JP2006199666A - Preventive and therapeutic agent for amnesia - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a safe agent for preventing and treating amnesia expressing good preventive and therapeutic effects for amnesia with little adverse effects. <P>SOLUTION: The preventive and therapeutic agent contains carnosic acid and/or rosmarinic acid or a salt of the same as effective ingredients. The agent may contain one species selected from vitamins and vitamin-like active materials (L-carnitine, coenzyme Q<SB>10</SB>and the like). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a prophylactic / therapeutic agent for amnesia containing carnosic acid and / or rosmarinic acid as an active ingredient.

  In recent years, dementia has become a social problem with aging. Causes of dementia are largely classified according to the pathological condition, and are classified into cerebrovascular dementia and Alzheimer's dementia, both of which are clinical symptoms such as intellectual impairment (amnestics, disorientation, memory impairment, Symptoms associated with intellectual disability (such as delirium, delusion, aggressive behavior, and abnormal behavior such as tension and excitement) are observed. In particular, for amnesia, there are no effective drugs so far, and development of such amnesia is desired, despite the fact that it is found in various diseases as well as the above-mentioned dementia.

  Carnosic acid and rosmarinic acid are widely known as one of typical extracts such as carnosol and rosemary (Rosmarinus offiicinalis L.) or sage (Salvia offiicinalis L.). is there. As its pharmacological effect, various activities have been known so far in the long history of herbs. Regarding carnodic acid, for example, Japanese Patent Application Laid-Open No. 2003-192564 (Patent Document 1) discloses a melanin production inhibitor containing ascorbic acid or an ascorbic acid derivative and carnodic acid as active ingredients. It is described that the agent is effective for skin whitening. Japanese Patent Laid-Open No. 2001-122777 (Patent Document 2) discloses an anti-ulcer agent containing carnosic acid and / or carnosol as an active ingredient, and is effective against ulcers such as alcoholic ulcers and stress ulcers. Is also described.

  JP 2001-158745 A (Patent Document 3) discloses a nerve growth factor synthesis promoter containing rosemary extract and / or sage extract (carnodic acid and / or carnosol) as an active ingredient. Japanese Patent Laid-Open No. 2001-233835 (Patent Document 4) discloses a nerve growth factor synthesis promoter containing a carnosic acid derivative as an active ingredient. These documents also describe that production of nerve growth factor is enhanced in an in vitro experimental system, and prevention and treatment for neurodegenerative diseases such as Alzheimer-type dementia and cerebral ischemic pathology are expected.

  Japanese Patent Application Laid-Open No. 7-305089 (Patent Document 5) discloses an idea promoter composed of a low boiling essence of Lamiaceae plants. Japanese Patent Application Laid-Open No. 2004-2237 (Patent Document 6) discloses a human or animal anti-aging food or medicine containing a specific herb component such as phenylpropanoid or a processed product thereof, wherein the herb is rosemary. Etc. are also described.

  On the other hand, in the case of rosmarinic acid, for example, JP-A-9-67251 (Patent Document 7) discloses a hyaluronidase inhibitor containing rosmarinic acid as an active ingredient, which is effective against rough skin. Japanese Patent Application Laid-Open No. 2000-72685 (Patent Document 8) discloses a food composition for suppressing digestive ulcer containing rosemary extract as an active ingredient, and Japanese Patent Application Laid-Open No. 2002-275061 ( Patent Document 9) discloses an antidepressant and anxiolytic agent containing rosmarinic acid as an active ingredient.

However, the knowledge which showed the effective preventive and therapeutic effect with respect to an amnesia regarding the said carnosic acid and rosmarinic acid has not been obtained until now.
JP 2003-192564 A (claims, column of effect of invention) JP 2001-122777 A (claims, column of effect of invention) JP 2001-158745 A (claims, column of effect of invention) JP-A-2001-233835 (claims, column of effect of invention) JP-A-7-305089 (Claims) JP 2004-2237 A (Claims) Japanese Patent Laid-Open No. 9-67251 (claims, column of effect of invention) Japanese Unexamined Patent Publication No. 2000-72685 (claims, column of effect of invention) JP 2002-275061 A (claims, column of effect of invention)

  Accordingly, an object of the present invention is to provide a preparation effective for the prevention and treatment of amnesia.

  Another object of the present invention is to provide a preparation that is highly safe and can more effectively prevent and treat amnesia.

  In the forgetfulness model using the living body to solve the above problems, the present inventors compared various components, and that carnosic acid and rosmarinic acid have a high preventive / therapeutic effect on amnesia, Furthermore, it discovered that the preventive / therapeutic effect with respect to forgetfulness could be further improved when used in combination with vitamin Bs and / or vitamin-like active substances. The present invention has been completed through further studies based on these findings. Such a prophylactic / therapeutic effect is completely unpredictable from the physiological or pharmacological actions of carnodic acid and rosmarinic acid known so far.

That is, the preventive / therapeutic agent for amnesia of the present invention comprises (1) at least one selected from carnodic acid and rosmarinic acid or a physiologically acceptable salt thereof as an active ingredient. (2) Carnosic acid and rosmarinic acid may be contained in a rosemary or sage extract. (3) The amnesia preventive / therapeutic agent may further contain at least one selected from vitamins and vitamin-like substances (such as carnitine and coenzyme Q such as coenzyme Q _6-10 ). For example, (4) an agent for the prophylaxis or treatment of amnesia may further include at least one selected from L- carnitine and coenzyme Q _10. (5) The ratio of at least one selected from carnodic acid and rosmarinic acid or a physiologically acceptable salt thereof and at least one selected from vitamins and vitamin-like agents is, for example, in a free form, About 0.001-10 weight part of the latter may be sufficient with respect to 1 weight part of the former. Furthermore, the preventive / therapeutic agent for amnesia may be in the form of (6) a solid or liquid, and (7) may be in the form of a medicine, quasi drug or food. The prophylactic / therapeutic agent of the present invention is useful for preventing / treating various amnesia. (8) Amnesia is transient global amnesia, temporal lobe epilepsy, head trauma, psychogenic amnesia Or a third ventricular tumor, Korsakoff syndrome, or amnesia due to sequelae of encephalitis. Further, (9) amnesia may be due to a decrease in memory and memory in Alzheimer type senile dementia, Alzheimer's disease, senile dementia or cerebrovascular dementia.

Since the preventive / therapeutic agent for amnesia of the present invention contains carnosic acid and / or rosmarinic acid or a physiologically acceptable salt thereof as an active ingredient, it exhibits an effective preventive / therapeutic effect on amnesia. . Furthermore, by combining with vitamins and / or vitamin-like active substances (coenzyme Qs such as coenzyme Q _6-10 ), amnesia can be more effectively prevented and treated. Furthermore, a highly safe preparation (pharmaceutical, quasi-drug, food, etc.) with few side effects can be provided.

  The carnosic acid and rosmarinic acid used in the present invention may be chemically synthesized compounds, or may be extracts from plants containing carnosic acid and rosmarinic acid, such as herbs. Examples of the plant include Lamiaceae plants such as rosemary (Rosmarinus officinalis L., sage or salvia Salvia officinalis L., Mentha piperita L., Melissa officinalis L, Thymus vulgaris. L Arid plant of the flowering stage), etc .; such as parsley plants such as Parsley Petroselinum crispum NYMAN var. Angustifolium HARA, Sanicula europaea L ..; purple plant such as Lithoapermum ruderale DOUGL. Ex LEHM It can be illustrated. Carnosic acid and rosmarinic acid are preferably included in the extract from rosemary or sage.

  Carnosic acid and rosmarinic acid can be obtained, for example, by the following extraction method. Predetermined parts of the plant (for example, leaves, stems, roots, whole herbs, etc.) are immersed in an extraction solvent, and plant components are extracted at room temperature or under heating, or heated to reflux, and plant residues Can be removed by filtration, the resulting extract is concentrated, and the concentrate is separated and purified by various column chromatography. Examples of the extraction solvent include alcohols (monohydric alcohols such as methanol, ethanol, propanol and butanol, polyhydric alcohols such as propylene glycol, 1,3-butylene glycol and glycerin), ketones (acetone and methyl ethyl ketone). Etc.), esters (such as ethyl acetate), ethers (chain ethers such as diethyl ether, cyclic ethers such as dioxane and tetrahydrofuran), cellosolves, carbitols, hydrocarbons or halogenated hydrocarbons (chloroform, Organic solvents such as dichloromethane) or water. The organic solvent may be a water-soluble solvent. These extraction solvents can be used alone or in combination. If necessary, a base (ammonia, an inorganic base such as an alkali metal compound (sodium hydroxide, potassium hydroxide, etc.) or an organic base such as an amine) may be added to the extraction solvent. Further, carnosic acid and rosmarinic acid obtained by extraction may not necessarily be 100% pure, and the content thereof is 0.001% to 100% by weight, preferably 0.1% to 100% by weight. If so, the effect can be sufficiently exhibited.

  Carnosic acid and rosmarinic acid can be extracted by the above method, but can also be extracted, for example, by the method described in JP-A No. 2001-122777 or JP-A No. 2001-158745.

Carnosic acid and rosmarinic acid may be used as derivatives such as physiologically acceptable salts thereof (particularly pharmacologically acceptable salts thereof) or esters. Examples of such salts include salts with inorganic bases (ammonium salts, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and aluminum salts), and salts with organic bases (trimethylamine). , Salts with alkylamines such as triethylamine, salts with cycloalkylamines such as dicyclohexylamine, salts with alkanolamines such as ethanolamine, diethanolamine and triethanolamine, salts with heterocyclic amines such as pyridine and picoline, Salts with alkylenediamine derivatives such as N, N-dibenzylethylenediamine), salts with inorganic acids (salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.), salts with organic acids (formic acid) , Salts with monocarboxylic acids such as acetic acid and trifluoroacetic acid, fumaric acid Salts with polyvalent carboxylic acids such as maleic acid, salts with oxycarboxylic acids such as oxalic acid, tartaric acid, citric acid, succinic acid and malic acid, sulfones such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid Salt with acid), salt with neutral amino acid (salt with glycine, valine, leucine, etc.), salt with basic amino acid (salt with arginine, lysine, ornithine), salt with acidic amino acid (asparagine) Salt with acid, glutamic acid, etc.). Examples of the ester include lower alkyl esters such as methyl ester and ethyl ester (for example, linear or branched C _1-4 alkyl ester).

In order to enhance the preventive / therapeutic effect of amnesia, various compounds (a physiologically active ingredient or a pharmacologically active ingredient) may be blended with the preparation or drug of the present invention as necessary. Examples of such compounds include vitamins and vitamin-like agents (or agents). As vitamins, fat-soluble vitamins (for example, vitamin A, vitamin A such as provitamin A, vitamin D, vitamin D, provitamin D, vitamin E, vitamin K), water-soluble vitamins (for example, And vitamin B1, vitamin B2, niacin (nicotinic acid amide, etc.), vitamin B6, pantothenic acid, biotin, holasin (folic acid group), vitamin B12 such as vitamin B12, and vitamin C). Examples of vitamin-like substances (or agents) include ubiquinone (coenzyme Q), lipoic acid (thioctic acid), essential fatty acids (linoleic acid, linolenic acid, arachidonic acid and other vitamin Fs, eicosapentaenoic acid (EPA), docosahexaene Acids (DHA), etc.), orotic acid (vitamin B ₁₃ ), carnitine (vitamin B _T ), inositol, choline, p-benzoic acid, vitamin Ps (rutin, hesperidin, eriocitrin), vitamins U (methionine methylsulfonium) And the like. These components include, for example, salts (organic or inorganic acid salts, salts with organic or inorganic bases, etc.), lower alkyl esters (for example, C _1-4 alkyl esters such as ethyl ester of EPA, etc.), phosphatidic acid described later It can also be used as a derivative such as an ester. Further, these components may be optically active forms (D-form, L-form, DL-form, etc.) or racemates.

These components can be used alone or in combination of two or more. For example, vitamins and vitamin-like active substances may be used in combination, or a plurality of vitamin-like active substances may be used in combination. Note that the vitamin-like substance (or agent) may constitute a coenzyme. Among these components, at least a vitamin-like substance (or an agent), for example, an active ingredient having an action of enhancing fat burning (such as L-carnitine), an active ingredient having an action of enhancing ATP production, or coenzyme Q is preferable. As coenzyme Q (CoQ), for example, coenzyme Q _1-12 can be used, and usually coenzyme Q _6-12 , preferably coenzyme Q _6-10 , particularly coenzyme Q ₁₀ is often used.

  Furthermore, the preparation of the present invention comprises a phosphatidic acid and an ester thereof, a methyl group donor, an acetylcholinesterase inhibitor together with or in place of the vitamins and / or vitamin-like substances. Etc. may be included. Examples of phosphatidic acid and esters thereof include phospholipids such as phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylcholine (lecithin), phosphatidylserine, bisphosphatidic acid, and diphosphatidylglycerol. Examples of the methyl group donor include choline, betaine, 5-methyltetrahydrofolic acid, and dimethyltetin, and examples of the acetylcholinesterase inhibitor include donepezil hydrochloride. These components can also be used alone or in combination of two or more. Phosphatidylserine has a brain function activation effect and may be used in combination with the vitamins and / or vitamin-like agents.

  The proportion of the above compound can be appropriately selected depending on the subject to be administered, age and weight of the subject to be administered, symptoms, administration time, dosage form, administration method, effects of compoundable compounds on amnesia and combinations thereof. The compounding ratio of the compound is, for example, 0.001 to 10 parts by weight, preferably 0.005 to 7 parts by weight, particularly 0.01 to 5 parts by weight with respect to 1 part by weight of free carnosic acid and rosmarinic acid. It may be about (for example, 0.01 to 0.5 parts by weight).

  Further, these compounds may be administered in the form of one preparation together with carnodic acid and rosmarinic acid or a salt thereof, depending on the administration form, administration method, etc., and carnodic acid and / or rosmarinic acid or a salt thereof. Based on the said ratio, the formulation which uses as an active ingredient, and the formulation or chemical | medical agent which uses the said compound which can be mix | blended as an active ingredient can also be used together.

  The preventive / therapeutic agent of the present invention is useful for amnesia. Here, amnesia refers to a disorder of recollection limited to a certain period or a certain matter, and further, transient or chronic Amnesia, organic forgetfulness due to organic causes, psychological forgetfulness due to psychosis, total amnesia that cannot be recalled at all within a certain period of time, partial amnesia that can be partly recalled, events before the occurrence of consciousness disorder An event after recovery from a disability-related forgetfulness or consciousness disorder may also include a forward-looking amnesia in which a recollection failure occurs. Specifically, the preparation or drug of the present invention is used for transient amnesia, temporal lobe epilepsy, head trauma, psychogenic amnesia, third ventricular tumor, Korsakoff syndrome or encephalitis sequelae. In addition, it is useful as a preventive / therapeutic agent for amnesia such as decreased memory and memory in Alzheimer type senile dementia, Alzheimer's disease, senile dementia or cerebrovascular dementia. .

  That is, the preparation or drug of the present invention brings about improvement in memorizing ability and memory ability that leads to the prevention and treatment of amnesia in a test using an amnesia animal model (scopolamine-induced amnesia model) described later. By the same test method, it is known that donepezil hydrochloride (trade name: Aricept), which is frequently used as a therapeutic agent for Alzheimer-type dementia, exhibits an amnestic effect (Jpn. J. Pharmacol. 89, 7-20). (2002)).

  The preparation or drug of the present invention may be composed of carnosic acid, rosmarinic acid or a salt thereof alone, may be in the form of a solid or liquid, and suitable for foods, pharmaceuticals, quasi drugs and the like. It may be processed into a form.

  When processed into foods, the carnosic acid, rosmarinic acid or their salts are mixed with food processing ingredients. Such a component is generally only required to be usable as a food material. For example, flours such as rice, wheat, corn, potato, sweet potato, soybean, kelp, wakame, tengusa or the like; , Sugars such as glucose, fructose, sucrose, mannitol; and combinations thereof. Furthermore, spices, colorants, sweeteners, edible oils, vitamins, minerals and the like may be added. These food processing ingredients and additives are used alone or in combination. The food may be solid, and may be processed into a desired semi-solid (including jelly-like) or liquid form by adding water as necessary.

  When processed into pharmaceuticals and quasi drugs, the preparation or drug may be a solid or liquid. In pharmaceuticals and quasi-drugs, the above carnosic acid, rosmarinic acid or salts thereof are mixed with physiologically acceptable carriers, excipients, binders, diluents, etc. to give oral or parenteral pharmaceutical compositions. Can be administered. Examples of oral preparations include, for example, solid preparations such as granules, powders, tablets (including sublingual tablets and orally disintegrating tablets), and capsules (including soft capsules and microcapsules), syrups, emulsions, suspensions, etc. Examples of parenteral preparations include injections (including subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and infusions), and external preparations (nasal preparations, transnasal administration). Skin preparations, ointments, suppositories) and the like. In addition, oral preparations and parenteral preparations include preparations (for example, immediate-release preparations and sustained-release preparations) in which release of active ingredients in the body is controlled using known preparation ingredients. These preparations can be produced by a method known per se generally used in the preparation process. In addition, in the above-mentioned preparations, components selected from known preparation additives (hereinafter sometimes referred to as “formulation ingredients”) can be used as appropriate regardless of the administration route. Specific formulation additives include, for example, (1) Pharmaceutical Additive Handbook, Maruzen Co., Ltd. (1989), (2) Pharmaceutical Additives Encyclopedia, 1st Edition, Yakuji Nipposha (1994), ( 3) From the ingredients listed in Supplementary Supplements for Pharmaceutical Additives, 1st Edition, Yakuji Nippo Inc. (1995) and (4) Pharmacology, Revised 5th Edition, Nanedo Co., Ltd. (1997), It can select suitably according to an administration route and formulation use. Below, the specific manufacturing method of the formulation of this invention is explained in full detail.

  As the above oral preparation, the active ingredient and the carrier ingredient are granulated, and the resulting granule is compression-molded with additives as necessary, and then, if necessary, taste masking, enteric or sustained itself It is manufactured by coating by a known method, and capsules can be prepared by filling capsules with granules. Examples of the carrier component or additive include excipients (sugars such as lactose, sucrose, and mannitol, starches such as corn starch, polysaccharides such as crystalline cellulose), and disintegrants (calcium carbonate, carboxymethylcellulose calcium (carmellose). Calcium), crospovidone, etc.), binders (polysaccharides such as pregelatinized starch, gum arabic, dextrin), synthetic polymers such as polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxy Propyl cellulose, low-substituted hydroxypropyl cellulose, cellulose ethers such as hydroxypropylmethylcellulose), lubricants (talc, stearic acid Neshiumu, polyethylene glycol 6000), and the like.

  Examples of the coating agent include saccharides, cellulose derivatives such as ethyl cellulose and hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and Eudragit (methacrylic acid / acrylic acid copolymer). The coating agent may be an enteric component such as hydroxypropylmethylcellulose phthalate, or may be a gastric component composed of a polymer containing a basic component such as dialkylaminoalkyl (meth) acrylate.

  The liquid preparation can be prepared by mixing an active ingredient, a liquid carrier component and an additive, and is sterilized as necessary. For example, as the injection, the active ingredient is a dispersing agent (including Tween 80 and polyethylene glycol), a preservative (including methyl paraben and propyl paraben), an isotonic agent (including sodium chloride and glycerin). In addition, it is dissolved, suspended, or emulsified in an aqueous solvent (including distilled water, physiological saline, Ringer's solution) or an oily solvent (including vegetable oils such as olive oil and sesame oil, propylene glycol, and macrogold). It is manufactured by. At this time, solubilizers (including sodium salicylate and sodium acetate), stabilizers (including human serum albumin), soothing agents (including benzalkonium chloride and procaine hydrochloride), pH adjusters and buffers, etc. These additives may be used. For liquids, emulsifiers, dispersants and suspending agents (polysaccharides such as gum arabic and locust bean gum, cellulose esters such as carboxymethyl cellulose, nonionic surfactants, etc.), sugars (glucose, sorbitol, xylitol, mannitol, etc.) ), Sodium benzoate and the like.

  The external preparation is produced by making the active ingredient into a solid, semi-solid or liquid composition. For example, in the solid composition, the active ingredient is added as it is, or excipients (including lactose, starch, microcrystalline cellulose), thickeners (natural gums, cellulose derivatives, etc.) are added and mixed. Manufactured by making powder. The liquid composition is produced in substantially the same manner as in the case of an injection. The semi-solid composition is preferably in the form of an aqueous or oily gel or ointment. In addition, these compositions all contain a pH adjuster (including an acid component such as carbonic acid and phosphoric acid, a base component such as sodium hydroxide), a buffering agent, and a preservative (paraoxybenzoic acid esters and chlorobutanol). ) And the like. Suppositories are produced by making an active ingredient into an oily or aqueous solid, semisolid or liquid composition.

  Since the drug of the present invention is a herbal ingredient that has been used in general life since ancient times, its toxicity is low and its safety has been established. For mammals (eg, humans, mice, etc.) Used safely. The dosage of the preparation or drug of the present invention can be appropriately selected depending on the administration subject, the age and weight of the administration subject, symptoms, administration time, dosage form, administration method and the like. For example, the daily dose per adult can be selected in the range of usually about 0.01 to 1000 mg, preferably about 0.1 to 500 mg per kg body weight in the case of oral administration. As for the number of administration, it is appropriate to divide it once a day or several times as needed. In the case of an injection, the amount is usually 1/10 to 1/5 that of an oral agent, and in the case of an external preparation, the amount is usually 2 to 5 times that of the oral agent.

  Since the preventive / therapeutic agent of the present invention contains carnosic acid and / or rosmarinic acid or a salt thereof as an active ingredient, it exhibits a good preventive / therapeutic effect on amnesia. In addition, since it is an active ingredient that has been used in general life since ancient times, it has few side effects and is useful as a highly safe pharmaceutical, quasi-drug, and food.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Preparation Example 1 (carnodic acid)
5 kg of rosemary (whole grass, coarsely cut) was immersed in 20 L of ethanol and extracted at 40 ° C. for 2 hours. After the obtained extract was concentrated to 1 L, the extract was filtered to remove insoluble matters. 2 L of purified water was added to the filtrate, and 105 g of the generated precipitate was collected by filtration. This precipitate was dissolved in ethyl acetate, purified by silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (volume ratio)), and precipitated in hexane to obtain 30 g of carnosic acid.

Preparation Example 2 (“Carnodic acid high concentration fraction”)
Rosemary (whole grass, coarsely cut) 4 kg was immersed in 20 L of 90% ethanol aqueous solution and extracted at 40 ° C. for 4 hours. The extract was filtered to remove insolubles, and the resulting solution was concentrated to 6 L under reduced pressure. After concentration, the extract was filtered again to remove insolubles. 12 L of purified water was added to the filtrate and left at 4 ° C. overnight. Subsequently, filtration was performed again to obtain an insoluble rosemary extract (dry weight: 173 g). Hereinafter, an extract containing a high concentration of carnodic acid is simply referred to as “carnodic acid high-concentration fraction”. When analyzed by high performance liquid chromatography (HPLC), the carnodic acid content in the high-concentration fraction of carnodic acid was 17% by weight, and the rosmarinic acid content was 0.2% by weight.

Preparation Example 3 (“Rosmarinic Acid High Concentration Fraction”)
20 times the amount of water was added to 15 kg of rosemary (whole grass, coarsely cut), and digested at 95 ° C. or higher for 2 hours. After cooling to 65 ° C., the mixture was centrifuged to obtain an extract. To the residue was added 8 times the amount of water again and digested in the same manner, and the resulting extract was combined with the previous extract. This extract was concentrated under reduced pressure at 60 ° C. to obtain 13 L of concentrated extract. This concentrated extract was spray-dried to obtain 3 kg of rosemary extract. The extract containing rosmarinic acid at a high concentration is hereinafter simply referred to as “high rosmarinic acid fraction”. When analyzed by high performance liquid chromatography (HPLC), the carnosic acid content of the rosmarinic acid high concentration fraction was 0.03% by weight, and the rosmarinic acid content was 6.9% by weight.

Example 1 (Effect of carnosic acid in a mouse amnesia model (repeated administration for 7 days))
5 weeks old mice whose average body weight in each group was equalized by stratified randomization method were divided into 10 groups, 2 groups in total, and carnodic acid obtained in Preparation Example 1 was used. 10 mg / mL of carnosic acid solution (solvent: carboxymethylcellulose; hereinafter simply referred to as “CMC”; carnosic acid administration group) and 1% solvent (control group; solvent administration group) were repeatedly orally administered (0.3 mL / mL) for 7 days each. 10 g). Subsequently, 60 minutes after the final administration, a scopolamine hydrobromide (SCOP) solution was intraperitoneally administered (0.1 mL / 10 g).

  Thereafter, as shown below, the test was continued according to the passive avoidance reaction test described in Toxicology (First Edition, First Edition, June 20, 2002). That is, 30 minutes after administration, one mouse is housed one by one in the light room of a mouse light / dark discrimination measuring device (manufactured by Neuroscience), and then the latency until the mouse enters the dark room after opening the guillotine door is digital stopwatch ( (SO51, manufactured by SEIKO) and immediately supplied a scrambled electric shock (1 mA) from the shock generator scrambler (NS-SG01, manufactured by Neuroscience) to the floor grid until the mouse escaped to the bright room. (Acquisition trial). The holding trial was carried out 24 hours after the acquisition trial, the mouse was again housed in the light room of the light / dark discrimination device, and then the guillotine door was similarly opened to measure the latency until the mouse entered the dark room. The measurement was performed under fluorescent lamp illumination with an illuminance of 480 Lx, and the measurement of latency during acquisition and holding trials was performed for a maximum of 300 seconds.

  The results are shown in Table 1. As shown in Table 1, in the retention trial, it was recognized that the latency was prolonged in the carnosic acid administration group compared to the control group.

Example 2 (Effects of carnodic acid high concentration fraction (7 days administration))
A high concentration fraction solution (high concentration fraction administration group) of 3.33 to 33.3 mg / mL was used using the carnodic acid high concentration fraction obtained in Preparation Example 2 instead of carnodic acid. The same procedure as in Example 1 was performed.

  The results are shown in Table 2. As shown in Table 2, in the retention trial, it was found that the latency in the carnosic acid high concentration fraction administration group was prolonged in a dose-dependent manner as compared with the control group.

Example 3 (Effect of fraction with high concentration of carnodic acid (administration for 28 days))
20-week-old mice with the average body weight of each group being equalized by stratified randomization method were divided into 20 groups, 2 groups in total, and high concentrations of carnosic acid at 5 mg / mL and 10 mg / mL The fraction solution (solvent: carboxymethylcellulose) and 1% CMC solvent were each orally administered (0.1 mL / 10 g) repeatedly for 27 days. Subsequently, on the 28th day, each group was regrouped into groups of 10 animals using the body weight as an index, and the 5 mg / mL carnodic acid high-concentration fraction was added to the 50 mg / kg administration group, and the 100 mg / kg administration group. Was 10 mg / mL carnodic acid high concentration fraction, and CMC solvent was orally administered (0.1 mL / 10 g) for solvent administration. Subsequently, 60 minutes after the final administration, SCOP solution (0.05 mg / mL) or physiological saline was intraperitoneally administered (0.1 mL / 10 g). The following tests were performed in the same manner as in Example 1.

  The results are shown in Table 3. As shown in Table 3, in the retention trial, it was confirmed that the latency of the carnodic acid high-concentration fraction administration group was longer than that of the solvent administration group.

Example 4 (Effect of high concentration rosmarinic acid fraction (7 days administration))
The same procedure as in Example 1 was performed except that the rosmarinic acid high-concentration fraction obtained in Preparation Example 3 was used in place of the carnosic acid obtained in Preparation Example 1.

  The results are shown in Table 4. As shown in Table 4, in the retention trial, it was confirmed that the latency of the rosmarinic acid high concentration fraction administration group was prolonged in a dose-dependent manner as compared with the solvent administration group.

Example 5 (Combination effect of carnodic acid high-concentration fraction and L-carnitine (administered for 7 days))
The same procedure as in Example 1 was carried out except that 10 mg / mL carnodic acid high concentration fraction and 3.33 mg / mL L-carnitine solution were used.

  The results are shown in Table 5. As shown in Table 5, in the retention trial, the combined administration group of 300 mg / kg of carnodic acid high-concentration fraction and 100 mg / kg of L-carnitine was latent compared with the control group (solvent administration group) and each single agent administration group. The time was allowed to extend.

Example 6 (combined effect of carnosic acid-rich fraction and coenzyme Q ₁₀ (7 daily doses))
Except for using coenzyme Q ₁₀ solution of 10 mg / mL carnosic acid-rich fraction and 0.67 mg / mL was carried out in the same manner as in Example 1.

The results are shown in Table 6. As shown in Table 6, in the retention trial, the carnodic acid high-concentration fraction 300 mg / kg and coenzyme Q ₁₀ 20 mg / kg combined administration group may have a longer latency compared to the solvent administration group and each single agent administration group. Admitted.

  As described above, it was confirmed by the above test that the prophylactic / therapeutic agent of the present invention is effective as a prophylactic / therapeutic agent for amnesia.

Formulation Example 1 (Granule)
A paste was prepared according to a conventional method using the carnodic acid obtained in Preparation Example 1, the following components, and water, and this paste was extruded and granulated by a conventional method to prepare granules.

Carnosic acid 10mg
Lactose 40mg
Crystalline cellulose 20mg
Corn starch 15mg
Carmellose calcium 10mg
Hydroxypropylcellulose 5mg
Formulation Example 2 (tablet)
Tablets were prepared by a conventional method using the carnodic acid obtained in Preparation Example 1 and the following components.

Carnosic acid 10mg
Lactose 135mg
Magnesium stearate 5mg
Microcrystalline cellulose 50mg
Formulation Example 3 (tablet)
Tablets were prepared by a conventional method using the rosmarinic acid high-concentration fraction obtained in Preparation Example 3 and the following components.

Rosmarinic acid high concentration fraction 10mg
Lactose 135mg
Magnesium stearate 5mg
Microcrystalline cellulose 50mg
Formulation Example 4 (Suspension)
A suspension having a carnodic acid concentration of 2% by weight was prepared by a conventional method using the carnodic acid obtained in Preparation Example 1 and the following components.

Carnosic acid 10mg
D-sorbitol 155mg
Magnesium aluminum silicate 2mg
Carboxymethylcellulose 4mg
Sodium benzoate 2.5mg
Purified water

Claims (9)

  A prophylactic / therapeutic agent for amnesia comprising, as an active ingredient, at least one selected from carnosic acid and rosmarinic acid or a physiologically acceptable salt thereof.   The preventive / therapeutic agent for amnesia according to claim 1, wherein carnodic acid and rosmarinic acid are contained in an extract of rosemary or sage.   Furthermore, the amnesia preventive / therapeutic agent of Claim 1 containing at least 1 type selected from vitamins and a vitamin-like active substance. Further, an agent for the prophylaxis or treatment of amnesia according to claim 1 comprising at least one member selected from L- carnitine and coenzyme Q _10.   The ratio of at least one selected from carnosic acid and rosmarinic acid or a physiologically acceptable salt thereof and at least one selected from vitamins and vitamin-like agents is 1 part by weight in the free form. The preventive / therapeutic agent for amnesia according to claim 3, which is 0.001 to 10 parts by weight of the latter.   The agent for preventing or treating amnesia according to claim 1, which is in the form of a solid preparation or a liquid preparation.   The prophylactic / therapeutic agent for amnesia according to claim 1, which is in the form of a medicine, quasi-drug or food.   The amnesia is amnesia due to transient global amnesia, temporal lobe epilepsy, head trauma, psychogenic amnesia, third ventricular tumor, Korsakoff syndrome or sequelae of encephalitis. A preventive or therapeutic agent for amnesia.   The agent for preventing or treating amnesia according to claim 1, wherein the amnesia is caused by a decrease in memorizing ability and memory in Alzheimer type senile dementia, Alzheimer's disease, senile dementia or cerebrovascular dementia.