JPH07233070A - Fatigue improver - Google Patents

Abstract

PURPOSE:To obtain a fatigue improver for promoting lactic acid metabolism in a body, having smoothing action on energy production, comprising biotin, carnitin and pantothenic acid as active ingredients. CONSTITUTION:This fatigue improver contains carnitin and pantothenic acid besides biotin as active ingredients. Biotin promotes lactic acid metabolism in a body by activating pyruvate carboxylase and smoothes energy production by supplying oxalacetic acid. Carnitin and pantothenic acid which are factors for supplying and adjusting acetyl COA to be reacted with the oxalacetic acid and to cause a starting reaction of TCA circuit are added to the fatigue improver to show an effective fatigue recovering action. An effective dose of biotin is 50-5,000mug per adult daily, that of carnitin is 0.25-1,000mg and that of pantothenic acid is 0.25-750mg. The fatigue improver is useful for preventing and treating physical and mental fatigue.

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 biotin, carnitine, and pantothenic acid as active ingredients.

[0002]

Biotin mainly acts as a coenzyme for four types of decarboxylation reactions in the living body and plays an important role in the energy production system and amino acid metabolism. By activating these enzyme reactions, biotin is generally used for treating dermatitis such as psoriasis, diabetes, and arthritis.

Japanese Unexamined Patent Publication (Kokai) No. 57-99520 discloses treatment of diabetes, and Japanese Unexamined Patent Publication (Kokai) No. 58-164510 discloses treatment of inflammatory disorders such as rheumatoid arthritis.

Carnitine is generally used for improving gastrointestinal symptoms such as gastric juice secretion promoting action and gastric peristaltic movement promoting action.

Japanese Unexamined Patent Publication No. 57-126421 discloses amelioration of anorexia, Japanese Unexamined Patent Publication No. 59-98018 discloses therapeutic agents for aging, and Japanese Unexamined Patent Publication No. 59-130213 discloses antitumor agents. Pantothenic acid is used for improving lipid metabolism, improving appetite, and treating flaccid constipation.

Japanese Unexamined Patent Publication No. 59-212431 discloses an antimutagenic agent, Japanese Unexamined Patent Publication No. 61-210021 discloses a hair cosmetic composition, and Japanese Unexamined Patent Publication No. 2-237906 discloses an external preparation for skin. Further, US Pat. No. 2,236,675 discloses a compounding agent component for weight loss.

Conventionally, vitamin B1 (including derivatives), vitamin B2, nicotinic acid, pantothenic acid and the like have been used as vitamin agents for fatigue recovery.
All of these are coenzymes or compound 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 TCA cycle starts with a reaction in which citric acid is produced from each molecule of acetyl CoA and oxaloacetate. After that, decarboxylation reaction and dehydrogenation reaction are repeated to reach oxaloacetic acid via cisaconitic acid, isocitric acid, succinyl CoA, α-ketoglutaric acid, fumaric acid, malic acid, succinic acid, etc., and react with new acetyl CoA to react with citric acid. , The circuit proceeds.

Since the organic acid produced in the TCA cycle is also used for other purposes such as amino acid synthesis, it was not always possible to secure a sufficient amount of oxaloacetic acid to react with acetyl CoA.

In view of the above problems, the present inventors have paid attention to the following points.

Since a series of reactions in the TCA cycle are carried out in mitochondria, acetyl Co which is a reaction initiation compound.
It is necessary to efficiently transport the fatty acid, which is one of the raw materials of A, into mitochondria.

However, it should not be said that it should be supplied unilaterally, and it is not possible to overlook the possibility of excessive supply of acetyl-CoA due to the recent tendency of Japanese dietary composition to have a high fat content and low sugar content. Excessive supply of acetyl-CoA causes acidosis in mitochondria, which also causes fatigue. From these facts, in order to realize effective fatigue improvement, in addition to the active supply of oxaloacetate in the energy generation system, acetyl CoA in mitochondria
In many cases, it is necessary to adjust the amount. Acetyl C
A more effective fatigue recovery method containing a regulator of oA has been investigated.

That is, the present invention is a fatigue-improving agent characterized by containing carnitine and pantothenic acid (pantethine) as active ingredients in addition to biotin, which is also effective for nutritional supplementation and mental fatigue during physical fatigue. It is a thing.

In the present invention, in addition to activating the oxaloacetate supply pathway of biotin, pantothenic acid, which is a constituent of acetyl-CoA, and in addition, mitochondrial surplus of acetyl-Co, which is essential for mitochondrial supply.
It is a more effective fatigue-improving agent characterized by containing carnitine, which has an action of excreting A, and these three types of compounds.

That is, biotin has the action of activating pyruvate carboxylase, promoting lactic acid metabolism in the body, and supplying oxaloacetic acid, thereby facilitating energy production. In addition, a more effective fatigue recovery action was realized by adding carnitine and pantothenic acid (including pantethine), which are factors that supply and regulate acetyl-CoA that reacts with oxaloacetic acid and causes the initiation reaction of the TCA cycle.

In the present invention, the effective dose of biotin is
The daily dose for healthy adults is 50 μg-5000 μg. For carnitine, the daily dose for healthy adults is 0.25 mg-1000 mg, and for pantothenic acid (pantethine), the daily dose for healthy adults is 0.25 mg-750 mg. The mixing ratio of each component is 1 part by weight of biotin to 5 parts of carnitine.
It is effective in the range of -200 parts by weight and pantethine 5-150 parts by weight. Fatigue improver composition is an active ingredient of the present invention, other known additives as they are, or as needed,
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 carboxymethylcellulose, 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 antioxidants 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 biotin preparation of the present invention is used prophylactically or therapeutically against physical fatigue and mental fatigue.

[0028]

EFFECTS OF THE INVENTION Biotin, carnitine, and pantothenic acid (pantethine) have the effects of promoting lactic acid metabolism in the body and facilitating energy production, and as a result, can treat various diseases associated with fatigue and prevent their occurrence.

[0029]

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

Example 1 (Formulation Example) Biotin 5 mg Carnitine 50 mg Pantethine 50 mg Hardened oil 180 mg L-Menthol 15 mg Light anhydrous silicic acid 5 mg

Biotin, carnitine and pantethine were mixed with hardened oil and L-menthol in the proportions of the above formulation examples, and the mixture was heated and granulated with stirring with a granulator. After cooling, particle size 50
The mixture was separated to 0 μm or less, and then light silicic acid anhydride was added, mixed and packaged (1.0 g) to obtain a granule.

Example 2 (Prescription example) The following medicines are mixed to prepare a liquid medicine.

1 bottle (in 50 ml) Biotin 500 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 Deer chanterelles 10 mg Spicy cauliflower 200 mg roasted beef roe 1 mg 50 mg

Example 3 Biotin and pantethine microencapsulated with solid fat by a conventional method were added to a commercially available drink at 1 mg / dl and 10 mg / dl, respectively, and 50 mg of carnitine chloride was added as it was, and the drink was added. Prepared.

Example 4 Biotin 500 μg, dl-carnitine chloride 50.5 m
g, pantethine 50 mg, vitamin C 50 mg, as an excipient D-mannitol 249 mg, lactose 100 m
g, 20 mg of crystalline cellulose, 50 mg of hydroxypropyl cellulose as a binder, and 30 mg of magnesium stearate as a lubricant were added, mixed and tableted. 1
The tablet was 600 mg.

Test Example 1 The following experiment was carried out using 10 Wistar rats ♂. The body weight at the time of the experiment was 250-300 g. A catheter was inserted into the left jugular vein of the rat before the experiment. Up to 1 week before the start of the forced exercise experiment on the treadmill, the usual diet and water were given ad libitum, but from 1 week before the start of the experiment until the end of the entire experiment, purified feed containing 20% of freeze-dried egg white and Bred in water. First, blood was collected from a 100 μl catheter, the rat was placed in a chamber equipped with a treadmill and an exhalation sampling pump, and the catheter was guided to the outside of the chamber. After running for 3 minutes at 20m / min and resting for 2 minutes,
The car was run at a speed of 0-120m / min, leading to overwork.
Immediately after the end of the exercise, blood was collected, followed by 4 μCi (U-
¹⁴ C) Lactic acid was injected. The rat then remains rested,
Blood was collected at 5, 10, 20, 40, 60, and 120 min, respectively. ¹⁴
CO ₂ collection is 5 minutes every 30 minutes until recovery, then 40,
The test was divided into 60, 90, and 120 minutes (control group).

Immediately after the end of the above experiment, the animals were divided into two groups,
Biotin alone (group B) at a rate of 5 μg / 100 g bw / day
Or, an equal amount of biotin, 25 μg / 100 g bw / day of sodium pantothenate, and 50 μg / 100 g bw / day of carnitine chloride were orally administered (group M), and after one week, the same exercise test as above was performed to collect blood. And ¹⁴ CO ₂ were simultaneously collected and compared with each other.

The collected blood was immediately cooled with ice-cold 0.6N HCl.
It was deproteinized with O ₄ . The lactic acid concentration in the deproteinized solution was determined by the enzymatic method. The radioactivity of ¹⁴ CO ₂ in the CO ₂ absorbing solution was determined by the liquid scintillation method.

Results: The maximum blood lactate amount in the control group, B group, and M group after completion of the forced exercise was 33.5 ± 2.4 mM, respectively.
26.3 ± 1.9 mM and 22.2 ± 2.8 mM, and administration of biotin significantly reduced the amount of lactic acid in the blood and shortened the time for lactic acid to disappear from the blood. Also biotin, carnitine chloride,
The simultaneous administration of pantothenic acid further reduced the lactic acid disappearance time (Fig. 1).

The blood oxidative reaction of the infused lactic acid was fast, and a large amount of ¹⁴ CO ₂ was exhaled by the 5th minute of recovery in both administration and non-administration of biotin (FIG. 2). However, it was revealed that administration of biotin accelerates the peak of the exhaled dose.
In addition, the M group showed almost the same excretion pattern as the B group,
It was revealed that the peak was high and that it was excreted more rapidly (Fig. 2). From these results, it was clarified that biotin intake promptly treats lactic acid produced during physical fatigue, and is effective for recovery from fatigue.

Example 2 10 healthy adults (25-40 years old) were divided into 2 groups of 5 persons each, and 500 μg of biotin, 50 mg of pantethine and 100 mg of carnitine chloride were administered to one of them (experimental group), and the other was administered. It was a placebo group. With the right foot of the volunteer kept in the MRI device, a load of 2 kg was suspended and the dorsiflexion exercise was performed to the limit. Since the tibialis anterior muscle is used specifically by the same exercise, only the tibialis anterior muscle extends the T2 relaxation time as compared with other muscles. The T2 relaxation time of this tissue was compared in both groups.
As a result, it was suggested that administration of the above three components significantly shortened the T2 relaxation time of the tibialis anterior muscle.

[Brief description of drawings]

FIG. 1 shows time on the horizontal axis and blood lactate amount on the vertical axis.

FIG. 2 shows time on the horizontal axis and ¹⁴ CO ₂ inhalation amount on the vertical axis.

Claims (1)

[Claims] 1. A fatigue-improving agent comprising biotin, carnitine, and pantothenic acid as active ingredients.