KR20150001109A - A composition for preventing or treating dementia through multi-target control - Google Patents

Abstract

The present invention relates to a composition for promoting memory and preventing or treating diseases related to cognitive dysfunction, including epigallocatechin-3-gallate, luteolin and ginsenoside Rg1 as active ingredients. More specifically, the epigallocatechin-3-gallate, luteolin and ginsenoside Rg1 are aimed at treating Alzheimer′s disease like generating beta amyloid (beta-secretase), neurotoxicity (anti-oxidant, anti-inflammation), tau phosphorylation, and nerve regeneration (brain-derived neurotrophic factor, BDNF), thereby improving the efficiency of treating Alzheimer′s disease while reducing side effects. Therefore, the epigallocatechin-3-gallate, luteolin and ginsenoside Rg1 are widely used in pharmaceutical compositions and health promoting functional food products for preventing and treating diseases related to memory disorder including memory impairment and Alzheimer′s disease.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition for preventing or treating dementia,

The present invention relates to a composition for preventing or treating a multi-target control dementia disease comprising epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ as an active ingredient.

Dementia is a complex clinical syndrome characterized by marked impairment in human cognitive function, intellectual ability, emotion, and behavior. It causes memory impairment such as memory, attention, language function, and spatio-temporal ability. It is in a state of difficulty. The term "dementia" refers to a condition in which one or more of the other cognitive functions, including memory, is present.

Alzheimer's Disease or Parkinson's Disease is the cause of dementia, which can be caused by cerebral hemorrhage, metabolic diseases such as hepatic encephalopathy, Wilson's Disease, infectious diseases such as neurosyphilis, acquired immunodeficiency, Such as drug addiction, brain trauma, etc. In some forms, diseases that may cause structural and functional abnormalities in the central nervous system may cause dementia. Among them, dementia caused by Alzheimer's disease is the most common with 50 ~ 60%, followed by dementia caused by cerebrovascular disease.

Particularly, the molecular pathology of Alzheimer's disease results in the formation of the nervous system due to accumulation of β-amyloid peptide, formation of nerve fiber concentrate due to accumulation of tau protein superphosphorylation and aggregation, oxidative damage, increase of intracellular calcium, Inflammatory response, energy metabolism abnormality, neurotransmitter abnormality, and neuronal apoptosis are presented as representative examples, and new drugs for treating dementia are being developed based on this.

That is, as a disease control / progressive and remedy for fundamental dementia treatment, there are a beta amyloid production inhibitor, a beta amyloid degradation promoter, a beta amyloid aggregation inhibitor, a beta amyloid toxicity inhibitor, a beta amyloid vaccine, a tau protein hyperphosphorylation inhibitor, Non-clinical / clinical studies on the efficacy and safety of stem cell therapy and the like are actively underway.

Therefore, in order to increase the treatment efficiency of dementia and reduce the side effects, it is very important to find a substance capable of controlling various therapeutic targets related to Alzheimer's disease and to treat dementia diseases through multi-target control.

On the other hand, Korean Patent Application Nos. 10-1148623 and 10-1141355 disclose compositions for treating and preventing memory impairment and cognitive dysfunction containing alpha-tunon or alpha-pinene as an active ingredient, There is no mention of the epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ of the invention.

Accordingly, an object of the present invention is to provide a method for preventing or treating memory-related and cognitive dysfunction-related diseases, which comprises epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ as active ingredients And to provide a pharmaceutical composition for administration.

Another object of the present invention is to provide a method for preventing or ameliorating memory-related and cognitive dysfunction-related disorders comprising epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ as an active ingredient, And a health functional food for improvement.

The present invention provides epigallocatechin-3-gallate (EGCG) represented by the following formula (1), luteolin (LUT) represented by the formula (2) The present invention provides a pharmaceutical composition for preventing or treating memory-related and cognitive dysfunction-related diseases, which comprises ginsenoside Rg ₁ as an active ingredient.

≪ Formula 1 >

(2)

(3)

Specifically, the cognitive dysfunction-related diseases include, but are not limited to, forgetfulness, Alzheimer's disease, cerebrovascular dementia, dementia caused by head injury, or Parkinson's disease.

The epigallocatechin-3-gallate used as an active ingredient in the present invention is a kind of polyphenol present in green tea leaves, and luteolin is a kind of green vegetables such as rooibos leaves, celery, Is a kind of flavonoid which is widely known in the world. Both of these substances are emerging as a neuroprotective substance having antioxidant and anti-inflammatory action. In addition, ginsenoside Rg ₁ is ginsenoside Rg ₁ as a saponin is the combined function component, that is specified as the indicator component ginsenoside Rg ₁ and Rb ₁ in the functional food revolution with Rb ₁ 0.8 to 34 mg / g. < / RTI >

Particularly, epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ are involved in the production of beta amyloid (beta-secretase, beta-secretase), neurotoxicity (antioxidant, antiinflammation) , Tau phosphorylation, and nerve regeneration (brain-derived neurotrophic factor, BDNF), which can improve not only the efficiency of dementia treatment but also the side effects.

The epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ according to the present invention are preferably contained in an amount of 0.1 to 50% by weight based on the total weight of the composition. However, the composition is not limited thereto, and may vary depending on the condition of the patient, the type of disease, and the progress of the disease.

In addition, the composition of the present invention may be provided in various forms selected from a pharmaceutical composition or a health food composition.

When the composition of the present invention is a pharmaceutical composition, the method of administration is determined depending on the severity of symptoms. The extract of the present invention can be administered to mammals such as rats, mice, livestock, and humans in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections. The dosage of the active ingredient in the pharmaceutical composition may vary depending on the route of administration, the severity of the disease, the age, sex, and weight of the patient, and may be administered once to several times per day. However, in order to obtain the desired effect, it is preferable to administer it at 0.01 mg / kg to 10 g / kg, preferably 1 mg / kg to 1 g / kg per day. The administration may be carried out once a day or divided into several doses. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

The epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ according to the present invention can be used in the form of a general pharmaceutical preparation. In actual clinical administration, oral or parenteral May be administered in a branched form. In addition, in the case of formulation, in addition to the active ingredients epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ , one or more additional pharmaceutically acceptable carriers are prepared can do. The pharmaceutically acceptable carrier may be a mixture of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components. If necessary, an antioxidant, , And other conventional additives such as a bacteriostatic agent may be added.

Solid formulations for oral administration may include tablets, pills, powders, granules, capsules, etc. These solid preparations may contain epigallocatechin-3-gallate, luteolin, The side Rg ₁ is prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. The liquid preparations for oral administration include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like May be included.

Further, the pharmaceutical composition of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, or intramuscular injection. In order to formulate parenteral administration formulations, epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ are mixed in water together with a stabilizer or buffer to prepare a solution or suspension And formulate it into unit dosage forms of ampoules or vials.

In addition, when the composition of the present invention is a health food composition, there is no particular limitation on the type of food to which the compound of the present invention can be added, but various foods such as beverage, gum, tea, , Health supplement foods, etc., and can be used in the form of pills, powders, granules, infusions, tablets, capsules or beverages.

The health beverage composition of the present invention is not particularly limited to liquid ingredients other than the above-mentioned compounds as essential ingredients in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as dextrin, cyclodextrins; And sugar alcohols such as xylitol, sorbitol, and erythritol. As natural flavors other than those described above, natural flavors (such as tau martin, stevia extract (e.g., rebaudioside A, glycyrrhizin)) and synthetic flavors (saccharin, aspartame, etc.) have. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.

In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

The present invention relates to a composition for preventing or treating memory-related and cognitive dysfunction-related diseases, which comprises epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ as an active ingredient Epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ are involved in the production of beta-amyloid (beta-secretase), neurotoxicity (antioxidant, antiinflammation) , Tau phosphorylation, brain-derived neurotrophic factor (BDNF), and the like, as it not only improves the efficiency of dementia treatment but also reduces side effects, Can be usefully used as a pharmaceutical composition and health functional food useful for the prevention and treatment of memory disorder related diseases.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

Example 1. Beta amyloid-induced inhibition of memory damage

1. Epigallocatechin-3-gallate (EGCG), luteolin (LUT) and ginsenoside Rg ₁

Epigallocatechin-3-gallate, luteolin and Rg ₁ represented by the following formulas 1, 2 and 3 were obtained from Sigma-Aldrich (St. Louis, USA) Were identified in comparison with the disclosed properties and dissolved in corn oil at a dose of 5 mg / kg and 15 mg / kg, respectively, and used as a test sample.

≪ Formula 1 >

(2)

(3)

2. Experimental animals

Male SD (Sprague-Dawley) rats, 7 weeks old, were used as experimental animals for one week. The test group and the control group were divided into five groups, respectively. Epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ in corn oil at doses of 5 mg / kg and 15 mg / kg during the experimental period (14 days after surgery) . The animals were kept at 21-26 ° C and 40-60% humidity in the animal breeding room.

3. Morris water-maze test

Confirming that the epigallocatechin-3-gallate, luteolin and ginsenoside Rg _{1 obtained} from the above exhibit memory enhancing effects in animal models induced by memory amyloid damage by beta amyloid (Morris water-maze test).

A beta-amyloid (Aβ _1-42 ) was infused at 600 pmoles / day (1 μl / min rate, 5 μl total volume) for 14 days in the lateral ventricle of 7-week-old male SD rats, (5 mg / kg and 15 mg / kg) of epigallocatechin gallate, ruteolin, and Rg ₁ (5 mg / kg and 15 mg / kg) for the same period of time were administered to the patients with the Morris water-maze test ).

Experiments with water have shown that the complex material of epigallocatechin gallate, luteolin, and ginsenoside Rg ₁ can contribute to the spatial perception of experimental animals and to their short- and long-term memory recovery It is an experiment to see. Experimental equipment consists of a round steel tank (180 cm in diameter, 60 cm in height) and a platform (12 cm in diameter, 33 cm in height). The height of the water in the water tank (temperature 22 ± 2 ° C) was up to 2 cm above the platform so that when the mouse sat on the escape platform, the body could come out of the water. In the experiment with water, the test animals were kept at the same level during the experiment period so that the environment was not changed because the animals were looking for the escape pods using the markers around the water tanks. The time taken for the animals to visit when they visited the escape pod for more than 20 seconds was defined as the escape latency, and the mean value obtained by performing this three times a day was the mean escape latency. The incubation latency was recorded by observing the computer program (Ethovision 3.1, Noduls, The Netherlands) by installing a camera on the ceiling above the tank. The experiment was carried out three times daily for 4 days. In this case, the possibility of visiting the esophagus by chance was minimized by sequentially changing the position of placing the experimental animals in the water tank every time. If the experimental animal can not find the escape pod within 90 seconds, the escape latency is set to 90 seconds, and if the experimental animal is sitting on the escape pod, it is placed for 20 seconds to remind the surrounding clues.

4. Passive avoidance test

To confirm the effect of epigallocatechin gallate, luteolin and ginsenoside Rg ₁ on memory, we performed the following experiment using passive avoidance experiment.

Experiments were carried out in a manual evasion experiment in a device with a light compartment and a dark compartment (26 cm by 28 cm, 15 cm by height) connected by a guillotine door. The light compartment is equipped with a light bulb and the dark compartment is provided with a 2 mm thick stainless steel rods at 1 cm intervals on the floor to provide electrical stimulation. The condition avoidance reaction proceeded for a total of 3 days. On the first day, the rats were placed in a bright compartment, adapted for 20 seconds, turned on, and opened the compartment door. In general, the rats are placed in a dark compartment without lighting, which automatically closes the compartment door. This training was repeated until the rats entered the room without illumination in 20 seconds. On the second day, the rats were placed in a bright compartment, acclimated for 20 seconds, illuminated, and then the compartment door was opened in the same manner. When the rats entered the darkened compartment without lighting, the partition door was automatically closed and the fire was turned off, and a current of 0.5 mA was applied to the bottom of the floor for 5 seconds to receive an electrical shock (training trial). On the third day of the experiment (after 24 hours), if the rats are placed back into the light compartment, the rats are reluctant to enter the dark compartment even when lit, and the time required for the rats to enter the dark compartment, ie, step-through latency (Retention trial). On the other hand, when the rat did not enter the dark compartment, the cut-off time was set to 300 seconds.

Hereinafter, examples of formulations using the compounds will be illustrated, but the present invention is not intended to be limited thereto, but is only specifically described.

Preparation Example 1. Preparation of powder

Epigallocatechin gallate 200 mg

200 mg luteolin

Ginsenoside Rg ₁ 200 mg

Lactose 100 mg

Talc 10 mg

The above components are mixed and filled in airtight bags to prepare powders.

Formulation Example 2. Preparation of tablets

Epigallocatechin gallate 200 mg

200 mg luteolin

Ginsenoside Rg ₁ 200 mg

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.

Formulation Example 3. Preparation of capsules

100 mg epigallocatechin gallate

Luteolin 100 mg

Ginsenoside Rg ₁ 100 mg

Crystalline cellulose 3 mg

Lactose 14.8 mg

Magnesium stearate 0.2 mg

The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.

Formulation Example 4. Preparation of injection

100 mg epigallocatechin gallate

Luteolin 100 mg

Ginsenoside Rg ₁ 100 mg

180 mg mannitol

Sterile sterilized water for injection 2974 mg

Na ₂ HPO ₄ .12H ₂ O 26 mg

(2 ml) per 1 ampoule in accordance with the usual injection preparation method.

Formulation Example 5. Preparation of a liquid preparation

100 mg epigallocatechin gallate

Luteolin 100 mg

Ginsenoside Rg ₁ 100 mg

10 g per isomer

5 g mannitol

Purified water quantity

Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was added with purified water to adjust the total volume to 100 ml, And sterilized to prepare a liquid preparation.

Formulation Example 6. Preparation of Healthy Foods

Epigallocatechin gallate 700 mg

Luteolin 700 mg

Ginsenoside Rg ₁ 600 mg

Vitamin mixture quantity

70 [mu] g of vitamin A acetate

Vitamin E 1.0 mg

0.13 mg vitamin B1

0.15 mg of vitamin B2

0.5 mg vitamin B6

0.2 [mu] g vitamin B12

10 mg vitamin C

Biotin 10 μg

Nicotinic acid amide 1.7 mg

50 ㎍ of folic acid

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

15 mg of potassium phosphate monobasic

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

100 mg of calcium carbonate

24.8 mg of magnesium chloride

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

Formulation Example 7. Preparation of health drink

100 mg epigallocatechin gallate

Luteolin 100 mg

Ginsenoside Rg ₁ 100 mg

Vitamin C 15 g

Vitamin E (powder) 100 g

19.75 g of ferrous lactate

3.5 g of zinc oxide

Nicotinic acid amide 3.5 g

Vitamin A 0.2 g

Vitamin B1 0.25 g

Vitamin B2 0.3g

Water quantity

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 ° C for about 1 hour. The resulting solution was filtered, sterilized in a sterilized 2 L container, It is used in the production of the health beverage composition of the present invention.

Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.

Claims (7)

Epigallocatechin-3-gallate (EGCG) represented by the following formula (1), luteolin (LUT) represented by the following formula (2) and ginsenoside Rg ₁ represented by the following formula Or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing or treating memory-related disorders and cognitive dysfunction-related disorders.

≪ Formula 1 >

(2)

(3)

The cognitive function disorder according to claim 1, wherein the cognitive dysfunction-related disorder is any one selected from the group consisting of forgetfulness, Alzheimer's disease, cerebrovascular dementia, dementia caused by head injury, and Parkinson's disease. A pharmaceutical composition for preventing or treating diseases associated with promotion and cognitive dysfunction. [3] The composition according to claim 1, wherein the epigallocatechin-3-gallate, luteolin and ginsenoside Rg ₁ are contained in an amount of 0.1 to 50% by weight based on the total weight of the composition. A pharmaceutical composition for preventing or treating diseases associated with promotion and cognitive dysfunction. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises an acetylcholinesterase (AChE) inhibitor selected from the group consisting of donepezil, galantamine, and rivastigmine A pharmaceutical composition for preventing or treating memory-related and cognitive dysfunction-related diseases. Epigallocatechin-3-gallate represented by the following formula (1), luteolin represented by the following formula (2), and ginsenoside Rg ₁ represented by the following formula (3) A health functional food for preventing or improving diseases associated with promotion and cognitive dysfunction.
≪ Formula 1 >

(2)

(3)

[Claim 7] The method according to claim 5, wherein the cognitive dysfunction-related disorder is any one selected from the group consisting of forgetfulness, Alzheimer's disease, cerebrovascular dementia, dementia caused by head injury, and Parkinson's disease. A health functional food for preventing or improving diseases associated with promotion and cognitive dysfunction. [Claim 6] The method of claim 5, wherein the health functional food further comprises an acetylcholinesterase (AChE) inhibitor selected from the group consisting of donepezil, galantamine, and rivastigmine And a health functional food for preventing or ameliorating cognitive dysfunction-related diseases.