JP5053535B2 - Oral for improving sleep or waking up - Google Patents

Description

  The present invention relates to an oral preparation for improving sleep or waking up, food or drink, and food additive, containing ornithine or a salt thereof as an active ingredient.

L-ornithine is used mainly in the United States as a food material to secrete growth hormone and enhance muscle synthesis, or to increase basal metabolism and prevent obesity. Moreover, L-ornithine is used in the form of L-ornithine L-aspartate in Europe as a pharmaceutical agent for improving liver damage.
It has been reported that kale, propolis, or extracts thereof have an affinity for melatonin receptors and are effective for poor waking as a disease related to melatonin receptors (see Patent Document 1).
For healthy sleep, such as theanine, antihistamines and flavoring ingredients, antihistamines and herbal medicines, wakefulness when waking up, reduced fatigue when waking up, extended sleep time, improved sleep, improved dreams, reduced mid-wakeness, Effects such as reduction in mid-wake awakening in the latter half of sleep and improvement in sleep efficiency have been reported (see Patent Documents 2 to 5).
JP 2003-335691 A JP 2005-289948 A International Publication No. 2005/097101 JP 2005-272388 A JP 2005-281001 A

  Drugs, nutritional foods, and the like are desired for those who have subjective symptoms such as poor sleep, sluggishness after waking up, and difficulty in recognizing their eyes. That is, an object of the present invention is to provide an oral preparation, a food or drink, or a food additive for improving sleep or waking up.

The present invention relates to the following (1) to (4).
(1) An oral preparation for improving sleep or waking, containing ornithine or a salt thereof as an active ingredient.
(2) A food or drink or food additive for improving sleep or waking up, comprising ornithine or a salt thereof as an active ingredient.
(3) A food or drink that contains ornithine or a salt thereof and has a label indicating that it is used to improve sleeping or waking up.
(4) A food or drink containing ornithine or a salt thereof that displays a sleeping or waking-up improving action on the main body, packaging, instructions, promotional material, or electronic information for advertising.

  According to the present invention, it is possible to provide a safe and effective oral preparation, food / beverage product, or food additive containing ornithine or a salt thereof as an active ingredient for improving sleep or waking up.

Examples of ornithine used in the present invention include L-ornithine and D-ornithine, with L-ornithine being preferred.
Ornithine can be obtained by a chemical synthesis method, a fermentation production method, or the like. Ornithine can also be obtained by purchasing a commercial product.
Examples of the method for chemically synthesizing L-ornithine include the method described in Coll.Czechoslov.Chem.Commun., 24 , 1993 (1959).

Examples of the method for fermentative production of L-ornithine include the methods described in JP-A Nos. 53-24096 and 61-119194.
L-ornithine and D-ornithine can also be purchased from Sigma-Aldrich.
Examples of ornithine salts include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.

Acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, malate, lactate, α-ketoglutarate And organic acid salts such as gluconate and caprylate.
Examples of the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt.

Examples of ammonium salts include salts such as ammonium and tetramethylammonium.
Examples of organic amine addition salts include morpholine, piperidine and the like.
Examples of amino acid addition salts include salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like.

Of the above ornithine salts, hydrochloride, citrate, malate, α-ketoglutarate and aspartic acid are preferably used, but other salts or two or more salts may be used in appropriate combination. .
In addition to ornithine or a salt thereof, the oral preparation, food or drink, or food additive of the present invention can contain an additive suitable for each application as appropriate.

Examples of the additive include amino acids such as valine, leucine, isoleucine, arginine, lysine, glutamine, alanine, serine, glycine, cysteine, and threonine.
Sleeping or waking up can be improved by administering or ingesting the oral preparation, food or drink, or food additive of the present invention.

In the present invention, the improvement of falling asleep or waking up means that a person who has a subjective symptom such as poor sleep, sluggishness after waking up, and difficulty in waking up, leads to sound sleep or awakening. .
The oral preparation of the present invention contains ornithine or a salt thereof, and optionally contains one or two or more pharmacologically acceptable carriers and, if necessary, other active ingredients for treatment. It may be.

The oral preparation of the present invention can be produced by any method well known in the technical field of pharmaceutics by mixing ornithine or a salt thereof together with a carrier as necessary.
When formulating the oral preparation of the present invention, excipients, binders, disintegrants, lubricants, dispersants, suspending agents, emulsifiers, diluents, buffers, antioxidants, bacterial inhibitors, etc. Can be used.
Examples of oral dosage forms include tablets, powders, granules, emulsions, syrups, capsules and the like.

  For example, when the dosage form of the oral preparation is tablets, powders, granules, etc., sugars such as lactose, sucrose, glucose, sucrose, mannitol, sorbitol, starches such as potato, wheat, corn, calcium carbonate, calcium sulfate , Inorganic substances such as sodium bicarbonate, sodium chloride, excipients such as plant powder such as licorice powder, gentian powder, starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, sodium bicarbonate , Disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil, polyvinyl alcohol, hydroxypropylcellulose, methylcellulose, ethylcellulose, carmellose, gelatin, starch paste, etc. Binder, fat Surfactants such as esters, with the addition of plasticizer such as glycerin, can be formulated.

  If the oral dosage form is a liquid preparation such as syrup, water, sucrose, sorbitol, sugars such as fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil, Preservatives such as p-hydroxybenzoic acid esters and flavors such as strawberry flavor and peppermint can be added to prepare a preparation.

The concentration of ornithine or a salt thereof in the oral preparation of the present invention is appropriately selected according to the type of oral preparation, the effect expected by the administration of the oral preparation, etc. It is -90 weight%, Preferably it is 0.5-80 weight%, Especially preferably, it is 1-70 weight%.
The dosage of the oral preparation of the present invention varies depending on the dosage form, age of the administered person, body weight, etc., but is usually 50 mg to 30 g, preferably 100 mg to 10 g as ornithine or a salt thereof per day for an adult. Particularly preferably, the dose is 200 mg to 3 g, and is administered once or divided into several times a day. The administration period is not particularly limited, but is usually 1 day to 1 year, preferably 1 week to 3 months.

The food additive of the present invention can be prepared by the same method as the above oral preparation. The food additive is usually processed and manufactured in the form of powder, granules, pellets, tablets, or various liquids by mixing or dissolving other food additives as required.
Examples of the food or drink of the present invention include ornithine or a salt thereof, or a food additive of the present invention added to the food or drink.

The food / beverage products of this invention can be processed and manufactured by using the general manufacturing method of food / beverage products, except adding ornithine or its salt, or the food additive of this invention in food / beverage products.
The food / beverage product of the present invention includes, for example, fluidized bed granulation, stirring granulation, extrusion granulation, rolling granulation, air flow granulation, compression molding granulation, pulverization granulation, spray granulation, spray granulation, and the like. Coating methods such as granulation method, pan coating, fluidized bed coating, dry coating, puff drying, excess steam method, foam mat method, expansion method such as microwave heating method, extrusion method such as extrusion granulator and extruder etc. Can also be manufactured.

  The food and drink of the present invention are juice products, soft drinks, teas, lactic acid bacteria beverages, fermented milk, frozen desserts, butter, cheese, yogurt, processed milk, skim milk, and other meat products such as ham, sausage, hamburg , Fish paste products such as bamboo shoots, bamboo rings, fried satsuma, egg products such as sushi rolls, egg tofu, cookies, jelly, chewing gum, candy, snacks, etc. Any form of salted products, soups, seasonings, etc. may be used.

The food and drink of the present invention may be in the form of, for example, powdered food, sheet food, bottled food, canned food, retort food, capsule food, tablet food, liquid food, and drink.
The food / beverage products of the present invention can be used as food / beverage products such as health foods for improving sleeping or waking up, functional foods, nutritional supplements, foods for specified health use.

The food / beverage products or food additives of the present invention include food additives generally used in food / beverage products, such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, colorants, bleaching agents, Molds, gum bases, bitters, enzymes, brighteners, acidulants, seasonings, emulsifiers, fortifiers, manufacturing agents, fragrances, spice extracts and the like may be added.
The amount of ornithine or a salt thereof or the food additive of the present invention added to the food or drink of the present invention is appropriately selected according to the type of food or drink, the effect expected from the intake of the food or drink, etc. Or as its salt, it is added so that it may contain 0.1 to 90 weight% normally, Preferably it is 0.5 to 80 weight%, Most preferably, it is 1 to 70 weight%.

  The intake of the food and drink according to the present invention varies depending on the intake form, the age, weight, etc. of the intake person, but usually 50 mg to 30 g, preferably 100 mg to 10 g, particularly as ornithine or a salt thereof per day for an adult. It is preferably 200 mg to 3 g, and is taken once a day or divided into several times. The intake period is not particularly limited, but is usually 1 day to 1 year, preferably 1 week to 3 months.

The following is a test example in which the effect of ornithine on bedtime and waking improvement was examined.
Test example 1
As a result of taking more than 8 tablets (product name: Remake Ornithine, manufactured by Kyowa Hakko Kogyo Co., Ltd.) containing 28 mg ornithine for 28 subjects, waking up was improved compared to before taking ornithine. There were 10 people.

Of the 28 subjects, 6 took ornithine before going to bed, and 3 of them improved waking up.
From the above results, the effects of ornithine intake on improving waking up were clarified, and it was shown that ingestion before bedtime is particularly effective.

Test example 2
14 healthy men and women from the age of 45 to 64 were divided into two groups of 7 each, and the tablets of Example 1 (tablets containing ornithine) or the tablets of Comparative Example 1 (tablets containing no ornithine) per day A test was conducted in which 6 tablets were taken for 3 weeks. The subjects' sleep and awakening at the start and end of the test were evaluated using the line segment scale (VAS) method.

  That is, the reference expression was written at both ends of the line segment, and the subject was asked to check which line segment corresponds to the contents of the question item shown in FIG. The distance (mm) from the left end of the line segment to the checked part was measured, and the difference before and after the test was determined. The ratio of this difference to the value before the test was expressed as a percentage, and the average value and standard deviation for each group were determined. Further, the average improvement rate (%) was obtained by subtracting the average value of the placebo group from the average value of the ornithine group. It was confirmed that there was no difference between the two groups at the start of the study.

The study was randomized and compared between double-blind parallel groups. The statistically significant difference between the two groups was an unpaired-t test with a two-sided distribution based on the difference between the start and end of the study.
The results are shown in FIG. All items showed the effects of ornithine intake. That is, from this result, it was shown that ornithine improves not only waking up but also sleeping.

  Examples of the present invention are shown below.

Manufacture of tablets containing ornithine Ornithine hydrochloride 136.2kg (product name: L-ornithine hydrochloride, manufactured by Kyowa Hakko Kogyo Co., Ltd.), microcrystalline cellulose 36.0kg (product name: Avicel FD101, manufactured by Asahi Kasei Chemicals), sucrose fatty acid Ester 6.6kg (Product name: DK Ester F-20W, Daiichi Kogyo Seiyaku Co., Ltd.), Calcium Phosphate 1.2kg (Product Name: Tricalcium Phosphate, Taihei Chemical Industrial Co., Ltd.) and β-cyclodextrin 20.0kg (Product Name: Celdex B-100 (manufactured by Nippon Shokuhin Kako Co., Ltd.) was mixed using a conical blender (CB-1200 blender, Nippon Dryer Co., Ltd.). The obtained mixture was compression molded at a compression molding pressure of 10 kN using a rotary compression molding machine (VIRGO524SS1AY, manufactured by Kikusui Seisakusho Co., Ltd.) to produce tablets with a diameter of 8 mm and 250 mg.

Manufacture of enteric capsules containing ornithine 20 kg of the mixture prepared in Example 1 and 0.2 kg of silicon dioxide were mixed and stirred into a capsule filling machine and filled into 20000 hard capsules made of gelatin. And hard capsules were obtained. The surface of the obtained hard capsule was coated with a zein solution using a high coater HCT-48 type (Freund Sangyo Co., Ltd.) to produce 20000 enteric capsules containing ornithine hydrochloride.

Manufacture of enteric tablet containing ornithine The surface of the tablet prepared in Example 1 was coated with a shellac solution using Hicoater HCT-48 (Freund Sangyo Co., Ltd.) to produce an enteric tablet.

Manufacture of beverages containing ornithine Ornithine hydrochloride 1.28 kg (Product name: L-ornithine hydrochloride, manufactured by Kyowa Hakko), Erythritol 3 kg (manufactured by Nikken Chemical), 0.05 kg of citric acid (manufactured by Kyowa High Foods), artificial 3 g of sweetener and 0.06 kg of fragrance are stirred and dissolved in 50 L of water at a liquid temperature of 70 ° C., adjusted to pH 3.3 with citric acid, sterilized using plate sterilization, filled into a bottle, pasteurized and sterilized, ornithine beverage Manufactured.

Comparative Example 1
The same amount of lactose was used instead of ornithine hydrochloride in Example 1 to produce tablets containing no ornithine.

FIG. 1 is a diagram showing questions in an evaluation using a line segment scale method. Reference expressions are shown at both ends of the line segment. FIG. 2 is a graph showing the effect of improving sleep and waking by ingestion of ornithine. The vertical axis shows the average improvement rate (%) of each index.

Claims (3)

An oral preparation for improving sleep or wakefulness containing ornithine or a salt thereof as an active ingredient (excluding those containing tryptophan as its active ingredient) .   The oral preparation according to claim 1, wherein the dosage form is a tablet, powder, granule, emulsion, syrup or capsule. A sleep-improving agent containing ornithine or a salt thereof as an active ingredient (except for those containing tryptophan as its active ingredient) .

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