Snoring and / or bruxism reducer

Abstract

To provide an agent for reducing snoring and / or bruxism capable of being easily employed in daily life without causing unpleasant feeling or sense of incongruity, excellent in safety, and ingestible for a long period of time while having excellent reaction action of snoring and / or bruxism.SOLUTION: Provided is the agent for reducing snoring and / or bruxism including orotic acid or a salt thereof as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for reducing snoring and / or bruxism, which contains orotic acid or a salt thereof as an active ingredient. [Background technology]

[0002] Snoring is a type of noise, such as a constricted or vibrating sound, caused by the narrowing of the upper airway during sleep. Snoring can have serious adverse effects not only on health but also on social life. For example, it can impair daytime activities due to a decrease in sleep quality, disrupt the sleep of people living with you, and even cause you to avoid traveling with others due to embarrassment.

[0003] Another type of noise that occurs during sleep is "teeth grinding." Teeth grinding, also known as bruxism, can involve grinding the teeth (grinding), clenching the teeth (clenching), or tapping the teeth (clicking), but it is the grinding sound that is generally recognized as the sound of teeth grinding. Due to this unpleasant sound, teeth grinding, like snoring, can have a negative impact on health and social life.

[0004] As means for preventing or improving snoring, tapes, rings, mouthpieces, etc. for widening the nostrils or preventing mouth breathing, as well as bedding for correcting sleeping posture, are commercially available. Furthermore, nasal drops containing vasoconstrictors such as naphazoline nitrate and tetrahydrozoline hydrochloride are sometimes used to alleviate nasal congestion, which can cause snoring. Furthermore, it is known that compositions containing vegetable oils such as eucalyptus oil, mint oil, peppermint oil, olive oil, and sunflower oil can also have an anti-snoring effect (Patent Documents 1 and 2), and such compositions have also been used as foods. Meanwhile, wearing a mouthpiece is a common means for preventing or improving teeth grinding.

[0005] However, tapes, rings, mouthpieces, and the like worn on the nose and mouth tend to cause discomfort and discomfort when used, potentially resulting in poor sleep quality. Bedding and other products designed to correct sleep posture can also cause discomfort and discomfort when used, and it can be difficult to select a product that fits one's body shape, making them difficult to incorporate into daily life. Furthermore, nasal drops containing vasoconstrictors have been reported to cause side effects such as hypersensitivity, irritability, elevated blood pressure, pain due to irritation, dryness, nausea, and palpitations. Long-term use may also cause thickening of the nasal mucosa, making them unsuitable for addressing the everyday problem of snoring. While compositions containing vegetable oil ingredients pose little concern regarding side effects, their effectiveness against snoring varies widely among reports and appears to vary greatly among individuals.

[0006] Orotate (also known as orotic acid, uracil 6-carboxylic acid, orotic acid, or vitamin B13) is a key intermediate in pyrimidine nucleotide biosynthesis. It is derived from dihydroorotic acid by dihydroorotic acid dehydrogenase and converted to orotidylic acid by orotate phosphoribosyltransferase (PRPP). Orotidylic acid is then rapidly converted to uridine monophosphate (UMP), which then synthesizes pyrimidine nucleotides such as uridine triphosphate and cytidine triphosphate.

[0007] In recent years, research into the physiological effects of orotic acid has been progressing. For example, it has been reported that orotic acid has the effect of lowering blood uric acid levels (Patent Document 3), that orotic acid has the effect of improving endurance (Patent Documents 4 and 5), and that orotic acid has the effect of reducing oxygen consumption and energy consumption (Patent Document 5). However, the effect of orotic acid on snoring and teeth grinding was unknown. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Publication No. 8-333244 [Patent Document 2] Japanese Patent Application Laid-Open No. 2013-121929 [Patent Document 3] Japanese Patent Application Laid-Open No. 2011-98896 [Patent Document 4] Japanese Patent Application Laid-Open No. 2011-136907 [Patent Document 5] Japanese Patent Application Laid-Open No. 2012-246280 Summary of the Invention [Problem to be solved by the invention]

[0009] The object of the present invention is to provide an agent for reducing snoring and / or teeth grinding that has an excellent effect of reducing snoring and / or teeth grinding, but does not cause discomfort or uneasiness, can be easily incorporated into daily life, is highly safe, and can be taken over the long term. [Means for solving the problem]

[0010] As a result of extensive research to solve the above problems, the present inventors have newly discovered that orotic acid has the effect of reducing snoring and / or teeth grinding, and have thus completed the present invention.

[0011] That is, the present invention is as specified by the following items. [1] An agent for reducing snoring and / or teeth grinding, containing orotic acid or its salt as an active ingredient. [2] The agent according to [1] above, wherein the reduction in snoring and / or teeth grinding is a reduction in the frequency of snoring and / or teeth grinding. [3] The agent according to [1] or [2] above, wherein the reduction in snoring and / or teeth grinding is a reduction in the duration of snoring and / or teeth grinding. [4] The agent according to any one of [1] to [3] above, wherein the reduction in snoring and / or teeth grinding is a reduction in the volume of snoring and / or teeth grinding. [5] The agent according to any one of [1] to [4] above, which is a food or pharmaceutical product.

[0012] Further, other embodiments of the present invention can be mentioned as follows. [6] Use of orotic acid or a salt thereof for producing an agent for reducing snoring and / or teeth grinding. [7] Orotic acid or a salt thereof for use in reducing snoring and / or teeth grinding. [8] A method for reducing snoring and / or teeth grinding, comprising administering orotic acid or a salt thereof to a subject in need of reducing snoring and / or teeth grinding. [Effects of the Invention]

[0013] Orotic acid, the active ingredient of the agent for reducing snoring and / or teeth grinding of the present invention, has the effect of reducing snoring and / or teeth grinding, is highly safe without causing side effects, and is a component that can be easily taken orally. It only needs to be taken before going to bed, and does not cause any discomfort or strange feeling. Therefore, according to the present invention, it is possible to provide an excellent agent for reducing snoring and / or teeth grinding that has the effect of reducing snoring and / or teeth grinding, does not cause any discomfort or strange feeling, can be easily incorporated into daily life, is highly safe, and can be taken over the long term without side effects. [Brief explanation of the drawings]

[0014] [Figure 1] 10 is a diagram showing an example of a waveform graph of a sound recorded by the application "Deep Sleep Alarm" in Example 2. The vertical axis of the graph represents amplitude, and the horizontal axis represents time. "A" in the diagram shows an example of a waveform shape that the inventors recognized as essentially snoring, and "B" in the diagram shows an example of a waveform shape that the inventors recognized as essentially teeth grinding. DETAILED DESCRIPTION OF THE INVENTION

[0015] The agent for reducing snoring and / or bruxism of the present invention contains orotic acid or a salt thereof as an active ingredient.

[0016] In the present invention, "orotic acid" includes not only the free form (anhydride) of orotic acid, but also orotic acid hydrates such as orotic acid monohydrate, orotic acid derivatives, and pharmacologically acceptable salts thereof.

[0017] Specific examples of the orotic acid include commercially available products such as free orotic acid monohydrate (Kyowa Hakko Bio Co., Ltd. and Matsumoto Kosho Co., Ltd.), orotic acid anhydride (Kyowa Hakko Bio Co., Ltd.), and orotic acid monohydrate (Sigma-Aldrich and Wako Pure Chemical Industries, Ltd.); and orotic acid produced and accumulated in a culture medium by fermentation using various microorganisms into which mutations such as pyrimidine auxotrophy or pyrimidine analog resistance have been introduced (see, for example, Japanese Patent No. 2927882), and then purified and collected from the culture or orotic acid-containing whey using conventional purification means, such as precipitation, chromatography using ion exchange resins, activated carbon, or the like.

[0018] The "salt of orotic acid" in the present invention may be any salt with a physiologically acceptable base, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; heavy metal salts such as zinc salt; ammonium salt; salts with basic amino acids and basic peptides; and the like.

[0019] The "agent for reducing snoring and / or teeth grinding" of the present invention is a substance or composition that has the effect of reducing snoring and / or teeth grinding. That is, it can be used for the purpose of "reducing snoring and / or teeth grinding." "Snoring and / or teeth grinding" means that it may be both snoring and teeth grinding, or it may be only either snoring or teeth grinding. In the present invention, "reducing snoring and / or teeth grinding" means that the degree of snoring and / or teeth grinding is reduced, alleviated, diminished, suppressed, improved, etc. Common concerns regarding snoring and / or teeth grinding include the frequency, duration, or volume of snoring and / or teeth grinding. Therefore, "reducing snoring and / or teeth grinding" can be determined by the frequency, duration, volume, etc. of snoring and / or teeth grinding.

[0020] As the "agent for reducing snoring and / or teeth grinding" of the present invention, orotic acid or a salt thereof can be used as is, or it can be used as a food, medicine, etc. by blending it with other ingredients as described below as appropriate within a range that does not impair the effects of the present invention.

[0021] The amount of orotic acid or a salt thereof, which is the active ingredient of the "agent for reducing snoring and / or bruxism" of the present invention, is selected appropriately depending on the type of agent for reducing snoring and / or bruxism, the degree of effect expected from administration, etc., but the total amount of the active ingredient is usually 0.0001 to 100% by weight, preferably 0.001 to 70% by weight, and particularly preferably 0.01 to 50% by weight.

[0022] The "agent for reducing snoring and / or teeth grinding" of the present invention can be suitably used for "reducing the frequency of snoring and / or teeth grinding," "reducing the duration of snoring and / or teeth grinding," or "reducing the volume of snoring and / or teeth grinding." The "number of times snoring and / or teeth grinding occurs" can be expressed as the total number of times snoring and / or teeth grinding occurs, the number of times snoring and / or teeth grinding occurs per unit time, or the like. The "duration of snoring and / or teeth grinding" can be expressed as the total duration of snoring and / or teeth grinding, the duration of snoring and / or teeth grinding per unit time, or the like. The "volume of snoring and / or teeth grinding" can be expressed by the average volume or maximum volume (peak volume) of snoring and / or teeth grinding, as well as the duration of snoring and / or teeth grinding at or above a certain volume set as loud (i.e., loud volume duration). In the present invention, the volume is preferably expressed in decibels (dB), which are generally used to express noise levels. "Reduction in frequency of snoring and / or teeth grinding," "reduction in duration of snoring and / or teeth grinding," and "reduction in volume of snoring and / or teeth grinding" can be evaluated by known methods, and are not particularly limited, and can be evaluated using, for example, a sleep apnea syndrome testing device, an application with a snoring and / or teeth grinding evaluation function, a volume meter, etc.

[0023] Furthermore, the present invention provides a food or pharmaceutical product containing the agent for reducing snoring and / or teeth grinding of the present invention.

[0024] The "food" in the present invention is a food containing an effective amount of orotic acid or a salt thereof. Here, "containing an effective amount" means that the amount of the active ingredient is such that when a typical amount of the food is ingested, the active ingredient is ingested in a range as described below.

[0025] The form of the food of the present invention may be in the form of a drink. The form of the food of the present invention is not particularly limited as long as it is ingestible by mammals and is suitable for consumption, and examples thereof include solid, liquid, semi-liquid, granular, particulate, powder, capsule, cream, and paste forms.

[0026] Orotic acid or a salt thereof may be blended alone in the food of the present invention, but is usually blended together with other ingredients depending on the form of each food.

[0027] Here, the other components are not particularly limited as long as they do not impair the effects of the present invention, and examples thereof include various proteins, sugars, fats, trace elements, vitamins, organic acid salts such as citric acid and acetic acid, etc. Furthermore, the food of the present invention may contain additives that are tolerated and commonly used in foods depending on the type of food, such as sweeteners such as aspartame and stevia, acidulants such as citric acid, malic acid and tartaric acid, excipients such as dextrin and starch, as well as colorants, flavorings, bittering agents, buffers, thickening and stabilizing agents, gelling agents, stabilizers, gum bases, binders, diluents, emulsifiers, dispersants, suspending agents, antioxidants, preservatives, antiseptics, fungicides, color formers, bleaching agents, brightening agents, enzymes, seasonings, spice extracts, etc.

[0028] In the present invention, the term "food" is used to include health foods, functional foods, foods for specified health uses, nutritional supplements, and foods for the sick. In particular, it is preferable to provide foods suitable for consumers who expect the function of reducing snoring and / or teeth grinding, i.e., foods for specified health uses. The term "foods for specified health uses" as used here refers to foods that may be subject to some legal restrictions from a health perspective when manufactured or sold for the purpose of reducing snoring and / or teeth grinding.

[0029] The health foods and the like may be in the form of ordinary foods, but are preferably in the form of supplements (tablets, granules, fine granules, tablets, chewable tablets, capsules (soft capsules, hard capsules), etc.).

[0030] In the present invention, examples of foods to which orotic acid or a salt thereof may be added include, but are not limited to, beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit drinks, and dairy drinks (including concentrated concentrates and powders for adjusting these beverages); carbohydrate-containing foods and beverages such as rice, noodles, bread, and pasta; Western-style sweets such as cookies and cakes, Japanese-style sweets such as buns and yokan, candies, chewing gum, and frozen and frozen desserts such as yogurt, pudding, and jelly; processed seafood and livestock foods such as kamaboko (fish paste), chikuwa (fish cake), hamburger steak, ham, and sausage; dairy products such as processed milk, fermented milk, yogurt, butter, and cheese; oils and fats and processed oil-and-fat foods such as margarine, mayonnaise, shortening, whipped cream, and dressing; and seasonings such as sauces and dressings.

[0031] When the agent for reducing snoring and / or bruxism of the present invention is provided in the form of a food product, the amount of orotic acid or a salt thereof as the active ingredient may be any amount sufficient to exert the effect of reducing snoring and / or bruxism. However, taking into consideration the general intake of the target food product, the amount is usually such that the total intake per adult is 1 mg to 10 g, preferably 5 mg to 5 g, and more preferably 10 mg to 1 g, of orotic acid or a salt thereof. Ingestion is usually once to several times a day, preferably once a day before bedtime. The intake period is not particularly limited, but is usually one day or more, preferably one week or more, more preferably one month or more, and even more preferably two months or more.

[0032] The food of the present invention can be taken daily by, for example, people who tend to snore and / or grind their teeth excessively in frequency, duration, or volume, as well as by normal people, for the purpose of preventing or improving snoring and / or teeth grinding.

[0033] Furthermore, the "drug" in the present invention is a drug containing an effective amount of orotic acid or a salt thereof. Here, "containing an effective amount" means that when a commonly prescribed amount of each drug is taken, the active ingredient is ingested in an amount within the range described below.

[0034] When the agent for reducing snoring and / or bruxism of the present invention is provided as a pharmaceutical product, orotic acid or a salt thereof can be provided as it is, or prepared into various formulations that can be administered orally or parenterally, systemically or locally, by various known methods using appropriate additives (e.g., carriers, excipients, diluents, binders, lubricants, disintegrants or disintegration aids, solubilizers, stabilizers, preservatives, antiseptics, bulking agents, thickeners, emulsifiers, dispersants, suspending agents, buffers, etc.) that are pharmaceutically acceptable and selected appropriately depending on the dosage form.

[0035] The pharmaceutical of the present invention can be administered orally or parenterally, preferably orally, and more preferably via the oral mucosa. When the pharmaceutical of the present invention is administered orally, it may be formulated into tablets (including sugar-coated tablets), capsules, granules, powders, pills, oral solutions, suspensions, emulsions, syrups, etc., or may be made into a dried product that is redissolved before use. When the pharmaceutical of the present invention is administered parenterally, it may be formulated into injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), drip infusions, suppositories (e.g., rectal suppositories, vaginal suppositories), etc., and injectable preparations are provided in unit-dose ampoules or multi-dose containers.

[0036] Here, formulations can be prepared, for example, as follows. Oral preparations can be prepared by adding excipients (e.g., lactose, sucrose, starch, mannitol), disintegrants (e.g., calcium carbonate, carboxymethylcellulose calcium), binders (e.g., pregelatinized starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose), and lubricants (e.g., talc, magnesium stearate, polyethylene glycol 6000) to the active ingredient, compressing the mixture, and then coating it by a method known per se, if necessary, for taste masking, enteric coating, or sustained release. Examples of coating agents that can be used include ethyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and Eudragit (Rohm, Germany, methacrylic acid-acrylic acid copolymer).

[0037] When preparing a formulation, one or more active ingredients other than the active ingredient of the present invention may be further blended. Furthermore, when administering the active ingredient of the present invention, one or more medically effective active ingredients other than the active ingredient of the present invention may be administered in combination.

[0038] The pharmaceutical of the present invention can be used as a pharmaceutical for preventing and / or treating snoring and / or teeth grinding, as well as a pharmaceutical for preventing and / or treating diseases whose pathology is improved by reducing snoring and / or teeth grinding. Examples of such diseases include, but are not limited to, lifestyle-related diseases (high blood pressure, diabetes, etc.), arrhythmia, arteriosclerosis, heart disease, stroke, tooth wear, tooth mobility, hypersensitivity, periodontal tissue breakdown, temporomandibular joint dysfunction, hypertonia of the masticatory muscles, and chronic sleep deprivation. The pharmaceutical of the present invention functions as a preventive drug to suppress the onset of the above diseases and / or as a therapeutic drug to improve the condition to a normal state.

[0039] When used as a pharmaceutical for the prevention and / or treatment of the aforementioned diseases, the pharmaceutical of the present invention can be safely administered orally or parenterally to mammals such as humans, mice, rats, rabbits, dogs, and cats. The dosage of the pharmaceutical of the present invention can be appropriately determined depending on the type of disease, the age, sex, and weight of the patient, the severity of symptoms, the administration method, and the like. For example, when orally administered to a patient requiring treatment for snoring and / or bruxism, the total amount of orotic acid or a salt thereof per adult per day is typically 10 mg to 30 g, preferably 50 mg to 10 g, and more preferably 100 mg to 3 g, administered once or several times a day. Administration once a day before bedtime is particularly preferred. The administration period is not particularly limited, but is typically one day to one year, with the lower limit of the administration period being preferably one week or more, more preferably one month or more, and even more preferably two months or more. [Example]

[0040] The present invention will be explained in more detail below with reference to examples, but the technical scope of the present invention is not limited to these examples. [Example]

[0041] Snoring frequency measurement: To confirm the effect of orotic acid intake on the frequency of snoring, the following test was conducted. Using a portable sleep apnea testing device, the SAS-2100 (manufactured by Teijin Pharma Co., Ltd.), the subject (a woman in her 50s) was measured for sleep time and the total number of snores during that time. The data was visualized using the measurement software QP-021W. The number of snores per hour of sleep was calculated from the measured values. Sleep time was defined as the time from falling asleep to waking up. Measurements were conducted at the subject's home for a total of four days. On days one and two, no orotic acid was taken (control), and on days three and four, a 200 mg orotic acid tablet (formulated by API Pharmaceuticals, Inc.; the formulation is shown in Table 1) was orally taken once daily (one tablet) before bedtime. During these four days, the subject made no significant changes to their usual lifestyle, including diet and exercise.

[0042] [Table 1] 1) Free orotic acid monohydrate, Lactoceram manufactured by Matsumoto Trading Co., Ltd.

[0043] The results are shown in Table 2. The average number of snores per hour on days 1 and 2 (days without orotic acid intake) (39.1 and 75.0 respectively) was 57.05, while the average number of snores per hour on days 3 and 4 (days with orotic acid intake) (36.1 and 29.2 respectively) was 32.65. These results suggest that orotic acid intake reduces the number of snores per hour of sleep.

[0044] [Table 2] [Example]

[0045] Measurement of duration and volume of snoring and / or teeth grinding: The following test was conducted to confirm the effect of orotic acid intake on the duration and volume of snoring and teeth grinding. Using the premium version of "Jukusui Alarm" (operated by C2 Corporation, https: / / jukusui.com / ), an application that can measure sleep and snoring, the subject (one man in his 60s) was measured for bedtime, snoring time, snoring rate, loud snoring time, and peak volume. Here, "bedtime" refers to the time from going to bed to waking up, "snoring time" refers to the total time spent snoring at a volume greater than low volume, "snoring rate" refers to the proportion of snoring time spent in bed, "loud volume time" refers to the total time spent snoring that was judged to be loud, and "peak volume" refers to the volume of the loudest snore recorded (the value obtained by converting the sound pressure of the signal input by the microphone into volume (dB)). Snoring is classified as "loud," "medium," or "soft" within the application, but the criteria for this classification have not been made public. Simultaneously with these measurements, snoring was recorded using the application's snoring recording function, and the recorded data was played back and checked as necessary. Measurements were conducted at the subjects' homes for a total of three months. In the first month, the subjects took 200 mg orotic acid tablets (Table 1) several times before going to bed. However, it was difficult to see any immediate effects when compared to days when they did not take the tablets. In the end, the subjects did not take orotic acid except for those few times during the first month, and most days during that month were days when they did not take orotic acid. In contrast, in the second and third months, the subjects took 200 mg orotic acid tablets once a day (one tablet) before going to bed almost every day. During this total of three months, the subjects did not make any significant changes to their usual lifestyle, including their diet or exercise.

[0046] The results are shown in Table 3. The values ​​of snoring time, snoring rate, loud noise time, and peak volume shown in Table 3 are the average values ​​of the measurements taken at the first, second, or third month, respectively. Compared to the first month, when orotic acid was hardly taken at all, a reduction in all four items (snoring time, snoring rate, loudness time, and peak volume) was observed in the second and third months, when orotic acid was taken almost daily. Furthermore, the reduction in all four items continued not only from the first month to the second month, but also from the second month to the third month.

[0047] [Table 3]

[0048] Furthermore, when the snoring recordings were played back and reviewed, many sounds were clearly recognized as teeth grinding rather than snoring. The application used in this study, "Deep Sleep Alarm," determines snoring when sounds exceed a certain volume and duration. It simultaneously records the snoring sound volume and waveform as a graph. Comparing these waveforms with the recording data revealed that the application actually identifies teeth grinding as snoring, and that snoring and teeth grinding sounds are treated without any particular distinction in various recording data. Therefore, the "snoring" referred to in the application was essentially understood to mean "snoring and / or teeth grinding." The waveform recognized by the inventors as essentially snoring has a shape similar to "A" in Figure 1, while the waveform recognized as essentially teeth grinding has a shape similar to "B" in Figure 1. Compared to "A," the waveform "B" has a more densely packed shape, making it easy to distinguish between "A" and "B." Therefore, we manually checked the various recorded data for sounds that were recognized as teeth grinding based on the audio recording data and waveform graphs, i.e., actual teeth grinding sounds. As a result, although the ratio of actual teeth grinding to actual snoring among what the application calls snoring varied from day to day, overall, the frequency, duration, and volume of actual teeth grinding, along with actual snoring, steadily decreased from the first month to the second month and then to the third month. These results suggest the following: (1) Intake of orotic acid reduces snoring duration, snoring rate, loudness duration, and peak volume. (2) The "snoring duration, snoring rate, loud duration, and peak volume" in (1) above essentially means "snoring and / or teeth grinding duration, snoring and / or teeth grinding rate, loud duration of snoring and / or teeth grinding, and peak volume of snoring and / or teeth grinding." (3) The effect of (2) above is more pronounced with continuous intake of orotic acid than with a single intake, and the longer the intake period, the more effective it is. [Industrial Applicability]

[0049] INDUSTRIAL APPLICABILITY The present invention can be effectively used in the fields of manufacturing foods, pharmaceuticals, and the like, such as supplements and functional foods, aimed at reducing snoring and / or teeth grinding.

Claims

1. An agent for reducing snoring and teeth grinding, comprising orotic acid or a salt thereof as an active ingredient, wherein the reduction in snoring and teeth grinding is a reduction in the number, duration, or volume of snoring and teeth grinding.

2. The agent according to claim 1, wherein the reduction of snoring and teeth grinding is a reduction in the frequency, duration, and volume of snoring and teeth grinding.

3. A food or medicine for reducing snoring and teeth grinding, as described in claim 1 or 2, wherein the reduction in snoring and teeth grinding is a reduction in the frequency, duration, or volume of snoring and teeth grinding.

4. The agent according to claim 3, which is a food product and is ingested by an adult in an amount that provides a total of 10 mg to 1 g of orotic acid or a salt thereof per day.

5. The agent according to claim 3 or 4, which is taken once a day before going to bed.

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