JPH07330584A - Fatigue ameliorant - Google Patents

Abstract

PURPOSE:To obtain a fatigue ameliorant which contains ubiquinone and carnitine as active ingredients, accelerates the oxidative phosphorylation in mitochondria, and smoothens the ATP production, thus is useful in therapy and prophylaxis for diseases accompanied by fatigue. CONSTITUTION:This medicinal preparation contains ubiquinone and carnitine as active ingredients. The dose of ubiquinone is preferably 50--5,000mug/day/ normal adult, while carnitine is 0.25-100-mg/day/normal adult. Additionally, the formulation ratio is preferably 5-20 pts.wt. of carnitine per 1 pt.wt. of ubiquinone. Addition of watersoluble vitamins such as biotin or pantothenic acid is recommended for ensuring the effect of the preparation.

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, which comprises ubiquinone and carnitine as active ingredients.

[0002]

Ubiquinone is commonly used as a peripheral vasodilator,
It is used as a metabolism-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 a preparation containing ubiquinone having a tissue metabolism activity and yeast extract, JP-A-52-99220 discloses improvement of symptoms of myasthenia gravis, and JP-A-52-99222 discloses. There are many disclosures, such as erythrocytosis.

Carnitine is generally a gastric juice secretagogue,
It is used to improve gastrointestinal symptoms such as gastric peristalsis.

In addition, JP-A-57-126421 discloses amelioration of anorexia, JP-A-59-98018 discloses an anti-aging agent, and JP-A-59-130213 discloses an antitumor agent. is there.

[0005]

Heretofore, vitamins B ₁ (including derivatives), B ₂ , nicotinic acid, pantothenic acid and the like have been used as fatigue-relieving vitamin agents. 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.

The production of ATP is based on the glycolytic process and oxidative phosphorylation, but it is also considered that the utilization of oxygen depends on the presence of ubiquinone in the energy production at the mitochondrial level. Should be included.

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 a crude material such as dried yeast extract is mixed. It was not observed and there was no evidence that its effect was sufficient.

[0009]

By combining ubiquinone with carnitine (l-form, dl-form, both can be used), the present inventors not only absorb ubiquinone but also the metabolic and ubiquitin-induced ubiquinone. It has been found that surprisingly a synergistic effect is exerted not only on energetic activity but also on fatigue protection during continuous muscle fatigue, and based on this finding, the present invention was completed.

That is, the present invention is a fatigue-improving agent containing ubiquinone and carnitine as active ingredients.

In fact, the surprising synergistic effect observed between ubiquinone and carnitine is the increase in mitochondrial enzyme activity due to continuous forced exercise and ³¹ P-N before and after forced exercise.
It was clarified by measuring changes in the dynamics of phosphorus molecules in the living body by MR. Both of these parameters show the ability to improve physical fatigue.

Therefore, a pharmaceutical composition comprising a combination of ubiquinone and carnitine, in a trace amount which is unexpected based on previously known data, is simply added by a single component. Unexpected pharmacological and therapeutic effects could be obtained due to the synergistic effects that cannot be obtained.

In the present invention, the effective dose of ubiquinone is 50 μg-50000 μg daily for healthy adults. For carnitine, the daily dose for healthy adults is 0.25mg-100mg. The compounding ratio of each component is effective in the range of 5-20 parts by weight of carnitine to 1 part by weight of ubiquinone. Adjuvants to further enhance the effect include water-soluble vitamins such as biotin, pantothenic acid, thiamine and nicotinic acid.

The fatigue-improving agent composition which is the active ingredient of the present invention may be used as it is, or as required, with other known additives.
For example, excipients, disintegrants, binders, lubricants, antioxidants,
By mixing a coating agent, a colorant, a cross-linking odorant, a surfactant, a plasticizer, etc., an oral preparation such as granules, powders, capsules, tablets, dry syrups, and liquids can be prepared by a conventional method. .

As the excipient, for example, 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 drinks, other physiologically active ingredients, minerals, vitamins, hormones, nutritional ingredients,
It is also possible to impart a palatability by mixing a fragrance or the like.

As these medicinal products, any of the additives generally used in the formulation can be used.

The ubiquinone preparation of the present invention is used prophylactically or therapeutically for physical fatigue and mental fatigue.

[0028]

EFFECTS OF THE INVENTION Ubiquinone and carnitine promote oxidative phosphorylation in the body, especially in mitochondria, and
It has the effect of smoothing production, and as a result, is effective in treating various diseases associated with fatigue, preventing their occurrence, and promoting recovery after their occurrence.

[0029]

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 Carnitine 50 g Biotin 50 g Hardened oil 180 g Lactose 500 g Gelatin 5 g L-menthol 15 g Light anhydrous silicic acid 5 g Biotin, carnitine, ubiquinone hardened oil and L-Menthol was mixed and heated and granulated with stirring with a granulator. After cooling, it is separated into particles with a particle size of 500μ or less, and then light anhydrous silicic acid is added and mixed to form a package (1.0
g) to obtain granules.

Example 2 (Formulation example) The following chemicals are dissolved in mixed distilled water to give a liquid preparation.

1 bottle (in 50 ml) Ubiquinone 50 μg Carnitine chloride 50 mg 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 Anchovy 10 g Roasted cauliflower 100 mg roasted cauliflower 100 mg 50 mg Example 3 Formulation of drink (in 100 ml) Taurine 1000 mg Nicotinic acid amide 30 mg Vitamin B ₁ 5 mg Vitamin B ₂ 5 mg Vitamin B ₆ 5 mg Nicotinic acid amide 20 mg 1 mg each of ubiquinone and pantethine microencapsulated with solid fat by a conventional method. / Dl and 10 mg
/ Dl, and 50 mg of carnitine chloride was added as it was, and a drink was prepared with distilled water so that the final concentration would be 100 ml.

Example 4 500 μg of ubiquinone and 5.5 m of dl-carnitine chloride
g, biotin 50 mg, vitamin C 50 mg, D-mannitol 299 mg, lactose 100 mg, crystalline cellulose 20 as an excipient
mg, hydroxypropyl cellulose as binder 50
mg, magnesium stearate 30 mg as a lubricant
Was added, mixed and tabletted. One tablet was 600 mg.

Test Example 1 The following experiment was carried out using 20 Wistar male rats.

The body weight at the time of the experiment was 250-300 g. For food, one week before the start of the forced exercise experiment on the treadmill,
They were allowed to take a regular commercial diet and water ad libitum.
After that, the rats were divided into 4 groups, the control group was given a commercial diet as it was, the C group received 5 mg / kg, day of d, l-carnitine, and the Q group received 0.5 mg / kg, day of ubiquinone.
In the QC group, both of them were taken with a commercial diet.

Continue at rest for 1 minute, then 3 at 100 m / min
I was allowed to overwork for a minute.

Five minutes after the end of exercise was defined as a recovery period. From the start of the experiment, ³¹ P NMR spectrum of the gastrocnemius muscle of the right hind leg was taken every minute using MRI for animals (FIG. 1).

From the left peak, inorganic phosphate (Pi), creatine phosphate (PCr), and the remaining three peaks are ATP.
Is. The information obtained from this figure is that the pH in muscle can be 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) The changes over time in muscle pH and ATP amount in the control group, C group, Q group, and CQ group are shown in FIGS. 2 and 3. .

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

Test Example 2 The following experiment was carried out using 20 Wistar male rats. The body weight at the time of the experiment was 250-300 g. The rats were divided into 4 groups, the control group was given the commercial diet as it was, the C group received 5 mg / kg, day of d, l-carnitine, the Q group received 0.5 mg / kg, day of ubiquinone, and the QC group received the same. Take both of them with a commercial diet, and at the same time do a forced exercise on a treadmill for 120 minutes a day at 40 m / mi.
It was carried out for 10 days under the condition of n.

Twenty days after the start of the experiment, the mice 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., Mitochondrion enzymatic activity, citrate synthetase, was measured by a spectrophotometer.

(Results) The enzyme activities of the control group, C group, Q group and CQ group were compared before and after the start of exercise.

As a result, 10 days after the start of exercise, Q group, C
A significant increase in enzyme activity was observed in group Q, but C
There was only a slight increase in the control and control groups. In addition, the surprisingly increased activity of the CQ group was significantly higher than the result expected from the simple addition of the C group and the Q group (Fig. 4).

[Brief description of drawings]

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

FIG. 2 shows time on the horizontal axis and intracellular pH on the vertical axis.

[FIG. 3] Time is plotted on the horizontal axis and total ATP amount (three ATP is plotted on the vertical axis).
The change in relative value of the sum of peaks) was shown (resting was set to 1.0).

FIG. 4 shows the type of experimental group on the horizontal axis and the enzyme activity on the vertical axis.

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Claims (1)

[Claims] 1. A fatigue-improving agent comprising ubiquinone and carnitine as active ingredients.