JP6800404B2 - Autonomic regulator - Google Patents

Description

The present invention relates to an autonomic nerve regulator.

The autonomic nervous system is composed of the sympathetic nervous system and the parasympathetic nervous system, and the balance between these two nervous systems controls the functions of blood vessels and internal organs, regulates the internal environment, and also respiration, blood circulation, digestion and absorption. It regulates the systems of excretion, endocrine system, heat production, etc., and plays a role in adjusting the internal circulation necessary for life support. When the sympathetic nervous system and parasympathetic nervous system are out of balance due to aging, poor physical condition, illness, stress, fatigue, etc., headache, nausea, tinnitus, slight fever, tremors, tinnitus, dizziness, vasoconstriction, fatigue and sweat become abnormal. Symptoms such as tinnitus appear. Also, mentally, it causes misanthropy, emotional instability, anxiety and irritability, and depressed mood.

Among the autonomic nerves, those that regulate the sympathetic nerve include odor stimulation by methyl 2-methoxybenzoate (Patent Document 1) and ingestion of an oral sympathetic nerve activator including Viburnum dilatatum of the family Viburnum dilatatum. Activation of sympathetic nerve activity and increase of blood flow (Patent Document 2), improvement of drowsiness by sympathetic nerve activation action of orotic acid or a salt thereof, increase in body temperature, promotion of lipolysis, or maintenance of concentration (Patent Document 3). Etc. are known.

JP 2015-221808 Japanese Unexamined Patent Publication No. 2013-194019 Japanese Unexamined Patent Publication No. 2012-126683

However, the autonomic nervous regulation effect of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one is not known. In addition, since the effect of autonomic nerve regulation differs depending on whether the nervous system of the sympathetic nervous system or the parasympathetic nervous system is activated or suppressed, more detailed treatment is performed according to various symptoms and purposes. In addition, the development of new autonomic nerve regulators is required.

An object of the present invention is to provide an autonomic nerve regulator that activates the function of the sympathetic nervous system.

The inventors of the present application have found that 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one activates the sympathetic nervous system, and completes the present invention. It came to. That is, the present invention includes the following.

(1) An autonomic nerve regulator containing 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one as an active ingredient.

(2) A sympathetic nerve activator containing 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one.

(3) A composition for autonomic nerve regulation, which comprises 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one as an active ingredient.

(4) A composition for sympathetic nerve activation, which comprises 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one.

(5) A food for autonomic nervous regulation, which comprises 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one as an active ingredient.

(6) A food for sympathetic nerve activation, which comprises 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one.

By using the autonomic nerve regulator of the present invention, it is possible to improve the disorder of the autonomic nerve, especially when the parasympathetic nervous system is relatively dominant. In addition, by regulating the autonomic nerves, in particular, prevention and / or improvement of fatigue of waking up, prevention and / or improvement of allergic symptoms such as dizziness, sneezing and runny nose, prevention and / or improvement of depression symptoms, prevention and / or of jet lag. It can be used for the purpose of improvement.

The time course of brown adipose tissue sympathetic nerve activity (BAT-SNA) of mice is shown.

Hereinafter, embodiments of the present invention will be described.

2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one (hereinafter, also referred to as "Compound 1") used in the present invention is a derivative of benzopyran. As the compound 1, a crushed product of a plant containing the same, the squeezed juice itself, or a dried product thereof may be used, or an extract or a purified product from the plant may be used. Further, a compound obtained by synthesis, a commercially available reagent, or the like may be used. In the present invention, the extract is preferable because the concentration of the active ingredient is high and it is easily available.

When extracting a compound from a plant, the extraction operation is not limited to one time, and the extraction operation may be repeated by adding a solvent to the extraction residue. At this time, different solvents can be used. Further, the extract of the plant containing compound 1 may be the extract itself obtained from the plant by an extraction operation, and is a concentrate (concentrated extract) or a dried product (dried extract) obtained by removing the solvent from the extract. However, it may be. Further, the extract may be an extract (purified product) obtained by adding purification to the extract obtained by the extraction operation. The purification method is not particularly limited, and may be purification using, for example, liquid-liquid distribution using two or more kinds of solvents or chromatography using an adsorbent (for example, column chromatography or high performance liquid chromatography).

The extraction solvent is not particularly limited and can be appropriately selected by those skilled in the art. The extraction solvent may be water, an organic solvent, or a mixture of water and an organic solvent. The organic solvent may be either a hydrophilic solvent or a lipophilic solvent. The organic solvent is, for example, hydrophilic alcohols having 4 or less carbon atoms such as methanol, ethanol, propyl alcohol, isopropyl alcohol, and butyl alcohol, and lipophilic alcohols having more carbon atoms, such as methyl ether and ethyl. It may be an ether such as ether, a hydrocarbon such as hexane or heptan, or a polyhydric alcohol such as ethylene glycol, propylene glycol, 1,3-butylene glycol or glycerin. Of these extraction solvents, one solvent or a mixed solvent of two or more is used for extraction. In the present invention, a solvent from which flavones are easily extracted is preferably selected. From this viewpoint, the extraction solvent is preferably one or a mixture of two or more hydrophilic solvents such as water, ethanol, and methanol.

Since the autonomic nerve regulator of the present invention activates the sympathetic nervous system, it activates the sympathetic nerve, in particular, prevents and or improves fatigue of waking up, and prevents and or improves allergic symptoms such as dizziness, sneezing, and runny nose. It can be given to animals or humans for the purpose of prevention and / or improvement of depressive symptoms, prevention and / or improvement of sneezing.
In addition, through the regulation of autonomic nerves, it becomes possible to adjust the daily rhythm, which may be accompanied by a body temperature raising action, a hypothermia improving action, or a dieting action.
Contrary to the present invention, as a substance that activates parasympathetic nerves, for example, pilocarpine hydrochloride is effective as a parasympathetic nerve stimulant for the treatment of old eyes (Japanese Patent Laid-Open No. 2010-513454), and phenyllactic acid is used. It is known that it is effective in treating or improving high blood pressure (WO2008 / 120713), and that γ-aminobutyric acid and glycine are effective in improving sleep (WO2007 / 125883), and activate parasympathetic nerves. Is known to have an action different from that of sympathetic nerve activation.

The autonomic nerve regulator of the present invention can be used as it is or mixed with other components as a parenteral administration agent, an oral administration agent, etc., depending on the above-mentioned purpose. As the parenteral administration agent, an intravenous administration agent, an intramuscular administration agent, a subcutaneous administration agent, a transdermal administration agent, and the like are used. It may be an intraperitoneal administration agent, which is one of the subcutaneous administration agents. Further, as an enteral administration agent, it is also preferable to directly administer it to the internal organs by injection or the like.

In addition, the autonomic nerve regulator of the present invention can also be used as a form suitable for cosmetics. For example, it can be processed into various forms such as lotions, emulsions, gels, creams and ointments. Specifically, it can be used as a lotion, a cosmetic cream, a milky lotion, a cream, a pack, a hair tonic, a hair cream, a shampoo, a hair rinse, a treatment, a facial cleanser, a foundation, a hair restorer, an aqueous ointment, a spray and the like.

Further, the autonomic nerve regulator of the present invention may be a parenteral administration agent from the viewpoint of preventing degeneration, but it is difficult to denature even by exposure to gastric juice or the like, so that a sufficient effect can be obtained as an oral administration agent. be able to. Examples of the orally administered agent include tablets, granules, powders, capsules and the like. As tablets or encapsulations, it is preferable to increase the amount that reaches the internal organs as it is.

As the orally-administered agent, for example, an additive (for example, an excipient or the like) usually used by those skilled in the art may be used to form a tablet, granules or the like, or it may be dissolved in water, a beverage or the like. It may be used as a liquid agent. It is preferably in the form of capsules, granules, tablets and the like.

As a method for producing a capsule, a conventionally known method for producing a soft capsule may be followed, except that the autonomic nerve regulator of the present invention is used as the content. Examples of such a manufacturing method include a method of encapsulating the contents with a rotary filling machine using a capsule film sheet and molding a capsule preparation, a method of manufacturing seamless capsules by a dropping method, and the like.

As for tablets, known tableting is performed by adding an appropriate binder, excipient, disintegrant and, if necessary, a lubricant to the granule or extract itself containing the autonomic nerve regulator of the present invention. It can be prepared by the method. For the granules, various known wet and dry granulation methods can be applied, and the granules can be molded together with an appropriate binder and excipient.

When the autonomic nerve regulator of the present invention is added to foods and used, for example, in beverages, granules, fine granules, capsules, tablets, powders, dairy products, gums, gummies, puddings, bars, and other solid foods. It is mixed. Foods containing the compound can be used as foods for specified health use, dietary supplements, foods with functional claims, foods for the sick, and the like, in addition to general foods.

The amount of the autonomic nerve regulator of the present invention is not particularly limited, but if it is an orally administered agent, it is preferably 0.00001% or more, more preferably 0.0001% or more in the composition. It is desirable that a parenteral administration agent such as cosmetics is preferably blended in the composition in an amount of 0.000001% or more, more preferably 0.00001% or more.

The daily dose of compound 1 used in the present invention is preferably 10 mg to 500 mg, more preferably 20 mg to 300 mg, and particularly preferably 30 to 150 mg if it is an orally administered agent.

Next, the invention of the present application will be described in more detail based on examples, but the invention of the present application is not limited thereto.

(Test substance)
Compound 1 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one as an example, and 2- (3,4-dimethoxyphenyl)-as a comparative example. A sympathetic nerve activity evaluation test was conducted using 3,5,7-trimethoxy-4H-1-benzopyran-4-one (hereinafter, also referred to as "Compound 2") using commercially available reagents. Compound 2 is a compound having a different number of methoxy groups (-OCH ₃ ) from compound 1.

(Sympathetic nerve activity evaluation test)
A Wistar male rat (about 9 weeks old) weighing about 300 g and bred in a homeothermic chamber at 24 ° C. for 1 week or more under a light-dark cycle (lights up from 8:00 to 20:00) every 12 hours was used. On the day of the experiment, after fasting for 3 hours, urethane anesthesia was performed, a cannula for duodenal administration was inserted, and then the distal branch of the interscapular brown adipose tissue sympathetic nerve was lifted with a silver electrode, and the electrical activity of the nerve was measured. When these measured values settled down, as Example 1, 1 ml of an aqueous suspension containing compound 1 at a concentration of 30 mg / ml was administered to the duodenum, and changes in autonomic nervous activity were electrophysiologically measured. As a control experiment, 1 ml of water was administered as a control, or 1 ml of a water suspension containing Compound 2 at a concentration of 30 mg / ml as Comparative Example 1 was administered to the duodenum, respectively, and changes in autonomic nervous activity were observed as in Example 1. Was measured electrophysiologically. In each test group, a tube was inserted into the trachea from the start of surgery to the end of measurement to secure the airway, and the body temperature (rat rectal temperature) was maintained at 35.0 ± 0.5 ° C. with a heat retaining device. The data of autonomic nerve activity in each test group was analyzed by the average value of firing frequency (pulse / 5s) per 5 seconds every 10 minutes, and the value before the start of stimulation (0 minute value) was set to 0 and the change value was taken as the value. expressed.

FIG. 1 shows the time course of brown adipose tissue sympathetic nerve activity (BAT-SNA) in mice by a solution diluted 100-fold, 1000-fold, and 10000-fold with 60% ethanol. FIG. 1 shows the change value of the brown adipose tissue sympathetic nerve activity (BAT-SNA) data of Example 1, Control and Comparative Example 1 as 0 before duodenal administration (0 minutes). It is a representation.

In FIG. 1, in Example 1, BAT-SNA gradually increased, and the change value of BAT-SNA reached the maximum value + 15.37 60 minutes after administration. On the other hand, in the control, BAT-SNA hardly changed during the measurement period, and in Comparative Example 1, the change value of BAT-SNA became negative during the entire measurement period after administration, and BAT-SNA 60 minutes after administration. The change value of was the lowest value of -15.74.

From the above experiments, it was clarified that administration of 1 ml of an aqueous suspension containing Compound 1 at a concentration of 30 mg / ml to the duodenum has an effect of increasing BAT-SNA. On the other hand, it was revealed that administration of 1 ml of a water suspension containing compound 2 at a concentration of 30 mg / ml to the duodenum has an effect of suppressing sympathetic nerve activity. From the above, compound 1 can regulate the autonomic nerves, and by the sympathetic nerve activating action, it prevents and or improves fatigue in particular, and prevents and or improves allergic symptoms such as dizziness, sneezing and runny nose. It was suggested that it has the effect of preventing and / or ameliorating depressive symptoms and preventing and / or ameliorating time lag.

Hereinafter, formulation examples relating to specific aspects of the composition of the present invention will be shown, but the present invention is not limited to these formulation examples, and the present invention has various aspects as long as the problems of the present invention can be solved. Can be taken.

(Formulation example 1: Toner)
Taking the whole as 100 parts by mass, 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 0.01 parts by mass, glycerin 10 parts by mass, diglycerin 3 parts by mass, 1,3-butylene glycol 12 parts by mass, pentylene glycol 3 parts by mass, sodium hyaluronate 0.1 parts by mass, citric acid 0.01 parts by mass, sodium citrate 0.02 parts by mass, xanthan gum 0.1 parts by mass, The composition of the present invention was prepared in the form of a lotion by mixing 0.15 parts by mass of methylparaben, 0.2 parts by mass of carbomer, 0.03 parts by mass of sodium hydroxide and the balance of water.

(Formulation example 2: shampoo)
With 100 parts by mass as a whole, 0.01 parts by mass of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 7.5 parts by mass of sodium laureth sulfate, cocamide 4.2 parts by mass of propylbetaine, 3 parts by mass of cocamide DEA, 0.1 parts by mass of 1,3-butylene glycol, 0.225 parts by mass of polyquaternium-10, 0.15 parts by mass of citric acid, 0.05 parts by mass of sodium citrate. The composition of the present invention was prepared in the form of shampoo by mixing parts, 0.9 parts by mass of phenoxyethanol and a water residue.

(Formulation example 3: Soap)
2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 0.5 parts by mass, elastin 0.1 parts by mass, glycerin 2 parts by mass, taking the whole as 100 parts by mass. The composition of the present invention was prepared in the form of soap by mixing and solidifying 1 part by mass of olive oil, 0.1 part by mass of EDTA-4 sodium, 0.2 part by mass of tetrasodium etidronate and the rest of the soap base. ..

(Formulation example 4: emulsion)
With 100 parts by mass as a whole, 0.1 parts by mass of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 0.1 parts by mass of alanine, 0.1 parts by mass of arginine 3 parts by mass, sucrose fatty acid ester 3 parts by mass, glycerin 12 parts by mass, squalane 6 parts by mass, dimethyl silicone oil 24 parts by mass, polypropylene glycol 1 part by mass, thickener 0.06 parts by mass, phenoxyethanol 0.2 parts by mass, The composition of the present invention was prepared in the form of a milky lotion by mixing 5 parts by mass of ethanol, 0.01 parts by mass of sodium hydroxide and the balance of purified water.

(Formulation example 5: Cosmetic cream)
2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 0.005 parts by mass, squalane 15.0 parts by mass, octyldodecyl myristate, taking the whole as 100 parts by mass. 4.0 parts by mass, hydrogenated soybean phospholipid 0.2 parts by mass, butyl alcohol 2.4 parts by mass, hardened oil 1.5 parts by mass, stearic acid 1.5 parts by mass, lipophilic glycerin monostearate 1. 5 parts by mass, 0.5 parts by mass of polyglyceryl monostearate, 0.8 parts by mass of behenyl alcohol, 0.7 parts by mass of polyglyceryl monomyristate, 0.3 parts by mass of Sarashimitsurou, 0.1 parts by mass of d-δ-tocopherol, 0.3 parts by mass of methylparaben, 0.2 parts by mass of C10-30 alkyl-modified carboxyvinyl polymer, 0.1 parts by mass of carboxyvinyl polymer, 18.0 parts by mass of 1,3-butanediol, 0.1 parts by mass of sodium hydroxide And the residue of purified water were mixed to prepare the composition of the present invention in the form of a cosmetic cream.

(Formulation example 6: Packing agent)
2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 0.1 part by mass, gallic acid 0.01 part by mass, polyvinyl alcohol 20 by mass, taking the whole as 100 parts by mass. .0 parts by mass, 5.0 parts by mass of glycerin, 20.0 parts by mass of ethanol, 6.0 parts by mass of kaolin, 0.2 parts by mass of preservative, 0.1 parts by mass of fragrance and the balance of purified water are mixed and packed. The composition of the present invention was prepared in the form of an agent.

(Formulation Example 7: Tablet 1)
2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 0.1 part by mass, ginger extract 8 parts by mass, caffeine 5 parts by mass, taking the whole as 100 parts by mass. The composition of the present invention was prepared in the form of tablets by mixing and tableting 20 parts by mass of crystalline cellulose, 50 parts by mass of lactose, 4 parts by mass of magnesium stearate and the balance of corn starch.

(Formulation Example 8: Granules)
With 100 parts by mass as a whole, 0.5 parts by mass of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 10 parts by mass of lactose, 1 part by mass of calcium stearate and The composition of the present invention was prepared in the form of granules by mixing and granulating the rest of the crystalline cellulose.

(Formulation Example 9: Capsule)
With 100 parts by mass as a whole, 5 parts by mass of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 20 parts by mass of ginger extract, 5 parts by mass of elastin, lecithin The composition of the present invention was prepared in the form of a capsule by encapsulating 8 parts by mass and the rest of olive oil as a content liquid and encapsulating it in a capsule shell.

(Formulation Example 10: Liquid agent)
2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 0.005 parts by mass, arginine 1 part by mass, alanine 1 part by mass, fructose, taking the whole as 100 parts by mass. Mix 10 parts by mass of glucose liquid sugar, 1 part by mass of citric acid, 0.02 parts by mass of sodium benzoate, 2 parts by mass of fragrance preparation, 0.05 parts by mass of sucralose, 0.03 parts by mass of acesulfam potassium, and the balance of purified water. The composition of the present invention was prepared in the form of a liquid preparation.

The present invention can be used in the field of manufacturing foods and drinks such as foods and supplements with functional claims and pharmaceuticals for the purpose of regulating autonomic nerves.

Claims (2)

An autonomic nerve regulator characterized by containing 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one as an active ingredient . A sympathetic nerve activator comprising 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one as an active ingredient .