Agent for preventing or improving nocturia, waking up in the middle of the night, or frequent urination

Abstract

To provide a preventive or improver for nocturia, to provide a preventive or improver for halfway awakening, or to provide a preventive or improver for frequent urination.SOLUTION: α- Mangostin can exhibit multiple effects of improving sleep disorders, improving bladder capacity, and improving nocturnal polyuria, and can be used as an active ingredient of a preventive or improver for nocturia, a preventive or improver for halfway awakening, and a preventive or improver for frequent urination.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an agent for preventing or improving nocturia, an agent for preventing or improving the agent for preventing or improving, and an agent for preventing or improving frequent urination.

Background Art

[0002] As urination dysfunction, there are frequent urination and nocturia presenting symptoms of increased urination frequency. Frequent urination is also called daytime frequent urination, which is a symptom of having a large number of urination times from waking up in the morning to going to bed. Generally, it refers to a symptom where the frequency of frequent urination is 8 times or more on average from waking up in the morning to going to bed. On the other hand, nocturia generally refers to a symptom where the number of urination times is 1 time or more on average from going to bed to waking up. The causes of frequent urination and nocturia are different, and the two do not necessarily coexist. Among patients with nocturia, many are normal during the daytime.

[0003] The causes of frequent urination are diverse, including prostatic hyperplasia, overactive bladder, residual urine, polyuria, urinary tract infection, cystitis, prostatic tumor, bladder cancer, psychogenic factors, etc. Frequent urination is accompanied by the annoyance and stress caused by frequent urination, which reduces QOL (Quality of life). Therefore, various pharmaceuticals and foods have been developed for the purpose of improving frequent urination. For example, Patent Document 1 describes that a β3 - adrenergic receptor stimulant can be used as an agent for preventing and treating frequent urination and urinary incontinence. Also, Patent Document 2 describes that a substituted guanidine compound or its salt having Na + / H + exchange transporter inhibitory activity can be used as an agent for preventing and treating frequent urination and urinary incontinence.

[0004] Moreover, nocturia is known to be caused by complex factors such as nocturnal polyuria, reduced bladder capacity, and sleep disorders. Nocturia causes nocturnal awakening due to the urge to urinate during sleep and is closely related to sleep disorders, significantly reducing QOL. Conventionally, various pharmaceuticals and foods have been developed for the improvement of nocturia. For example, Patent Document 3 describes that a specific pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or a salt thereof can be used as a prophylactic or therapeutic agent for nocturia. Further, Patent Document 4 describes that rosmarinic acid or a salt thereof can be used as a prophylactic or improving agent for nocturia.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0006] Conventionally, components for improving frequent urination or nocturia have been developed, but there are cases where the effects are insufficient, or they cannot be applied to foods and cannot be taken daily. There is an urgent need to develop new components that can prevent or improve frequent urination or nocturia. In addition, there is also an urgent need to develop new components that can prevent or improve intermediate awakening, which is one of the causes of nocturia.

[0007] Therefore, one of the problems of the present invention is to provide a prophylactic or improving agent for nocturia. Another problem of the present invention is to provide a prophylactic or improving agent for intermediate awakening. Still another problem of the present invention is to provide a prophylactic or improving agent for frequent urination.

Means for Solving the Problems

[0008] The present inventors intensively studied to solve the above problems, and found that α-mangostin can exhibit a combined effect of improving sleep disorder, improving bladder capacity, and improving nocturia, and can be used as an active ingredient of a prophylactic or therapeutic agent for nocturia, a prophylactic or therapeutic agent for middle-of-the-night awakening, and a prophylactic or therapeutic agent for frequent urination. The present invention has been completed by further studies based on such findings.

[0009] That is, the present invention relates to the prophylactic or therapeutic use of nocturia, and provides inventions in the following aspects. Item 1-1. A prophylactic or therapeutic agent for nocturia containing α-mangostin. Item 1-2. The prophylactic or therapeutic agent according to Item 1-1, wherein the α-mangostin includes an extract and / or processed product of mangostin. Item 1-3. The prophylactic or therapeutic agent according to Item 1-1 or 1-2, which is used for the prevention or improvement of nocturia caused by at least one selected from the group consisting of sleep disorder, decreased bladder capacity, and nocturia. Item 1-4. The prophylactic or therapeutic agent according to any one of Items 1-1 to 1-3, which is used for the prevention or improvement of nocturia not caused by prostatic hyperplasia or nocturia in women. Item 1-5. Use of α-mangostin for the manufacture of a prophylactic or therapeutic agent for nocturia. Item 1-6. A method for preventing or improving nocturia, which comprises administering or ingesting α-mangostin to a person who requires prevention or improvement of nocturia. Item 1-7. α-Mangostin, which is used for a treatment for the prevention or improvement of nocturia.

[0010] In addition, the present invention relates to the prophylactic or therapeutic use of middle-of-the-night awakening, and provides inventions in the following aspects. Item 2-1. A prophylactic or therapeutic agent for middle-of-the-night awakening containing α-mangostin. Item 2-2. The prophylactic or therapeutic agent according to Item 2-1, wherein the α-mangostin includes an extract and / or processed product of mangostin. Item 2-3. The preventive or ameliorating agent according to Item 2-1 or 2-2, which is used for preventing or ameliorating middle-of-the-night awakening in a person having symptoms of nocturia. Item 2-4. The preventive or ameliorating agent according to any one of Items 2-1 to 2-3, which is used for preventing or ameliorating middle-of-the-night awakening in a person having symptoms of nocturia not caused by prostatic hyperplasia or in a woman. Item 2-5. Use of α-mangostin for producing a preventive or ameliorating agent for middle-of-the-night awakening. Item 2-6. A method for preventing or ameliorating middle-of-the-night awakening, which comprises administering or causing a person in need of prevention or amelioration of middle-of-the-night awakening to ingest α-mangostin. Item 2-7. α-Mangostin, which is used for a treatment for preventing or ameliorating middle-of-the-night awakening.

[0011] Furthermore, the present invention relates to use for preventing or ameliorating frequent urination, and provides inventions in the following aspects. Item 3-1. A preventive or ameliorating agent for frequent urination, which contains α-mangostin. Item 3-2. The preventive or ameliorating agent according to Item 3-1, wherein the α-mangostin includes an extract and / or a processed product of mangostin. Item 3-3. The preventive or ameliorating agent according to Item 3-1 or 3-2, which is used for preventing or ameliorating frequent urination caused by a decrease in bladder capacity. Item 3-4. The preventive or ameliorating agent according to any one of Items 3-1 to 3-3, which is used for a person having symptoms of both frequent urination and nocturia. Item 3-5. The preventive or ameliorating agent according to any one of Items 3-1 to 3-4, which is used for preventing or ameliorating frequent urination not caused by prostatic hyperplasia or frequent urination in a woman. Item 3-6. Use of α-mangostin for producing a preventive or ameliorating agent for frequent urination. Item 3-7. A method for preventing or ameliorating frequent urination, which comprises administering or causing a person in need of prevention or amelioration of frequent urination to ingest α-mangostin. Item 3-8. α-Mangostin, which is used for a treatment for preventing or ameliorating frequent urination.

Advantages of the Invention

[0012] According to the present invention, the use of alpha-mangosteen can exert a combined effect of improving sleep disorders, bladder capacity, and nocturnal polyuria, thereby making it possible to effectively prevent or improve nocturnal frequency of urination, waking up in the middle of the night, or frequent urination. [Brief explanation of the drawings]

[0013]

Figure 1

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Figure 3

Figure 4

Figure 5

[0014] 1. Definition As used herein, "nocturia" refers to a condition in which the number of urination times between going to bed and waking up is one or more on average, and a person has to wake up during sleep to urinate.

[0015] In this specification, "urinary urge stress" refers to stress such as worry (anxiety), bother, tension, pain, fatigue, lethargy, irritation (irritability), depression (depression), and the like caused by the urge to urinate.

[0016] As used herein, the term "agent for preventing or ameliorating nocturia" refers to an agent used to prevent the onset of nocturia, or to alleviate, relieve or inhibit the progression of the symptoms of nocturia.

[0017] In this specification, "awakening during the night" refers to a state in which one wakes up during sleep and is unable to fall asleep thereafter, and is also called "night awakening."

[0018] As used herein, the term "agent for preventing or ameliorating middle-of-the-night awakenings" refers to an agent used to prevent middle-of-the-night awakenings or reduce the number of middle-of-the-night awakenings.

[0019] As used herein, "frequent urination" refers to a symptom of frequent urination (generally an average of 8 times or more) between waking up in the morning and going to bed.

[0020] As used herein, the term "agent for preventing or ameliorating frequent urination" refers to an agent used to prevent the onset of frequent urination, or to relieve, alleviate, or inhibit the progression of the symptoms of frequent urination.

[0021] 2. Agent for preventing or improving nocturia The agent for preventing or ameliorating nocturia of the present invention is characterized by containing α-mangostin as an active ingredient. The prevention or amelioration of nocturia of the present invention will be described in detail below.

[0022] [α-Mangosteen] The prophylactic or ameliorating agent for nocturia of the present invention uses α-mangostin as an active ingredient. α-Mangostin has an effect of improving sleep disorders (such as effects on melatonin receptors and orexin receptors), an effect of improving bladder capacity, and an effect of improving nocturia, and can comprehensively improve the causes of nocturia.

[0023] α-Mangostin is a xanthone derivative present in Garcinia mangostana. The α-mangostin used in the present invention may be derived from mangostin, or may be produced by microbial engineering techniques or chemical synthesis. The α-mangostin used in the present invention may be a purified product, a crude purified product, or an unpurified product.

[0024] Also, an extract and / or processed product of mangostin containing α-mangostin may be used as an active ingredient in the prophylactic or ameliorating agent for nocturia of the present invention.

[0025] The mangostin extract is an extract obtained by subjecting mangostin to an extraction process.

[0026] In the production of the mangostin extract, the pericarp of mangostin can be preferably used as an extraction raw material, but in addition to the pericarp, fruits, fruit juices, stems, leaves, branches, branch leaves, trunks, barks, root barks, roots, seeds, etc. may also be included. The extraction raw material may be in a raw state, but may be subjected to pretreatment such as pulverization, cutting, steaming, kneading, drying, roasting, etc. as necessary.

[0027] In addition, for the extraction process to obtain the mangosteen extract, any common extraction method used in the production of plant extracts may be employed. For example, solvent extraction, supercritical extraction, steam distillation, etc. may be mentioned. Among these, solvent extraction is preferably used. Examples of the extraction solvent used in the solvent extraction process include water; lower alcohols having 1 to 4 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, and n-butanol; polyhydric alcohols such as propylene glycol and 1,3-butylene glycol; ketones such as acetone; chain and cyclic ethers such as tetrahydrofuran and diethyl ether; polyethers such as polyethylene glycol; and mixtures thereof. Among these extraction solvents, water, lower alcohols, and mixtures thereof are preferably used, more preferably water, ethanol, and aqueous ethanol, and even more preferably aqueous ethanol. The ethanol content in the aqueous ethanol is, for example, 10 to 95% by volume, preferably 50 to 95% by volume, and more preferably 70 to 90% by volume.

[0028] The solvent extraction process may be carried out by immersing or refluxing the extraction target site of mangostin in the extraction solvent. After the extraction process, the solid matter is removed by solid-liquid separation to obtain a mangostin extract containing α-mangostin. The obtained extract may be used as a liquid extract as it is, or if necessary, part or all of the solvent may be removed and used as a concentrated extract or a dried extract.

[0029] In addition, the processed product of mangostin may be any processed product of the mangostin site containing α-mangostin. It is preferably a processed product of the pericarp of mangostin. However, in addition to the pericarp, processed products containing fruits, fruit juices, stems, leaves, branches, branch leaves, trunks, barks, root barks, roots, seeds, etc. may also be used. The processed product of mangostin includes dried products, crushed products, etc. of the mangostin site containing α-mangostin.

[0030] [Dosage form · Form] The dosage form of the agent for preventing or ameliorating nocturia of the present invention is not particularly limited, and may be any of solid, semi-solid, and liquid forms.

[0031] The agent for preventing or ameliorating nocturia of the present invention is preferably in a form that is taken orally orally administered, but may also be in a form that is administered enterally or by injection.

[0032] Specific examples of the agent for preventing or ameliorating nocturia of the present invention include foods and beverages and oral pharmaceuticals (including oral quasi-drugs).

[0033] When the agent for preventing or improving nocturia of the present invention is in the form of a food (i.e., when provided as a food for preventing or improving nocturia), the active ingredient may be prepared into the desired form either as is or in combination with other food materials or additives. Examples of such foods include general foods and beverages, as well as foods with health claims (including foods for specified health uses, foods with nutrient functions, and supplements), foods for patients, and the like. The form of these foods is not particularly limited, but specific examples include supplements such as capsules (soft capsules and hard capsules), tablets, granules, powders, jellies, and liposome preparations; luxury items such as gummies, candies, and jellies; and beverages such as tea drinks, energy drinks, fruit juice drinks, carbonated drinks, and lactic acid drinks. Among these foods, supplements are preferred.

[0034] When the agent for preventing or ameliorating nocturia of the present invention is in the form of a food, the content of α-mangostin in the food may be appropriately determined based on the daily intake / administration amount, taking into consideration the type of food, the physique, age, symptoms, etc. of the subject, and may be, for example, 1 to 80% by weight, preferably 5 to 50% by weight, and more preferably 10 to 25% by weight. Here, when an extract or processed product of mangosteen is used, the content of α-mangostin is the value converted into the amount of α-mangostin in the extract or processed product.

[0035] When the agent for preventing or ameliorating nocturia of the present invention is formulated as an oral medicine (including oral quasi-drugs), the active ingredient may be prepared into a desired form either as is or in combination with other additives, etc. Specific examples of such oral medicines include drinks, tablets, pills, powders, fine granules, granules, capsules (including hard capsules and soft capsules), lozenges, chewable tablets, extracts (including soft extracts, dry extracts, etc.), jellies, syrups, spirits, elixirs, liposome preparations, etc.

[0036] When the agent for preventing or improving nocturia of the present invention is in the form of an oral medicine, the content of α-mangostin in the oral medicine may be appropriately determined based on the daily intake / administration amount, taking into consideration the type of oral medicine, the physique, age, symptoms, etc. of the subject, and may be, for example, 1 to 80% by weight, preferably 5 to 70% by weight, and more preferably 10 to 65% by weight. Here, when a mangosteen extract or processed product is used, the content of α-mangostin is the value converted into the amount of α-mangostin in the extract or processed product.

[0037] [Application / Dosage] The agent for preventing or improving nocturia of the present invention is used for those who require prevention of nocturia or those who have the symptoms of nocturia.The agent for preventing or improving nocturia of the present invention reduces the frequency of frequent urination during sleep, thereby reducing awakenings during the night and improving sleep quality.In addition, the agent for preventing or improving nocturia of the present invention reduces the frequency of frequent urination during sleep, thereby alleviating the psychological burden (worry, anxiety, bother, etc.) caused by waking up to urinate during sleep and improving vitality.

[0038] The prophylactic or ameliorating agent for nocturia of the present invention has an effect of improving sleep disorder, an effect of improving bladder capacity, and an effect of improving nocturia. Therefore, it can exhibit an excellent ameliorating effect on nocturia caused by one or more (preferably two or more, more preferably three) of sleep disorder, decreased bladder capacity, and nocturia. For example, it can exhibit an excellent ameliorating effect on nocturia not caused by prostatic hyperplasia and nocturia in women.

[0039] In one aspect of the prophylactic or ameliorating agent for nocturia of the present invention, for example, sleep disorder caused by aging (for example, 40 years old or older); sleep disorder caused by urinary urgency; sleep-wake rhythm disorder caused by modulation of the body clock; sleep disorder caused by diseases of the body such as hypertension and heart disease (chest pain), mental diseases such as depression, etc.; sleep disorder caused by administration of therapeutic drugs such as antihypertensive agents, thyroid preparations, anticancer agents, etc., intake of stimulants such as caffeine, etc., administration or intake of drugs and stimulants; sleep disorder caused by disruption of the body rhythm due to shift work, jet lag, etc.; sleep disorder caused by the environment such as noise and light, etc. It can improve nocturia caused by such sleep disorders. From the viewpoint of more effectively improving nocturia, in one aspect of the prophylactic or ameliorating agent for nocturia of the present invention, preferably, it is used for improving nocturia caused by sleep disorder caused by aging, urinary urgency, disease of the body or mental disease, more preferably, for improving nocturia caused by sleep disorder caused by aging or urinary urgency, and still more preferably, for improving nocturia caused by sleep disorder caused by urinary urgency.

[0040] Since the prophylactic or ameliorating agent for nocturia of the present invention can improve anxiety (uneasiness), annoyance, tension, pain, fatigue, lassitude, irritation (irritability), depression (mood drop), etc. caused by nocturnal urinary urgency, it is possible to reduce or improve urinary urgency stress.

[0041] In particular, the nocturia preventive or ameliorating agent of the present invention can also exhibit an excellent ameliorating effect on nocturia in persons with sleep disorders with short-term intake or administration. Therefore, the nocturia preventive or ameliorating agent of the present invention can be suitably used for preventing or ameliorating nocturia in persons with sleep disorders. Here, the "person with sleep disorder" refers to a person with a total score of Pittsburgh Sleep Quality Index (PSQIG) of less than 6.5.

[0042] In one aspect of the nocturia preventive or ameliorating agent of the present invention, for example, among those who require prevention or amelioration of nocturia, those who are concerned about urinary troubles such as frequent urination and urgency of urination, those who are worried about going out due to urinary troubles, those who are concerned about urinary troubles due to aging, those who are concerned about urinary troubles associated with aging (for example, 40 years old or older), etc. can be preferably applied. In addition, the nocturia preventive or ameliorating agent of the present invention can also be preferably applied to healthy persons who feel stress due to worry (anxiety), annoyance, etc. caused by urinary urge among those who require prevention or amelioration of nocturia, although they do not require treatment at a hospital or the like.

[0043] The target subjects for application of the nocturia preventive or ameliorating agent of the present invention may be mammals including humans, preferably humans.

[0044] As the intake or dosage of the nocturia preventive or ameliorating agent of the present invention, for example, about 1 to 2000 mg, preferably about 1 to 500 mg of α-mangostin per day can be mentioned. Here, the daily intake or dosage of α-mangostin is a value converted to the amount of α-mangostin in the extract or processed product in the case of using an extract or processed product of mangostin. The nocturia preventive or ameliorating agent of the present invention may be taken or administered once a day or divided into multiple times a day, preferably 1 to 5 times a day.

[0045] 3. Agent for preventing or improving middle-of-the-night awakening The agent for preventing or ameliorating middle-of-the-night awakening of the present invention is characterized by containing α-mangostin as an active ingredient. Hereinafter, the prevention or amelioration of middle-of-the-night awakening of the present invention will be described in detail.

[0046] [α-Mangosteen] The agent for preventing or improving awakening during the night of the present invention uses α-mangostin as an active ingredient. As mentioned above, α-mangostin has the effect of improving sleep disorders (such as acting on melatonin receptors and orexin receptors), improving bladder capacity, and improving nocturnal polyuria. In other words, α-mangostin can effectively prevent or improve awakening during the night by improving sleep quality and reducing the number of times urination occurs during sleep.

[0047] The α-mangostin used in the agent for preventing or ameliorating awakening during the night of the present invention is the same as that in the above-mentioned "1. Agent for preventing or ameliorating nocturia."

[0048] [Dosage form / shape] The dosage form of the agent for preventing or ameliorating awakening during the night of the present invention is not particularly limited, and may be any of solid, semi-solid, or liquid. The agent for preventing or ameliorating awakening during the night of the present invention is preferably in a form that is taken orally orally administered, but may also be in a form that is administered enterally or by injection.

[0049] Specific examples of the form of the agent for preventing or improving awakening during the night of the present invention include foods and beverages and oral medicines (including oral quasi-drugs). When the agent for preventing or improving awakening during the night of the present invention is in the form of a food, the type of food, the α-mangostin content in the food, etc. are the same as those in the above-mentioned "1. Agent for preventing or improving nocturia." Furthermore, when the agent for preventing or improving awakening during the night of the present invention is in the form of an oral medicine, the type of oral medicine, the α-mangostin content in the oral medicine, etc. are the same as those in the above-mentioned "1. Agent for preventing or improving nocturia."

[0050] [Application / Dosage] The agent for preventing or ameliorating awakening during the night of the present invention is used for those who are required to prevent or ameliorate awakening during the night. The agent for preventing or ameliorating awakening during the night of the present invention improves the quality of sleep by improving awakening during the night.

[0051] In addition, since the agent for preventing or improving middle-of-the-night awakening of the present invention also has the effect of reducing the number of urinations during sleep, it can also be used for preventing or improving middle-of-the-night awakening in those with symptoms of nocturia. Further, the agent for preventing or improving middle-of-the-night awakening of the present invention can be used for preventing or improving middle-of-the-night awakening in those with nocturia not caused by prostatic hyperplasia, or for preventing or improving middle-of-the-night awakening in women.

[0052] Furthermore, the agent for preventing or improving middle-of-the-night awakening of the present invention can also be used for preventing or improving middle-of-the-night awakening in those with sleep disorders. Here, "those with sleep disorders" refers to those with a total score (PSQIG) of less than 6.5 on the Pittsburgh Sleep Quality Index questionnaire.

[0053] In one aspect of the agent for preventing or improving middle-of-the-night awakening of the present invention, for example, sleep disorders caused by aging (e.g., 40 years old or older); sleep disorders caused by the urge to urinate; sleep-wake rhythm disorders caused by modulation of the body clock; sleep disorders caused by physical illnesses such as hypertension and heart disease (chest pain), mental illnesses such as depression, etc.; sleep disorders caused by administration of therapeutic drugs such as antihypertensive agents, thyroid preparations, anticancer agents, etc., ingestion of stimulants such as caffeine, etc., i.e., sleep disorders caused by administration or ingestion of drugs and stimulants; sleep disorders caused by disruption of the body rhythm due to shift work, jet lag, etc.; sleep disorders caused by the environment such as noise and light, etc. The middle-of-the-night awakening caused by such sleep disorders can be improved. From the viewpoint of more effectively improving nocturia, in one aspect of the agent for preventing or improving nocturia of the present invention, preferably, it is used for improving middle-of-the-night awakening caused by sleep disorders due to aging, the urge to urinate, physical illness or mental illness, more preferably for improving middle-of-the-night awakening caused by sleep disorders due to aging or the urge to urinate, and even more preferably for improving middle-of-the-night awakening caused by sleep disorders due to the urge to urinate.

[0054] In one aspect of the agent for preventing or improving nocturia of the present invention, among those who require prevention or improvement of nocturia, those who are concerned about urinary troubles such as frequent urination and a strong urge to urinate, those who are concerned about urinary troubles and have anxiety about going out, those who are concerned about urinary troubles due to aging, those who are concerned about urinary troubles associated with aging (for example, 40 years old or older), etc. can be preferably applied. Further, the agent for preventing or improving nocturia of the present invention can also be preferably applied to normal persons who feel stress about the worry (anxiety), annoyance, etc. caused by urinary urgency, although they do not require treatment at a hospital or the like, among those who require prevention or improvement of nocturia.

[0055] The target subjects to which the agent for preventing or improving nocturia of the present invention is applied may be mammals including humans, and preferably humans.

[0056] Regarding the intake and dosage of the agent for preventing or improving nocturia of the present invention, it is the same as in the case of the above-mentioned "1. Agent for preventing or improving nocturia at night".

[0057] 4. Agent for preventing or improving frequent urination The agent for preventing or improving frequent urination of the present invention is characterized by containing α-mangostin as an active ingredient. Hereinafter, the prevention or improvement of frequent urination of the present invention will be described in detail.

[0058] [α-Mangostin] The agent for preventing or improving frequent urination of the present invention uses α-mangostin as an active ingredient. As described above, α-mangostin has an effect of improving bladder capacity and can prevent or improve frequent urination.

[0059] Regarding α-mangostin used in the agent for preventing or improving frequent urination of the present invention, it is the same as in the case of the above-mentioned "1. Agent for preventing or improving nocturia at night".

[0060] [Dosage form · Form] The dosage form of the agent for preventing or improving urinary frequency of the present invention is not particularly limited and may be in any form of solid, semi-solid, or liquid. The agent for preventing or improving urinary frequency of the present invention is preferably in a form for oral intake or oral administration, but may also be in a form for enteral administration or injection administration.

[0061] Specific examples of the form of the agent for preventing or improving urinary frequency of the present invention include food and drink products and oral pharmaceuticals (including oral quasi-drugs). When the agent for preventing or improving urinary frequency of the present invention is in the form of a food, the type of food, the α-mangostin content in the food, etc. are the same as in the case of the above-mentioned "1. Agent for preventing or improving nocturia". Also, when the agent for preventing or improving urinary frequency of the present invention is in the form of an oral pharmaceutical, the type of oral pharmaceutical, the α-mangostin content in the oral pharmaceutical, etc. are the same as in the case of the above-mentioned "1. Agent for preventing or improving nocturia".

[0062] [Use and Dosage] The agent for preventing or improving urinary frequency of the present invention is used for those who require prevention or improvement of urinary frequency.

[0063] Since the agent for preventing or improving urinary frequency of the present invention has an effect of improving bladder capacity, it can exhibit an excellent preventive or therapeutic effect on urinary frequency caused by a decrease in bladder capacity.

[0064] In addition, since the agent for preventing or improving urinary frequency of the present invention also has an effect of reducing the number of urinations during sleep, it can also be used for those who have both symptoms of urinary frequency and nocturia.

[0065] In addition, the agent for preventing or improving urinary frequency of the present invention can also exhibit an excellent improvement effect on urinary frequency not caused by prostatic hyperplasia, urinary frequency in women, urinary frequency in those with sleep disorders, etc. Here, "those with sleep disorders" refers to those with a total score (PSQIG) of less than 6.5 on the Pittsburgh Sleep Quality Index.

[0066] The target subjects to which the agent for preventing or improving urine of the present invention is applied may be mammals including humans, but preferably humans.

[0067] The intake and dosage of the agent for preventing or improving frequent urination of the present invention is the same as in the above-mentioned "1. Agent for preventing or improving nocturia." [Example]

[0068] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0069] The mangosteen extract used in the following test examples is an extract (powdered) obtained by extracting mangosteen peel with aqueous ethanol, and contains 10% by weight of α-mangosteen on a dry weight basis.

[0070] Test Example 1: Verification of binding ability to melatonin receptor It is known that melatonin receptors, when stimulated by melatonin, induce sleep and improve sleep disorders that cause nocturia. Therefore, in this study, we evaluated the binding ability of α-mangostin to the melatonin 2 receptor.

[0071] First, 8 × 10 HEK293 cells (human fetal kidney-derived cells) (gift from ATCC) expressing human melatonin 2 receptor were placed in each well of a 96-well plate using DMEM medium (containing 10% FBS (fetal bovine serum)). 3 The cells were seeded at 100 μg / ml and cultured at 5% CO2 and 37°C for 1 day. The culture supernatant was then removed from the wells, and DMEM medium (containing 10% FBS) containing the samples shown in Table 1 and 0.05 nM of radiolabeled melatonin receptor agonist ([125I]2-iodomelatonin) was added. The cells were then cultured at 5% CO2 and 37°C for 120 hours. The radiation dose (amount of radiolabeled melatonin receptor agonist bound to human melatonin 2 receptor-expressing cells) was then measured using a microplate scintillation counter. A control was also measured under the same conditions except for the absence of the sample. The binding activity of α-mangostin to the melatonin 2 receptor was calculated according to the following formula:

Number

[0072] The results are shown in Table 1. From these results, it was revealed that the mangosteen extract has the ability to bind to the melatonin receptor. As will be described later, since α-mangostin has been recognized to have the effect of improving middle-of-the-night awakening, from the results of this test, it is strongly suggested that α-mangostin contained in the mangosteen extract acts as an agonist of the melatonin 2 receptor, induces sleep, and has the effect of suppressing sleep disorders that cause nocturia.

[0073]

Table 1

[0074] Test Example 2: Verification of orexin receptor inhibitory activity Orexin is a brain substance that maintains wakefulness, and orexin receptor antagonists are known to promote sleep and improve sleep disorders that cause nocturia by suppressing the system related to wakefulness. Therefore, in this test, the orexin receptor inhibitory activity of α-mangostin was evaluated.

[0075] First, in each well of a 96-well plate, HEK293 cells expressing the human orexin 1 receptor or HEK293 cells expressing the human orexin 2 receptor were added at 3×10 using DMEM medium (containing 10% FBS). 4Cells were seeded at a density of cells / ml and cultured at 5% CO2 and 37°C for 1 day. Subsequently, the culture supernatant in the wells was removed, and DMEM medium (containing 10% FBS) containing the samples shown in Table 2 and human orexin receptor agonists (orexin-A at 3 nM for HEK293 cells expressing the human orexin 1 receptor and orexin-B at 10 nM for HEK293 cells expressing the human orexin 2 receptor) was added, and the cells were cultured at 5% CO2 and 37°C for 1 hour. Then, an intracellular calcium measurement kit was used to determine the intracellular calcium concentration. Also, as a control, the intracellular calcium concentration was determined under the same conditions as above, except that no sample was added. The orexin receptor inhibitory activity was calculated according to the following formula. Since it is known that when the orexin receptor is activated by the stimulation of an agonist, it causes the activation of phospholipase C and the hydrolysis of phosphatidylinositol, resulting in an increase in the intracellular calcium concentration, it can be said that the lower the intracellular calcium concentration measured in this test, the higher the orexin receptor inhibitory activity.

Number

[0076] The results are shown in Table 2. As a result, it was confirmed that α-mangostin and mangostin extract have orexin receptor inhibitory activity, promote sleep, and have an effect of improving sleep disorders, which are the cause of nocturia.

[0077]

Table 2

[0078] Test Example 3: Verification of improvement effect on bladder capacity in overactive bladder model The effect of α-mangostin on improving bladder capacity was evaluated using an overactive bladder model.

[0079] First, rats (7-week-old, female, SD) underwent laparotomy under anesthesia, and both common iliac and uterine veins were ligated to induce bladder ischemia. The rats were then housed under this condition for 14 days to create an overactive bladder model. Starting 14 days after bladder ischemia, 2 ml of a sample containing 160 mg / ml of α-mangostin was orally administered once daily. The rats were then housed under standard conditions for 14 days. A catheter was then inserted into the bladder via the urethra, and saline was continuously infused into the bladder at 3 ml / h. Continuous cystometry was performed to measure the bladder contraction interval (micturition interval). Residual urine volume after micturition was then measured, and bladder capacity was calculated from the residual urine volume and bladder contraction interval. A control group was also orally administered saline instead of the sample, and bladder capacity was measured under the same conditions. Furthermore, as an untreated group, rats were kept under normal conditions for the same number of days as above without bladder ischemia treatment or administration of the test substance, and the bladder capacity was also measured. Note that this test was carried out with n=8.

[0080] The results are shown in Figure 1. These results confirmed that α-mangosteen has the effect of improving bladder capacity and can improve nocturia and frequent urination.

[0081] Test Example 4: Verification of improvement effect on nocturia in acetic acid-induced cystitis model The effect of α-mangostin on improving nocturnal polyuria was evaluated using an acetic acid-induced cystitis model.

[0082] First, the urination intervals of rats (7-week-old, male, SD) were measured. Next, 1.6 ml of 0.3 wt% acetic acid was injected into the bladders of the rats (7-week-old, male, SD), and cystitis was induced by breeding them for one day. One day after the injection of acetic acid, 2 ml of a specimen containing 160 mg / ml of α-mangostin was orally administered. The urination interval from the first urination after 30 minutes from the administration of the specimen to the next urination was measured. Also, as a control group, physiological saline was orally administered instead of the specimen, and the urine interval was measured under the same conditions as above. Note that this test was conducted with n = 6. In this test, rats acclimated in an environment where a 12-hour light period under fluorescent lamp irradiation conditions and a 12-hour dark period under non-fluorescent lamp irradiation conditions were repeated were used, and the administration of the specimen and the measurement of the urination interval were performed during the light period (i.e., the sleep period of the rats).

[0083] The results are shown in Figure 2. From these results, it was confirmed that α-mangostin has the effect of lengthening the urination interval during the light period (i.e., the sleep period) in cystitis model rats and can improve nocturia.

[0084] Test Example 5: Verification of improvement effect on nocturia and middle-of-the-night awakening in humans Ten subjects (4 males and 6 females) who complained of nocturia were continuously administered 3 capsules (400 mg as the amount of α-mangostin) containing the content of the composition shown in Table 3 once a day for 4 weeks. On the day before the start of the intake of the capsules, 2 weeks after the intake, and 4 weeks after the intake, the total number of mid-sleep awakenings and the total number of urinations during sleep in the past week were counted. Also, on the day before the start of the intake of the capsules and 4 weeks after the intake, the Pittsburgh Sleep Quality Questionnaire and the Nocturia QOL Questionnaire (N-QOL) were answered. Note that the subjects of this test did not include those with sleep disorders caused by disrupted internal rhythms.

[0085]

Table 3

[0086] The average values of the subjects were calculated for the total number of awakenings during sleep, the total number of urinations during sleep, the Pittsburgh Sleep Quality Index (PSQIG) score, the total score of N-QOL, and the N-QOL score (total score for questions related to sleep / vitality, total score for questions related to worries / concerns, and score for questions related to the bother of urination), and the results are shown in Figure 3. These results confirmed that the intake of α-mangostin can reduce the number of urinations during sleep and awakenings during sleep, and that α-mangostin can improve nocturia and awakenings during sleep in humans.

[0087] Test Example 6: Verification of improvement effect on nocturia and frequent urination in humans Thirteen subjects (6 men, 7 women) complaining of nocturia completed the Pittsburgh Sleep Quality Index (PSQIG). Subjects with a Pittsburgh Sleep Quality Index (PSQIG) total score of 6.5 or higher were divided into a "no sleep disorder group" (1 man, 6 women) and a "sleep disorder group" (5 men, 1 woman) with a total score of less than 6.5. Note that the subjects in this study did not include those with sleep disorders caused by circadian rhythm disruption; the "sleep disorder group" consisted of those with sleep disorders caused by factors other than circadian rhythm disruption. Subjects were instructed to take three capsules (400 mg of α-mangostin) containing the ingredients shown in Table 3 once daily for four weeks. The total number of urinations during sleep during the past week was counted the day before, two weeks after, and four weeks after capsule ingestion. In addition, the subjects were asked to answer a nocturia quality of life (N-QOL) questionnaire the day before and four weeks after starting the ingestion of the capsules.

[0088] For each group, the average total number of urinations during sleep and the N-QOL score (total score for questions regarding worries / concerns and score for questions regarding the hassle of urination) were calculated. The results are shown in Figure 4. As shown in Figure 4, the group with sleep disorders had a lower number of frequent urinations during sleep than the group without sleep disorders, indicating that α-mangostin is effective in improving nocturia in people with sleep disorders.

[0089] Test Example 7: Verification of improvement effect on nocturia and frequent urination in humans Thirteen subjects (6 males and 7 females) who complained of nocturia were made to continuously ingest 3 capsules (400 mg as the amount of α-mangostin) containing the contents of the composition shown in Table 3 once a day for 4 weeks. Note that subjects with prostate hypertrophy were not included. At the day before the start of capsule ingestion, 2 weeks after ingestion, and 4 weeks after ingestion, the total number of urinations during sleep in the past week was counted. Also, on the day before the start of capsule ingestion and 4 weeks after ingestion, the subjects were made to answer the Nocturia QOL Questionnaire (N-QOL).

[0090] The subjects were divided into male and female groups, and for each group, the average values of the total number of urinations during sleep and the scores of N-QOL (total score for questions regarding annoyance / worry and score for questions regarding the nuisance of urination) were determined. The results are shown in Fig. 5. As shown in Fig. 5, a decrease in the number of urinations during sleep was observed due to the ingestion of α-mangostin. Also, compared to males, the effect of decreasing the number of urinations during sleep was significantly observed in females in a shorter period from the start of α-mangostin ingestion. That is, this result indicates that α-mangostin has a high effect of improving nocturia in females and that α-mangostin has an improving effect on nocturia not caused by prostate hypertrophy, etc.

Claims

1. A prophylactic or ameliorative agent for nocturia containing α-mangostin.

2. The prophylactic or ameliorative agent according to Claim 1, wherein the α-mangostin includes an extract and / or processed product of mangostin.

3. The prophylactic or ameliorative agent according to Claim 1 or 2, which is used for the prevention or amelioration of nocturia caused by at least one selected from the group consisting of sleep disorder, decreased bladder capacity, and nocturia.

4. The prophylactic or ameliorative agent according to any one of Claims 1 to 3, which is used for the prevention or amelioration of nocturia not caused by prostatic hyperplasia or nocturia in women.

5. A prophylactic or ameliorative agent for middle-of-the-night awakening containing α-mangostin.

6. The prophylactic or ameliorative agent according to Claim 5, wherein the α-mangostin includes an extract and / or processed product of mangostin.

7. The prophylactic or ameliorative agent according to Claim 5 or 6, which is used for the prevention or amelioration of middle-of-the-night awakening in a person having the symptom of nocturia.

8. The prophylactic or ameliorative agent according to any one of Claims 5 to 7, which is used for the prevention or amelioration of middle-of-the-night awakening in a person having the symptom of nocturia not caused by prostatic hyperplasia or in a woman.

9. A prophylactic or ameliorative agent for frequent urination and nocturia, which contains α-mangostin and is used for a person having both symptoms of frequent urination and nocturia.

10. The prophylactic or ameliorative agent according to Claim 9, wherein the α-mangostin includes an extract and / or processed product of mangostin.

11. The prophylactic or ameliorative agent according to Claim 9 or 10, wherein the frequent urination is caused by a decrease in bladder capacity.

12. The prophylactic or ameliorative agent according to any one of Claims 9 to 11, wherein the frequent urination is frequent urination not caused by prostatic hyperplasia or frequent urination in a woman.

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