JPH07330593A - Improve for fatigue - Google Patents

Abstract

PURPOSE:To obtain the medicine, containing ubiquinone and biotin as active ingredients useful for treating or preventing diseases caused by physical and mental fatigues due to promotion of oxidizing phosphorylation in mitochondria and smoothing of the production of adenosine 5'-triphosphate (ATP). CONSTITUTION:This improver for fatigues contains ubiquirlone and biotin as active ingredients. The daily dose of the ubiquinone for a healthy adult is preferably 50-5000mug and the daily dose of the biotin for the healthy adult is preferably 500-2000mug. Furthermore, the blending ratio of the respective ingredients is preferably 0.2-10 pts.wt. biotin based on 1 pt.wt. ubiquinone. A water-soluble vitamin such as pantothenic acid or nicotinic acid is preferably blended therein in order to further ensure effects.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a fatigue improving agent.
More specifically, it relates to an agent for improving fatigue containing ubiquinone and biotin as active ingredients.

[0002]

Ubiquinone is generally used as a peripheral vascular improving drug and a metabolic improving drug, and its effects such as pericardial protective action, activation of ATP synthesis in myocardial mitochondria and improvement of cardiac function have been confirmed. In addition, JP-A-62-59208 discloses the tissue metabolic activity of a preparation containing ubiquinone and yeast extract, JP-A-52-99220 discloses the effect of improving the symptoms of myasthenia gravis, and JP-A-52-99222. There is a lot of disclosure in the publication, such as the effect of increasing red blood cells.

Biotin acts as a coenzyme for decarboxylase in the living body, and plays an important role especially in the glycolysis system and the TCA cycle among amino acid metabolism and energy production systems. By activating these enzymes, biotin is generally used for treating dermatitis such as infection, diabetes, and arthritis. Further, JP-A-57-99520 discloses treatment of diabetes, and JP-A-58-164510 discloses treatment of inflammatory disorders of rheumatoid arthritis.

[0004]

Conventionally, vitamin B ₁ (including derivatives), vitamin B ₂ , nicotinic acid, pantothenic acid and the like have been used as vitamin agents for fatigue recovery.
All of these are coenzymes or groups involved in the reaction of the TCA cycle. As a result, these vitamins are said to efficiently produce ATP and indirectly promote the metabolism of lactic acid. Although ATP production is based on the glycolytic process and oxidative phosphorylation, it should also be taken into account that oxygen utilization is dependent on the presence of ubiquinone in mitochondrial energy production. is there.

As mentioned above, ubiquinone has been used for the purpose of improving metabolism and producing ATP, but is not effective unless it is limited to the heart muscle or a large amount of crude material such as dried yeast extract is mixed. It was not observed and there was no evidence that its effect was sufficient.

An object of the present invention is to provide a more effective fatigue improver containing ubiquinone in a trace amount.

[0007]

The present inventors have found that the combination of ubiquinone and biotin has a surprising synergistic effect on fatigue protection during continuous muscle fatigue, as well as on the metabolic and energetic activity performed by ubiquinone. Found to have.

[0008] In fact, the surprising synergistic effect of ubiquinone and biotin is the increase of mitochondrial enzyme activity by continuous forced exercise and ³¹ P-NM before and after forced exercise.
It was demonstrated by measuring the change in the kinetics of the phosphorus molecule in vivo by R. Both of these parameters show the ability to improve physical fatigue. Therefore, a pharmaceutical composition comprising a combination of ubiquinone and biotin can be obtained from a simple addition of a single component in a trace amount that is unexpected based on previously known data. Unexpected pharmacological and therapeutic effects could be obtained due to the inability to synergize.

The present invention is a fatigue-improving agent containing ubiquinone and biotin as active ingredients.

In the present invention, the effective dose of ubiquinone is 50 to 50,000 μg / day, preferably 5 / day, for healthy adults.
It is 0 to 5000 μg. With biotin, 250 μg to 10000 μg / day, preferably 500 μg / day, for healthy adults.
~ 2000 μg. The mixing ratio of each component is effective in the range of 0.2 to 10 parts by weight of biotin to 1 part by weight of ubiquinone. In the present invention, water-soluble vitamins such as pantothenic acid, thiamine, and nicotinic acid can be used as adjuvants in order to further enhance the effect.

The fatigue-reducing composition which is the active ingredient of the present invention is used as it is or as required, and other pharmaceutically acceptable additives such as excipients, disintegrants, binders, lubricants, antioxidants. Oral formulation such as granules, powders, capsules, tablets, dry syrups, liquids, etc. can be prepared by mixing a coating agent, a coloring agent, a cross-linking agent, a cross-linking agent, a surfactant, a plasticizer, etc. it can.

All of these pharmaceutically acceptable additives are generally used in oral preparations and include the following.

Examples of the excipient include mannitol,
Xylitol, sorbitol, glucose, sucrose, lactose,
Crystalline cellulose, crystalline cellulose / sodium carboxymethyl cellulose, calcium hydrogen phosphate, wheat starch, rice starch, corn starch, potato starch, sodium carboxymethyl starch,
Dextrin, α-cyclodextrin, β-cyclodextrin, carboxyvinyl polymer, light anhydrous silicic acid, titanium oxide, magnesium aluminometasilicate,
Examples thereof include polyethylene glycol and medium chain fatty acid triglyceride.

As the disintegrant, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium.
Type A (actisol), starch, crystalline cellulose, hydroxypropyl starch, partially pregelatinized starch and the like can be mentioned.

Examples of the binder include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, taragant, sodium alginate and propylene glycol alginate. Is mentioned.

As the lubricant, for example, stearic acid,
Magnesium stearate, calcium stearate,
Polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethyl polysiloxane,
Examples include microcrystalline wax, beeswax, and beeswax.

Examples of the antioxidant include dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), α-tocopherol and citric acid.

As the coating agent, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate,
Carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer, cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate, shellac and the like. .

Examples of colorants include tar dyes and titanium oxide.

Examples of the corrigent include citric acid, adipic acid, ascorbic acid, menthol and the like.

Examples of the surfactant include polyoxyethylene hydrogenated castor oil, glyceryl monostearate,
Examples thereof include sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene polyoxypropylene block copolymer, polysorbates, sodium lauryl sulfate, macrogols and sucrose fatty acid ester. Examples of the plasticizer include triethyl citrate, triacetin, cetanol and the like.

In the case of a drink, if desired, other physiologically active ingredients, minerals, vitamins, hormones, nutritional ingredients, flavors and the like may be mixed to impart palatability.

[0023]

Industrial Applicability The ubiquinone- and biotin-containing composition of the present invention has an action of promoting oxidative phosphorylation in the body, particularly in mitochondria, and facilitating ATP production. As a result, it is associated with physical fatigue and mental fatigue. It is effective in treating various diseases, preventing their occurrence, and promoting recovery after fatigue.

[0024]

EXAMPLES The present invention will be specifically described with reference to the following examples and test examples.

Example 1 (Formulation example) Ubiquinone 0.5 g Biotin 5 g Hardened oil 225 g L-Menthol 15 g Light anhydrous silicic acid 5 g Biotin, ubiquinone, hardened oil and L-
Menthol was mixed and heated and granulated with stirring with a granulator.
After cooling, the particle size was separated to 500 μm or less, then light anhydrous silicic acid was added, mixed and packaged (1.0 g) to obtain a granule.

Example 2 (Formulation example) The following agents were mixed and distilled water to obtain a total amount of 10
The solution was 0 ml.

1 bottle (in 100 ml) Ubiquinone 50 μg Biotin 500 μg Na Pantothenate 50 mg Taurine 1500 mg Nicotinic Acid Amide 30 mg Vitamin B ₁ 5 mg Vitamin B ₂ 5 mg Vitamin B ₆ 5 mg Ginseng 600 mg Deer edible roe 100 mg Caulis roe 1 mg 200 g Example 3 Drinking agent (in 100 ml, taurine 1000 mg, vitamin B ₁ 10 mg, vitamin B ₂ 5 mg, vitamin B ₆
5 mg and 20 mg of nicotinic acid amide), 1 mg / dl and 0.5 mg / dl of ubiquinone and biotin microcapsulated with solid fat by a conventional method, respectively.
And 50 mg of d, l-carnitine chloride was added to prepare a drink preparation.

Example 4 Ubiquinone 0.5 g, d, l-carnitine chloride 5.5
g, biotin 5 g and vitamin C 50 g are mixed, and D-mannitol 299 g, lactose 100 g, as an excipient,
20 g of crystalline cellulose, 50 g of hydroxypropyl cellulose as a binder, and 30 g of magnesium stearate as a lubricant were added, mixed and tableted. One tablet 600m
It was set to g.

Test Example 1 Kuno et al. (Science of Fatigue and Rest, Vol. 6, p. 81, 199)
1 year), using 20 male Wistar rats,
The following experiment was conducted. The weight during the experiment is 250-300g
Met. As a diet, a normal commercial diet and water were allowed to freely ingest until one week before the start of the forced exercise experiment on the treadmill. Then, the rats were divided into 4 groups, the control group was given the commercial diet as it was, and the group B was 1 m.
g / kg / day of biotin was 0.5 mg / group in Q group
Ubiquinone (kg / day) and, in the QB group, ubiquinone and biotin were ingested with the same amount of commercial diet as above.

100 m / min continued after resting for 1 minute
It made me run overloaded for 3 minutes. The recovery period was 5 minutes after the end of the exercise. From the beginning of the experiment, using animal MRI,
A ³¹ P NMR spectrum of the gastrocnemius muscle of the right hind leg was taken every 1 minute (FIG. 1). From the left peak, inorganic phosphate (Pi), creatine phosphate (PCr), and the remaining three peaks are AT
P. From this figure, the pH in muscle was determined from the amount of ATP in muscle and the chemical shift value of the peak of inorganic phosphate with respect to creatine phosphate.

Results: Changes over time in muscle pH and ATP amount in the control group, B group, Q group and QB group are shown in FIGS. 2 and 3.

A significant synergistic effect was observed in the QB group for both parameters of ATP production and blood pH stability. Further, there was a tendency of improvement in the B group and the Q group. From these results, it was revealed that simultaneous ingestion of ubiquinone and biotin has an ATP production and anti-acidosis effect which is not predicted by existing data, and it is clarified that it is effective for fatigue recovery.

Test Example 2 Oscai et al. (J. Biol. Chem., No. 2)
46, page 6968, 1971).
The following experiment was conducted using 20 male ar rats. The body weight at the time of the experiment was 250 to 300 g. The rats were divided into 4 groups, the control group was given a commercial diet as it was, the B group was given 5 mg / kg / day of biotin, the Q group was given 0.5 mg / kg / day of ubiquinone, and the QB group was given ubiquinone and biotin. The same amount as above is taken with a commercial diet, and at the same time forced exercise with a treadmill is performed for 120 minutes a day at 40 m / min.
The above conditions were followed for 10 days. Twenty days after the start of the experiment, the animals were sacrificed, the gastrocnemius muscle was separated, homogenized, and then subjected to differential centrifugation to separate mitochondria. According to the method of Oscai et al., The citrate synthetase activity, which is a mitochondrial enzyme activity, was measured by a spectrophotometer.

Results: The enzyme activities in the control group, B group, Q group and QB group were compared before and after the start of exercise. As a result, a significant increase in enzyme activity was observed in the Q group and the QB group 10 days after the start of exercise, but a slight increase was observed in the B group and the control group. In addition, the surprisingly increased activity of the QB group was significantly higher than the result expected from simple addition of the B and Q groups (Fig. 4).

[Brief description of drawings]

FIG. 1 shows a ³¹ P NMR spectrum at rest.

FIG. 2 shows changes in pH in muscle over time. Time on the horizontal axis,
The vertical axis shows the intracellular pH.

FIG. 3 shows changes over time in the amount of ATP in muscle. The horizontal axis shows the time, and the vertical axis shows the change in the relative value of the total ATP amount (sum of three ATP peaks) (rest time was set to 1.0).

FIG. 4 shows changes in mitochondrial citrate synthetase activity due to continuous exercise load. The horizontal axis shows the type of experimental group, and the vertical axis shows the enzyme activity.

Claims (1)

[Claims] 1. A fatigue-improving agent containing ubiquinone and biotin as active ingredients.