(19)
(11)EP 2 077 111 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
21.12.2011 Bulletin 2011/51

(21)Application number: 07829459.2

(22)Date of filing:  10.10.2007
(51)International Patent Classification (IPC): 
A61K 31/198(2006.01)
A61P 25/24(2006.01)
A61K 31/7004(2006.01)
A61P 43/00(2006.01)
(86)International application number:
PCT/JP2007/069721
(87)International publication number:
WO 2008/044691 (17.04.2008 Gazette  2008/16)

(54)

ANTIDEPRESSANT AGENT

ANTIDEPRESSIVUM

AGENT ANTIDÉPRESSEUR


(84)Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

(30)Priority: 10.10.2006 JP 2006276611

(43)Date of publication of application:
08.07.2009 Bulletin 2009/28

(73)Proprietor: OTSUKA PHARMACEUTICAL FACTORY, INC.
Naruto-shi, Tokushima 772-8601 (JP)

(72)Inventor:
  • DOI, Masako
    Naruto-shi, Tokushima 772-0003 (JP)

(74)Representative: Scheuermann, Erik et al
Witte, Weller & Partner Patentanwälte Postfach 10 54 62
70047 Stuttgart
70047 Stuttgart (DE)


(56)References cited: : 
WO-A1-02/34257
WO-A1-2005/089774
JP-A- 08 283 148
RU-C1- 2 151 596
WO-A1-2005/065692
WO-A1-2006/077954
JP-A- 2005 336 176
  
  • RIEF WINFRIED ET AL: "Psychobiological aspects of somatoform disorders: Contributions of monoaminergic transmitter systems." NEUROPSYCHOBIOLOGY, vol. 49, no. 1, January 2004 (2004-01), pages 24-29, XP9128876 ISSN: 0302-282X
  • KIDO TOSHITAKA MANSEI STRESS TO HIRO, IGAKU NO AYUMI vol. 204, no. 5, 2003, pages 365 - 369, XP003024699
 
Remarks:
The file contains technical information submitted after the application was filed and not included in this specification
 
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

Technical field



[0001] The present invention relates to an antidepressant containing, (a) as an active ingredient, a branched amino acid selected from L-valine, L-leucine and L-isoleucine, and (b) glucose.

Background art



[0002] In recent years, an increasing number of people suffer from depression. When patients suffering so-called masked depression without any psychotic manifestation are included, the total number of such people accounts for a significant proportion, and it is said that one out of every five Japanese will experience depression once in their lives.

[0003] The causes of depression still remain uncertain at this time, and are not limited to biological factors and personality factors. For example, the current severe changes in the social environment, the social structure where the weak are abandoned, and the tendency to think the same way as other people and to treat individualists as outcasts are involved in the increase of depression patients.

[0004] The therapy of depression includes: first of all, rest; next, drug therapy; and a combination thereof. However, most people are not really allowed to take a rest, and therefore they actually distract themselves with antidepressants.

[0005] There are various kinds of antidepressants from those called first generation including imipramine to those called fourth generation including the latest milnacipran. However, these antidepressants can cause side effects such as dry mouth, constipation, urination disorder and anuresis. In addition, there is concern about interaction with other drugs.

[0006] Meanwhile, examples of known agents containing a branched amino acid that is an active ingredient of the present invention include an agent for relieving muscular pain and muscle strain and stiffness by oral ingestion of a branched amino acid (see JP-A 2000-26289) and an agent for maintaining instantaneous or sustaining muscular power during exercise by oral ingestion of a branched amino acid (see JP-A 2000-26290). By focusing on the fact that branched amino acids such as leucine, isoleucine and valine have organ-specificity so that they can be utilized mainly in muscles and in tissues other than liver, such as kidney, it is found that the branched amino acids are useful in ameliorating muscular pain and muscle stiffness or in maintaining instantaneous or sustaining muscular power during exercise. Also known is an agent for relieving fatigue in the central nervous system containing a branched amino acid (see WO2002/034257) or the like. The document elucidates the mechanism of fatigue in the central nervous system and simultaneously demonstrates that 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid that is a specific inhibitor of L-system transporter in the blood-brain barrier, can suppress the fatigues in the central nervous system, particularly almost completely when used in combination with a branched amino acid such as leucine, isoleucine or valine. In addition, a composition for improving brain cell metabolism (see JP-A 2-172915) and an antidementia drug (see JP-A 3-275631), both containing a branched amino acid, are known. However, these documents do not describe that branched amino acids have antidepressant activity.

[0007] Known pharmaceutical preparations containing branched amino acids include: a pharmaceutical jelly containing, as active ingredients, only branched amino acids having excellent flavor and excellent feel in swallowing, the jelly being administered in reduced dosage (see JP-A 2003-221330); a pharmaceutical dry syrup containing branched amino acids, a suspending agent and a surfactant, the dry syrup having improved flavor and feel in drinking, and keeping excellent suspensibility when suspended (see JP-A 2003-221329); and a chewable tablet containing, as active ingredients, branched amino acids, the tablet remaining uncolored during storage because of its excellent storage stability (see JP-A 2003-221327). However, none of these documents describes antidepressant activity.

[0008] RU 2 151 596 discloses compositions comprising ten natural amino acids, four trace elements and calcium. The compositions disclosed therein are described as having antitumor, antidepressent and anti-arrhythmic activity.

[0009] Rief et al. (Neuropsychobiology, 2004; 49; pages 24-29) describe investigations into the contributions of monoaminergic transmitter systems in somatoform disorders including studies of patients with depression.

[0010] WO 2006/077954 discloses compositions for treating a neurological disease; a neurogenesis or a nerve regeneration promoter, whereby these compositions contain a substance which promotes the activity of mTOR.

[0011] J P 2005 336176 A describes a composition in order to treat body fatigue, whereby the composition comprises D-ribose and at least one member selected from the group consisting of a magnesium salt, an amino acid, and carnitine.

[0012] WO 2005/089774 describes an agent for improving depression-like symptoms, whereby the agent comprises D-ribose.

[0013] JP 08 283148 A describes a composition for improving depressive symptoms caused by stress and mental fatigue. The composition described contains carnitines and vitamin B1s.

[0014] WO 2005/065692 A1 describes a treatment regime for the treatment of conditions which result from the abnormal secretion of cortisol. This method comprises the administration of hydrocortisone.

[0015] Toshitaka (MANSEI STRESS TO HIRO, IGAKU NO AYUMI, vol. 204, No. 5, 2003, pages 365-369) reports investigations into chronic stress and fatigue.

Summary of invention


Technical problem



[0016] An object of the present invention is to provide an antidepressant.

Solution to problem



[0017] The present inventors made extensive investigation to solve the problem described above, found that a branched amino acid can suppress depressive symptoms, and finally completed the present invention.

[0018] That is, the present invention relates to:
  1. (1) a composition which contains (a) at least one compound selected from L-valine, L-leucine and L-isoleucine and (b) glucose for use in the prevention or treatment of depression;
  2. (2) the composition for use according to the above-mentioned (1), wherein the composition contains at least L-isoleucine;
  3. (3) the composition for use according to the above-mentioned (2), wherein the content ratio of L-isoleucine, L-leucine and L-valine in terms of molar ratio is 1 : (0 to 3) : (0 to 2);
  4. (4) the composition for use according to any one of the above (1) to (3), wherein the content ratio of glucose is 0.2 to 10 moles per 1 mole of the branched amino acid.
  5. (5) the composition for use according to any one of the above-mentioned (1) to (4), which is in the form of an injection or granules.


[0019] The present invention also relates to:

(6) a use of a composition comprising (a) at least one compound selected from a branched amino acid, a pharmaceutically acceptable salt thereof and a derivative thereof and (b) glucose, for producing a medicament for the prevention or treatment of depression.



[0020] The present invention also relates to:

(7) a food composition for use in improving depression, which contains (a) at least one compound selected from a branched amino acid, a pharmaceutically acceptable salt thereof and a derivative thereof and (b) glucose.


Advantageous effects of invention



[0021] According to the present invention, it is possible to improve depression or prevent falling into depression since a branched amino acid, especially isoleucine, has antidepressant activity. The antidepressant of the present invention is almost free of side effects such as dry mouth, constipation, urination disorder and anuresis caused by conventional antidepressants, and basically has no risk of interaction with other drugs. Therefore, the antidepressant of the present invention has high safety and can be continuously administered.

Brief description of drawing



[0022] 

Fig. 1 shows the time rats took to come out of a cylinder in Test Example 1. In the graph, the ordinate shows time.


Description of embodiments



[0023] Hereinafter, the antidepressant of the present invention containing, as an active ingredient, at least one compound selected from L-valine, L-leucine and L-isoleucine will be described in detail.

[0024] The branched amino acids used in the present invention are not particularly limited so long as they meet the standards of the Japanese Pharmacopoeia. The branched amino acids used in the present invention are L-valine, L-leucine and L-isoleucine. The above-mentioned branched amino acids may be prepared by hydrolyzing plant-derived or animal-derived proteins with a protease etc., or by microbial fermentation methods, or may be synthetic amino acids prepared by introducing amino groups into organic acids, etc.

[0025] In the antidepressant of the present invention, these branched amino acids can be used alone or as a mixture of two or more thereof, but at least L-isoleucine, in particular at least L-isoleucine is preferably contained.

[0026] In the present invention, when two or more of these branched amino acids are used, their mixing ratio is not particularly limited. Specifically when, L-isoleucine, L-leucine and/or L-valine are used, these compounds may be used alone or as a mixture of two or more thereof, and the mixing ratio of the compounds, in terms of molar ratio, is preferably L-isoleucine : L-leucine : L-valine = about 1 : (0 to 3) : (0 to 2), and more preferably about 1 : (0 to 2.5) : (0 to 1.5).

[0027] The antidepressant of the present invention further contains glucose. Glucose can serve as an immediately-usable energy source in a living organism.

[0028] The content ratio of carbohydrates is not particularly limited, but is preferably for example about 0.1 to 50 moles in terms of glucose per 1 mole of a branched amino acid. The content ratio of carbohydrates is preferably about 0.1 to 20 moles, and more preferably about 0.2 to 10 moles in terms of glucose per 1 mole of a branched amino acid.

[0029] The antidepressant of the present invention can be provided in the form of medicine containing a pharmaceutically acceptable additive or in the form of food containing an additive approved under the food sanitation law.

[0030] The antidepressant of the present invention, when formed into a medicine, can be used for example as a solid preparation for oral administration, a liquid medicine for oral administration, or an injection for parenteral administration (subcutaneous, intravenous, intramuscular or intraperitoneal injection etc.). The solid preparation for oral administration includes, for example, tablets, pills, capsules, powder and granules.

[0031] The additives that can be used in the solid preparation for oral administration include, for example, an excipient, a binder, a disintegrating agent, a lubricant, a stabilizer and a wetting agent. The excipient includes, but is not limited to, sucrose, lactose, glucose, starch and mannitol. The binder includes, but is not limited to, gum arabic, carmellose, gelatin, crystalline cellulose, hydroxypropyl cellulose, methyl cellulose and povidone. The disintegrating agent includes, but is not limited to, carmellose, starch, crystalline cellulose and low-substituted hydroxypropyl cellulose. The lubricant includes, but is not limited to, talc, magnesium stearate, calcium stearate and silica. The stabilizer and the wetting agent include, but are not limited to, citric anhydride, sodium laurate and glycerol. These additives can be used alone or in combination of two or more kinds. The solid preparation for oral administration can be prepared for example by mixing a branched amino acid, with an additive etc., and then forming the mixture into a pharmaceutical preparation according to general methods described in, for example, general rules in the Japanese Pharmacopoeia, 14th revised edition. Specifically, the granules can be preferably prepared for example by adding the above-described excipient, binder, disintegrating agent, etc. to a branched amino acid, kneading the mixture uniformly, and then forming the mixture into granules through compression granulation, tumbling granulation, spray drying granulation, extrusion granulation, milling granulation, fluidization granulation, agitation granulation or the like. The tablets can be produced for example by adding the above-described excipient, binder, disintegrating agent, etc. to a branched amino acid, keading the mixture uniformly, and then directly performing compression molding; or by preparing granules from a branched amino acid, and the excipient, binder, disintegrating agent, etc., and then forming the granules, as they are or after being uniformly mixed with the above-described additive added thereto, into tablets by compression molding. The granules or tablets may be coated if necessary with a suitable coating (gelatin, sucrose, gum arabic, carnauba wax etc.) or an enteric coating (for example, cellulose acetate phthalate, a methacrylic acid copolymer, hydroxypropyl cellulose phthalate, carboxymethylethyl cellulose, etc.). The capsules can be produced for example by adding the above-described excipient, binder, disintegrating agent, etc. to a branched amino acid, kneading the mixture uniformly, optionally forming the mixture into granules, optionally coating the granules with a coating agent, and charging the mixture, granules, or coated granules into capsules.

[0032] The content ratio of a branched amino acid, in the solid preparation for oral administration is not particularly limited, but preferably the total amount of branched amino acids is about 1 to 90% by mass relative to the whole solid preparation.

[0033] The liquid medicine for oral administration includes, for example, a drench, a suspension, an emulsion, a syrup and an elixir. Additives usable in such a liquid medicine include, for example, a solvent such as purified water, ethanol, a mixture thereof, etc. The liquid medicine for oral administration may further contain, for example, a suspending agent (for example, gum arabic, agar, carmellose, hydroxypropyl cellulose, etc.), an emulsifying agent (for example, polysorbate 80, gum arabic, etc.), a flavoring substance (for example, simple syrup, honey, sucrose, tartaric acid etc.), an aromatic substance (for example, methyl salicylate, fennel oil, orange oil, menthol etc.), a preservative (for example, benzoic acid, sodium benzoate, etc.) and a buffering agent (for example, citric acid, hydrogen carbonate, etc.). These additives can be used alone or in combination of two or more kinds.

[0034] Additives that can be used in an injection for parenteral administration include, for example, a solvent, a stabilizer, a solubilizing agent, a suspending agent, a surfactant, an emulsifying agent, a soothing agent, a buffering agent and a preservative. The solvent includes, but is not limited to, distilled water for injection, physiological saline, vegetable oil such as sesame oil, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol and polyethylene glycol. The stabilizer and the solubilizing agent include, but are not limited to, glutamic acid, aspartic acid and polysorbate 80. The suspending agent includes, but is not limited to, cellulose derivatives such as carboxymethyl cellulose sodium and methyl cellulose, and natural gum such as tragacanth and gum arabic. The surfactant includes, but is not limited to, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil, and lecithin. The emulsifying agent includes, but is not limited to, polyoxyl stearate, lauromacrogol, polysorbate 80 and gum arabic. The soothing agent includes, but is not limited to, ethyl aminobenzoate, inositol, meprilcaine hydrochloride, lidocaine hydrochloride, chlorobutanol, propylene glycol and benzyl alcohol. The buffering agent includes, but is not limited to, citric acid or a salt thereof, glucose, phosphoric acid or a salt thereof, and acetic acid or a salt thereof. The preservative includes, but is not limited to, p-hydroxybenzoate ester, benzalkonium chloride, and sorbitan acid salt. These additives can be used alone or in combination of two or more kinds.

[0035] The injection can be produced in a usual manner, for example by suitably dissolving a branched amino acid, and an additive etc., by aseptic manipulation. The produced injection is charged into an ampoule, a vial container, a glass or polyethylene infusion container (including a bag) or the like and then sterilized. The polyethylene infusion container (including a bag) may be packaged for example in a gas-barrier packaging material together with a deoxygenating agent etc. The injection may be produced in a form of a sterile solid preparation, for example a lyophilized product, which can be used by being dissolved in sterilized or sterile distilled water for injection or in another solvent just before use.

[0036] The content ratio of a branched amino acid, is not particularly limited, but in the case of an infusion preparation, the total amount in terms of free branched amino acids is preferably about 0.1 to 10 w/v%, more preferably about 0.1 to 5 w/v%, more preferably about 0.5 to 3 w/v%, relative to the whole injection.

[0037] The antidepressant of the present invention may further contain nutrients such as vitamins (for example, vitamin A, vitamins B1, B2, B6, B12, vitamin C, vitamin D, vitamin E, niacin, pantothenic acid, folic acid, biotin, vitamin F, vitamin P, vitamin Q, vitamin U, choline, inositol, p-aminobenzoic acid, etc.) and amino acids other than branched amino acids (for example, lysine, phenylalanine, methionine, threonine, valine, histidine, tryptophan, alanine, proline, arginine, glutamic acid, serine etc.).

[0038] The dosage of the medicine containing the antidepressant of the present invention is not particularly limited and may be determined depending on the formulation, administration route, the age and weight of the patient, the severity of the disease, etc. General daily dosage per 1 kg of adult body weight may be within the range of about 1 to 1000 mg, preferably about 1 to 500 mg, more preferably about 10 to 500 mg, further more preferably about 50 to 300 mg in terms of free branched amino acids, and may be suitably increased or decreased as desired. The medicine may also be administered in several doses a day.

[0039] When the antidepressant of the present invention is formed into a food, at least one of a branched amino acid, preferably L-isoleucine, is mixed with an additive approved under the food sanitation law or with other various components used for food to form a food or drink product. The form of the food to be produced is not particularly limited, and the food may be in every possible form such as tablets, capsules, powder, granules, a liquid medicine for oral administration, a solid food, a semi-liquid food in the form of cream or jam, a gelatinous food and a drink. Specific examples of the food include, for example, drinks such as soft drinks, juice or lactic acid bacteria beverage, jelly, candies, biscuits and cookies. The method for producing the food is not particularly limited, and any means known in the art can be used.

[0040] The above-mentioned food preferably contains, in addition to a branched amino acid, glucose. The content ratio of carbohydrates in proportion to a branched amino acid is the same as in the case of the above-mentioned antidepressant.

[0041] The tablets, capsules, powder, granules or liquid preparation for oral administration can be produced in the same manner as in the production of the above-described medicine except that an additive approved under the food sanitation law (for example, hydroxypropylmethyl cellulose, crystalline cellulose, tartaric acid, mannitol, saccharine sodium, stevia, dimethylpolysiloxane, p-hydroxybenzoate ester, etc.) is used in place of the additive used in the tablets, capsules, powder, granules or liquid medicine for oral administration as the medicine described above.

[0042] The drink to be produced may contain additives, for example, a flavor, a colorant, natural juice, fruit pulp, flavoring substances such as cheese and chocolate, and a synthetic sweetener as needed. The additives may be used alone or in combination of two or more kinds.

[0043] The semi-liquid food in the form of cream or jam or the gelatinous food such as jelly, to be produced, may preferably contain one or more gelling agents selected from agar, gelatin, carrageenan, gellan gum, xanthan gum, locust bean gum, pectin, sodium alginate, potassium alginate and other ordinarily used polysaccharide thickeners, in addition to the above-mentioned components of a drink. The blending amount of the gelling agent is about 2 parts by mass or less, preferably about 0.5 to 2 parts by mass per 100 parts by mass of jelly.

[0044] The content ratio of a branched amino acid, in such a food is not particularly limited, but preferably the total amount in terms of free branched amino acids is preferably about 1 to 60% by mass. The total amount in terms of free branched amino acids in the food is preferably about 10 to 60% by mass, more preferably about 15 to 60% by mass.

[0045] The food produced in this manner can be used as a functional food for improving depression. A food composition for improving depression, containing at least one compound selected from such a branched amino acid, is also included in the present invention. An indication of its effect of improving depression is preferably provided on the package etc. of such a food product.

[0046] The food is ingested preferably in a daily amount of about 0.1 to 20 g in terms of free branched amino acids per adult (about 60 kg). The daily food intake in terms of free branched amino acids per adult (about 60 kg) is more preferably about 1 to 20 g, further preferably about 3 to 20 g, and particularly preferably about 5 to 20 g.

[0047] By administering a mammal an effective dose of a) at least one compound selected from L-valine, L-leucine and L-isoleucine and b) glucose, depression can be prevented, improved or treated. The mammal as the subject of administration is typically a human, and preferable examples include a human with depression, and a human in a state with risk of moving into depression (a human with masked depression, a human with extreme stress, etc.). Prevention includes, for example, suppression of the progress into depression from a state with risk of moving into depression, suppression of the development of depression from a healthy condition.

Examples



[0048] Hereinafter, the present invention is described in more detail by reference to Production Examples and Test Example, but the present invention is not limited to these examples. Only production example 3 is covered by the claims.

<Production Example 1>



[0049] 300 g of L-isoleucine was dissolved in distilled water for injection. The solution was adjusted to pH 6.50 with sodium hydroxide and then adjusted to a total volume of 10 L with distilled water for injection. The resulting solution was filtered through a membrane filter, introduced into polyethylene infusion bags so that each bag would contain 500 mL, sealed, and sterilized at 105°C for 40 minutes by autoclaving. The bag, together with an oxygen absorber (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Inc.), was packaged in a gas-barrier packaging material made of a polyvinyl alcohol multilayer film, to give an injection.

<Production Example 2>



[0050] 150 g of L-isoleucine and 150 g of L-valine were dissolved in distilled water for injection. The solution was adjusted to pH 6.50 with sodium hydroxide and then adjusted to a total volume of 10 L with distilled water for injection. The resulting solution was filtered through a membrane filter, introduced into polyethylene infusion bags so that each bag would contain 500 mL, sealed, and sterilized at 105°C for 40 minutes by autoclaving. The bag, together with an oxygen absorber (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Inc.), was packaged in a gas-barrier packaging material made of a polyvinyl alcohol multilayer film, to give an injection.

<Production Example 3>



[0051] 300 g of L-isoleucine was dissolved in distilled water for injection. The solution was adjusted to pH 6.50 with sodium hydroxide, adjusted to a total volume of 10 L with distilled water for injection, and filtered through a membrane filter.

[0052] Separately, 1000 g of glucose was dissolved in distilled water for injection. The solution was adjusted to a total volume of 10 L with distilled water for injection, and filtered through a membrane filter.

[0053] 500 ml each of these solutions were separately introduced into different chambers of a polyethylene two-chamber infusion bag, sealed, and sterilized at 105°C for 40 minutes by autoclaving. The bag, together with an oxygen absorber (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Inc.), was packaged in a gas-barrier packaging material made of a polyvinyl alcohol multilayer film, to give an injection.

[0054] When used, by pressing one chamber or two chambers of the bag, the two chambers are linked to each other to prepare a mixture to be used as an injection.

<Production Example 4>



[0055] 1000 g of L-alanyl-L-leucine, 300 g of L-isoleucine and 240 g of L-valine were dissolved in distilled water for injection. The solution was adjusted to pH 6.50 with sodium hydroxide and then adjusted to a total volume of 10 L with distilled water for injection. The resulting solution was filtered through a membrane filter, introduced into polyethylene infusion bags so that each bag would contain 100 mL, sealed and sterilized at 105°C for 40 minutes by autoclaving. The bag, together with an oxygen absorber (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Inc.), was packaged in a gas-barrier packaging material made of a polyvinyl alcohol multilayer film, to give an injection.

<Production Example 5>



[0056] 120 g of hydroxypropylmethyl cellulose and 10 g of crystalline cellulose carmellose sodium were added to, and dispersed in, 10 L of purified water. To this dispersion, 100 g of tartaric acid, 1000 g of mannitol, 10 g of saccharine sodium, 5 g of stevia, 40 g of dimethylpolysiloxane, 2 g of propyl p-hydroxybenzoate and 5 g of methyl p-hydroxybenzoate, were added and dissolved. Subsequently, 950 g of L-isoleucine, 1900 g of L-leucine and 1150 g of L-valine were added thereto and suspended with a homogenizer. This suspension was adjusted to pH 6.5 with sodium hydroxide and further suspended with a homogenizer to prepare a uniform suspension.

[0057] Separately, 40 g of agar powder was added to 2 L of purified water and dissolved by heating to about 80°C. To this, 6000 g of the above suspension and 40 g of a pineapple flavor were added, and mixed. The resulting mixture was introduced into containers so that each container would contain 100 g, sealed, and chilled to prepare a jelly.

<Production Example 6>



[0058] 500 g of L-isoleucine, 1000 g of L-leucine, 600 g of valine, 100 g of citric anhydride and 50 g of hydroxypropyl cellulose were mixed uniformly, and then 300 g of distilled water was added to the mixture, which was then granulated.

[0059] The granulated product was dried at 60°C for 2 hours and passed through a 24-mesh sieve to give granules. The resulting granules were introduced into aluminum laminate stick bags so that each bag contains 4.5 g, and sealed, to give a final product.

<Test Example 1>


Antidepressant activity of orally administered branched amino acid



[0060] SD rats (10-week-old) were divided into two groups (10 rats in each group). One group (control group) was kept for 6 days with free access to food (standard AIN-76 diet manufactured by Nosan Corporation) and water. The other group (present invention group) was kept for 6 days with free access to food (standard AIN-76 diet containing 1% by mass of L-isoleucine) and water. Using these subject animals, depression-improving activity in rats under stress was tested according to the defensive withdrawal test method by Gutman, D.A. et al. (The Journal of Pharmacology and Experimental Therapeutics, 304 (2), 874(2003)).

[0061] That is, a rat (one from each group) was dropped, tail first, into an upright black cylinder 10 cm in diameter and 20 cm in length, and immediately covered with a lid. After 10 seconds, the cylinder was placed in an open field (100 cm long, 100 cm wide, and 45 cm high) made up of white acrylic boards, facing one corner, at a position 20 cm from the corner. The lid was taken off immediately, and behavior of the rat was observed for 5 minutes to measure the time the rat took to come out of the cylinder.

[0062] The test was carried out under an illuminance of 200 1x in a soundproof room, and behavior of the rat was videotaped from above and observed using a monitor outside the soundproof room.

[0063] Statistical processing was performed by two-sided Student's t-test.

[0064] The results are shown in FIG. 1. Compared to the control group, the present invention group took significantly shorter time to come out of the cylinder, which proved the antidepressant effect of L-isoleucine.

[0065] The same tests were done using L-leucine or L-valine, and the same antidepressant effect as that of L-isoleucine was confirmed.

Industrial applicability



[0066] The antidepressant of the present invention can improve depression or prevent falling into depression and can be continuously administered because of its high safety. Therefore, the antidepressant can be used in medicine or food.


Claims

1. A composition which contains (a) at least one compound selected from L-valine, L-leucine and L-isoleucine and (b) glucose for use in the prevention or treatment of depression.
 
2. The composition for use according to claim 1, wherein the composition contains at least L-isoleucine.
 
3. The composition for use according to claim 1 or 2, wherein the content ratio of L-isoleucine, L-leucine and L-valine in terms of molar ratio is 1 : to (0 to 3) : (0 to 2).
 
4. The composition for use according to any one of claims 1 to 3, wherein the content ratio of glucose is 0.2 to 10 moles per 1 mole of the branched amino acid.
 
5. The composition for use according to any one of claims 1 to 4, which is in the form of an injection or granules.
 
6. A use of a composition comprising (a) at least one compound selected from L-valine, L-leucine and L-isoleucine and (b) glucose, for producing a medicament for the prevention or treatment of depression.
 
7. A food composition for use in improving depression, which contains (a) at least one compound selected from L-valine, L-leucine and L-isoleucine and (b) glucose.
 


Ansprüche

1. Zusammensetzung, die Folgendes enthält, nämlich (a) zumindest eine Verbindung ausgewählt aus L-Valin, L-Leucin und L-Isoleucin und (b) Glukose zur Verwendung in der Prophylaxe oder Behandlung von Depression.
 
2. Zusammensetzung zur Verwendung nach Anspruch 1, wobei die Zusammensetzung zumindest L-Isoleucin enthält.
 
3. Zusammensetzung zur Verwendung nach Anspruch 1 oder 2, wobei das Verhältnis des enthaltenen L-Isoleucin, L-Leucin und L-Valin als molares Verhältnis ausgedrückt 1 : zu (0 bis 3) : (0 bis 2) beträgt.
 
4. Zusammensetzung zur Verwendung nach einem der Ansprüche 1 bis 3, wobei das Verhältnis der enthaltenen Glukose 0,2 bis 10 Mol pro 1 Mol der verzweigten Aminosäure beträgt.
 
5. Zusammensetzung zur Verwendung nach einem der Ansprüche 1 bis 4, die in Form einer Injektion oder eines Granulats vorliegt.
 
6. Verwendung einer Zusammensetzung, die Folgendes aufweist, nämlich

(a) zumindest eine Verbindung ausgewählt aus L-Valin, L-Leucin und L-Isoleucin und

(b) Glukose zur Herstellung eines Medikaments zur Prophylaxe oder Behandlung von Depression.


 
7. Lebensmittelzusammensetzung zur Verwendung in der Besserung einer Depression, die Folgendes aufweist, nämlich (a) zumindest eine Verbindung ausgewählt aus L-Valin, L-Leucin und L-Isoleucin und (b) Glukose.
 


Revendications

1. Composition qui contient (a) au moins un composé sélectionné parmi la L-valine, L-leucine et L-isoleucine et (b) du glucose, destinée à être utilisée dans la prévention ou le traitement de la dépression.
 
2. Composition destinée à être utilisée selon la revendication 1, où la composition contient au moins de la L-isoleucine.
 
3. Composition destinée à être utilisée selon la revendication 1 ou 2, dans laquelle le rapport de la teneur en L-isoleucine, L-leucine et L-valine en termes de rapport molaire est de 1 : à (0 à 3) : (0 à 2).
 
4. Composition destinée à être utilisée selon l'une quelconque des revendications 1 à 3, dans laquelle le rapport de la teneur en glucose est de 0,2 à 10 moles pour 1 mole de l'acide aminé ramifié.
 
5. Composition destinée à être utilisée selon l'une quelconque des revendications 1 à 4, qui est sous la forme d'une injection ou de granules.
 
6. Utilisation d'une composition comprenant (a) au moins un composé sélectionné parmi la L-valine, L-leucine et L-isoleucine et (b) du glucose, afin de produire un médicament destiné à la prévention ou au traitement de la dépression.
 
7. Composition alimentaire destinée à être utilisée pour améliorer la dépression, qui contient (a) au moins un composé sélectionné parmi la L-valine, L-leucine et L-isoleucine et (b) du glucose.
 




Drawing








Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description