JP7016071B2 - Appetite suppressant - Google Patents

Description

Application of Article 30, Paragraph 2 of the Patent Law 1. Summary of the 137th Yearly Meeting of the Pharmaceutical Society of Japan Publication date February 1, 2017 Publication address http: // nenkai. pharm. or. jp / 137 / pc / ipdfview. asp? i = 2993 2. The 137th Annual Meeting of the Pharmaceutical Society of Japan Organizer The Date of the Pharmaceutical Society of Japan March 25, 2017

The present invention relates to medicines, foods and methods for suppressing appetite. The present invention also relates to an agent and a method for suppressing the production and secretion of octanoyl ghrelin, which is an active ghrelin.

Targets of obesity therapeutic agents include suppression of lipolysis (for example, inhibition of lipase activity), suppression of fat absorption, suppression of appetite, and the like. When choosing an obesity treatment, it is important to choose the right target.

Cetilistat, which has been approved as a therapeutic agent for obesity, is said to have an inhibitory effect on lipid absorption from the intestinal tract by inhibiting lipase in the gastrointestinal tract, but it is not listed in the drug price standard in Japan. Yes, it has not been released (started selling). The Chinese medicines daisaikoto, boiogito, and bofutsushosan have not been approved for the indication of obesity depending on the manufacturer. There is little evidence. The above drugs are considered to mainly act on lipid absorption or lipid metabolism, and their effects on feeding behavior are unknown.

As appetite suppressants, mazindol and sibutramine, which act on the appetite center, have been developed. Mazindol, which has been clinically applied as an anti-obesity drug for a long time, has the possibility of dependence in animal experiments and the development of resistance in a short period of time, although its dependence in humans is not clear. Mazindol has similar pharmacological properties as amphetamine and exhibits feeding suppression by acting on the feeding control center in the hypothalamus. Currently, mazindol is the only approved drug that exhibits anti-obesity effects by suppressing feeding. However, it is necessary to pay attention to addiction to mazindol, and "drugs, psychotropic drugs, addictive drugs" are designated as regulatory categories, and the administration period is limited to 3 months. Sibutramine has not been put into practical use because it is said that there is a problem that adverse events (cardiovascular side effects) exceed the efficacy.

Ghrelin is a peptide hormone consisting of 28 amino acids discovered as a growth hormone secretagogue (Patent Document 1). This ghrelin is mainly produced from the stomach and secreted into the blood, and acts on the pituitary gland to promote the secretion of growth hormone, and also acts on the hypothalamic feeding control region to promote appetite. Therefore, improvement of eating disorders by utilizing the activity of ghrelin and prevention of obesity by suppressing the activity of ghrelin are expected as drug discovery targets.

In order to express the activity of ghrelin, it is essential that the third serine from the N-terminal of the 28 amino acids is acylated (alkanoylated) with the fatty acid octanoic acid (caprylic acid), which is used for acylation. Animal experiments have shown that fatty acids in food are utilized.

It has been shown that the production of active ghrelin can be suppressed by using oleic acid or eicosapentaenoic acid together with octanoic acid (Patent Document 2). However, the activity of suppressing the production and secretion of the active ghrelin is not sufficient.

International release WO01 / 07475 Japanese Unexamined Patent Publication No. 2014-19666

An object of the present invention is to provide an excellent inhibitor and a method for suppressing the production and secretion of active ghrelin. The present invention also comprises pharmaceuticals, pharmaceutical compositions, combined pharmaceuticals, appetite-suppressing food and drink compositions, appetite-suppressing food compositions, appetite-suppressing combined foods and drinks, and appetite-suppressing combined foods and drinks for appetite suppression, which have excellent effects. The subject is to provide a combination food for suppressing appetite.

The inventors of the present invention have completed the present invention by finding that docosahexaenoic acid (DHA) is a much superior agent for suppressing octanoyl ghrelin production and / or secretion than eicosapentaenoic acid (EPA). Therefore, the present invention provides, for example, the following.
(Item 1)
An appetite suppressant comprising a substance selected from the group consisting of docosahexaenoic acid and derivatives of docosahexaenoic acid.
(Item 2)
The appetite suppressant according to item 1, wherein the derivative of docosahexaenoic acid is selected from the group consisting of a salt of docosahexaenoic acid, an ester, an amide, a phospholipid, a glyceride, a choline derivative, an amino acid derivative, and an ascorbic acid derivative.
(Item 3)
The derivative of docosahexaenoic acid
Alkyl ester of docosahexaenoic acid,
Alkenyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more double bonds,
Alkynyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more triple bonds,
Esters of docosahexaenoic acid with unsaturated alcohols containing one or more triple bonds and one or more double bonds,
Docosahexaenoic acid monoglyceride,
Diglyceride of docosahexaenoic acid,
Triglyceride of docosahexaenoic acid, as well,
The appetite suppressant according to item 1, selected from the group consisting of docosahexaenoic acid-bound phospholipids.
(Item 4)
Less than:
(A) Derivatives of docosahexaenoic acid and
(B) An appetite suppressant containing a fatty acid absorption inhibitor.
(Item 5)
Less than:
(A) Derivatives of docosahexaenoic acid and
(B) A combination drug for suppressing appetite, which comprises a fatty acid absorption inhibitor.
(Item 6)
Item 4. The appetite suppressant or item according to Item 4, wherein the derivative of docosahexaenoic acid is selected from the group consisting of a salt of docosahexaenoic acid, an ester, an amide, a phospholipid, a glyceride, a choline derivative, an amino acid derivative, and an ascorbic acid derivative. 5. The combination drug for suppressing appetite according to 5.
(Item 7)
The derivative of docosahexaenoic acid
Alkyl ester of docosahexaenoic acid,
Alkenyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more double bonds,
Alkynyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more triple bonds,
Esters of docosahexaenoic acid with unsaturated alcohols containing one or more triple bonds and one or more double bonds,
Docosahexaenoic acid monoglyceride,
Diglyceride of docosahexaenoic acid,
Triglyceride of docosahexaenoic acid, as well,
The appetite suppressant according to item 4 or the combination drug for appetite suppression according to item 5, selected from the group consisting of docosahexaenoic acid-bound phospholipids.
(Item 8)
Item 4. The appetite suppressant or item 5 wherein the fatty acid absorption inhibitor is selected from the group consisting of ezetimib, sulfated polysaccharide, oleyl alcohol, lecithin, water-insoluble cellulose derivative, and farnesoid X receptor. The described combination drug for appetite suppression.
(Item 9)
An appetite-suppressing food and drink composition comprising a substance selected from the group consisting of docosahexaenoic acid and docosahexaenoic acid derivatives.
(Item 10)
Item 9. The food and drink composition for suppressing appetite according to Item 9, wherein the derivative of docosahexaenoic acid is selected from the group consisting of a salt of docosahexaenoic acid, an ester, an amide, a phospholipid, a glyceride, a choline derivative, an amino acid derivative, and an ascorbic acid derivative. thing.
(Item 11)
The derivative of docosahexaenoic acid
Alkyl ester of docosahexaenoic acid,
Alkenyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more double bonds,
Alkynyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more triple bonds,
Esters of docosahexaenoic acid with unsaturated alcohols containing one or more triple bonds and one or more double bonds,
Docosahexaenoic acid monoglyceride,
Diglyceride of docosahexaenoic acid,
Triglyceride of docosahexaenoic acid, as well,
Item 9. The food and drink composition for appetite suppression, which is selected from the group consisting of docosahexaenoic acid-bound phospholipids.
(Item 12)
Less than:
(A) Derivatives of docosahexaenoic acid and
(B) An appetite-suppressing food and drink composition containing a fatty acid absorption inhibitor.
(Item 13)
Less than:
(A) Derivatives of docosahexaenoic acid and
(B) A combination food for suppressing appetite containing a fatty acid absorption inhibitor.
(Item 14)
Item 13. The food and drink composition for suppressing appetite according to Item 13, wherein the derivative of docosahexaenoic acid is selected from the group consisting of a salt of docosahexaenoic acid, an ester, an amide, a phospholipid, a glyceride, a choline derivative, an amino acid derivative, and an ascorbic acid derivative. Derivatives or combination foods for appetite suppression according to item 14.
(Item 15)
The derivative of docosahexaenoic acid
Alkyl ester of docosahexaenoic acid,
Alkenyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more double bonds,
Alkynyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more triple bonds,
Esters of docosahexaenoic acid with unsaturated alcohols containing one or more triple bonds and one or more double bonds,
Docosahexaenoic acid monoglyceride,
Diglyceride of docosahexaenoic acid,
Triglyceride of docosahexaenoic acid, as well,
The appetite-suppressing food and drink composition according to item 13, or a combination food for appetite suppression according to item 14, selected from the group consisting of docosahexaenoic acid-bound phospholipids.
(Item 16)
The appetite-suppressing food or drink composition according to item 13, wherein the fatty acid absorption inhibitor is selected from the group consisting of ezetimib, sulfated polysaccharide, oleyl alcohol, lecithin, water-insoluble cellulose derivative, and farnesoid X receptor. Item 14 is a combination food for suppressing appetite.

According to the present invention, a pharmaceutical, a pharmaceutical composition, a combination drug, an appetite-suppressing food / drink composition, an appetite-suppressing food composition, an appetite-suppressing combination food / drink, and an appetite-suppressing combination for appetite suppression. Serve food. The present invention also provides such pharmaceuticals, pharmaceutical compositions, combined pharmaceuticals, appetite-suppressing food and drink compositions, appetite-suppressing food compositions, appetite-suppressing combined foods and drinks, and appetite-suppressing combined foods. Provides a method of preparation.

The present invention also administers a drug comprising (1) a method for appetite suppression comprising administering DHA and / or a DHA derivative, and (2) a DHA and / or a DHA derivative and a fatty acid absorption inhibitor. Provided are a method for suppressing appetite, which comprises (3) a step of administering DHA and / or a DHA derivative, and a step of administering a fatty acid absorption inhibitor. ..

FIG. 1 is a graph showing the effect of various concentrations of DHA on cell viability. FIG. 2 is a graph showing the results of testing the effects of 12.5 μmol / L and 25 μmol / L DHA on the production and secretion of active ghrelin (octanoyl ghrelin). FIG. 3 is a graph showing changes in octanoyl ghrelin concentration in mouse plasma due to DHA administration (FIG. 3 left) or EPA administration (FIG. 3 right). FIG. 4 is a graph showing the effect of DHA administration on the expression level of the ghrelin gene in the stomach.

Hereinafter, the present invention will be described. Throughout the specification, it should be understood that the singular representation also includes its plural concept, unless otherwise noted. It should also be understood that the terms used herein are used in the sense commonly used in the art unless otherwise noted. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, this specification (including definitions) takes precedence. Also, in the present specification, "wt%" is used interchangeably with "mass percent concentration". “%” Means “wt%” or “w / w%” or “mass percent concentration” unless otherwise specified.

The following is a list of definitions of terms specifically used herein.

The term "docosahexaenoic acid" as used herein is used interchangeably with "DHA". The term "eicosapentaenoic acid" as used herein is used interchangeably with "EPA".

The term used herein, a derivative of DHA, is selected from the group consisting of (1) salts, esters, amides, phospholipids, glycerides, choline derivatives, amino acid derivatives, and ascorbic acid derivatives.

Alternatively, the derivative of DHA is
Alkyl ester of docosahexaenoic acid,
Alkenyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more double bonds,
Alkynyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more triple bonds,
Esters of docosahexaenoic acid with unsaturated alcohols containing one or more triple bonds and one or more double bonds,
Docosahexaenoic acid monoglyceride,
Diglyceride of docosahexaenoic acid,
Triglyceride of docosahexaenoic acid, as well,
It is selected from the group consisting of docosahexaenoic acid-bound phospholipids. In the ester-type induction, the alcohol moiety is methanol, ethanol, propanol, isopropanol, butanol and its isomers, pentanol and its isomers, hexanol and its isomers, heptanol and its isomers, octanol and its isomers, or It may be an alcohol having a larger molecular weight. The glyceride-type induction may be monoglyceride, diglyceride, triglyceride, or various positional isomers thereof. In the case of phospholipid-type derivatives, the phospholipid moiety may be selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, their lysotypes, and their positional isomers.

As used herein, the term "glyceride" includes components selected from the group consisting of triglycerides, diglycerides, and monoglycerides of fatty acids. In the present invention, "glyceride" does not include phospholipids or glycolipids unless otherwise specified.

As used herein, the term "ethyl esterification" refers to the reaction of esterifying glycerides and / or fatty acids in the presence of ethyl alcohol. Methods of ethyl esterifying glycerides are well known in the art. Methods of ethyl esterifying fatty acids are well known in the art. For example, when the raw material fat and oil is treated with a lipid-degrading enzyme in the presence of ethyl alcohol, the obtained free fatty acid fraction is an ethyl esterified free fatty acid.

In the present invention, in order to exert an appetite-suppressing effect through suppression of production and secretion of active ghrelin (octanoyl ghrelin), a fatty acid absorption inhibitor may be used in addition to DHA or a DHA derivative. This is because, in order for ghrelin to become active ghrelin (octanoyl ghrelin), it is necessary for the serine residue at the 3-position from the N-terminal to be octanoilized. This is because inhibition of (caprylic acid) uptake suppresses the conversion of ghrelin to active ghrelin (octanoyl ghrelin). Since a fatty acid absorption inhibitor may also inhibit the absorption of docosahexaenoic acid (DHA), when a fatty acid absorption inhibitor is combined, a docosahexaenoic acid derivative whose uptake into cells is less likely to be inhibited by the fatty acid absorption inhibitor is used. It is preferable to use it.

(DHA preparation method)
The DHA contained in the composition of the present invention can be prepared, for example, using a fish oil crude oil ester as a starting material.

Ethyl esterification methods for fractions containing fatty acids are well known. For example, the fatty acid in the fractionated glyceride fraction is ethyl esterified by an acid catalyst or an alkali catalyst or an enzyme (lipase) in the presence of ethyl alcohol. Preferably, the fatty acids in the glycerin fatty acid ester contained in the fractionated glyceride fraction are ethyl esterified by an alkali catalytic method or an enzymatic method. The fatty acid in the fractionated free fatty acid fraction is ethyl esterified by an acid catalyst or an enzyme (lipase) in the presence of ethyl alcohol. When an enzyme is used, the amount of ethyl alcohol to be added is preferably an amount that does not inactivate the enzyme, and is preferably 4 molar equivalents or less, more preferably 2 molar equivalents or less, relative to the glyceride or free fatty acid. Is not limited to these.

Highly unsaturated fatty acids such as DHA in fats and oils containing ethyl esterified ω3 fatty acids are described by the urea addition method (Japanese Patent Laid-Open No. 2007-89522, JP-A-2009-504588), silver nitrate complex method (Japanese Patent Laid-Open No. 2010). -64974, JP-A-7-242895), vacuum precision distillation method including vacuum thin film distillation method (Japanese Patent Laid-Open No. 11-209786), liquid chromatography (hereinafter referred to as HPLC), pseudo-mobile phase chromatography, etc. It is purified to a relatively high purity by one or more kinds of combination methods such as the chromatographic method of No. 11-209786 (Japanese Patent Laid-Open No. 11-209786). You may also use SMB chromatography.

(Pharmaceutical composition)
The drug, pharmaceutical composition, and combination drug of the present invention exert an effect on appetite suppression by suppressing the production and secretion of active ghrelin. In addition, the medicine, the pharmaceutical composition, and the combination medicine of the present invention exert an anti-obesity effect through appetite suppression.

(Prescription of pharmaceutical composition)
The present invention also provides a method of treating and / or preventing a disease or disorder that can be treated and / or prevented by administration of an effective amount of an appetite suppressant to a subject. The appetite suppressant means the composition of the invention in combination with a pharmaceutically acceptable carrier type (eg, sterile carrier).

Appetite suppressants should be taken into account in individual patient clinical conditions (particularly the side effects of appetite suppressant monotherapy), delivery site, method of administration, dosing regimen and other factors known to those of skill in the medical practice (GMP). = Prescribe and administer in a manner that complies with good medical practice, General Medical Council). Therefore, the "effective amount" intended in the present specification is determined by taking such consideration into consideration. The appetite suppressant of the present invention may be formulated and administered in soft capsules, tablets, powders, granules and the like. "Pharmaceutically acceptable carrier" means a non-toxic solid, semi-solid or liquid filler, diluent, encapsulant or any type of prescribing aid.

As a general suggestion, the total pharmaceutically effective amount of an appetite suppressant administered orally per dose ranges from about 500 μg / kg / day to about 200 mg / kg / day of patient body weight, as described above. So this is left to therapeutic discretion. More preferably, for the extracts of the invention, this dose is at least about 1 mg / kg / day, most preferably between about 2 mg / kg / day and about 50 mg / kg / day for humans. Also, as a general suggestion, the total pharmaceutically effective amount of appetite suppressant administered parenterally per dose ranges from about 250 μg / kg / day to about 100 mg / kg / day of patient body weight. , As mentioned above, this is left to the therapeutic discretion. More preferably, for the extracts of the invention, this dose is at least about 0.5 mg / kg / day, most preferably between about 1 mg / kg / day and about 25 mg / kg / day for humans. ..

The preferred dosage form of the pharmaceutical composition of the present invention is oral administration, but parenteral administration may also be used. For parenteral administration, in one embodiment, the appetite suppressant is generally toxic to the recipient with a pharmaceutically acceptable carrier, i.e. the dosage and concentration used, to the desired degree of purity. It is formulated by mixing in an injectable form (solution, suspension or emulsion) in a unit dosage with one that is free and compatible with the other components of the formulation. For example, this formulation is preferably free of oxidation and other compounds known to be detrimental to appetite suppressants.

Generally, an appetite suppressant is uniformly and intimately contacted with a liquid carrier and / or a finely divided solid carrier to prepare a formulation. Then, if necessary, the product is molded into the desired formulation. Preferably, the carrier is a parenteral carrier, more preferably a solution that is isotonic with the recipient's blood. Examples of such carrier vehicles include water, saline, Ringer's solution and dextrose's solution. Non-volatile oils and non-aqueous vehicles such as ethyl oleate are also useful herein as well as liposomes.

The carrier appropriately contains trace additives such as substances that enhance isotonicity and chemical stability. Such substances are not toxic to the recipient at the dosage and concentration used, and such substances include phosphates, citrates, succinates, acetic acids and other organic acids or salts thereof. Buffers such as; antioxidants such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides (eg, polyarginine or tripeptide); proteins such as serum albumin, gelatin or immunoglobulins; polyvinylpyrrolidone. Hydrophilic polymers such as; amino acids such as glycine, glutamic acid, aspartic acid or arginine; cellulose or derivatives thereof, monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose or dextrin; chelating agents such as EDTA. Sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and / or nonionic surfactants such as polysorbate, poroxamer or PEG.

Any drug to be used for appetite suppressant administration can be sterile. Aseptic conditions are easily achieved by filtering with a sterile filtration membrane (eg 0.2 micron membrane). For example, the appetite suppressant is placed in a container with a sterile access port, eg, an intravenous solution bag or vial with a stopper that can be punctured with a hypodermic needle.

The appetite suppressant may be stored in a unit dose or multi-dose container, eg, a sealed ampoule or vial, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, a 10 ml vial is filled with 5 ml of sterile filtered 5% (w / v) aqueous appetite suppressant and the resulting mixture is lyophilized. The lyophilized appetite suppressant may be reconstituted with bacteriostatic water for injection to prepare an infusion solution.

The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more components of the appetite suppressant of the invention. A notice in the form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceutical or biological products may accompany such containers, and this notice may be attached to the government regarding manufacture, use or sale for administration to humans. Represents institutional approval. Furthermore, an appetite suppressant / appetite suppressant food or drink can be used in combination with other anti-obesity agents.

The appetite-suppressing agent / appetite-suppressing food / drink of the present invention may be administered alone or in combination with other appetite-suppressing agents / appetite-suppressing food / drink. The combination can be administered, for example, as a mixture simultaneously; simultaneously or in parallel but separately; or either over time. This includes the presentation that the combined agents are administered together as a therapeutic mixture, and also the procedure in which the combined agents are administered separately but simultaneously, eg, to the same individual through separate intravenous lines. .. The "combination" administration further comprises a separate administration of one of the first and second given compounds or agents.

(Manufacturing of food and drink composition)
A preferred embodiment of the present invention is a food and drink composition. That is, a pharmaceutical composition or a food or drink composition containing DHA and / or a DHA derivative as an active ingredient is a liquid, gel or solid food as it is, for example, juice, soft beverage, coffee, tea, Japanese tea, oolong tea. , Vegetable juice, natural fruit juice, milk drink, milk, soy milk, sports drink, near water drink, nutritional drink, coffee drink, cocoa, soup, dressing, mousse, jelly, yogurt, pudding, sprinkle, baby powder, processing Milk, sports drinks, nutritional drinks, cake mixes, bread, pizza, pies, crackers, biscuits, cakes, cookies, spaghetti, macaroni, pasta, udon, buckwheat, ramen, candy, soft candy, gum, chocolate, okaki, potato chips. , Snacks, ice cream, sherbet, cream, cheese, powdered milk, condensed milk, dairy products such as milk drinks, buns, porridge, glutinous rice cakes, rice cakes, soy sauce, sauce, noodle soup, sauce, dashi no moto, stew Drinks, juices, complex seasonings, curry, mayonnaise, ketchup, retort curry, retort stew, retort soup, retort drinks, canned ham, hamburgers, meat balls, croquettes, dumplings, pilafs, rice balls, frozen foods And added to refrigerated foods, chikuwa, gamo, lunch rice, sushi, baby milk, baby foods, baby foods, sports foods, nutritional supplements, supplements, health foods, etc., and dextrin, lactose, starch, etc. as necessary. It can be processed into pellets, tablets, granules, etc. together with the template, fragrance, pigment, etc., or it can be coated with gelatin, etc. and molded into capsules for use as health foods, nutritional supplements, etc.

When the composition of the present invention is used as a supplement, the active ingredient may be used as it is, or it may be formulated and administered as a soft capsule, a tablet, a powder, a granule or the like. When the composition of the present invention is used for food and drink, it may be added to the raw material of food and drink for administration.

Hereinafter, the present invention will be described in detail with reference to Examples and the like, but the present invention is not limited thereto. The following experiments were conducted with the approval of the Institutional Review Board of the Faculty of Pharmaceutical Sciences, Nagasaki International University.

(Example 1: Effect of DHA on octanoyl ghrelin production / secretion)
AGS-GHRL8 cells were used to test the effect of DHA on octanoylgrelin production and secretion. AGS-GHRL8 cells were cultured in D-MEM medium supplemented with 10% FBS under 37 ° C. and 5% CO ₂ conditions. MTT test on the effect of DHA (0-100 μmol / L) on the survival rate of AGS-GHRL8 cells in order to set the concentration to examine the active ghrelin production / secretion inhibitory effect of the test substance docosahexaenoic acid (DHA). Investigated by. As a result, as shown in FIG. 1, DHA at concentrations up to 25 μmol / L did not cause a significant change in cell viability.

Based on the above results, the effects of 12.5 μmol / L and 25 μmol / L DHA, which did not affect cell viability, on the production and secretion of active ghrelin (octanoyl ghrelin) were tested. A predetermined concentration of DHA was added to the medium of AGS-GHRL8 cells together with 100 μmol / L of octanoic acid, and the concentration of active ghrelin in the medium after culturing for 24 hours was measured by ELISA. The active ghrelin production / secretion inhibitory effect of DHA was evaluated by comparing with the active ghrelin concentration obtained by the same operation by adding only octanoic acid. To the sample medium for ELISA, 1/10 volume of 1 mol / L hydrochloric acid was added in order to suppress the decomposition of active ghrelin. As a result, as shown in FIG. 2, the octanoylgrelin concentration in the medium of AGS-GHRL8 cells decreased at both concentrations. Data are shown as mean ± standard deviation. (N = 6, p <0.05, Tukey's method).

(Example 2: Suppression of production / secretion of active ghrelin (octanoyl ghrelin) in mice)
(1) Measurement of active ghrelin in mouse plasma 6-week-old C57BL / 6J male mice were bred on a normal diet under normal temperature and 12-hour light-dark cycle conditions. 300 mg / kg of DHA (suspended in 5% aqueous gum arabic) was orally administered once daily for 7 days. Mice in the control group received a 5% aqueous solution of gum arabic. In both groups, blood was obtained by cardiac blood sampling after completion of administration, and 1/10 volume of 1 mol / L hydrochloric acid was added to the centrifuged plasma to prepare a sample for ELISA. The plasma active ghrelin concentration was measured by ELISA, and the effect of DHA administration was examined. A similar experiment was performed using an EPA. As a result, as shown in FIG. 3, when DHA was administered, the plasma octanoylgrelin concentration in mice was significantly decreased as compared with the control (Fig. 3, left, reduction rate 45.1%). The decrease in octanoylgrelin plasma concentration due to DHA administration showed a decrease rate more than double that of EPA administration (Fig. 3, right, decrease rate 21.8%). This result shows that the effect of DHA is unexpectedly significantly superior to that of EPA.

This result indicates that DHA can suppress feeding behavior like mazindol, and as a result, can effectively suppress obesity. This result also shows that DHA exerts a very excellent medicinal effect as compared with EPA. Unlike mazindol, DHA is a fish oil component, is highly safe, and can be administered for a long period of time. Therefore, it can be concluded that DHA is an excellent appetite suppressant and a therapeutic drug for obesity.

(2) Measurement of ghrelin mRNA expression level in mouse stomach The stomach tissue was collected from the mouse of (1) above, RNA was extracted, a reverse transcription reaction was performed, and the ghrelin mRNA expression level was measured by real-time PCR. Similarly, that of the control group was also measured and compared. 18s rRNA was used as an endogenous control. As a result, it was shown that DHA administration did not significantly change the expression level of the ghrelin gene in the stomach (Fig. 4).

As described above, the present invention has been exemplified by using the preferred embodiment of the present invention, but the present invention should not be construed as being limited to this embodiment. It is understood that the invention should be construed only by the claims. It will be understood by those skilled in the art that from the description of the specific preferred embodiments of the present invention, the equivalent scope can be carried out based on the description of the present invention and common general technical knowledge. The patents, patent applications and documents cited herein are to be incorporated by reference in their content as they are specifically described herein. Understood.

The present invention relates to a pharmaceutical, a pharmaceutical composition, a combination drug, an appetite-suppressing food / drink composition, an appetite-suppressing food composition, an appetite-suppressing combination food / drink, and an appetite-suppressing combination for appetite suppression. Serve food. The present invention also provides such pharmaceuticals, pharmaceutical compositions, combined pharmaceuticals, appetite-suppressing food and drink compositions, appetite-suppressing food compositions, appetite-suppressing combined foods and drinks, and appetite-suppressing combined foods. Provides a method of preparation.

Claims (2)

A composition for improving eating disorders by suppressing appetite , which comprises a substance selected from the group consisting of docosahexaenoic acid and derivatives of docosahexaenoic acid, wherein the derivative of docosahexaenoic acid is a salt of docosahexaenoic acid. , A composition selected from the group consisting of esters, amides, phospholipids, glycerides, choline derivatives, amino acid derivatives, and ascorbic acid derivatives. The derivative of docosahexaenoic acid
Alkyl ester of docosahexaenoic acid,
Alkenyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more double bonds,
Alkynyl ester of docosahexaenoic acid,
Esters of docosahexaenoic acid and unsaturated alcohols containing two or more triple bonds,
Esters of docosahexaenoic acid with unsaturated alcohols containing one or more triple bonds and one or more double bonds,
Docosahexaenoic acid monoglyceride,
Diglyceride of docosahexaenoic acid,
Triglyceride of docosahexaenoic acid, as well,
The composition according to claim 1, which is selected from the group consisting of docosahexaenoic acid-bound phospholipids.

Images