JP2008214338A - Agent for ameliorating lowering of high-order brain function and agent for ameliorating lowering of short-term memory - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an agent for ameliorating lowering of a high-order brain function, ameliorating or improving lowering of the high-order brain function caused by organic brain disorder and to provide an agent for ameliorating lowering of short-term memory, ameliorating lowering of short-term memory which is a symptom most becoming a core in memory loss and dementia. <P>SOLUTION: The agent for ameliorating lowering of a high-order brain function and the agent for ameliorating lowering of short-term memory each contains α-lipoic acid, a ginkgo leaf extract, creatine, carnitine, a black pepper extract and L-cystine. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an agent for improving lower brain function having an action to improve lowering of higher brain function caused by organic brain injury, and more particularly to an agent for improving lower brain function having a large action to improve lowering of delayed memory. Is.

  Higher brain function refers to cerebral functions such as attention, memory, perception, language, calculation, etc., ischemic stroke such as cerebral infarction, transient ischemic attack, cerebral hemorrhage, hemorrhagic stroke such as subarachnoid hemorrhage, Higher brain dysfunction is observed when traumatic diseases such as concussion and brain contusion or organic brain damage occurs due to aging. Higher cerebral dysfunctions include hemilateral body agnosia, topographical disorders, agnosia, aphasia, memory impairment, apraxia, attention disorders, executive dysfunction and behavioral and emotional disorders.

  Research and development of various therapeutic drugs for such higher brain dysfunction is underway, but most of them are symptomatic treatments for the cause of organic brain damage, which improves or reduces reduced higher brain function. Unfortunately, no effective compounds have been found for improving compounds. In other words, methods for assessing higher brain dysfunction and evaluating the improvement effects include mini-mental states test (MMSE), revised Hasegawa-style simplified intelligence evaluation scale (HDS-R), and Wexler intelligence test (WAIS-R). Can be mentioned. However, MMSE and HDS-R have the drawbacks that accuracy and reproducibility are insufficient to evaluate improvement or enhancement of higher brain function, and WAIS-R takes too much time and effort. Therefore, in order to develop and study a drug for the purpose of objectively improving or improving higher brain function, an effective means for objectively evaluating higher brain function was necessary.

  Recently, attention has been focused on the RBANS neuropsychological test as a method for evaluating higher-order brain functions with higher accuracy and reproducibility. The RBANS neuropsychological test is an abbreviation of Repeatable Battery for the Assessment of Neuropsychological Status developed by Randolph of the United States, and is a neuropsychological test task that can be repeatedly evaluated in a short time of about 30 minutes. This RBANS neuropsychological test is useful for early diagnosis and follow-up of neuropsychiatric disorders such as senile dementia and schizophrenia, and judgment of therapeutic effects. It is considered useful for the determination of sequelae, that is, higher brain dysfunction (Non-patent Document 1). Therefore, it has become possible to determine human higher brain function in a short time with good reproducibility by the RBANS neuropsychological test.

  In recent years, this RBANS neuropsychological test has been used to examine an improving effect on the lowering of higher brain function caused by organic brain injury. A compound containing arachidonic acid and / or arachidonic acid as a constituent fatty acid and docosahexaenoic acid and / or A composition having an action of improving lowering of higher brain function resulting from an organic brain disorder containing a compound containing docosahexaenoic acid as a constituent fatty acid has been developed (see Patent Document 1).

JP2007-8863 Tetsumori Yamashima et al. Neurology Vol.54 463-471 (2002)

  However, using the above RBANS neuropsychological test, there are still few high-level brain function-improving agents that improve the decline in higher-order brain function in humans, particularly the decline in delayed memory that is noticeable in forgetfulness and dementia. In fact, there is a need to develop further active ingredients.

  The present invention has been made in response to the conventional circumstances as described above, and provides an agent for improving lower brain function that can improve or improve lowering of higher brain function due to organic brain damage. For the purpose.

  As a result of the study, the present inventor has found that a composition containing six specific components can improve or improve the lowering of higher brain function due to organic brain damage, particularly delayed memory.

  That is, the present invention is an agent for improving lower brain function, comprising α-lipoic acid, ginkgo biloba extract, creatine, carnitine, black pepper extract and L-cystine.

  The present invention also relates to a delayed memory lowering improving agent comprising α-lipoic acid, ginkgo biloba extract, creatine, carnitine, black pepper extract and L-cystine.

  The agent for improving lower brain function of the present invention is a brain function related to attention, memory, perception, language, calculation, etc., as a result of evaluation using a highly reliable RBANS neuropsychological test for human higher brain function. It has the effect of preventing or improving the lower brain function.

  Further, the higher brain function lowering improving agent of the present invention exhibits a marked improvement effect on delayed memory, which is the most core symptom in forgetfulness and dementia, and is therefore extremely effective particularly as a delayed memory lowering improving agent. .

The best mode of the present invention will be described below.
The α-lipoic acid used in the present invention may be pure α-lipoic acid (also known as thioctic acid or 6,8-dithiooctanoic acid), α-lipoic acid derivatives, salts thereof, or mixtures thereof. Include. Examples include lipoic acid sodium salt, potassium salt, alkyl ester, alkenyl ester, amides, and reduced dihydrolipoic acid, dihydrolipoamide, and the like.

  α-Lipoic acid is a coenzyme present in the mitochondria of cells (for example, it acts as a coenzyme in the decarboxylation of pyruvate and other keto acids in biochemical reactions in the Krebs cycle) and has antioxidant capacity. In addition to being known to have, active ingredients of therapeutic agents such as arteriosclerosis and cataracts, wrinkles, stains, buckwheat, active ingredients of prevention and treatment of pigmentation, active ingredients of antidiabetic drugs, therapeutic agents of liver diseases It is known as an active ingredient, and an active ingredient of a therapeutic agent for peripheral nerves accompanied by a substance metabolic disease.

  The ginkgo biloba extract used in the present invention is not particularly limited as long as it is a ginkgo biloba extract obtained by a method commonly used by those skilled in the art. Generally, ginkgo biloba leaves are dried and powdered, extracted with water or organic solvents such as ethanol, acetone, ethyl acetate, etc., and then treated with alkali or adsorbent to remove harmful substances (eg ginkgolic acid, alkylphenol). Is obtained. From the viewpoint of safety, the contents of ginkgolic acid and alkylphenol are preferably 10 ppm or less, more preferably 5 ppm or less.

  The ginkgo biloba extract generally contains physiologically active substances such as flavonoid glycosides (kaempferol, quercetin, isorhamnetin and the like), terpenoids (terpene lactone), shikimic acid and carboxylic acid. In particular, flavonoid glycosides and terpenoids are known to have excellent physiological activities such as vasodilatory action, platelet aggregation action, anti-inflammatory action, and blood flow improving action. The ginkgo biloba extract may contain prodelphinidin as the proanthocyanidins remaining in the harmful substance removal step.

  Creatine used in the present invention is a kind of amino acid formed by decomposing a substance called creatine contained in muscles, and is also a component of NMF (natural moisturizing factor) also present in the skin. The muscle contains a nitrogen compound that stores energy called creatine phosphate. When it is broken down into creatine by the action of enzymes, it releases energy, and the muscle moves using that energy. When creatine finishes its role, it is converted into a substance called creatinine, and excess creatinine is excreted in the urine from the kidney. Creatinine is an index of proteolytic function and kidney function of blood filtration. Creatinine is also NMF, but NMF derived from the same waste is less in the corneum than urea.

Carnitine used in the present invention is 4-hydroxy-3-trimethylaminobutyric acid (β-hydroxy-γ-trimethyl ammonium butyrate: (CH3) 3N + -CH2-CH (OH) -CH2- COOH), a substance that was formerly called vitamin BT.
Carnitine can be synthesized from the essential amino acids lysine and methionine in the body (liver, kidney, brain) and taken into muscle via blood. Carnitine is also abundant in mutton, red meat, chicken, fish, dairy products, etc., and is also supplied from the diet.

  The black pepper extract (black pepper extract) used in the present invention is a general spice that has been used for a long time, and the active ingredient `` piperin '' contained in the black pepper extract has a function to help absorb curcumin. It is known that there is.

  L-cystine used in the present invention is one of sulfur-containing amino acids, and is known to have an action of accelerating wound recovery, promoting glucose metabolism, and protecting the body from harmful substances by an excellent detoxifying action.

  The RBANS neuropsychological test used for the evaluation of the higher brain function improving agent and delayed memory lowering improving agent of the present invention is also called an urban neuropsychological test. -It is a method of evaluation with 5 items of composition, language, attention (concentration), and delayed memory.

  Among them, the immediate memory is composed of list learning and story memory, and the list learning is memory regarding reproduction of a list of words presented orally, and the story memory is memory regarding reproduction of a short story presented orally. The visual space / configuration consists of graphic replication and line orientation, which is a memory related to the replication of complex geometric figures, and line orientation is a semicircular line segment that is arranged at regular angles radially from the center point. This is a memory related to the match. Language consists of picture designation and semantic fluency, picture designation is a memory related to recognition of 10 kinds of pictures (answering names), and semantic fluency is a memory related to responses of names belonging to a given category (such as animal species). It is. Attention is made up of numbers and codes, and numbers are memories related to the storage of sequences, and codes are memories related to the selection and judgment of correspondence to geometric figures. Delayed memory playback consists of list playback, list recognition, story playback, and graphic reproduction, all of which relate to storage after a certain period of time.

  The higher brain function lowering improver and delayed memory lowering improver according to the present invention can be used as raw materials and additives for foods, beverages, pharmaceuticals, and quasi drugs. And there is no restriction on the purpose and amount of use.

  For example, food compositions include functional foods, dietary supplements, foods for specified health use, formulas for premature babies, formulas for infants, infant foods, maternal foods or foods for the elderly, in addition to general foods. be able to. Examples of foods that contain fats and oils include natural foods that originally contain fats and oils such as meat, fish, and nuts, foods that add fats and oils during cooking such as soups, foods that use fats and oils as a heating medium such as donuts, fats and foods such as butter, and cookies Processed foods to which fats and oils are added at the time of processing such as, or foods to which fats and oils are sprayed or applied at the time of processing and finishing of hard biscuits and the like. Furthermore, it can be added to agricultural foods, fermented foods, livestock foods, marine foods, or beverages that do not contain fats and oils. Furthermore, it may be in the form of functional foods, pharmaceuticals, and quasi-drugs called supplements. For example, enteral nutrients, powders, granules, troches, liquids for internal use, suspensions, emulsions Processing forms such as liquid and syrup may be used.

  In addition to the active ingredient of the present invention, the higher brain function lowering improver and delayed memory lowering improver of the present invention may contain various carriers and additives generally used for foods and drinks, pharmaceuticals or quasi drugs. . For example, an antioxidant can be included for the purpose of preventing oxidation of the active ingredient of the present invention. Antioxidants include, for example, tocopherols, flavone derivatives, phyllozulcins, kojic acid, gallic acid derivatives, catechins, fucic acid, gossypol, pyrazine derivatives, sesamol, guaiaol, guaiac acid, p-coumaric acid, nordihydrogua Natural antioxidants such as yattic acid, sterols, terpenes, nucleobases, carotenoids, lignans, and ascorbyl palmitate, ascorbate stearate, butylhydroxyanisole (BHA), butylhydroxytoluene Examples include synthetic antioxidants such as (BHT), mono-t-butylhydroquinone (TBHQ), 4-hydroxymail-2,6-di-t-butylphenol (HMBP).

  Examples of tocopherols include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, ε-tocopherol, ξ-tocopherol, η-tocopherol and tocopherol esters (such as tocopherol acetate). Furthermore, examples of carotenoids include β-carotene, canthaxanthin, astaxanthin and the like.

  In addition to the active ingredient of the present invention, the higher brain function lowering improver and delayed memory lowering improver of the present invention include various carrier carriers, extender agents, diluents, extenders, dispersants, excipients as carriers. Binder solvent (eg, water, ethanol, vegetable oil), solubilizer, buffer, solubilizer, gelling agent, suspending agent, flour, rice flour, starch, corn starch, polysaccharides, milk protein, collagen, rice Additives such as oil and lecithin include, for example, vitamins, sweeteners, organic acids, colorants, fragrances, anti-wetting agents, fibers, electrolytes, minerals, nutrients, antioxidants, preservatives, fragrances Examples include, but are not limited to, agents, wetting agents, natural food extracts, vegetable extracts and the like.

When the composition of the present invention is used as a pharmaceutical, it can be produced according to a method commonly used in the pharmaceutical technical field, for example, a method described in the Japanese Pharmacopoeia or a method analogous thereto.
When the composition of the present invention is used as a pharmaceutical, the amount of the active ingredient in the composition is not particularly limited as long as the object of the present invention is achieved, and can be used in an appropriate blending ratio. When the composition of the present invention is used as a pharmaceutical, it is desirable to administer it in a dosage unit form, and oral administration is particularly preferred.

  The total dose of α-lipoic acid, ginkgo biloba extract, creatine, carnitine, black pepper extract and L-cystine of the present invention varies depending on the age, body weight, symptoms, frequency of administration, etc., for example, adults (about 60 kg) As) usually about 0.001 g to 20 g, preferably about 0.01 g to 10 g, more preferably about 0.05 to 5 g, most preferably about 0.1 g to 2 g once a day. It is better to administer in 3 divided doses.

  EXAMPLES Next, an Example is given and this invention is demonstrated further in detail. The present invention is not limited thereby. Here, a compounding quantity is the mass%.

Example 1
The test product (Example 1) shown in the following Table 1 was prepared by a conventional method to prepare tablets of 400 mg per tablet (4 tablets per day). Using this test product, higher brain function was evaluated by the following method.

Comparative Example 1
As a placebo (placebo), a test product (Comparative Example 1) shown in the following Table 2 was prepared by a conventional method to prepare a tablet of 400 mg per day (4 daily intakes). Using this test product, higher brain function was evaluated by the following method.

(Evaluation methods)
1. Target Japanese men and women aged 50 and older, those who have subjective symptoms of forgetfulness, those who have subjective symptoms of forgetfulness by self-report, or those who have subjective symptoms of forgetting by relatives and acquaintances An urban neuropsychological test (A-form, immediate memory, visual space / configuration, language, attention (concentration), delayed memory) was evaluated on 61 subjects recommended as 31 subjects were selected as subjects in order from the lowest.

2. Ingestion method Among the 31 subjects, the intake group of Example 1 was 22 and the intake group of Comparative Example 1 was 9; each test article was 4 tablets a day, and 2 tablets each were taken as needed twice a day in the morning and evening did.

3. Measurement method An Urban neuropsychological test (A-form) was performed before and 12 weeks after the intake of each test product, and the score was evaluated.
Table 3 shows the score of each test product before ingestion. A score is a relative value when the average of Japanese men and women 50 years old or older and 70 years old or younger is 50. From Table 3, it can be seen that the persons evaluated in the present example are intended for general persons with a slightly lower higher brain function whose score is 50 or less as a whole.

  Table 4 shows the score values after ingestion when the score before ingestion of each test product is 1. From Table 4, the group administered the test product of Example 1 as a whole was higher in terms of language, attention (concentration), and delayed memory than the group administered the test product of Comparative Example 1 which was a placebo. It can be seen that an improvement in brain function is observed, and in particular, a marked improvement effect is observed for delayed memory.

  In Table 1, α-lipoic acid, ginkgo biloba extract, creatine, carnitine, black pepper extract, and L-cystine were replaced with starch, and the same as above using test products having the same formulation as in Table 1. As a result of evaluation, the improvement effect of higher brain function was not recognized.

Claims (2)

  An agent for improving lower brain function, comprising α-lipoic acid, ginkgo biloba extract, creatine, carnitine, black pepper extract and L-cystine.   An agent for improving delayed memory decline, comprising α-lipoic acid, ginkgo biloba extract, creatine, carnitine, black pepper extract and L-cystine.