JP6787944B2 - Muscle fatigue recovery agent - Google Patents

Description

The present invention relates to a recovery agent for muscle fatigue associated with exercise.

Exercise is achieved by muscle activity, and when exercise causes muscle fatigue, exercise performance is transiently reduced as a result. In recent years, the decline in motor performance caused by muscle fatigue is not necessarily due to inhibition of the brain-to-muscle pathway that produces muscle activity, but a defensive central nervous system action to avoid disruption of human homeostasis. It is also said that working can be a cause, and muscle fatigue means a decrease in muscle strength or the ability to generate muscle power itself caused by exercise, or a suppression of muscle strength or muscle power caused to prevent the collapse of these abilities. It is said that (Non-Patent Document 1).

Muscle hardness is used as an index for objective evaluation of muscle fatigue. For example, as a result of measuring changes in muscle hardness of the extensor carpi radialis longus muscle during and after dorsiflexion-palm flexion exercise, a significant increase in muscle hardness was observed during exercise compared to before loading. A significant decrease in muscle hardness was observed by resting after loading (Non-Patent Document 2), and immediately after the isometric knee extension exercise with maximum effort, the muscle hardness of the rectus femoris muscle increased significantly compared to before the exercise. It has been reported that after the exercise, the muscle hardness decreased (recovered) to the same level as before the exercise (Non-Patent Document 3), and the muscle hardness increased transiently due to the exercise, although the peak time and the like differed depending on the exercise mode and the degree of load. It is said that. Changes in muscle hardness before and after exercise include vascular compression and blood retention due to muscle contracture due to increased calcium ion concentration in muscle cells and tension generation during muscle contraction, volume increase due to interstitial fluid retention in muscle cells, and muscle damage. It is thought that various factors such as swelling due to swelling due to circulatory factors and an increase in intramuscular pressure due to an increase in tissue volume due to circulatory factors (for example, Non-Patent Document 4) are involved in a complex manner, but there are many unclear points.

Muscle hardness is also used as an index to evaluate recovery from muscle fatigue after exercise. Conventionally, it has been reported that the muscle hardness increased by exercise decreases due to passive stretching, ultrasonic therapy, cold water bath, light rubbing, etc., and these stretching and the like are performed as a means for promoting recovery of muscle fatigue after exercise. ing. On the other hand, it has also been reported that vibration stimulation is not effective in reducing / recovering muscle hardness during muscle fatigue due to exercise (Non-Patent Document 3). Since muscle fatigue is related to exercise performance and affects the superiority or inferiority of results in sports competitions and leads to the occurrence of injuries, a more effective method for recovery is desired.

On the other hand, hesperidin is a type of flavonoid that is abundant in the peel of citrus fruits. Hesperidins have been reported to have various physiological functions such as serum lipid improving action, muscular atrophy suppressing action, and blood circulation improving action (for example, Patent Documents 1 and 2).
However, the effect of hesperidins on exercise-related muscle fatigue is unknown.

Japanese Unexamined Patent Publication No. 11-171778 JP-A-2009-7313

Ryota Matsuura, Bulletin of Graduate School of Education, Hokkaido University, 2016, No. 125 Kamiyama Kazuyuki et al., Showa Medical Association Journal, 2004, 64 (6), p.494-498 Yumiko Matsubara et al., Society of Physical Therapy Science, 2004, 19 (4), p.341-345 Mitsuyoshi Murayama, Journal of the Society of Biomechanism, 2016, 40 (2), p. 79-84

The present invention relates to a muscle fatigue recovery agent useful for recovering muscle fatigue associated with exercise.

As a result of diligent studies in view of the above problems, the present inventor found that when hesperidins were orally ingested, the decrease in muscle hardness increased by exercise was promoted, and hesperidins were useful for recovery from muscle fatigue associated with exercise. I found.

That is, the present invention provides the following.
(1) A muscle fatigue recovery agent associated with exercise containing hesperidins as an active ingredient.
(2) A recovery promoter from an increase in muscle hardness associated with exercise containing hesperidins as an active ingredient.
(3) A food composition for recovering muscle fatigue associated with exercise containing hesperidins as an active ingredient.
(4) A food composition containing hesperidins as an active ingredient for promoting recovery from an increase in muscle hardness associated with exercise.

According to the present invention, it is possible to recover from muscle fatigue caused by exercise.

The graph which shows the time-dependent change of the gastrocnemius muscle hardness. A graph showing changes over time regarding recovery of foot fatigue (foot fatigue score over time).

The hesperidins used in the present invention include hesperidin, glycosyl adducts and methylated products whose water solubility has been enhanced by enzymatic or chemical treatment thereof.
Hesperidin is a glycoside in which rutinose (L-rhamnose- (α1 → 6) -D-glucose) is β-bonded to the hydroxyl group at the 7-position of hesperidin (5,7,3'-trihydroxy-4'-methoxyflabanone). The sugar adduct of hesperidin is a compound in which another sugar such as glucose, maltose, fructose, rhamnose, or lactose is bound to the sugar moiety (rutinose moiety) of hesperidin. Among them, glucosyl hesperidin in which 1 to 10 glucoses are bound to hesperidin is preferable, and monoglucosyl hesperidin in which 1 glucose is bound is preferable from the viewpoint of solubility. The number of glucose additions may have a distribution, and the average number of moles of glucose added per mol of hesperidin is preferably 1-10.

The position and number of methylated hesperidin methylates are not particularly limited. It is known that the methyl hesperidin mainly contains a chalcone type compound (1) and a flavanone type compound (2), and examples of the constituent components thereof include those having the following structures.

(In the formula, R represents a hydrogen atom or a methyl group.)

Here, methyl hesperidin as a pharmaceutical additive and a food additive is mainly treated as a mixture of compounds (3) and (4).

(In the formula, Gl represents a glucose residue and Rh represents a rhamnose residue. Gl-2 is a 2-position of a glucose residue (including the 3-position in the case of (3-1)), Rh- 2 represents the second position of the rhamnose residue.)
Hesperidin methyl chalcone as a raw material for cosmetics is treated as the compound shown in (5). In the case of a composition containing a large amount of chalcone-type compounds, it is also called hesperidin methyl chalcone.

(In the formula, R represents a hydrogen atom or a methyl group.)

In the present invention, the methyl hesperidin may contain both the chalcone-type compound (1) and the flavanone-type compound (2) shown above, or may contain only one of them.
More suitable methyl hesperidin in the present invention includes a mixture of compound (3) and compound (4).

Hesperidins can be obtained by known methods. Hesperidin can also be obtained by extracting from a natural product containing it, preferably a plant. For the hesperidin glycosyl adduct, for example, the description of Japanese Patent No. 3060227 can be referred to. Methyl hesperidin is prepared by dissolving hesperidin in an aqueous solution of sodium hydroxide, allowing a corresponding amount of dimethyl sulfuric acid to act on the alkaline solution, neutralizing the reaction solution with sulfuric acid, extracting with n-butyl alcohol, distilling off the solvent, and then distilling off the solvent. A method of recrystallizing with isopropyl alcohol (Sakiburo, Journal of Japanese Chemistry, 1958, 79, p.733-6) and the like can be referred to.
Commercially obtained hesperidins may be used. For example, as commercially available hesperidin-containing preparations, hesperidin (manufactured by Nakahara Co., Ltd.), hesperidin S (manufactured by Hayashihara Co., Ltd.), αG hesperidin H, αG hesperidin PA-T (all manufactured by Toyo Refinery Co., Ltd.), methyl Examples include hesperidin (manufactured by Tokyo Chemical Industry Co., Ltd.) and hesperidin methyl chalcone (manufactured by Sigma).
Hesperidins can be used alone or in combination of two or more. In addition, in this specification, the amount of hesperidin is a hesperidin conversion value.

As shown in Examples below, an increase in muscle hardness is observed by exercise, but oral ingestion of hesperidins significantly promotes a decrease (recovery) in muscle hardness after the exercise as compared with the non-ingestion group. It also improves the foot fatigue recovery score. It has been reported that muscle hardness changes transiently with exercise, and is an index for objectively evaluating muscle fatigue (Kazuyuki Kamiyama et al., Showa Medical Association Journal, 2004, 64 (6), p.494). -498; Yumiko Matsubara et al., Society of Physical Therapy Science, 2004, 19 (4), p.341-345). From this, hesperidins have an action of recovering muscle fatigue caused by exercise.
Therefore, hesperidins can be a muscle fatigue recovery agent associated with exercise or a recovery promoter from an increase in muscle hardness associated with exercise (hereinafter, also referred to as "muscle fatigue recovery agent associated with exercise"), and produce these. Can be used for. In addition, hesperidins can be applied to animals including humans to recover muscle fatigue associated with exercise or to promote recovery from increased muscle hardness associated with exercise.
In the present invention, "muscle fatigue" refers to a decrease in muscle strength or the ability to generate muscle power itself caused by exercise, or suppression of muscle strength or muscle power caused by preventing the collapse of these abilities (Ryota Matsuura, Bulletin of Hokkaido University Graduate School of Education, 2016, No. 125). "Recovery from muscle fatigue" also includes the concept of avoiding, reducing, and improving muscle fatigue.
"Muscle hardness" refers to the latter of the muscle hardness (muscle tone), which is roughly divided into the resistance when extending from the long axis direction and the resistance force provided by the muscle against vertical pressure (Takahisa Yonezu). Et al., Sports Medicine, 2014, No. 166). Muscle hardness can be evaluated by measuring the pushing reaction force from above the skin.
"Exercise" refers to physical exercise in a broad sense including, for example, sports, training, exercise in a narrow sense such as aerobic exercise, work involving muscular exertion, daily movement, and the like.
"Use" can be administration or ingestion to humans or non-human animals and may be therapeutic or non-therapeutic use. "Non-therapeutic" is a concept that does not include medical practice, that is, a concept that does not include a method of surgery, treatment or diagnosis of a human being, more specifically a doctor or a person who has been instructed to perform surgery on a human being. , A concept that does not include a method of performing treatment or diagnosis.

The exercise-related muscle fatigue recovery agent and the like of the present invention are pharmaceuticals, quasi-drugs or foods that exert a muscle fatigue recovery effect when ingested or administered to animals including humans, and also muscle fatigue recovery associated with the exercise. The agent or the like can be a material or preparation used in combination with the drug, quasi-drug or food.

The foods include foods (foods for specified health use, foods with functional claims) that appeal for recovery of muscle fatigue associated with exercise and are permitted to be labeled to that effect as necessary. An example of the display is "do not accumulate muscle fatigue associated with daily life and exercise". Foods that have been approved for functional labeling can be distinguished from general foods.

The administration form of the above-mentioned drug (including non-pharmaceutical products, the same applies hereinafter) may be solid, semi-solid or liquid, for example, tablets (including chewable tablets, effervescent tablets, etc.), capsules, granules (foaming). Oral administration with granules), powders, lozenges, liquids, syrups, drinks, etc .; parenteral administration with injections, suppositories, inhalants, transdermal absorbents, external preparations, etc. It is preferably a solid preparation for oral administration, and more preferably a tablet or a granule.
Formulations of such various dosage forms are optionally prepared with pharmaceutically acceptable carriers such as excipients, binders, bulking agents, disintegrants, surfactants, lubricants, dispersants, etc. It can be prepared by appropriately combining a buffer, a preservative, a flavoring agent, a fragrance, a coating agent, a carrier, a diluent and the like, and medicinal ingredients other than hesperidines.

The content of hesperidins in a pharmaceutical product varies depending on the mode of use, but is generally 2.5 to 80% by mass.

The form of the food may be solid, semi-solid or liquid, and various food compositions (breads, cakes, noodles, confectionery, jellies, frozen foods, ice creams, dairy products, beverages, etc.), Further, a nutritional supplement composition and a supplement in the same form as the above-mentioned orally administered preparation (solid preparation such as tablets, capsules and lozenges) can be mentioned. Of these, supplements are preferably in the form of solid preparations.

Various forms of foods are, as required, other food materials such as solvents, softeners, oils, emulsifiers, preservatives, acidulants, sweeteners, bitterness agents, pH regulators, stabilizers, colorants, Antioxidants, moisturizers, thickeners, fluidity improvers, foaming agents, fragrances, seasonings and the like, and active ingredients other than hesperidines can be appropriately combined and prepared.

The content of hesperidins in foods varies depending on the mode of use, but in the form of beverages, it is preferably 0.01 to 1.5% by mass, more preferably 0.012 to 1. From the viewpoint of flavor and effect. It is 4% by mass, more preferably 0.02-1% by mass.

In the form of solid foods such as tablets and processed foods, the content of hesperidins is preferably 2.5 to 80% by mass, more preferably 3 to 75% by mass, still more preferably 5 to 5 from the viewpoint of flavor and effect. It is 55% by mass.

The dose or intake of the muscle fatigue relieving agent or the like associated with exercise of the present invention may vary depending on the body weight, sex, age, condition or other factors of the subject to be administered or ingested. The dose, route, interval, and amount and interval of ingestion can be appropriately determined by those skilled in the art, but usually, as hesperidins per adult (60 kg) per day, from the viewpoint of flavor and effect. , Preferably 0.05 to 1.5 g, more preferably 0.06 to 1.4 g, still more preferably 0.1 to 1.0 g.
In the present invention, it is preferable to administer or ingest such an amount once to a plurality of times, preferably once a day.

The above formulations may be administered or ingested according to any plan.
The administration or ingestion period is not particularly limited, but it is preferable to administer or ingest repeatedly and continuously, more preferably to administer or ingest continuously for 1 day or more, and to administer or ingest continuously for 3 days or more. More preferred.
The preparation of the present invention is preferably administered or ingested during or before exercise from the viewpoint of effectively exerting its effect. More preferably, it is administered or ingested during exercise or within 30 minutes before exercise.

The subject to be administered or ingested is not particularly limited as long as it is a human or non-human animal that requires or desires recovery of muscle fatigue associated with exercise. A preferred example of the subject is human.

〔examined goods〕
As test products, tablets containing 1.0 g of hesperidins (including 0.7 g of monoglucosyl hesperidin) per 8 tablets and placebo tablets containing no hesperidins were used.
The analysis of hesperidins was performed as follows.
[Analysis of hesperidins]
Using a high performance liquid chromatograph manufactured by Hitachi, Ltd., a column Cadenza CD-C18 (4.6 mmφ × 150 mm, 3 μm) manufactured by Intact Co., Ltd. was attached, and the column temperature was 40 ° C. by the gradient method. The mobile phase A solution was a 0.05 mol / L acetic acid aqueous solution, and the B solution was acetonitrile, and the solution was fed at 1.0 mL / min. The gradient conditions are as follows.
Hours (minutes) Solution A (%) Solution B (%)
0 85 15
20 80 20
35 10 90
50 10 90
50.1 85 15
60 85 15
The sample injection volume was 10 μL, and the detection of hesperidin glycosylation was quantified by the absorbance at a wavelength of 283 nm.

[Examination outline]
1. 1. Subjects and methods A single-blind crossover study was conducted in 10 healthy adult men and women in their 20s and 50s. The rest period was 3 weeks.
Subjects were divided into two groups, a group ingested from monoglucosyl hesperidin (GHES) (5 subjects) and a group ingested from placebo (5 subjects), and the group ingested from GHES received 8 tablets containing GHES and placebo. In the group to be ingested from, 8 tablets containing no GHES were ingested while drinking water as appropriate 5 minutes before the lower limb exercise load on the first day of the test (1st day). The lower limb exercise load was performed only on the first day of the test, and the content was 150 Calf Raise exercises (raise the heel in 2 seconds and lower the heel in 2 seconds, which was continued for 10 minutes / 0.25 Hz). The following objective and subjective evaluations were performed before the lower limb exercise load (before taking the tablet), immediately after the lower limb exercise load, 6 hours and 24 hours after taking the tablet on the first day of the test. After a rest period of 3 weeks, the test products to be ingested were replaced and the same test was conducted.

2. Evaluation item (1) Muscle hardness The muscle hardness of the lateral head of the gastrocnemius muscle was measured 5 times in a standing position using a muscle hardness tester (NEUTONE / Triol Co., Ltd.). Subjects were instructed to look straight ahead during the measurement. The measurement site was marked and the same site was measured.
The measured values were recorded immediately after the lower limb exercise load, 6 hours and 24 hours after the tablet was ingested.

(2) Foot fatigue recovery score This was performed by a visual analog scale (VAS). The lower limb exercise load pre-score was set to 100, and the leg fatigue recovery score associated with exercise was calculated immediately after the lower limb exercise load, 6 hours and 24 hours after the tablet intake.

3. 3. All the subjects of statistical analysis were selected as the final subjects of analysis. For statistics, paired t-test was used, and the significance level was set to 5%. In addition, it was judged that 5% or more and less than 10% tended (* p <0.05, +0.05 <p <0.1).

4. Results Figures 1 and 2 show the results.
From these results, GHES intake significantly reduced (recovered) the muscle hardness that increased after exercise compared to placebo 6 hours after tablet intake, and improved the foot fatigue recovery score to recover muscle fatigue. It was confirmed that.

Claims (10)

An exercise-related muscle fatigue recovery agent containing glucosyl hesperidin as an active ingredient. A recovery promoter from increased muscle hardness associated with exercise, which contains glucosyl hesperidin as an active ingredient. The exercise-related muscle fatigue recovery agent according to claim 1, or the recovery promoter from an increase in muscle hardness associated with exercise according to claim 2, wherein the glucosyl hesperidin is monoglucosyl hesperidin . The muscle fatigue recovery agent associated with exercise according to claim 1 or the recovery promoter from an increase in muscle hardness associated with exercise according to claim 2, wherein the form is an oral solid preparation. The muscle fatigue recovery agent associated with the exercise according to claim 1 or the promotion of recovery from the increase in muscle hardness associated with the exercise according to claim 2, in which 0.05 to 1.5 g of glucosyl hesperidin is administered or ingested daily per adult. Agent. A food composition for relieving muscle fatigue associated with exercise containing glucosyl hesperidin as an active ingredient. A food composition containing glucosyl hesperidin as an active ingredient for promoting recovery from an increase in muscle hardness associated with exercise. The food composition for recovering muscle fatigue associated with exercise according to claim 6 or the food composition for promoting recovery from increased muscle hardness associated with exercise according to claim 7, wherein the glucosyl hesperidin is monoglucosyl hesperidin . The food composition for recovering muscle fatigue associated with exercise according to claim 6, or the food composition for promoting recovery from an increase in muscle hardness associated with exercise according to claim 7, wherein the form is an oral solid preparation. From the food composition for recovery from muscle fatigue associated with exercise according to claim 6 or the increase in muscle hardness associated with exercise according to claim 7, wherein 0.05 to 1.5 g of glucosyl hesperidin is administered or ingested daily per adult. Food composition for promoting recovery.

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