JP2024066467A - Creatine compound-containing agent - Google Patents

Abstract

The present invention provides a drug, quasi-drug, food, drink, etc. that has the effect of reducing muscle stiffness. The present invention provides a muscle stiffness reducing agent that contains a creatine compound.

Description

The present invention relates to an agent for reducing muscle stiffness.

Muscles are divided into striated and smooth muscles, and striated muscles include cardiac and skeletal muscles. After continuous contraction load on skeletal muscles or after attempting unfamiliar exercise, muscle stiffness increases. Specific situations in which muscle stiffness increases include stepping in sports competitions and descending stairs. Continuing to exercise with reduced flexibility of skeletal muscles increases the load on joints and muscle tissue, increasing the risk of injury such as muscle tears, and can also cause a breakdown in the form required to demonstrate original athletic performance.

Other factors that can increase muscle stiffness include electrolyte imbalance, muscle diseases, and taking medications such as statins. Poor posture and physical inactivity due to long hours of PC work, which have become problematic in recent years as causes of lower back pain and stiff shoulders, can also be factors that increase muscle stiffness (Non-Patent Document 1). Supporting this, it has been reported that there is a significant correlation between subjective symptoms of stiff shoulders in the trapezius muscle and muscle stiffness evaluated by ultrasound elastography (Non-Patent Document 2).

Conventionally, static stretching, cooling with ice packs, cold water baths, and massage have been used to improve muscle stiffness. Static massage is generally performed to increase the range of motion of joints, and has been reported to reduce muscle stiffness, but it takes a certain amount of time to be fully effective (Non-Patent Document 3). Self-massage is said to have little effect on reducing muscle stiffness and to last for a short time (Non-Patent Document 4). Oral medications are also used as a method to improve muscle stiffness. Tizanidine, methocarbamol, epirizone, chlorzoxazone, and other muscle relaxants are used, but these are pharmaceuticals and cannot be taken easily, and side effects have been reported, although they occur infrequently.

To reduce muscle stiffness, gel-type topical preparations (Patent Document 1) that contain as an active ingredient a squeezed liquid, extract, or distillate from a plant of the genus Abies in the family Pinaceae, and a food composition (Patent Document 2) that contains glucosyl hesperidin as an active ingredient have been proposed, but there is still a demand for substances that are safe to use and that reduce muscle stiffness or improve muscle flexibility.

Creatine compounds have been widely used by athletes and training enthusiasts as a food that can be safely used to improve performance or increase muscle mass. Creatine monohydrate ingested from food is taken up by various organs, including skeletal muscles, and stored in tissues as creatine phosphate. It then reacts with adenosine diphosphate (ADP) to restore the amount of adenosine triphosphate (ATP), thereby providing an energy source for muscle activity. It is known that regular intake of creatine compounds can increase the amount of creatine in tissues and maintain high muscle activity, not only for athletes but also for ordinary people, and is expected to have effects such as increasing muscle mass and improving muscle strength (Non-Patent Document 5). However, there have been no reports on muscle flexibility using creatine compounds.

Creatine compounds in the body not only increase when ingested through food, but can also be synthesized in tissues such as the kidneys, liver, and pancreas, and are distributed throughout the body.

JP 2021-46377 A Patent No. 6787944

Appl Ergon. 2020;82:102947. Kagawa Prefectural University of Health Sciences Journal 2021;12:27-31. J Physiol. 2008;586:97-106. Scand J Med Sci Sports. 2015;25(5):e490-6. Nutrients. 2021;13(6):1915.

The object of the present invention is to provide, as one embodiment, an agent for reducing muscle stiffness.

Means for Solving the Problems The present inventors conducted extensive research to solve the above problems and unexpectedly discovered that creatine compounds have the effect of reducing muscle stiffness and easing muscle tension, which led to the completion of the present invention.
That is, the present invention provides
(1) A muscle stiffness reducing agent, characterized by containing a creatine compound;
(2) A muscle tension relaxant, characterized by containing a creatine compound.
(3) A recovery promoter for muscle stiffness or muscle tension caused by exercise, comprising a creatine compound.
(4) The agent according to any one of (1) to (3), in which 0.001 to 20 g of the creatine compound is administered or ingested per day.
(5) The agent according to any one of (1) to (4), wherein the creatine compound is at least one selected from the group consisting of creatine, creatine monohydrate, creatine anhydrous, creatine phosphate, creatine citrate, creatine hydrochloride, creatine nitrate, creatine malate, creatine orotate, creatine pyruvate, creatine maleate, creatine phosphate, creatine nitrate, creatine maleate, creatine methyl ester, creatine ethyl ester, creatine sulfate, creatine leucinate, creatine gluconate, cyclocreatine, and polyethylene glycosylate creatine.
It is.

The present invention makes it possible to provide an agent for reducing muscle stiffness or improving muscle flexibility. The agent of the present invention can help perform sports movements with the correct posture (form), reduce the risk of sports injuries, and prevent and improve stiff shoulders and lower back pain.

1 is a graph showing the change over time in muscle hardness of the biceps (10 cases per group, the average value ± standard deviation of the rate of change from baseline (Pre) is shown. The Pre points indicate muscle hardness after 28 days of intake of the creatine compound or placebo. *p<0.05, **p<0.01 vs. placebo group (after two-way analysis of variance, post-hoc testing was performed using the Bonferroni method, and the risk rate was set to less than 5%)). 1 is a graph showing the change over time in muscle circumference of the upper arm (10 cases per group, the average value ± standard deviation of the rate of change from baseline (Pre) is shown. The Pre points indicate the muscle circumference after 28 days of intake of the creatine compound or placebo. *p<0.05, **p<0.01 vs. placebo group (after two-way ANOVA, post-hoc test was performed using the Bonferroni method, and the risk rate was set to less than 5%)).

The agent of the present invention is characterized by containing a creatine compound.

"Creatine compound" refers to creatine or its derivatives, their salts, or their hydrates. Derivatives of creatine refer to esterified creatine, creatine with an amino acid added, creatine with gluconic acid added, creatine with sugar added, cyclized creatine, etc. Preferred are creatine, creatine monohydrate, creatine anhydrate, creatine phosphate, creatine citrate, creatine hydrochloride, creatine nitrate, creatine malate, creatine orotate, creatine pyruvate, creatine maleate, creatine phosphate, creatine nitrate, creatine maleate, creatine methyl ester, creatine ethyl ester, creatine sulfate, creatine leucinate, creatine gluconate, cyclocreatine, and polyethylene glycosylate creatine, more preferably creatine, creatine monohydrate, creatine hydrochloride, creatine ethyl ester, creatine nitrate, creatine malate, and even more preferably creatine monohydrate.

These creatine compounds are commercially available as foods or chemically synthesized products, but they may also be synthesized from arginine, glycine, methionine, guanidinoacetic acid, sarcosinic acid, cyanamide, etc., or may be extracted from natural products containing creatine compounds. The creatine compounds used in the present invention may be used as they are in the form of extracts or separated products, or as a dilution solution diluted with an appropriate solvent, or may be prepared as a concentrated extract, dried powder, or paste.

The purity of the creatine compound used in the present invention is not particularly limited, but considering the characteristics, palatability, intake amount, safety, etc. of various food compositions and pharmaceuticals, a high purity compound is preferable. High purity means a purity of 99.9% or more.

The creatine compound of the present invention can be administered or ingested by animals, preferably mammals, and more preferably humans. When ingested by humans, the daily intake of the creatine compound (when multiple creatine compounds are contained, the total amount, the same applies below) can be appropriately increased or decreased taking into account age, sex, body weight, etc., but is preferably 1 mg to 30 g, more preferably 0.5 g to 20 g, and even more preferably 3 g to 20 g. When ingested at one time, if the amount exceeds 30 g, a bad texture on the tongue or discomfort in the oral cavity may occur.

The creatine compound of the present invention is preferably taken for 7 days or more, more preferably 14 days or more, and even more preferably 28 days or more. By continuing to take it, it is possible to maintain a favorable muscle condition, such as reducing muscle stiffness and muscle tension, and it can be safely taken for a long period of time.

In the present invention, "reducing muscle stiffness" refers to reducing or decreasing muscle stiffness, and reducing muscle stiffness includes improving muscle flexibility, and the agent of the present invention has the effect of improving the soft and supple properties of muscles.

Muscle stiffness increases when muscles are repeatedly stretched in a certain direction, when muscles are not moved for a certain period of time, when muscles are overexercised, or due to neuromuscular diseases, but increased muscle stiffness can lead to muscle stiffness and stiffness. When muscle stiffness decreases, muscles can better perform their natural functions, such as movement, maintaining posture, stabilising joints, and protecting bones and joints.

In one embodiment, "muscle stiffness" can also be expressed as the resistance a muscle has when stretched, or the resistance a muscle offers or exerts against an external pressure.

Muscle hardness can be evaluated by palpation from the body surface or by a push-in muscle hardness meter, and can also be measured using elastography with an ultrasound device (elastography method). A push-in muscle hardness meter can measure hardness, and the shear wave method, which is one of the elastography methods, can measure stiffness. Hardness is the resistance provided by a muscle against vertical pressure from the outside, such as the body surface, and stiffness is the resistance to change in length along the muscle's long axis. Muscle hardness may be hardness and/or stiffness.

Stiffness evaluated by the shear wave method, which is one of the elastography methods, can evaluate the pressure and stress of each tissue in absolute values (units: kPa) from the tissue-specific difference in the propagation speed of shear waves irradiated from the ultrasound probe of an ultrasound device to the tissue. If the muscle is stiff, the shear wave propagates quickly, and if the muscle is soft, the shear wave propagates slowly. It is known that hardness measured with a push-in muscle hardness meter is affected by factors such as the hardness of skin tissue, while stiffness measured with the shear wave method can objectively evaluate the hardness of the muscle tissue itself.

In the present invention, "relieving muscle stiffness" refers to reducing or alleviating muscle stiffness, for example, reducing or alleviating muscle stiffness, muscle contracture, muscle rigidity, and muscle swelling. When muscles are stretched and stiffened for a long period of time due to maintaining a certain posture, etc., the muscles become tense, and this can mean alleviating such a condition or alleviating a state in which the muscles are persistently and strongly rigid.

In one embodiment, "muscle stiffness" can be expressed as resistance when trying to extend or bend the body, and when muscles are tense, it can manifest as symptoms such as difficulty in moving, awkwardness, and lack of smooth movement. Reducing or alleviating muscle stiffness or muscle stiffness can make it easier to extend or bend the body, and the above symptoms can improve.

Muscle firmness can be assessed by measuring the circumference of each part of the muscle; as muscle firmness increases, so does muscle circumference.

In one embodiment, increasing muscle stiffness increases muscle tension and stiffness, and decreasing muscle stiffness (increasing muscle flexibility) reduces muscle stretching and reduces tension and stiffness.

In the present invention, "exercise" includes physical exercise in the broad sense, including walking, labor, daily movements, etc., in addition to exercise in the narrow sense, such as strength training, aerobic exercise, and sports competitions. The agent of the present invention can shorten the time it takes for muscle stiffness or muscle tension to return to the normal state when muscle stiffness or tension increases due to the above exercise.

The muscle stiffness reducing agent, muscle stiffness relieving agent, and agent for promoting recovery from exercise-induced muscle stiffness or exercise-induced muscle stiffness of the present invention include agents for preventing an increase in muscle stiffness and preventing the occurrence or increase of muscle stiffness.

Examples of conditions in which physiological functions or tissue functions related to muscle stiffness or muscle tension are impaired include stiff shoulders, stiff neck, back stiffness, back stiffness, lower back pain, sports injuries, impaired athletic performance, and muscle fatigue, and further impaired conditions include skeletal muscle damage, contracture, edema, convulsions, and neuromuscular diseases. Therefore, the agent of the present invention can be used as an agent for preventing or improving stiff shoulders, stiff neck, back stiffness, back stiffness, lower back pain, sports injuries, impaired athletic performance, muscle fatigue, and the like. It can also be used as an agent for preventing or improving skeletal muscle damage, contracture, edema, convulsions, and neuromuscular diseases.

In addition to the creatine compound, the agent of the present invention may contain vitamins, amino acids, minerals, herbal medicines and their extracts, etc., within the scope of the present invention. Then, excipients, disintegrants, binders, lubricants, antioxidants, coating agents, colorants, flavorings, etc. may be added, and further pH adjusters, cooling agents, suspending agents, antifoaming agents, thickening agents, solubilizing agents, surfactants, fragrances, etc. may be added as necessary, and the agent may be provided in the form of oral solid preparations such as tablets, capsules, powders, granules, dry syrups, or oral liquid preparations such as drinks, beverages, concentrated beverages, solid effervescent beverages, and powdered beverages, in a conventional manner. The state of the creatine compound in the oral liquid preparation may be either dissolved or dispersed, and the state of its existence is not important.

The administration form of the agent of the present invention is not particularly limited and may be oral or parenteral, with oral administration being preferred. Dosage forms for oral administration include tablets, powders, granules, liquids, capsules, dry syrups, jellies, etc. Dosage forms for parenteral administration include external preparations such as lotions, creams, ointments, and patches, as well as injections, etc.

When the agent of the present invention is used as a food or drink, specific examples include liquid foods such as powders, granules, drinks, soups, milk drinks, soft drinks, tea drinks, alcoholic drinks, jelly drinks, and functional drinks; oil-containing products such as edible oils, dressings, mayonnaise, and margarine; carbohydrate-containing foods such as rice, noodles, and bread; processed livestock foods such as ham and sausage; processed seafood foods such as kamaboko, dried fish, and salted fish; processed vegetable foods such as pickles; semi-solid foods such as jelly and yogurt; fermented foods such as miso and fermented drinks; various confectioneries such as Western confectioneries, Japanese confectioneries, candies, gummies, frozen desserts, and ice desserts; retort products such as curry, thickened sauce, and Chinese soup; instant foods such as instant soup and instant miso soup, and microwaveable foods. Furthermore, health foods and drinks prepared in the above shapes are also included. These can be produced by manufacturing techniques known in the art.

The muscle stiffness reducing agent, muscle stiffness relieving agent, or agent for promoting muscle stiffness increase or muscle stiffness increase associated with exercise (medicine, quasi-drug, food, drink, etc.) of the present invention and its instruction manual may be labeled with a label indicating that it is used to reduce muscle stiffness, a label indicating that it is used to relieve muscle stiffness, or a label indicating that it is used to promote muscle stiffness increase associated with exercise or muscle stiffness increase associated with exercise. Here, "labeled" includes a label indicating that it is written on the main body, container, packaging, etc. of the product containing the muscle stiffness reducing agent, muscle stiffness relieving agent, or agent for promoting muscle stiffness increase associated with exercise or muscle stiffness increase associated with exercise, or a label indicating that it is written on documents such as instructions, package inserts, pamphlets, and other printed materials disclosing product information, and a label indicating that it is written on various leaflets and advertisements used for advertising including the Internet. In addition, even if it is labeled with a label indicating that it has other functions, or there is no label indicating a function, the scope of the present invention includes a product that substantially has a muscle stiffness reducing effect, a muscle stiffness relieving effect, an increase in muscle stiffness associated with exercise, or a muscle stiffness increase associated with exercise, or a muscle stiffness increase associated with exercise, or a muscle stiffness increase associated with exercise, or a muscle stiffness increase associated with exercise, but does not have such a label indicating a function.

Representative examples of the present invention will be described in detail below.
Example 1

Evaluation of 1) muscle stiffness and 2) muscle circumference using eccentric muscle contraction load in humans A double-blind parallel group comparative study was conducted on 20 healthy adult males. The subjects were divided into two groups, a creatine group and a placebo group, and the creatine group was given 3 g of creatine monohydrate (Creapure (trademark), AlzChem Trostberg GmbH) and the placebo group was given 3 g of crystalline cellulose for 28 days.
After that, the subject sat on an arm curl bench at a height where the hip joint was flexed 85 degrees, and performed eccentric muscle contraction load (exercise load) using a dumbbell. The exercise load was based on the maximum isometric muscle strength (100%) of the elbow flexion muscles measured using a manual muscle dynamometer (Mobie, Sakai Medical Co., Ltd.), and was set to a load of 50% of the maximum isometric muscle strength (adjusted weight of dumbbell) x 10 times, with a total of 5 sets (2 minutes interval between sets). The load was applied by holding a dumbbell and extending the elbow joint from 90° to 180° for 5 seconds, and then bending it to 90° for 2 seconds without holding a dumbbell (extension and flexion counted as one time).
The measurement points (time points) were before exercise load (Pre), immediately after exercise load (Post), 1 hour, 24 hours, 48 hours, 72 hours, 96 hours, and 168 hours after the exercise load on the test day. A marking was made at a location that was approximately 50% of the length of the upper arm from the acromion process of the scapula to the lateral epicondyle of the humerus, and 1) muscle hardness and 2) muscle circumference were measured at the marking location.

1) Muscle stiffness measurement Using an ultrasound imaging diagnostic device (Aplio 300, Canon Inc.), muscle stiffness was measured at each time point at the marking site. The rate of change in muscle stiffness at each time point relative to the muscle stiffness before eccentric muscle contraction load (exercise load) was calculated using the following (Equation 1). The results are shown in Figure 1 (rate of change in muscle stiffness).

(Equation 1)
Percentage change in muscle stiffness (%) = muscle stiffness at each time point / muscle stiffness before exercise × 100

When the placebo was taken, muscle stiffness increased immediately after exercise and tended to increase further over time, whereas when creatine monohydrate was taken, the increase in muscle stiffness was suppressed, and it was revealed that muscle stiffness was significantly lower than in the placebo group after 96 hours and 168 hours. It was confirmed that application of the product of the present invention can improve muscle flexibility after exercise and suppress the increase in muscle stiffness over time after exercise or maintain flexibility.

2) Muscle circumference measurement The circumference of the muscle at the marking was measured at each time point using a tape measure. The rate of change in muscle circumference at each time point relative to the muscle circumference before eccentric muscle contraction load (exercise load) was calculated using the following (Equation 2). The results are shown in Figure 2 (rate of change in muscle circumference).

(Equation 2)
Change in muscle circumference (%) = muscle circumference at each time point / muscle circumference before exercise × 100

When the placebo was taken, muscle circumference increased immediately after exercise and tended to increase over time again from 24 hours later, whereas when creatine monohydrate was taken, the increase in muscle circumference was suppressed, and it was revealed that muscle circumference was significantly lower than the placebo group after 96 hours and 168 hours. It was confirmed that the application of the product of the present invention can alleviate muscle stiffness after exercise and suppress the increase in muscle stiffness over time after exercise.

Therefore, it has become clear that creatine compounds can be used to reduce muscle stiffness or muscle tension, and have the effect of maintaining physiological functions and tissue functions related to muscle stiffness or muscle tension in good condition, improving deteriorated functions, and preventing the deterioration of functions.

(Formulation Examples 1 to 11)
The following formulations were prepared. In the table, creatine monohydrate may be a creatine compound other than creatine monohydrate.
[Formulation Example 1]
The raw materials of Formulation 1 shown in Table 1 were mixed in powder form to prepare a powder formulation.
[Formulation Example 2]
The raw materials of Formulation 1 shown in Table 1 were mixed in powder form and subjected to wet granulation to prepare granules.
[Formulation Example 3]
The raw materials of Formulation 2 shown in Table 2 were mixed in powder form to prepare a powder formulation.
[Formulation Example 4]
The raw materials of Formulation 3 shown in Table 2 were mixed in powder form to prepare a powder formulation.
[Formulation Example 5]
The raw materials of Formulation 4 shown in Table 2 were mixed in powder form to prepare a powder formulation.
[Formulation Example 6]
The raw materials of Formulation 5 shown in Table 2 were mixed in powder form to prepare a powder formulation.
[Formulation Example 7]
The raw materials of Formulation 2 shown in Table 2 were mixed in powder form and subjected to wet granulation to prepare granules.
[Formulation Example 8]
The raw materials of Formulation 3 shown in Table 2 were mixed in powder form and subjected to wet granulation to prepare granules.
[Formulation Example 9]
The raw materials of Formulation 4 shown in Table 2 were mixed in powder form and subjected to wet granulation to prepare granules.
[Formulation Example 10]
The raw materials of Formulation 5 shown in Table 2 were mixed in powder form and subjected to wet granulation to prepare granules.
[Formulation Example 11]
The raw materials of Formulation 4 shown in Table 2 were mixed in powder form, and granules were prepared by wet granulation, which were then compressed into tablets.

The present invention can provide medicines, quasi-drugs, food and beverages, etc. that are highly safe and can be taken for a long period of time and have the effect of reducing muscle stiffness. The agent of the present invention can be effectively used as medicines, quasi-drugs, food and beverages, etc. for the purpose of preventing and improving stiff shoulders, lower back pain, sports injuries, and other muscle damage, and for helping to improve athletic performance by reducing muscle stiffness. In addition, it can be used for the purpose of maintaining physiological functions and tissue functions of the body related to muscle stiffness, improving deteriorated functions, and preventing functional decline.

Claims (5)

A muscle stiffness reducing agent that contains a creatine compound. A muscle relaxant characterized by containing a creatine compound. An agent for promoting recovery from exercise-induced muscle stiffness or muscle stiffness, characterized by containing a creatine compound. The agent according to any one of claims 1 to 3, in which 0.001 to 20 g of the creatine compound is administered or ingested per day. The agent according to any one of claims 1 to 3, wherein the creatine compound is at least one selected from the group consisting of creatine, creatine monohydrate, creatine anhydrous, creatine phosphate, creatine citrate, creatine hydrochloride, creatine nitrate, creatine malate, creatine orotate, creatine pyruvate, creatine maleate, creatine phosphate, creatine nitrate, creatine maleate, creatine methyl ester, creatine ethyl ester, creatine sulfate, creatine leucinate, creatine gluconate, cyclocreatine, and polyethylene glycosylate creatine.