.

[Brief description of the drawings]

[Fig. 1] 0% for rats subjected to psychological stress.
017 mM biotin + 40 mM L-histidine hydrochloride aqueous solution and
It is the graph which showed the concentration change of blood corticosterone and 3-methyl histidine when 0.017 mM biotin +40 mM L-arginine hydrochloride was administered.

[Fig. 2] 0% for rats subjected to psychological stress.
017 mM biotin + 40 mM L-histidine hydrochloride aqueous solution and
It is the graph which showed the density | concentration change of the blood taurine, leucine, isoleucine, valine and alanine when 0.017 mM biotin +40 mM L-arginine hydrochloride was administered.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kyoko Taguchi 3-24-1, Takada, Toshima-ku, Tokyo Inside Taisho Pharmaceutical Co., Ltd. (72) Inventor Kiyotaka 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Toshiaki Nakajima 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. F-term (reference) 4C086 AA01 AA02 BC38 CB28 MA02 MA17 MA52 NA03 ZA18 4C206 AA01 AA02 FA44 MA02 MA37 MA72 ZA18

Claims (3)

[Claims] 1. A stress ameliorating agent comprising, as active ingredients, biotin and one or more amino acids selected from the group consisting of histidine, arginine, methionine and glutamic acid. 2. One or two selected from the group consisting of histidine, arginine, methionine and glutamic acid.
The stress improving agent according to claim 1, wherein the compounding amount of at least one kind of amino acid is 1 to 200 parts by weight based on 1 part by weight of biotin. 3. The stress ameliorating agent according to claim 1, which is an oral liquid preparation having a pH in the range of 2 to 6.