Preventive or therapeutic agent for childhood obesity caused by passive smoking

Abstract

The present invention provides a preventive or remedy for obesity caused by exposure to nicotine, in particular, passive exposure to tobacco smoke during fetal life and / or childhood, and a composition for preventing or treating the same.　Provided are a preventive or remedy for obesity which controls overeating induced by exposure to nicotine during fetal life and / or childhood until 14 years old, said preventive or remedy comprising γ-oryzanol as an active ingredient, and a composition for preventing or treating the same.

Description

[Technical field]

[0001] The present invention relates to an agent for preventing or treating obesity caused by exposure to nicotine during fetal and / or childhood, particularly passive smoking. [Background technology]

[0002] In recent years, in addition to the health hazards to smokers themselves, the health effects of passive smoking have become known, and smoking bans and separate smoking areas are becoming more common in public facilities, restaurants, etc.

[0003] However, in the case of smoking in the home, third parties are unlikely to be able to keep an eye on it, and passive smoking measures tend to be insufficient. In particular, in the case of passive smoking among children, because they are in close proximity to smokers and have long contact times, the amount and duration of passive smoking tends to be large, which can cause serious health damage.

[0004] In fact, the 2017 Special Report of the Ministry of Health, Labor and Welfare in Japan (Non-Patent Document 1) reports the relationship between parental smoking and passive smoking in the home and the overweight and obesity rates of children. In this report, the impact of parental smoking at 6 months of age on the overweight and obesity rates of the target children from 2.5 to 13 years of age is investigated. Here, the smoking status of parents is classified into three groups, "non-smoking group", "smoking group (children are not exposed to passive smoking)", and "smoking group (children are exposed to passive smoking)", based on whether the father and mother smoke and where they smoke (whether they smoke indoors or not). As a result of the survey, the overweight and obesity rates of boys were about 20 to 30% higher in the "smoking group (children are not exposed to passive smoking)" than in the "non-smoking group" from 5 years and 6 months of age, and about 20 to 60% higher in the "smoking group (children are exposed to passive smoking)" than in the "non-smoking group" from 4 years and 6 months of age. Additionally, the overweight and obesity rates for girls were approximately 20-30% higher in the "smoking group (children not exposed to passive smoking)" from age 5 years 6 months onwards compared to the "non-smoking group," and approximately 20-70% higher in the "smoking group (children exposed to passive smoking)" from age 2 years 6 months onwards compared to the "non-smoking group." Therefore, it has been made clear that for both boys and girls, the overweight and obesity rates were highest in the "smoking group (children exposed to passive smoking)," followed by the "smoking group (children not exposed to passive smoking)," with the "non-smoking group" being the lowest.

[0005] It is also known that fetal exposure to nicotine (fetal exposure to nicotine through maternal nicotine exposure during pregnancy) can also cause obesity. Maternal smoking during pregnancy is associated with overweight and obesity in children, and it has been reported that the effect of maternal smoking during pregnancy on childhood overweight and obesity is particularly greater than that of paternal smoking (Non-Patent Document 2).

[0006] On the other hand, it is known that passive smoking in adulthood does not increase the number of obese people (Non-Patent Document 3). Therefore, obesity caused by passive smoking is thought to be an effect unique to passive smoking during fetal and childhood periods.

[0007] Obesity causes diabetes, hyperlipidemia, hypertension, and 11 other obesity-related complications (Non-Patent Document 4), and so countermeasures against it are one of the most important medical and medical-economic issues. Therefore, effective countermeasures against obesity caused by passive smoking during fetal and childhood are required.

[0008] However, the mechanism by which passive smoking and active smoking during fetal and childhood increases childhood obesity and obesity after adulthood has not been clarified at all. Furthermore, no ingredients or drugs that can prevent or reduce these are known. Therefore, there is a need to develop a drug to prevent or treat obesity caused by passive smoking during fetal and childhood. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Ministry of Health, Labor and Welfare, Special Report on the Longitudinal Survey of Newborns in the 21st Century (born in 2001) (2017) [Non-Patent Document 2] Riedel C, et al., Int J Epidemiol., 2014, 43(5):1593-1606. [Non-Patent Document 3] Ministry of Health, Labor and Welfare, Smoking and Health - Report of the Study Group on the Health Effects of Smoking (2016) [Non-Patent Document 4] Japan Society for the Study of Obesity, Obesity Treatment Guidelines 2016 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide an agent and a composition for preventing or treating obesity caused by exposure to nicotine, particularly passive smoking, during the fetal and / or childhood stages. [Means for solving the problem]

[0011] The present inventors recently discovered that the bioactive substance γ-oryzanol functions as a molecular chaperone that promotes the folding of secretory proteins, has the effect of reducing ER stress in the brain, and has the effect of reducing the preference for high-fat foods (JP Patent Publication 2013-144656; Masuzaki et al., Glycative Stress Research 2017; 4(1): 058-066). γ-oryzanol is an ester of ferulic acid and unsaturated triterpene alcohol or plant sterol, and is known to be contained in rice bran, etc. (Taniguchi et al., Journal of the Japanese Society of Food Science and Technology, Vol. 59, No. 7, 2012).

[0012] The present inventors have intensively studied further activities of γ-oryzanol and found that γ-oryzanol is useful for preventing and treating overeating and obesity that may occur in children who are continuously exposed to nicotine, thus completing the present invention. The present invention is based on the above-mentioned research results and provides the following. (1) A preventive or therapeutic agent for obesity, which contains γ-oryzanol as an active ingredient and suppresses overeating induced by exposure to nicotine during fetal development and / or childhood up to 14 years of age. (2) The preventive or therapeutic agent for obesity according to (1), wherein the nicotine exposure is passive smoking. (3) A pharmaceutical composition for preventing or treating obesity, comprising γ-oryzanol as an active ingredient, which suppresses overeating induced by exposure to nicotine during fetal development and / or childhood up to 14 years of age. (4) A food composition for preventing or treating obesity, comprising γ-oryzanol as an active ingredient, which suppresses overeating induced by exposure to nicotine during fetal development and / or childhood up to 14 years of age. This specification includes the disclosures of Japanese Patent Application No. 2019-165406, which is the priority basis of this application. Effect of the Invention

[0013] According to the present invention, it is possible to provide an agent for preventing or treating obesity caused by exposure to nicotine during the fetal stage and / or during childhood of 14 years of age or younger, and a composition for the prevention or treatment thereof. [Brief description of the drawings]

[0014] [Figure 1] (A) Changes in body weight from 10 weeks of age onwards in adulthood, and (B) body weight at 14 weeks of age, for mice groups administered saline or nicotine at 4-5 weeks of age (referred to as the "saline group" and "nicotine group," respectively). The figure shows the average value for n=5 mice in each group, and the error bars show the standard error. * indicates P<0.05 (t-test). [Diagram 2] This figure shows the change in daily food intake from 10 weeks of age onwards in adulthood for mice groups administered saline or nicotine at 4-5 weeks of age (saline group or nicotine group, respectively), and the average daily food intake at each age (B). The figure shows the average value for n=5 mice in each group, and the error bars show the standard error. * indicates P<0.05 (t-test). [Diagram 3]The graphs show the changes in body weight from 10 weeks of age until adulthood (A) and at 14 weeks of age (B) for mice that were administered saline or nicotine at 4-5 weeks of age (saline group or nicotine group, respectively), mice that were co-administered with nicotine and mecamylamine at 4-5 weeks of age (nicotine-mecamylamine group), and mice that were administered nicotine at 4-5 weeks of age and then γ-oryzanol for 28 days from 10 weeks of age (nicotine + γ-oryzanol group). The graphs show the average values ​​for n=5 mice in each group, and the error bars show the standard error. * indicates P<0.05 (t-test). [Figure 4] The graph shows the change in daily food intake from 10 weeks of age onwards in adulthood (A) and the average daily food intake at each age (B) for mice given saline or nicotine at 4-5 weeks of age (saline group or nicotine group, respectively), mice given nicotine and mecamylamine at 4-5 weeks of age (nicotine-mecamylamine group), and mice given nicotine at 4-5 weeks of age and then given γ-oryzanol for 28 days from 10 weeks of age (nicotine + γ-oryzanol group). The graph shows the average value for n=5 mice in each group, and the error bars show the standard error. * indicates P<0.05 (t-test). [Diagram 5] The graphs show (A) changes in body weight from 14 weeks of age onward and (B) average body weights at 18 weeks of age for mice groups administered saline or nicotine at 8-9 weeks of age (saline group or nicotine group, respectively). The graphs show the average values ​​for n=5 mice in each group. [Figure 6] The graphs show (A) the change in daily food intake from 14 weeks of age onwards in mice groups administered saline or nicotine at 8-9 weeks of age (saline group or nicotine group, respectively), and (B) the average daily food intake at each age. The graphs show the average values ​​for n=5 mice in each group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] 1. Preventive or therapeutic agents 1-1. Overview A first aspect of the present invention is an agent for preventing or treating obesity. The prophylactic or therapeutic agent for obesity of this embodiment contains γ-oryzanol as an active ingredient, and has an inhibitory effect on hyperphagia induced by exposure to nicotine during fetal and / or childhood, thereby preventing or treating obesity.

[0016] 1-2.Definition The following terms frequently used in this specification are defined below. In this specification, "nicotine exposure" refers to contact of a living body with nicotine based on any route or action. For example, nicotine exposure due to active smoking, passive smoking, or thirdhand smoking, nicotine exposure of a fetus due to nicotine exposure during pregnancy, and nicotine exposure of an infant through breast milk due to nicotine exposure during breastfeeding can be included. Nicotine exposure can result in nicotine intake into the body.

[0017] "Passive smoking" means that other people inhale the smoke produced by a smoker. Specifically, it means that other people inhale the smoke rising from a cigarette smoked by a smoker, or the smoke contained in a smoker's breath. Therefore, even non-smokers can be subject to passive smoking.

[0018] "Thirdhand smoking", also known as residual passive smoking, refers to the inhalation of harmful substances from smoke residues that adhere to materials exposed to cigarette smoke. For example, smoke residues that adhere to clothing in a smoking room are released outside the smoking room and inhaled by others. In this specification, thirdhand smoking is considered to be included in passive smoking.

[0019] In this specification, "tobacco" includes any type of tobacco, so long as it can result in the ingestion of harmful substances through passive or third-hand smoking, including cigarettes, cigars, hookahs, electronic cigarettes, heated tobacco, chewing tobacco, snuff, etc.

[0020] In general, tobacco smoke contains a large number of harmful substances, including nicotine, tar, and carbon monoxide. Nicotine is an alkaloid that is naturally produced in plants of the Solanaceae family, including tobacco. Nicotine ingested into the body from tobacco smoke binds to and activates nicotinic acetylcholine receptors (nAchR) in the nervous system, resulting in a variety of effects, including stimulant and sedative effects. Nicotine is highly addictive to the body, causing nicotine addiction.

[0021] "Nicotinic acetylcholine receptor (nAchR)" is a type of receptor (acetylcholine receptor) that responds to the neurotransmitter acetylcholine. Nicotinic acetylcholine receptors are ionotropic receptors that respond to nicotine in addition to acetylcholine. Nicotinic acetylcholine receptors are distributed in the central nervous system, peripheral nervous system, muscles, etc. Mecamylamine and other substances are known as antagonists of nicotinic acetylcholine receptors.

[0022] "Tar" contained in cigarette smoke refers to the particulate components of cigarette smoke excluding carbon monoxide and gaseous components. Tar contains many harmful substances such as carcinogens. Tar also contains nicotine.

[0023] "γ-oryzanol" is a general term for esters of ferulic acid and unsaturated triterpene alcohol or plant sterol. In general, γ-oryzanol is a general term for a mixture composed of multiple components, for example, about 10 types of molecular species. The main components include, for example, cycloartenyl ferulic acid represented by the following chemical formula (I), 24-methylenecycloartanyl ferulic acid represented by the chemical formula (II), campesteryl ferulic acid represented by the chemical formula (III), and β-sitosteryl ferulic acid represented by the chemical formula (IV).

[0024] [ka]

[0025] [ka]

[0026] [ka]

[0027] [ka]

[0028] γ-oryzanol is generally found in high concentrations in brown rice (rice bran), and is also known to be present in the seeds of grasses such as corn and barley.

[0029] γ-oryzanol is known to have various physiological activities, such as suppressing psychosomatic symptoms (anxiety, tension, depression), preventing Alzheimer's disease, and reducing the preference for high-fat foods.

[0030] "Overeating" refers to excessive eating that exceeds the range of standard food intake. In this specification, it means excessive eating that can lead to obesity, and is not limited to eating disorders generally associated with extreme overeating, such as bulimia nervosa.

[0031] "Obesity" refers to a state in which one's body weight is greater than the average correlation value calculated based on the height and weight of a healthy group, or a state in which body fat has accumulated excessively. In this specification, the specific definition of obesity differs between those aged 18 years or older and those under 18 years old. The degree of obesity in adults aged 18 years or older is determined using the body mass index (BMI = weight (kg) / height (m)) based on height and weight. 2 ) is used, and a BMI of 25.0 or more is classified as obese. On the other hand, for those under 18 years of age, the body mass index (BMI = weight (kg) / height (m)) is used based on height and weight. 2) was required, and the International Obesity Task Force established the BMI at age 18 for those aged 24 months or older as 25.0 kg / m 2 Obesity is defined using sex- and age-specific cutoff values ​​equivalent to (Cole et al., BMJ 2000;320(7244):1240-3).

[0032] As used herein, the term "childhood" refers to the period from birth to under 15 years of age, including the neonatal period, infancy, and early childhood. However, as used herein, childhood does not include the fetal period.

[0033] In the present specification, the term "fetal period" is not limited to the period before birth. In particular, it may be the period from the ninth week after fertilization to birth, excluding the period up to the eighth week after fertilization (embryonic period) in the fetal period.

[0034] As used herein, the term "fetal period and / or childhood" may refer to either the fetal period and childhood, or either the fetal period or childhood. Thus, the term "fetal period and / or childhood" includes a period consisting of only the fetal period, only the childhood period, or both the fetal period and the childhood period.

[0035] 1-3.Configuration 1-3-1. γ-Oryzanol The preventive or therapeutic agent of the present invention contains γ-oryzanol as an active ingredient. γ-oryzanol is an essential component of the preventive or therapeutic agent of the present invention.

[0036] The specific component of γ-oryzanol included in the preventive or therapeutic agent of the present invention is not limited. Any γ-oryzanol component can be used. For example, the component may be one or more components selected from any γ-oryzanol components such as, but not limited to, the above-mentioned cycloartenyl ferulic acid, 24-methylenecycloartanyl ferulic acid, campesteryl ferulic acid, β-sitosteryl ferulic acid, etc.

[0037] The γ-oryzanol contained in the preventive or therapeutic agent of the present invention may be naturally derived, synthetically obtained, or a combination thereof. When the γ-oryzanol contained in the preventive or therapeutic agent of the present invention is naturally derived, γ-oryzanol contained in any plant containing γ-oryzanol, such as rice, corn, barley, etc., can be used. For example, γ-oryzanol contained in brown rice, rice bran, or germ, more specifically, γ-oryzanol contained in rice bran oil or rice germ oil can be used as γ-oryzanol contained in rice. There are no particular limitations on the method of extraction from raw materials and purification method of γ-oryzanol contained in the preventive or therapeutic agent of the present invention. The γ-oryzanol contained in the preventive or therapeutic agent of the present invention is preferably an extract derived from brown rice.

[0038] 1-3-2. Dosage form The dosage form of the preventive or therapeutic agent of the present invention is not particularly limited as long as it does not or is unlikely to inactivate the active ingredient γ-oryzanol and can fully exert its pharmacological effect in vivo after administration.

[0039] Dosage forms can be classified into liquid dosage forms or solid dosage forms (including semisolid dosage forms such as gels) depending on their form, and the prophylactic or therapeutic agent of the present invention may be either of them. Dosage forms can also be roughly classified into oral dosage forms and parenteral dosage forms depending on the administration method, and either of them may be used.

[0040] Specific dosage forms include, for example, liquid dosage forms such as suspensions, emulsions, and syrups, and solid dosage forms such as powders (including powders), granules, tablets, capsules, sublingual tablets, and lozenges, in the case of oral dosage forms. In addition, for example, liquid dosage forms such as injections, suspensions, and emulsions are included in the case of parenteral dosage forms. The preferred dosage form is an oral dosage form.

[0041] 1-3-3. Method of administration The preventive or therapeutic agent of the present invention can be applied to any method known in the art, so long as it is a method capable of administering an effective amount of γ-oryzanol, an active ingredient, to a living body in order to suppress hyperphagia induced by exposure to nicotine during fetal and / or childhood and prevent or treat obesity.

[0042] As used herein, the term "effective amount" refers to the amount of an active ingredient required to exert its function, i.e., in the present invention, the amount of the prophylactic or therapeutic agent for obesity required to suppress overeating caused by nicotine exposure in fetal and / or childhood and to prevent or treat obesity, and which gives little or no harmful side effects to the living body to which it is applied. This effective amount may vary depending on conditions such as information on the subject, the route of administration, and the number of administrations.

[0043] The "subject" refers to an individual, particularly a human individual, to whom the prophylactic or therapeutic agent for obesity of this embodiment, the pharmaceutical composition of the second embodiment, or the food composition of the third embodiment is to be applied.

[0044] The subject to which the preventive or therapeutic agent or composition of the present invention is applied is an individual who may be exposed to, is currently exposed to, and / or has been exposed to nicotine in the fetal stage and / or childhood. The age of the subject at the time of nicotine exposure is 15 years or less, 14 years or less, 13 years or less, 12 years or less, 11 years or less, 10 years or less, 9 years or less, 8 years or less, 7 years or less, 6 years or less, 5 years or less, 4 years or less, 3 years or less, 2 years or less, or 1 year or less, and / or 0 years or more, 1 years or more, 2 years or more, 3 years or more, 4 years or more, 5 years or more, 6 years or more, 7 years or more, 8 years or more, 9 years or more, 10 years or more, 11 years or more, 12 years or more, 13 years or more, or 14 years or more in childhood, and / or 36 weeks or less of pregnancy, 31 weeks or less of pregnancy, 23 weeks or less of pregnancy, 15 weeks or less of pregnancy, or 7 weeks or less of pregnancy, and / or 0 weeks or more of pregnancy, 8 weeks or more, 16 weeks or more, 24 weeks or more, or 32 weeks or more of pregnancy in fetal stage. Preferably, the subject's age etc. at the time of nicotine exposure is during the fetal stage and / or childhood of 14 years or younger.

[0045] On the other hand, the age of the subject at the time of application of the preventive or therapeutic agent or composition of the present invention (hereinafter referred to as "at the time of application") is different from the age at the time of nicotine exposure and is not limited. For example, the age at the time of application may be any of fetal stage, childhood, and / or adulthood. Furthermore, the time of application may be any of before nicotine exposure, during nicotine exposure, and / or after nicotine exposure. To give a specific example, the preventive or therapeutic agent or composition of the present invention may be applied to an individual exposed to nicotine in the fetal stage and / or childhood of 14 years or less in the fetal stage and / or childhood of 14 years or less. Alternatively, the preventive or therapeutic agent or composition of the present invention may be applied to an individual exposed to nicotine in the fetal stage and / or childhood of 14 years or less in the childhood and / or adulthood.

[0046] The term "nicotine exposure" as used herein refers to any exposure that can induce overeating due to nicotine exposure during fetal and / or childhood, and the exposure time, frequency, and amount of nicotine intake resulting from the exposure are not limited. In addition, the nicotine exposure in this embodiment is not particularly limited as long as it can cause nicotine intake into the body, and includes, for example, nicotine exposure due to active smoking, passive smoking, and thirdhand smoking, fetal nicotine exposure due to nicotine exposure during pregnancy, and infant nicotine exposure through breast milk due to nicotine exposure during breastfeeding. Nicotine exposure is preferably continuous exposure. The term "continuous exposure" as used herein refers to, but is not limited to, exposure for an average of 10 minutes or more, 20 minutes or more, 30 minutes or more, 1 hour or more, 2 hours or more, 3 hours or more, or 4 hours or more per day for, for example, 1 month or more, 2 months or more, 4 months or more, 6 months or more, 1 year or more, 2 months or more, 3 months or more, 4 hours or more, 5 years or more, 6 hours or more, 7 years or more, 8 years or more, 10 years or more, or 12 years or more.

[0047] "Subject information" refers to various individual information of the subject, including, for example, the subject's age, weight, sex, overall health condition, drug sensitivity, and whether or not the subject is taking any medication. The effective amount and the dosage calculated based thereon are determined according to the information of each individual subject. When it is necessary to administer a large amount of the preventive or therapeutic agent of the present invention to obtain a sufficient effect of preventing or treating obesity, the agent can be administered in several divided doses to reduce the burden on the subject.

[0048] The method of administration of the preventive or therapeutic agent of the present invention may be either systemic administration or local administration. Examples of systemic administration include oral administration and intravascular injection such as intravenous injection. For fetuses, it is possible to indirectly administer the agent to the mother by any of the above methods. For infants, in addition to direct administration to infants by any of the above methods, it is also possible to indirectly administer the agent via breast milk by administering the agent to the mother by any of the above methods.

[0049] The prophylactic or therapeutic agent of the present invention is administered, for example, 1 to 4 times per day, but is not limited thereto, or may be administered at various administration frequencies, such as daily, every other day, once a week, every other week, or once a month.

[0050] As an example of a specific dosage, the active ingredient γ-oryzanol is administered at 1 mg to 100 g per day, for example, 1 mg to 10 g, 1 mg to 1 g, 1 mg to 300 mg, 1 mg to 100 mg, or 10 mg to 50 mg, preferably 300 mg or 10 mg to 50 mg. Note that an amount outside the above range can also be used as necessary, and the dosage is not limited to these ranges.

[0051] The administration time of the preventive or therapeutic agent of the present invention is not particularly limited. The preventive or therapeutic agent of the present invention may be administered before, during, and / or after nicotine exposure in order to prevent and / or treat overeating caused by nicotine exposure. For example, it may be administered after overeating and / or obesity caused by overeating caused by nicotine exposure is established.

[0052] 1-4.Effects According to the preventive or therapeutic agent of the present invention, it is possible to suppress overeating caused by nicotine exposure in fetal and / or childhood, thereby preventing and / or treating obesity. Nicotine exposure in fetal and / or childhood can cause overeating during childhood and / or after childhood, for example, in adulthood. If the preventive or therapeutic agent of the present invention is administered before the onset of overeating, it is possible to prevent obesity by suppressing overeating. Alternatively, if the preventive or therapeutic agent of the present invention is administered after the onset of overeating, it is possible to treat obesity by suppressing overeating.

[0053] According to the prophylactic or therapeutic agent for obesity of this embodiment, there is also provided a method for preventing or treating obesity by suppressing hyperphagia induced by exposure to nicotine during fetal and / or childhood, comprising the step of administering the prophylactic or therapeutic agent for obesity of this embodiment to a subject, wherein the administration step is in accordance with the administration method described in "1-3-3. Administration method" above.

[0054] According to the obesity preventive or therapeutic agent of this embodiment, an overeating suppressant is also provided. The composition of the overeating suppressant of the present invention is similar to that of the preventive or therapeutic agent of this embodiment, except that it is administered for the purpose of suppressing overeating. The overeating suppressant of the present invention can suppress overeating caused by nicotine exposure during fetal and / or childhood.

[0055] Furthermore, the preventive or therapeutic agent of the present invention can suppress hyperphagia induced by exposure to nicotine during fetal and / or childhood (excluding hyperphagia caused by a reduction in the preference for high-fat foods), thereby preventing and / or treating obesity.

[0056] γ-oryzanol has a long history of being consumed by humans in the form of brown rice and is therefore highly safe, and therefore the preventive or therapeutic agent of the present invention can be said to be highly safe.

[0057] 2. Pharmaceutical composition for preventing or treating obesity 2-1. Overview A second aspect of the present invention is a pharmaceutical composition for preventing or treating obesity, which comprises γ-oryzanol as an active ingredient.

[0058] 2-2.Configuration The pharmaceutical composition for preventing or treating obesity in this embodiment contains an active ingredient as an essential component, and a pharma- ceutically acceptable carrier or other medicinal agents as optional components.

[0059] 2-2-1. Components Each of the constituent components will be specifically described below. (1) Active ingredient The active ingredient in the pharmaceutical composition for preventing or treating obesity of the present invention is γ-oryzanol. The constitution of γ-oryzanol has already been described in detail in the first embodiment, so a detailed description thereof will be omitted here.

[0060] The content of γ-oryzanol in the pharmaceutical composition of the present invention is not particularly limited. For example, the pharmaceutical composition of the present invention may contain 0.001 to 99 wt%, 0.01 to 10 wt%, or 0.1 to 10 wt% of γ-oryzanol as an active ingredient, for example, 90 wt%, 50 wt%, 10 wt%, 5 wt%, 3 wt%, 2 wt%, 1 wt%, 0.1 wt%, or 0.01 wt% of γ-oryzanol.

[0061] (2) A pharma- ceutically acceptable carrier The term "pharmaceutical acceptable carrier" refers to a solvent and / or additive that can be commonly used in the technical field of pharmaceutical formulations and that is little or not harmful to living organisms.

[0062] Pharmaceutically acceptable solvents include, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like.

[0063] Furthermore, examples of pharma- ceutically acceptable additives include excipients, binders, disintegrants, fillers, emulsifiers, flow regulators, lubricants, and the like.

[0064] Excipients include, for example, sugars such as monosaccharides, disaccharides, cyclodextrins, and polysaccharides (more specifically, including, but not limited to, glucose, sucrose, lactose, raffinose, mannitol, sorbitol, inositol, dextrins, maltodextrins, starch, and cellulose), metal salts (e.g., sodium chloride, sodium or calcium phosphate, calcium sulfate, magnesium sulfate, calcium carbonate), citric acid, tartaric acid, glycine, low, medium, or high molecular weight polyethylene glycols (PEGs), Pluronic®, kaolin, silicic acid, or combinations thereof.

[0065] Examples of binders include starch paste using corn, wheat, rice, or potato starch, simple syrup, glucose solution, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, shellac, and / or polyvinylpyrrolidone.

[0066] Disintegrants include, for example, the above-mentioned starches, lactose, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, laminaran powder, sodium bicarbonate, calcium carbonate, alginic acid or sodium alginate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearate monoglyceride, or salts thereof.

[0067] Fillers include, for example, the sugars and / or calcium phosphate (eg, tricalcium phosphate or calcium hydrogen phosphate).

[0068] Examples of the emulsifier include sorbitan fatty acid esters, glycerin fatty acid esters, sucrose fatty acid esters, and propylene glycol fatty acid esters.

[0069] Flow regulators and lubricants include, for example, silicates, talc, stearates or polyethylene glycol.

[0070] In addition to the above additives, the composition may contain, as necessary, flavoring agents, dissolution aids (solubilizers), suspending agents, diluents, surfactants, stabilizers, absorption promoters (e.g., quaternary ammonium salts, sodium lauryl sulfate), bulking agents, moisturizing agents (e.g., glycerin, starch), adsorbents (e.g., starch, lactose, kaolin, bentonite, colloidal silicic acid), disintegration inhibitors (e.g., sucrose, stearin, cocoa butter, hydrogenated oils), coating agents, coloring agents, preservatives, preservatives, antioxidants, fragrances, flavorings, sweeteners, buffers, and the like.

[0071] The pharma- ceutically acceptable carrier may be a component of biocompatible particles that encapsulate γ-oryzanol to improve the pharmacokinetics of γ-oryzanol. The biocompatible particles can be made of, for example, a polymer. The polymer is preferably a biocompatible polymer that is less irritating and toxic to the living body and is degraded and metabolized after administration. The biocompatible polymer is preferably polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, or lactic acid / aspartic acid copolymer. The biocompatible particles suitably contain polylactide glycolide copolymer (PLGA) or polyethylene glycol / chitosan modified-PLGA (PEG / CS-PLGA) as the biocompatible polymer.

[0072] 2-2-2. Dosage form The dosage form of the pharmaceutical composition for preventing or treating obesity of the present invention is in accordance with the dosage form described in "1-3-2. Dosage form" of "1. Agent for preventing or treating obesity".

[0073] 2-2-3. Method of administration The method of administration of the pharmaceutical composition for preventing or treating obesity of the present invention is in accordance with the method described in "1-3-3. Administration method" of "1. Agent for preventing or treating obesity".

[0074] 2-3.Effects In a subject administered the pharmaceutical composition for preventing or treating obesity of the present invention, hyperphagia caused by exposure to nicotine during fetal and / or childhood can be suppressed, thereby preventing and / or treating obesity.

[0075] Furthermore, the pharmaceutical composition for preventing or treating obesity of the present invention can suppress hyperphagia caused by exposure to nicotine during fetal and / or childhood (excluding hyperphagia caused by a reduction in the preference for high-fat foods), thereby making it possible to prevent and / or treat obesity.

[0076] According to the pharmaceutical composition for preventing or treating obesity of this embodiment, there is also provided a method for preventing or treating obesity by suppressing hyperphagia induced by exposure to nicotine during fetal and / or childhood, comprising the step of administering the pharmaceutical composition for preventing or treating obesity of this embodiment to a subject, wherein the administration step is in accordance with the administration method described in "1-3-3. Administration method" above.

[0077] The pharmaceutical composition for preventing or treating obesity according to this embodiment also provides a pharmaceutical composition for suppressing overeating. The pharmaceutical composition for suppressing overeating of the present invention has the same configuration as the pharmaceutical composition for preventing or treating obesity according to this embodiment described above, except that it is administered for the purpose of suppressing overeating.

[0078] 3. Food composition for preventing or treating obesity 3-1. Overview A third aspect of the present invention is a food composition for preventing or treating obesity.

[0079] The food composition for preventing or treating obesity of this embodiment contains γ-oryzanol as an active ingredient. The food composition of the present invention is ingested (eaten or drink) as, for example, a functional food, a food with functional claims, a food for specified health uses, or a nutritionally functional food.

[0080] 3-2.Configuration 3-2-1. Active ingredients The active ingredient in the food composition for preventing or treating obesity of the present invention is γ-oryzanol. The composition of γ-oryzanol has already been described in detail in the first embodiment, so a detailed description thereof will be omitted here.

[0081] 3-2-2.Food composition The "food composition" of the present invention includes, but is not limited to, foods, beverages, functional foods, etc. The type of food composition of the present invention is not particularly limited, but examples of foods include confectionery such as candy, cookies, tablet candy, chewing gum, and jelly, processed grain products such as noodles, bread, cooked rice, and biscuits, paste products such as sausage, ham, and kamaboko, dairy products such as butter and yogurt, instant foods, furikake, and seasonings. Examples of beverages include tea beverages (green tea, black tea, oolong tea, etc.), fruit or vegetable beverages, alcoholic beverages, oral rehydration solutions, carbonated beverages, soft drinks, nutritional drinks, and water.

[0082] The food composition of the present invention may be a functional food. The "functional food" of the present invention means a food having functionality for the living body. For example, it includes so-called health foods in general, such as health functional foods including foods for specified health uses and foods with nutrient functions, functional foods, foods with functional claims, foods for special uses, nutritional supplements, health supplements, supplements (e.g., liquids, powders, tablets, capsules, etc.), beauty foods, diet foods, etc. In addition, the packaging, attached document, or sales pamphlet of the food composition of the present invention may state that the food composition is ingested for the purpose of suppressing overeating caused by nicotine exposure in the fetal and / or childhood stage and preventing or treating obesity.

[0083] The functional food of the present invention may be in the form of a solid preparation (e.g., tablets, granules, powders, pills, capsules, etc.), a liquid preparation (e.g., liquids, suspensions, syrups, etc.), or a gel or paste, or may be in the form of a normal food or beverage (e.g., beverages, sweets, etc.).

[0084] The method of adding γ-oryzanol to the food composition of the present invention is not particularly limited. γ-oryzanol may be added in a state where it is completely or partially extracted from any raw material containing γ-oryzanol (e.g., brown rice), or it may be added in an unextracted state contained in the raw material (e.g., brown rice). In one embodiment, the food composition of the present invention is a food composition other than brown rice, but may be a food obtained by processing brown rice or a food containing brown rice.

[0085] The amount of γ-oryzanol to be added to the food composition of the present invention is not particularly limited. The specific amount of γ-oryzanol to be added can be appropriately determined by those skilled in the art, taking into consideration the type of food composition and the desired taste and texture. Usually, the amount of γ-oryzanol to be added is 0.001 to 99% by weight, 0.01 to 10% by weight, or 0.1 to 10% by weight, for example, 90% by weight, 50% by weight, 10% by weight, 5% by weight, 3% by weight, 2% by weight, 1% by weight, 0.1% by weight, or 0.01% by weight, based on the total weight of the food.

[0086] The food composition of the present invention may further contain any food ingredient. The food composition of the present invention may contain water, proteins, carbohydrates, lipids, vitamins, minerals, amino acids, organic acids, organic bases, fruit juice, flavors, etc. The food composition of the present invention may also contain additives such as sweeteners, flavors, and colorants.

[0087] 3-2-3. How to take The subjects, frequency of administration, amount, and timing of administration of the food composition of the present invention are the same as those described in "1-3-3. Administration method" in "1. Agent for preventing or treating obesity."

[0088] 3-3.Effects In a subject who ingests the food composition for preventing or treating obesity of the present invention, overeating caused by exposure to nicotine during fetal and / or childhood can be suppressed, thereby preventing and / or treating obesity.

[0089] Furthermore, the food composition for preventing or treating obesity of the present invention can suppress overeating caused by exposure to nicotine during fetal and / or childhood (excluding overeating caused by a reduction in the preference for high-fat foods), thereby making it possible to prevent and / or treat obesity.

[0090] According to the food composition for preventing or treating obesity of this embodiment, there is also provided a food composition for suppressing overeating. The food composition for suppressing overeating of the present invention has the same composition as the food composition for preventing or treating obesity of this embodiment described above, except that it is ingested for the purpose of suppressing overeating. EXAMPLES

[0091] <Example 1: Preparation of obesity / overeating model due to early-life nicotine exposure> (the purpose) We will examine whether early-life nicotine exposure induces obesity and / or hyperphagia in mice, similar to the obesity in humans that is caused by passive smoking during fetal and / or childhood.

[0092] (method) Male C57BL / 6J mice (Japan SLC Co., Ltd.) were used in the experiment. Unless otherwise specified, the mice were fed rodent diet D10001 (Research Diets) at 24°C under a 12-hour light / dark cycle. Note that rodent diet D10001 (Research Diets) is a normal diet and does not qualify as a high-fat diet.

[0093] For the continuous administration of nicotine in the young stage, a micro-osmotic pump (Alzet, PUMP MODEL 1002) filled with a solution of nicotine (Sigma-Aldrich, N3876) dissolved in 0.9% saline (Otsuka Pharmaceutical) was implanted subcutaneously in 4-week-old mice, and nicotine was continuously administered at a dose of 0.75 mg / kg / day for two weeks (nicotine group). As a control group, mice with a micro-osmotic pump filled with 0.9% saline (Otsuka Pharmaceutical) implanted subcutaneously were used (saline group). The body weight and daily food intake of the mice in the nicotine and saline groups were monitored daily from the age of 10 weeks into adulthood. Daily food intake was measured by subtracting the amount of remaining food from the amount of food administered. Five mice were used in the experiment for each of the nicotine and saline groups.

[0094] (result) Compared with the saline group, the mice in the nicotine group had significantly higher body weights and daily food intakes from 11 weeks of age onwards (Fig. 1A and B, Fig. 2A). In particular, the mice in the nicotine group had significantly higher average daily food intakes than the saline group at each age from 11 to 13 weeks of age (Fig. 2B).

[0095] These results indicate that nicotine exposure during early childhood can induce obesity and hyperphagia in mice, similar to obesity caused by passive smoking during fetal and / or childhood. Furthermore, it was found that this experimental system can serve as a model for obesity caused by passive smoking during fetal and / or childhood.

[0096] Example 2: Effects of γ-oryzanol on hyperphagia and obesity induced by nicotine exposure in adolescents (the purpose) To verify the efficacy of γ-oryzanol against hyperphagia and obesity induced by nicotine exposure in early life, using nicotine-induced hyperphagia and obesity model mice.

[0097] (method) To investigate the efficacy of γ-oryzanol against hyperphagia and obesity induced by nicotine exposure in adolescents, four mouse groups were prepared based on Example 1: a group of mice administered saline for 2 weeks from 4 weeks of age (referred to as the “saline group”), a group of mice administered nicotine for 2 weeks from 4 weeks of age (referred to as the “nicotine group”), a group of mice administered nicotine and mecamylamine together for 2 weeks from 4 weeks of age (referred to as the “nicotine-mecamylamine group”), and a group of mice administered nicotine for 2 weeks from 4 weeks of age and then administered γ-oryzanol for 28 days from 10 weeks of age (referred to as the “nicotine + γ-oryzanol group”). The body weight and daily food intake of each group were monitored daily from 10 weeks of age onwards to analyze the effect of γ-oryzanol on hyperphagia and obesity.

[0098] Mecamylamine is an antagonist of the nicotinic acetylcholine receptor (nAchR) and blocks the effects of nicotine.

[0099] Nicotine or saline was administered to each group using a micro osmotic pump implanted subcutaneously, as in Example 1. Mecamylamine was administered to the nicotine-mecamylamine group by subcutaneous injection of 1 mg / kg of mecamylamine (Sigma-Aldrich, M9020) dissolved in 0.9% saline once a day. In the nicotine + γ-oryzanol group, mice were fed a diet containing 1% γ-oryzanol (Fujifilm Wako Pure Chemical Industries, Biochemical Grade, Product Code 152-01272) (solid diet with the same composition as D10001) for 28 days from 10 weeks of age. Five mice were used in each of the four groups.

[0100] (result) Compared with the saline group, mice in the nicotine group showed a tendency to have higher body weights and daily food intakes from 11 weeks of age onwards (Fig. 3A, Fig. 4A). On the other hand, no differences in body weights or daily food intakes were observed between the saline group and the nicotine-mecamylamine group or the nicotine + γ-oryzanol group at any age. In particular, the body weights at 14 weeks of age (Fig. 3B) and the average daily food intakes at each age from 11 to 13 weeks of age (Fig. 4B) were significantly higher in the nicotine group than in the saline group, whereas the nicotine-mecamylamine group and the nicotine + γ-oryzanol group were not significantly different from the saline group and were significantly lower than the nicotine group.

[0101] The above results indicate that γ-oryzanol has an inhibitory effect on hyperphagia and obesity induced by nicotine exposure during fetal and / or adolescent stages.

[0102] <Example 3: Examination of the effect of nicotine exposure on body weight and food intake in adulthood> (the purpose) We will verify whether the obesity- and hyperphagia-inducing effects observed in Example 1 are also caused by nicotine exposure in adulthood.

[0103] (method) Micro-osmotic pumps (Alzet) filled with nicotine (Sigma-Aldrich) were implanted subcutaneously in 8-week-old mice, and nicotine was administered continuously at a dose of 0.75 mg / kg / day for 2 weeks (nicotine group). As a control group, mice were used that had micro-osmotic pumps filled with 0.9% saline (Otsuka Pharmaceutical) implanted subcutaneously (saline group). Body weights and daily food intakes of mice in the nicotine and saline groups were monitored daily from the age of 14 weeks. The number of animals used in the experiment was 5 for each of the nicotine and saline groups.

[0104] (result) In the adulthood exposure, no significant differences were observed between the nicotine and saline groups in body weight and daily food intake (Fig. 5A, Fig. 6A). In particular, no significant differences were observed between the nicotine and saline groups in body weight at 18 weeks of age (Fig. 5B) or average daily food intake at each age from 14 to 17 weeks of age (Fig. 6B).

[0105] Unlike the case of Example 1, in which nicotine exposure in early life caused obesity and overeating, in this Example, nicotine exposure in adulthood did not cause obesity and overeating. This result indicates that the induction of obesity and overeating by nicotine exposure is a phenomenon specific to exposure in the fetal and / or early life stages. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A preventive or therapeutic agent for obesity, which contains gamma-oryzanol as an active ingredient and suppresses overeating caused by nicotine exposure in children aged 14 years or younger, excluding the neonatal and infant stages.

2. The method according to claim 1, wherein the childhood stage is 3 years of age or older.

3. The method for preventing or treating obesity according to claim 1 or 2, wherein the nicotine exposure is passive smoking.

4. A pharmaceutical composition for preventing or treating obesity, which contains γ-oryzanol as an active ingredient and suppresses overeating caused by nicotine exposure in children aged 14 years or younger, excluding the neonatal and infant stages.

5. A food composition for preventing or treating obesity, which contains γ-oryzanol as an active ingredient and suppresses overeating caused by nicotine exposure in children aged 14 years or younger, excluding the neonatal and infant stages.

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