Citrulline-containing composition

Abstract

To provide new applications for citrulline-containing compositions. [Solution] A composition containing citrulline or a salt thereof, which is for (1) improving lower back pain, stiff shoulders, or fatigue, (2) improving facial complexion (however, the person to whom the composition is administered is not a person who has subjective symptoms of poor blood circulation, fatigue, or coldness), or (3) maintaining or improving vascular function (however, the person to whom the composition is administered is not a patient with coronary artery disease or an obese postmenopausal woman).

Description

Technical Field

[0001] The present invention relates to a composition containing citrulline or a salt thereof.

Background Art

[0002] Citrulline is a kind of amino acid that does not constitute proteins in vivo and exists in vivo as a free amino acid. It is known that citrulline plays an important role in the production of nitric oxide (NO) in vivo (Non-Patent Document 1).

[0003] Citrulline is known to improve vascular functions such as the FMD value (flow-mediated dilation) of patients with coronary artery disease (Non-Patent Document 2) and the baPWV value (brachial-ankle pulse wave velocity) of postmenopausal obese women (Non-Patent Document 3). It is also known that citrulline shows a tendency to improve the perceived improvement of facial blood color in the VAS (visual analog scale) questionnaire in healthy men and women who feel cold and fatigue (Non-Patent Document 4), and that citrulline shows an effect of improving the perceived fatigue of muscles during exercise (Non-Patent Document 5).

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

[0005] The purpose of this disclosure is to investigate the effects of citrulline on vascular function and to provide new applications for citrulline-containing compositions. [Means for solving the problem]

[0006] The inventors investigated the effects of citrulline on vascular function in healthy subjects and further conducted a stratified analysis in individuals with high-normal blood pressure. Through these findings, they discovered a new function of citrulline, leading to the completion of the present invention.

[0007] In other words, this disclosure relates to the following [1] to

[10] . [1] A composition containing citrulline or a salt thereof for improving lower back pain, stiff shoulders, or fatigue. [2] A composition for improving facial complexion, containing citrulline or a salt thereof. [3] The composition described in [2], wherein the person to whom the composition is ingested or administered is not a person who has subjective symptoms of poor blood circulation, fatigue, or coldness. [4] A composition for maintaining or improving vascular function, comprising citrulline or a salt thereof. [5] The composition according to [4], wherein the person to whom the composition is ingested or administered is not a patient with coronary artery disease or an obese postmenopausal woman. [6] The composition according to any one of [1] to [5], wherein the person to whom the composition is ingested or administered is a healthy person with high-normal blood pressure. [7] The composition according to any one of [1] to [6], which is used to ingest or administer 800 mg to 5000 mg of citrulline or a salt thereof per day in terms of citrulline equivalent. [8] The composition according to any one of [1] to [7], wherein the composition is a pharmaceutical composition. [9] The composition according to any one of [1] to [7], wherein the composition is a food or beverage composition.

[10] The composition according to [9], wherein the food and beverage composition is a quasi-drug. This disclosure also relates to the following

[11] -

[41] .

[11] A method for improving lower back pain, stiff shoulders, or fatigue in a subject, by administering citrulline or a salt thereof.

[12] A method for improving the complexion of a subject's face by administering citrulline or a salt thereof.

[13] The method according to

[12] , wherein the subject is not a person who has subjective symptoms of poor blood circulation, fatigue, or coldness.

[14] A method of maintaining or improving the vascular function of a subject by administering citrulline or a salt thereof.

[15] The method according to

[14] , wherein the subject is not a patient with coronary artery disease or an obese postmenopausal woman.

[16] The method according to any one of

[11] to

[15] , wherein the subject is a healthy person with high-normal blood pressure.

[17] The method according to any one of

[11] to

[16] , wherein the subject is administered citrulline or a salt thereof in an amount of 800 mg to 5000 mg per day in citrulline equivalent.

[18] Use of citrulline or a salt thereof for the manufacture of a composition for improving lower back pain, stiff shoulders or fatigue.

[19] Use of citrulline or a salt thereof for the manufacture of a composition for improving facial complexion.

[20] Use as described in

[19] , provided that the person to whom the composition is ingested or administered is not a person who has subjective symptoms of poor blood circulation, fatigue, or coldness.

[21] Use of citrulline or a salt thereof for the manufacture of a composition for maintaining or improving vascular function.

[22] Use according to

[21] , wherein the person to whom the composition is ingested or administered is not a patient with coronary artery disease or an obese postmenopausal woman.

[23] The use according to any one of

[18] to

[22] , wherein the person to whom the composition is ingested or administered is a healthy person with high-normal blood pressure.

[24] The use described in any of

[18] to

[23] , wherein the drug is used so that 800 mg to 5000 mg of citrulline or a salt thereof is ingested or administered daily in citrulline equivalent.

[25] The use according to any one of

[18] to

[24] , wherein the composition is a pharmaceutical composition or a quasi-drug.

[26] The use according to any one of

[18] to

[24] , wherein the composition is a food or beverage composition.

[27] The use according to

[26] , wherein the food and beverage composition is a quasi-drug.

[28] Citrulline or a salt thereof for use in therapeutic methods to improve lower back pain, stiff shoulders or fatigue. Citrulline or a salt thereof for use in a therapeutic method for improving facial complexion. The citrulline or a salt thereof according to

[29] , wherein the subject to be administered with the citrulline or a salt thereof does not have subjective symptoms of poor blood circulation, fatigue or coldness. Citrulline or a salt thereof for use in a therapeutic method for maintaining or improving vascular function. The citrulline or a salt thereof according to

[31] , wherein the subject to be administered with the citrulline or a salt thereof is not a patient with coronary artery disease or a postmenopausal obese woman. The citrulline or a salt thereof according to any one of

[28] to

[32] , wherein the subject to be administered with the citrulline or a salt thereof is a healthy person with high normal blood pressure. The citrulline or a salt thereof according to any one of

[28] to

[33] , which is used such that 800 mg to 5000 mg of citrulline or a salt thereof is administered per day in terms of citrulline. Use of citrulline or a salt thereof in a non-therapeutic method for improving low back pain, shoulder stiffness or fatigue proneness. Use of citrulline or a salt thereof in a non-therapeutic method for improving facial complexion. The use according to

[36] , wherein the subject who ingests the citrulline or a salt thereof does not have subjective symptoms of poor blood circulation, fatigue or coldness. Use of citrulline or a salt thereof in a non-therapeutic method for maintaining or improving vascular function. The use according to

[38] , wherein the subject who ingests the citrulline or a salt thereof is not a patient with coronary artery disease or a postmenopausal obese woman. The use according to any one of

[35] to

[39] , wherein the subject who ingests the citrulline or a salt thereof is a healthy person with high normal blood pressure. The use according to any one of

[35] to

[40] , which is used such that 800 mg to 5000 mg of citrulline or a salt thereof is ingested per day in terms of citrulline.

Advantages of the Invention

[0008] According to the present disclosure, there is provided a composition containing citrulline or a salt thereof, which is for (1) improving low back pain, stiff shoulders or easy fatigue, (2) improving facial complexion (however, the subject of its intake or administration is not a person with subjective symptoms of poor blood circulation, fatigue or coldness), or (3) maintaining or improving vascular function (however, the subject of intake or administration of the composition is not a coronary artery disease patient or a postmenopausal obese woman).

Brief Description of the Drawings

[0009] [Figure 1] It is a graph showing the change in vascular function due to citrulline intake. (A) FMD value of all subjects, (B) baPWV value of all subjects, (C) FMD value of subjects with high-normal blood pressure, and (D) baPWV value of subjects with high-normal blood pressure. The values in the figure are represented as mean ± standard error. #: There is a significant difference from the baseline of each group (p < 0.05). *: There is a significant difference from the placebo intake group (p < 0.05). [Figure 2] It is a graph showing the amount of change from the baseline of the VAS values of low back pain and stiff shoulders due to citrulline intake. It shows the amount of change from the baseline of the VAS values of (A) low back pain and (B) stiff shoulders in subjects with high-normal blood pressure. The values in the figure are represented as mean ± standard error. *: There is a significant difference from the placebo intake group (p < 0.05).

Modes for Carrying Out the Invention

[0010] The compositions of this disclosure contain citrulline or a salt thereof. Citrulline may be the L-isomer, the D-isomer, or a mixture of the L-isomer and D-isomer in any ratio (e.g., a racemic mixture), preferably the L-isomer. Citrulline may also be a salt, but the free form is preferred. The salt of citrulline is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, malic acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with amino acids such as arginine, with salts with malic acid being preferred. Furthermore, citrulline or a salt thereof may be a solvate (e.g., a hydrate).

[0011] Citrulline or its salts may be used for therapeutic purposes or for non-therapeutic purposes. Therapeutic purposes may include, for example, medical procedures, and more specifically, procedures performed on the human body for therapeutic purposes. Non-therapeutic purposes may include, for example, purposes that do not include medical procedures, and more specifically, purposes that do not include procedures performed on the human body for therapeutic purposes. Examples of non-therapeutic purposes include health promotion and cosmetic purposes.

[0012] A composition according to one embodiment of the present disclosure is a composition for improving lower back pain, stiff shoulders, or fatigue. The target recipients of the above composition may be healthy individuals, healthy individuals with high-normal blood pressure, and preferably healthy individuals with high-normal blood pressure. In the present disclosure, hypertension means a systolic blood pressure of 140 mmHg or higher and / or a diastolic blood pressure of 90 mmHg or higher, as measured in a doctor's office (hereinafter, unless otherwise specified, blood pressure means blood pressure measured in a doctor's office), and high-normal blood pressure means blood pressure that does not meet the criteria for hypertension but is higher than the normal value. High-normal blood pressure, in one embodiment, refers to a systolic blood pressure of 130 mmHg or higher and 139 mmHg or lower and a diastolic blood pressure of 89 mmHg or lower, or a systolic blood pressure of 139 mmHg or lower and a diastolic blood pressure of 85 mmHg or higher and 89 mmHg or lower (according to the definition in the 2024 classification table of the Japan Society for Human Dock and Preventive Medicine) (https: / / www.ningen-dock.jp / other_inspection / ), and in another embodiment, refers to a systolic blood pressure of 120 mmHg or higher and 129 mmHg or lower and a diastolic blood pressure of 79 mmHg or lower (according to the definition in the Japanese Society of Hypertension's "Hypertension Treatment Guidelines 2019") (https: / / www.jpnsh.jp / guideline.html).

[0013] Improvement in lower back pain, stiff shoulders, or fatigue refers to an improvement in subjective symptoms, particularly those reported using a visual analog scale (VAS), based on the subjective evaluation of the recipient of citrulline. Note that these subjective symptoms may be temporary. Here, "lower back pain" refers to a condition in which pain or discomfort is felt in the lower back, and one aspect of "improvement of lower back pain" is, for example, the improvement or reduction of discomfort, strain, strange feeling, or pain in the lower back. Here, "stiff shoulders" refers to a condition in which the neck or the base of the neck is tight, stiff, or painful, and one aspect of "improvement of stiff shoulders" is, for example, the improvement, reduction, or alleviation of discomfort, strain, unease, pain, or stiffness in the neck or shoulders. Here, "ease with fatigue" does not refer to muscle fatigue caused by exercise, but rather to fatigue in daily life. As one aspect of "improving ease with fatigue," examples include improving, reducing, or alleviating various types of fatigue, such as physical or mental fatigue, fatigue from work or studying, or fatigue from office work or housework.

[0014] A composition according to one embodiment of this disclosure is a composition for improving facial complexion. The person to whom the above composition is administered may not be a person who has subjective symptoms of poor blood circulation, fatigue, or coldness, and / or a healthy person with high-normal blood pressure. Improvement of facial complexion refers to an improvement in subjective symptoms based on the subjective evaluation of the person who has ingested or been administered citrulline, particularly evaluation using the Visual Analog Scale (VAS) method. For example, improvement in complexion, improvement in skin tone, and improvement in a brighter complexion (healthy skin color) are also examples of "improvement of facial complexion".

[0015] A composition according to one embodiment of this disclosure is a composition for maintaining or improving vascular function. The target recipients of the above composition are not patients with coronary artery disease or obese postmenopausal women, and / or healthy individuals with high-normal blood pressure. In this disclosure, vascular function means vascular function as evaluated based on FMD value and / or baPWV value. FMD value and baPWV value are academically agreed-upon evaluation methods for vascular function, as listed in the "Guidelines on Non-Invasive Evaluation Methods for Vascular Function" created jointly by the Japanese Circulation Society and several other academic societies. FMD value has recently attracted attention as an examination method for evaluating vascular endothelial function, and since it is the degree of endothelium-dependent expansion after constricting the blood vessel, it serves as an indicator of vascular flexibility. PWV value is the speed at which a pulse wave travels through an artery. A pulse wave is a wave that is transmitted to the periphery from the impact of blood being pumped out from the heart. baPWV value means the PWV value between the upper arm and ankle. Since the PWV value increases as the artery stiffens, it serves as an indicator of vascular elasticity. Maintaining or improving vascular function means improving vascular function, suppressing the decline of vascular function (maintaining vascular function), or mitigating (delaying) the decline of vascular function. The degree of maintenance or improvement of vascular function can be evaluated using the above-mentioned FMD value and / or baPWV value as indicators. For FMD values, the higher the value, the better the vascular function, and for baPWV values, the lower the value, the better the vascular function. Furthermore, one aspect of "maintaining or improving vascular function" is, for example, maintaining or improving the flexibility of blood vessels, maintaining or improving the suppleness of blood vessels, and maintaining or improving the degree of vascular dilation.

[0016] The compositions of this disclosure are preferably used to ingest or administer 800 mg to 5000 mg of citrulline or a salt thereof per day in terms of citrulline equivalent. "In terms of citrulline equivalent" means the amount excluding the mass of the salt when it is a salt of citrulline. For example, if the salt of citrulline is citrulline malate, then 1412 mg to 8827 mg of citrulline malate corresponds to 800 mg to 5000 mg of citrulline. The above amount of ingestion or administration may be 800 mg to 3000 mg, 1500 mg to 3000 mg, 2000 mg to 3000 mg, or 2500 mg to 3000 mg. The frequency of ingestion or administration may be once a day or multiple times a day (for example, two or three times).

[0017] The compositions of this disclosure may be, for example, food and beverage compositions or pharmaceutical compositions. That is, this disclosure provides, for example, food and beverage compositions for improving lower back pain, stiff shoulders, or fatigue, food and beverage compositions for improving facial complexion, and food and beverage compositions for maintaining or improving vascular function. This disclosure also provides, for example, pharmaceutical compositions for improving lower back pain, stiff shoulders, or fatigue, pharmaceutical compositions for improving facial complexion, and pharmaceutical compositions for maintaining or improving vascular function. Each food and beverage composition or pharmaceutical composition can be manufactured according to conventional methods. Furthermore, the content of citrulline or its salts in the food and beverage composition or pharmaceutical composition is not particularly limited and can be freely set according to the purpose.

[0018] If the composition of this disclosure is a food or beverage composition or a pharmaceutical composition, the food or beverage composition or pharmaceutical composition may contain, in addition to citrulline or a salt thereof as an active ingredient, components that can be commonly used in food or beverage compositions or pharmaceutical compositions. A food or beverage composition or pharmaceutical composition according to one embodiment may contain bases, carriers, additives, etc., that are commonly used in food or beverage compositions or pharmaceutical compositions. Examples of additives include excipients, oils, powders, buffers, solubilizers, antioxidants, surfactants, thickeners, preservatives, pH adjusters, chelating agents, stabilizers, irritation reducers, antiseptics, pigments, colorants, fragrances, gloss enhancers, gelling agents, alcohols, water-soluble polymers, film-forming agents, resins, etc. The bases, carriers, and the various additives described above can be used individually or in combination as needed.

[0019] The food and beverage compositions of this disclosure are not particularly limited, as long as they contain citrulline or a salt thereof as an active ingredient. The food and beverage compositions may be provided in any form, such as liquid, paste, solid, or powder.

[0020] Food and beverage compositions may be, for example, food and beverages themselves, or materials used in the manufacture of food and beverages. Such materials include seasonings, food additives, and other food ingredients. Specifically, food and beverage compositions include beverages (lactic acid bacteria beverages, soft drinks, alcoholic beverages, carbonated beverages, milk beverages, fruit juices, tea, coffee, nutritional drinks, etc.), powdered beverages (powdered juices, powdered soups, etc.), concentrated beverages, wheat flour products, instant foods, processed agricultural products, processed marine products, processed livestock products, dairy products (fermented milk, cheese, infant formula, etc.), oils and fats, basic seasonings, compound seasonings, frozen foods, confectionery, and other commercially available food and beverages. Specifically, food and beverage compositions may also include health foods, functional foods, enteral nutrition foods, foods for special dietary uses, health functional foods (foods for specified health uses, nutrient function foods, foods with functional claims, etc.), nutritional supplements, and quasi-drugs. Food and beverage compositions may also include, for example, tablet-shaped supplements.

[0021] The food and beverage compositions of this disclosure can be manufactured, for example, by combining citrulline or a salt thereof, which is an active ingredient, with additional ingredients. The operation of combining an active ingredient with additional ingredients is also referred to as "addition of the active ingredient." The method of manufacturing the food and beverage compositions of this disclosure is not particularly limited. Except for the addition of the active ingredient, the food and beverage compositions of this disclosure can be manufactured, for example, using the same raw materials as ordinary foods and beverages and in the same manner as ordinary foods and beverages. The same applies when the food and beverage compositions of this disclosure are manufactured as materials used in the manufacture of foods and beverages. The addition of the active ingredient may be carried out at any stage of the manufacturing process of the food and beverage composition. The addition of the active ingredient may be carried out, for example, during or after the manufacture of the food and beverage composition. That is, for example, the food and beverage compositions of this disclosure may be manufactured by adding the active ingredient to a pre-prepared food or beverage.

[0022] Furthermore, other food and beverage compositions can be manufactured using the food and beverage compositions of this disclosure. That is, for example, if the food and beverage compositions of this disclosure are provided as materials used in the manufacture of food and beverages (seasonings, food additives, other food and beverage ingredients, etc.), other food and beverage compositions may be manufactured by adding the food and beverage compositions of this disclosure. Such other food and beverage compositions are also examples of food and beverage compositions of this disclosure. The description of the addition of active ingredients in the manufacture of food and beverage compositions may be applied mutatis mutandis to the addition of the food and beverage compositions of this disclosure in the manufacture of food and beverage compositions.

[0023] The food and beverage compositions disclosed herein may be provided and sold as food and beverages labeled with intended uses (including health uses) such as improving lower back pain, stiff shoulders, or fatigue, improving facial complexion, and maintaining or improving vascular function. The food and beverage compositions disclosed herein may be provided and sold as food and beverages labeled with intended targets.

[0024] "Display" includes all actions taken to inform consumers of the aforementioned uses, and any expression that can evoke or infer the aforementioned uses constitutes a "display," regardless of the purpose, content, object, or medium of the display. In particular, the display may be carried out using expressions that allow consumers to directly recognize the aforementioned uses.

[0025] Specifically, examples of indications include transferring, delivering, displaying for transfer or delivery, or importing products relating to the food and beverage compositions of this disclosure or products whose packaging includes the above-mentioned uses; displaying or distributing advertisements, price lists, or transaction documents relating to the products that include the above-mentioned uses; or providing information containing these materials by electromagnetic means (such as the Internet). Examples of indications include indications on packaging, containers, catalogs, brochures, promotional materials at sales sites (such as POP displays), or other documents.

[0026] Examples of labeling include labels for health foods, functional foods, enteral nutrition foods, foods for special dietary uses, health functional foods (foods for specified health uses, nutrient function foods, foods with functional claims, etc.), nutritional supplements, and quasi-drugs. Preferably, the labeling is approved by the government of each country (for example, a labeling approved under various systems established by the government and carried out in accordance with such approval). Examples of labeling approved by the government include labels approved by the Consumer Affairs Agency of Japan. Examples of labeling approved by the Consumer Affairs Agency of Japan include labels approved under the health functional food system (foods for specified health uses, nutrient function foods, foods with functional claims, etc.) and similar systems. Specifically, examples of labeling approved by the Consumer Affairs Agency of Japan include labels as foods for specified health uses, labels as conditionally specified health uses, labels indicating an effect on the structure or function of the body, labels indicating a reduction in disease risk, and labels indicating scientifically based functionality. More specifically, the labels approved by the Consumer Affairs Agency of Japan include labels for Foods for Specified Health Uses (especially labels for health purposes) and similar labels as defined in the Cabinet Office Ordinance concerning the Permission for Special Use Labeling under the Health Promotion Act (Cabinet Office Ordinance No. 57 of August 31, 2009).

[0027] The content of citrulline or its salt in the food and beverage composition of this disclosure is not particularly limited, as long as it is within a range where, for example, 800 mg to 5000 mg, 800 mg to 3000 mg, 1500 mg to 3000 mg, 2000 mg to 3000 mg, or 2500 mg to 3000 mg of citrulline or its salt can be ingested per day in terms of citrulline equivalent.

[0028] The pharmaceutical compositions of this disclosure are not particularly limited, as long as they contain citrulline or a salt thereof as an active ingredient.

[0029] The pharmaceutical compositions disclosed herein may be formulated into desired dosage forms as appropriate. The dosage forms of the pharmaceutical compositions disclosed herein are not particularly limited. The dosage forms of the pharmaceutical compositions disclosed herein can be appropriately selected according to various conditions such as the method of administration. The pharmaceutical compositions disclosed herein may be for oral administration or for parenteral administration. The pharmaceutical compositions disclosed herein may be particularly for oral administration. In the case of oral administration, examples of dosage forms include solid preparations such as powders, granules, tablets, and capsules, and liquid preparations such as solutions, syrups, suspensions, and emulsions. In the case of parenteral administration, examples of dosage forms include suppositories and ointments.

[0030] The method of formulation is not particularly limited. Formulation can be carried out, for example, by known methods depending on the dosage form. Physiologically acceptable additives can be used in formulation. Examples of additives include various organic and inorganic components. Specifically, examples of additives include excipients, binders, disintegrants, lubricants, stabilizers, flavoring and odor-correcting agents, pH adjusters, colorants, diluents, surfactants, and solvents. These additives can be appropriately selected, for example, depending on various conditions such as the dosage form.

[0031] Excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate.

[0032] In addition to the above-mentioned excipients, other examples of binders include gelatin, polyvinylpyrrolidone, and macrogol.

[0033] In addition to the above-mentioned excipients, disintegrants include chemically modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium, and cross-linked polyvinylpyrrolidone.

[0034] Examples of lubricants include talc; stearic acid; metal stearate salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as beecam and gayl wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid and silicic acid hydrate; and starch derivatives.

[0035] Examples of stabilizers include para-hydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; and sorbic acid.

[0036] Flavoring and odor-modifying agents include sweeteners, acidulants, and flavorings.

[0037] The citrulline or salt content in the pharmaceutical composition of this disclosure is not particularly limited, as long as it is within a range where, for example, 800 mg to 5000 mg, 800 mg to 3000 mg, 1500 mg to 3000 mg, 2000 mg to 3000 mg, or 2500 mg to 3000 mg of citrulline or salt thereof can be administered per day in citrulline equivalent.

[0038] The method disclosed herein is a method comprising administering citrulline or a salt thereof to a subject. This step is also referred to as the “administration step.” The subject to which citrulline or a salt thereof is administered is also referred to as the “administration target.”

[0039] The method of the present invention can be used, for example, to improve lower back pain, stiff shoulders, or fatigue in a target recipient, to improve the complexion of the target recipient's face, or to maintain or improve the vascular function of a target recipient. When the method of this disclosure is used to improve lower back pain, stiff shoulders, or fatigue in a target recipient, the target recipient may be a healthy person, or a healthy person with high-normal blood pressure, preferably a healthy person with high-normal blood pressure. When the method of this disclosure is used to improve the complexion of the target recipient's face, the target recipient may not be a person with subjective symptoms of poor circulation, fatigue, or coldness, and / or a healthy person with high-normal blood pressure. When the method of this disclosure is used to maintain or improve the vascular function of a target recipient, the target recipient may not be a patient with coronary artery disease or an obese postmenopausal woman, and / or a healthy person with high-normal blood pressure. The target recipient may be of any age, such as infants, children, adults, middle-aged and elderly people, but adults, middle-aged and elderly people are preferred.

[0040] Furthermore, "administering citrulline or its salts to the target" can be used interchangeably or equivalently with "ingesting citrulline or its salts to the target." Administration may be oral or parenteral, but oral administration is preferred. Examples of parenteral administration include enteral administration, rectal administration, and intranasal administration.

[0041] The administration conditions for citrulline or its salts (e.g., target population, duration of administration, frequency of administration, dosage, and other administration conditions) are not particularly limited, as long as the target population's lower back pain, stiff shoulders, or fatigue improves, their facial complexion improves, or their vascular function is maintained or improved. The administration conditions for citrulline or its salts can be appropriately set according to various conditions such as the type of citrulline or its salt, the type of target population, age, and health condition. It is preferable to administer citrulline or its salts in amounts of 800 mg to 5000 mg per day in citrulline equivalent, but these may be 800 mg to 3000 mg, 1500 mg to 3000 mg, 2000 mg to 3000 mg, or 2500 mg to 3000 mg. The frequency of administration may be once a day or multiple times a day (e.g., two or three times). The duration of administration of citrulline or its salts may be, for example, 1 day or more, 3 days or more, 1 week or more, 2 weeks or more, 4 weeks or more, 2 months or more, 3 months or more, 4 months or more, 6 months or more, 9 months or more, or 12 months or more, or 10 years or less, 5 years or less, 1 year or less, or 6 months or less, or within a range of non-inconsistent combinations thereof. Citrulline or its salts may be administered, for example, throughout the subject's lifetime, or for a period of the subject's lifetime. Citrulline or its salts may be administered, for example, until the subject's lower back pain, stiff shoulders or fatigue improves, until the subject's facial complexion improves, or until the subject's vascular function is maintained or improved.

[0042] Citrulline or its salts may be administered to a subject as is, for example, or prepared as a composition such as a food or beverage composition or a pharmaceutical composition containing citrulline or its salts and administered to a subject. The descriptions of compositions in this disclosure may be applied mutatis mutandis to compositions containing citrulline or its salts. Citrulline or its salts may be administered alone or in combination with additional components. Examples of additional components include food and beverages, pharmaceuticals, and components contained therein. Furthermore, the descriptions of additional components contained in compositions in this disclosure may be applied mutatis mutandis to additional components used in the methods of this disclosure.

[0043] Citrulline or a salt thereof may also be administered to a subject, for example, by using the composition of the Disclosure (specifically, by administering the composition of the Disclosure to the subject). That is, one aspect of the method of the Disclosure may include administering the composition of the Disclosure to the subject. In other words, "administration of citrulline or a salt thereof" also includes the administration of the composition of the Disclosure. The administration conditions of the composition of the Disclosure (e.g., the subject, duration of administration, number of administrations, dosage, and other administration conditions) are not particularly limited, as long as the subject's lower back pain, stiff shoulders, or fatigue is improved, the subject's facial complexion is improved, or the subject's vascular function is maintained or improved. The administration conditions of the composition of the Disclosure may be set as appropriate depending on various conditions such as the type and amount of citrulline or a salt thereof, the type and amount of additional components, the type and dosage form of the composition, the type of subject, age, and health condition. The description of the administration conditions for citrulline or a salt thereof may be applied mutatis mutandis to the administration conditions of the composition of the Disclosure. Furthermore, the dosage of the composition of this disclosure can be set to obtain, for example, the dosage of citrulline or a salt thereof as illustrated above. The composition of this disclosure may also be administered alone or in combination with additional components.

[0044] This disclosure also relates to the use of citrulline or its salts for manufacturing compositions for improving lower back pain, stiff shoulders, or fatigue; for manufacturing compositions for improving facial complexion; or for manufacturing compositions for maintaining or improving vascular function. This disclosure also relates to citrulline or its salts for use in therapeutic methods for improving lower back pain, stiff shoulders, or fatigue; for use in therapeutic methods for improving facial complexion; or for use in therapeutic methods for maintaining or improving vascular function. This disclosure also relates to the use of citrulline or its salts in non-therapeutic methods for improving lower back pain, stiff shoulders, or fatigue; in non-therapeutic methods for improving facial complexion; or in non-therapeutic methods for maintaining or improving vascular function. [Examples]

[0045] The effects of citrulline were investigated based on the following studies.

[0046] 1. Subjects

[0047] 1) Target The candidates were Japanese men and women who met the following selection criteria and did not violate any exclusion criteria.

[0048] 2) Selection Criteria The subjects were healthy adult men and women who met all of the following criteria. (1) Healthy men and women aged 45 to 70: However, women must be postmenopausal. Menopause is defined as the absence of menstruation for at least one year. (2) Individuals with an FMD value of 5.5% or less. (3) Those whose baPWV value is 1400 cm / sec or higher. (4) Those who have received a full explanation of the purpose and content of the examination, have the capacity to give consent, fully understand it, voluntarily apply to participate, and give written consent to participate in this examination.

[0049] 3) Exclusion criteria (1) Persons suffering from or with a history of severe cardiovascular disorders, hepatic disorders, renal disorders, respiratory disorders, endocrine disorders, or metabolic disorders. (2) Persons receiving medical treatment (prescription of medication by a doctor). (3) Anyone who takes supplements or health foods (including Foods for Specified Health Uses and Foods with Function Claims) during the examination period. (4) Any person who regularly uses pharmaceuticals, supplements, health foods, or cosmetics containing L-citrulline, L-arginine, L-ornithine, procyanidin, bonito elastin, linolenic acid, DHA, EPA, CoQ10, nattokinase, lutein, blueberry, blackcurrant, vitamin E, ginkgo biloba extract, melilot, or polyphenols (such as hesperidin, flavangenol, and pycnogenol). (5)(4) Any person who regularly uses any medicine, supplement, health food, or cosmetic product intended to improve blood flow and blood pressure, in addition to the ingredients listed in (4). (6) Persons currently participating in or willing to participate in studies involving the intake of other foods or the use of pharmaceuticals, or persons who have participated as subjects in other clinical trials within the past three months prior to participating in this study. (7) Individuals who consume excessive amounts of alcohol (more than 20g of pure alcohol per day on average). (8) Persons with a smoking habit (those who have smoked daily or occasionally in the past three months). (9) Anyone who has received hormone replacement therapy within three months prior to participating in the study. (10) Persons suffering from asthma. (11) Persons with severe anemia. (12) Persons whose lifestyle becomes irregular multiple times during the research period due to day and night shift work or night work, or persons who are engaged in physical labor such as carrying heavy objects. (13) Anyone who is pregnant or plans to become pregnant or breastfeed during the examination period. (14) Any person whom the principal investigator deems unsuitable as a subject based on the results of the screening tests. (15) Any person who is diagnosed by the principal investigator as suffering from any disease or any other person whom the principal investigator deems unsuitable as a subject.

[0050] Test design Randomized, double-blind, placebo-controlled, parallel-group comparative trial

[0051] 2.Analysis method 1) Analysis of effectiveness Within each group, the values ​​at baseline, week 6, and week 12 of intake were compared using Dunnett's test. Between groups, the Mann-Whitney U test was performed on the measured values ​​at week 6 and week 12, as well as the change from baseline.

[0052] Each evaluation item is expressed as mean ± SEM (standard error), except for baseline subject characteristic data, which is expressed as mean ± SD (standard deviation). Statistical analysis was performed using SAS® (SAS 9.4), and all tests were performed at a significance level of 5%.

[0053] 2) Stratified analysis A subgroup analysis was conducted on individuals with high-normal blood pressure (systolic blood pressure of 130 mmHg or higher and 139 mmHg or lower and diastolic blood pressure of 89 mmHg or lower, or systolic blood pressure of 139 mmHg or lower and diastolic blood pressure of 85 mmHg or higher and 89 mmHg or lower) based on baseline blood pressure values.

[0054] 3. Measurement of vascular function FMD value: The vascular diameter expansion rate (in %) was calculated from the value obtained by dividing the maximum vascular dilation width (mm) by the resting vascular diameter (mm) using the UNEX EF38G (manufactured by UNEX). baPWV value: The baPWV value was measured using a Vascular Profiler BP-203RPETM system (manufactured by Omron Corporation).

[0055] 4. Blood pressure measurement Measurements were taken using the HEM-705IT (manufactured by Omron Healthcare). Systolic and diastolic blood pressure were measured at least twice in a resting state, and the last value was used.

[0056] 5. Evaluation of subjective indicators Using the Visual Analog Scale (VAS) method, a questionnaire was administered to assess the subjects' subjective experiences regarding four items related to vascular function: "lower back pain," "stiff shoulders," "ease of fatigue," and "facial complexion."

[0057] The VAS (Visual Analog Scale) questionnaire evaluation uses a numerical value from 0 to 100 points for each evaluation item. Specifically, in this study, participants answered questions about their current condition regarding the evaluation items "lower back pain," "stiff shoulders," "ease of fatigue," and "facial complexion" by drawing a line on a 100mm linear scale, with the left end representing "not feeling at all," the middle representing "neither," and the right end representing "feeling very strongly." They then used a ruler to record the length from the left end, which was used as the evaluation value (1mm equivalent to 1 point).

[0058] 6. Test product We purchased L-citrulline (free form) from Kyowa Hakko Bio Co., Ltd. and prepared two types of granular powder test products. Specifically, we prepared a citrulline product containing 3,000 mg of L-citrulline per serving and a placebo product containing 3,000 mg of maltose instead of L-citrulline. The nutritional components of each test product are shown in Table 1.

[0059] [Table 1]

[0060] 7. Test results 1) Test subjects Sixty-six participants who met the selection criteria were randomly assigned to either the citrulline intake group or the placebo intake group using a stratified block randomization method with sex, age, and vascular function (FMD value, baPWV value) as allocation factors. After randomization, one participant dropped out from each group before the start of intake of the test product, resulting in 32 participants completing the study in both the citrulline and placebo groups. Case review revealed no other excluded cases besides the dropouts, and the 32 participants in the citrulline group and 32 participants in the placebo group were designated as the efficacy analysis subjects (FAS population: full analysis set population), and PPS (per protocol set) analysis was not performed.

[0061] The baseline characteristics of all subjects (Table 2) and those with high-normal blood pressure (Table 3) are shown below. In Tables 2 and 3, "Variables" indicates the analysis items, "Placebo" indicates the placebo group, "Citrulline" indicates the citrulline group, and "p" indicates the significance probability between the placebo group and the citrulline group. The explanations of the abbreviations in Tables 2 and 3 are given below. BMI: Body Mass Index FMD: Flow-mediated dilation baPWV:brachial-ankle Pulse Wave Velocity ABI: Ankle Brachial Index WBC: White Blood Cell RBC: Red Blood Cell HGB: hemoglobin HCT: hematocrit PLT: platelet TP: Total Protein ALB: albumin CRE: creatinine BUN: Blood Urea Nitrogen UA: Uric Acid AST: Aspartate Aminotransferase ALT: Alanine Aminotransferase γ-GT: gamma-Glutamyl Transferase ALP: Alkaline Phosphatase LD: Lactate Dehydrogenase ​​​​​​​​​​​​​​​​​​​​​​​​​​ [Table 3]

[0064] 2) Vascular function In the analysis of all subjects, no significant differences were observed between the citrulline intake group and the placebo intake group in FMD values ​​and baPWV values ​​(Figure 1(A) and (B)). On the other hand, in the stratified analysis of subjects with high-normal blood pressure at baseline, the citrulline intake group showed a significant improvement in FMD values ​​compared to the placebo intake group (Mann-Whitney U test) (Figure 1(C)). Furthermore, only in the citrulline intake group did the baPWV values ​​(measured values) at week 6 and week 12 of intake show a significant improvement compared to the measured values ​​at baseline (Dunnett test) (Figure 1(D)). The Smirnov-Grubbs test was also performed as an outlier test.

[0065] 3) Evaluation of subjective indicators In the analysis of all subjects, no significant differences were observed between the citrulline intake group and the placebo intake group for any VAS score. However, only in the citrulline intake group were the measured values ​​for "lower back pain" at 12 weeks of intake, "stiff shoulders" at 6 and 12 weeks of intake, "fatigue" at 12 weeks of intake, and "facial complexion" at 6 and 12 weeks of intake significantly lower than baseline measured values ​​(Dunnet test). Furthermore, in the stratified analysis of individuals with high-normal blood pressure at baseline, only in the citrulline intake group were the measured values ​​for "lower back pain" at 12 weeks of intake, "stiff shoulders" at 12 weeks of intake, "fatigue" at 12 weeks of intake, and "facial complexion" at 6 and 12 weeks of intake significantly lower than baseline measured values ​​(Dunnet test) (Table 4). Furthermore, a significant decrease in the change from baseline was observed in the citrulline intake group compared to the placebo intake group, both for "lower back pain" at 12 weeks of intake and for "stiff shoulders" at 6 weeks of intake (Mann-Whitney U test) (Figures 2(A) and (B)).

[0066] [Table 4]

[0067] 4) Conclusion The results of this study revealed the following effects of citrulline. 1) Improvement in lower back pain, stiff shoulders, fatigue, and facial complexion in all subjects compared to before citrulline intake at 6 weeks and / or 12 weeks of intake. 2) Improvement in lower back pain and stiff shoulders at 6 or 12 weeks of intake in subjects with normal-high blood pressure, compared to the placebo group. 3) Improvement in FMD values ​​and baPWV values ​​at 6 weeks and / or 12 weeks of citrulline intake compared to before intake in subjects with high-normal blood pressure. Improvement in FMD values ​​at 12 weeks of intake compared to the placebo group in subjects with high-normal blood pressure.

Claims

1. A composition containing citrulline or a salt thereof for improving lower back pain, stiff shoulders, or fatigue.

2. A composition for improving facial complexion, containing citrulline or a salt thereof (however, the person to whom the composition is administered is not a person who has subjective symptoms of poor blood circulation, fatigue, or coldness).

3. A composition for maintaining or improving vascular function, containing citrulline or a salt thereof (however, the target recipients of the composition are not patients with coronary artery disease or obese postmenopausal women).

4. The composition according to any one of claims 1 to 3, wherein the person to be ingested or administered the composition is a healthy person with high-normal blood pressure.

5. The composition according to any one of claims 1 to 3, which is used to ingest or administer 800 mg to 5000 mg of citrulline or a salt thereof per day in terms of citrulline equivalent.

6. The composition according to any one of claims 1 to 3, wherein the composition is a pharmaceutical composition.

7. The composition according to any one of claims 1 to 3, wherein the composition is a food or beverage composition.

8. The composition according to claim 7, wherein the food and beverage composition is a quasi-drug.

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