CN115919836A - Green tea extract with improved blood brain barrier permeability of GCG or EGCG and composition comprising the same - Google Patents
Green tea extract with improved blood brain barrier permeability of GCG or EGCG and composition comprising the same Download PDFInfo
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- CN115919836A CN115919836A CN202210866590.0A CN202210866590A CN115919836A CN 115919836 A CN115919836 A CN 115919836A CN 202210866590 A CN202210866590 A CN 202210866590A CN 115919836 A CN115919836 A CN 115919836A
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Abstract
The present disclosure relates to a green tea extract having improved blood brain barrier permeability of one or more of GCG and EGCG, and a composition for improving blood brain barrier permeability or cognitive function decline comprising the same as an active ingredient. Specifically, the green tea extract according to an aspect of the present invention changes the component content of the green tea extract through high temperature treatment, so that the blood-brain barrier permeability of EGCG can be greatly improved as compared to the existing green tea extract. In addition, the composition according to another aspect of the present invention comprises the green tea extract as an active ingredient, so that the safety is high, and the effective concentration of GCG or EGCG in brain tissue can be increased due to high blood brain barrier permeability of GCG or EGCG, thereby greatly improving the cognitive function decline improvement activity thereof.
Description
Technical Field
The present disclosure relates to a green tea extract having an enhanced blood brain barrier permeability of GCG or EGCG and a composition for enhancing blood brain barrier permeability or improving cognitive function decline comprising GCG or EGCG as an active ingredient.
Background
There have been many studies showing that catechins including GCG and EGCG have antioxidant and anti-inflammatory activities and, at the same time, exhibit activities of inhibiting the production of β -amyloid (β -amyloid), which is known to be one of the most important causes for degenerative brain diseases, and inhibiting neurotransmitter degrading enzymes (acetylcholinesterase, achE), thereby preventing memory impairment and protecting cognitive ability.
However, since the Blood Brain Barrier (BBB) permeability of EGCG is low, the concentration of EGCG actually permeating into the brain is low, and it is limited because it cannot effectively exert the above functions.
Therefore, it is required to develop a method for improving the blood-brain barrier permeability of EGCG to improve the prevention or treatment effect of EGCG for brain diseases.
Disclosure of Invention
The purpose of the present disclosure is to provide a composition that is non-toxic, has excellent blood-brain barrier permeability of GCG or EGCG, and has excellent efficacy in improving cognitive function decline.
In order to achieve the above objects, the present invention provides a green tea extract with enhanced Blood Brain Barrier (BBB) permeability of more than one of GCG and EGCG, comprising 3 to 10 wt% of (-) -epigallocatechin gallate ("GCG") and 3 to 10 wt% of (-) -epigallocatechin gallate ("EGCG"), based on the total weight of the extract.
In another aspect, the present invention provides a composition for improving cognitive function decline, comprising, as an active ingredient, a green tea extract having an increased Blood Brain Barrier (BBB) permeability of one or more of GCG and EGCG, wherein the green tea extract comprises 3 to 10% by weight of (-) -epigallocatechin gallate ((-) -gallocatechin gallate, GCG) and 3 to 10% by weight of (-) -epigallocatechin gallate ((-) -epigallocatechin gallate, EGCG), based on the total weight of the extract.
The green tea extract according to an aspect of the present invention changes the component content of the green tea extract by high temperature treatment, so that the blood brain barrier permeability of one or more of GCG and EGCG can be greatly improved as compared to the existing green tea extract.
The composition according to another aspect of the present invention comprises the green tea extract as an effective ingredient, so that the safety is high and at the same time, the effective concentration of GCG or EGCG in brain tissue can be increased due to the high blood-brain barrier permeability of GCG or EGCG, thereby greatly enhancing the cognitive function decline improvement activity thereof.
Detailed Description
In the present specification, the "green tea extract" includes, regardless of the extraction method, the extraction solvent, the extracted components or the form of the extract, an extract extracted from tea (Camellia sinensis) which is a evergreen tree belonging to the family theaceae, tea leaves inoculated with Bacillus subtilis spp, or the like, and includes a fraction obtained by fractionating the extract with a specific solvent. The tea includes one or more selected from the group consisting of tea leaves, flowers, stems, fruits, roots, stems, and heartwood of roots, and may preferably be leaves. Further, the form of the extract may preferably be a powder form. The extraction or fractionation may be performed using water, an organic solvent, or a mixed solvent thereof. The organic solvent may be alcohol, isopropanol, acetone, hexane, ethyl acetate, carbon dioxide or a mixed solvent of two or more thereof, but is not limited thereto, and may be extracted or fractionated at room temperature or by heating under conditions that the effective components of green tea are not damaged or minimized. The alcohol may be C 1 ~C 5 A lower alcohol of (2). The number of times or method of extraction or fractionation is not particularly limited, and for example, cold-maceration extraction, ultrasonic extraction, reflux-cooling extraction, hot-water extraction, or the like can be used, and preferably, the active ingredient is extracted or fractionated by cold-maceration or heating, filtered, and the filtrate is concentrated under reduced pressure to obtain the green tea extract of the present invention.
In the present specification, "epicatechin" includes Epigallocatechin (EGC), (-) epicatechin ((-) epicatechin, EC), (-) -epigallocatechin gallate ((-) -epigallocatechin gate, EGCG) and epicatechin 3-O-gallate (ECG).
In the present specification, "epicatechin epimers" include Gallocatechin (GC), catechin (C), (-) -gallocatechin gallate ((-) -gallocatechin gallate, GCG), and Catechin Gallate (CG).
Hereinafter, the present invention will be described in detail.
In one aspect, the present invention relates to a green tea extract having enhanced Blood Brain Barrier (BBB) permeability of one or more of GCG and EGCG, comprising 3 to 10 wt% of (-) -epigallocatechin gallate ((-) -gallocatechin gate, GCG) and 3 to 10 wt% of (-) -epigallocatechin gallate ((-) -epigallocatechin gate, EGCG), based on the total weight of the extract.
In one embodiment, the GCG is included in the green tea extract in an amount of 3 wt% or more, 3.2 wt% or more, 4 wt% or more, 4.8 wt% or more, 5 wt% or more, 5.2 wt% or more, 6 wt% or more, 6.4 wt% or more, 7 wt% or more, 7.2 wt% or more, 8 wt% or more, 9 wt% or more, or 9.6 wt% or more based on the total weight of the extract. The GCG is contained in the green tea extract in an amount of 10 wt% or less, 9.6 wt% or less, 9 wt% or less, 8 wt% or less, 7.2 wt% or less, 7 wt% or less, 6.4 wt% or less, 6 wt% or less, 5.2 wt% or less, 5 wt% or less, 4.8 wt% or less, 4 wt% or less, or 3.2 wt% or less based on the total weight of the extract.
In one embodiment, the EGCG is included in the green tea extract in an amount of 3 wt% or more, 3.2 wt% or more, 4 wt% or more, 4.8 wt% or more, 5 wt% or more, 5.2 wt% or more, 6 wt% or more, 6.4 wt% or more, 7 wt% or more, 7.2 wt% or more, 8 wt% or more, 9 wt% or more, or 9.6 wt% or more based on the total weight of the extract. The EGCG is contained in the green tea extract in an amount of 10 wt% or less, 9.6 wt% or less, 9 wt% or less, 8 wt% or less, 7.2 wt% or less, 7 wt% or less, 6.4 wt% or less, 6 wt% or less, 5.2 wt% or less, 5 wt% or less, 4.8 wt% or less, 4 wt% or less, or 3.2 wt% or less based on the total weight of the extract.
In one embodiment, the total content of GCG and EGCG in the extract may be 9-15 wt% based on the total weight of the extract. Specifically, the total content of GCG and EGCG in the extract may be 9 wt% or more, 9.5 wt% or more, 10 wt% or more, 10.5 wt% or more, 11 wt% or more, 11.5 wt% or more, 12 wt% or more, 12.5 wt% or more, 13 wt% or more, 13.5 wt% or more, 14 wt% or more, or 14.5 wt% or more, based on the total weight of the extract, and the total content of GCG and EGCG in the extract may be 15 wt% or less, 14.5 wt% or less, 14 wt% or less, 13.5 wt% or less, 13 wt% or less, 12.5 wt% or less, 12 wt% or less, 11.5 wt% or less, 11 wt% or less, 10.5 wt% or less, or 9.5 wt% or less, based on the total weight of the extract.
In one embodiment, the weight ratio of GCG to EGCG in the extract (GCG: EGCG) may be 1:0.5 to 1:2. specifically, the weight ratio of GCG to EGCG (GCG: EGCG) in the extract may be 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1. 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.
in one embodiment, the extract may be an extract extracted more than once with any one of water and C1 to C4 alcohols. In one aspect, the alcohol may be ethanol. In another aspect, the alcohol may be 20% (v/v) or more, 30% (v/v) or more, 40% (v/v) or more, 50% (v/v) or more, 60% (v/v) or more, or 70% (v/v) or more ethanol. In yet another aspect, the alcohol may be ethanol at 70% (v/v) or less, 60% (v/v) or less, 50% (v/v) or less, 40% (v/v) or less, or 30% (v/v) or less.
In one embodiment, the blood brain barrier permeability of one or more of GCG and EGCG may be 30% or more relative to the initial dose. Specifically, the blood-brain barrier permeability of one or more of GCG and EGCG may be 30% or more, 32% or more, 35% or more, 40% or more, 43% or more, 45% or more, 50% or more, 53% or more, or 55% or more, based on the weight of GCG or EGCG relative to the initial amount of administration.
The present invention in another aspect relates to a composition comprising the green tea extract as an active ingredient.
In one embodiment, the green tea extract may be present in the composition in an amount of 1 to 100 wt% relative to the total weight of the composition. More specifically, the content of the green tea extract in the composition may be 1 wt% or more, 5 wt% or more, 10 wt% or more, 15 wt% or more, 20 wt% or more, 25 wt% or more, 30 wt% or more, 35 wt% or more, 40 wt% or more, 45 wt% or more, 50 wt% or more, 55 wt% or more, 60 wt% or more, 65 wt% or more, 70 wt% or more, 75 wt% or more, 80 wt% or more, 85 wt% or more, 90 wt% or more, or 95 wt% or more. In another aspect, the content of the extract in the composition can be 100 wt% or less, 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 75 wt% or less, 70 wt% or less, 65 wt% or less, 60 wt% or less, 55 wt% or less, 50 wt% or less, 45 wt% or less, 40 wt% or less, 35 wt% or less, 30 wt% or less, 25 wt% or less, 20 wt% or less, 15 wt% or less, 10 wt% or less, or 5 wt% or less. Preferably, the content of the green tea extract in the composition may be 100 wt% relative to the total weight of the composition.
In one embodiment, the dosage of the green tea extract may be 5 mg/kg/day to 1000 mg/kg/day. Specifically, the dose may be 5 mg/kg/day or more, 10 mg/kg/day or more, 30 mg/kg/day or more, 50 mg/kg/day or more, 70 mg/kg/day or more, 100 mg/kg/day or more, 200 mg/kg/day or more, 300 mg/kg/day or more, 400 mg/kg/day or more, 500 mg/kg/day or more, 600 mg/kg/day or more, 700 mg/kg/day or more, 800 mg/kg/day or more, or 900 mg/kg/day or more. In another aspect, the dose can be 1000 mg/kg/day or less, 900 mg/kg/day or less, 800 mg/kg/day or less, 700 mg/kg/day or less, 600 mg/kg/day or less, 500 mg/kg/day or less, 400 mg/kg/day or less, 300 mg/kg/day or less, 200 mg/kg/day or less, 100 mg/kg/day or less, 70 mg/kg/day or less, 50 mg/kg/day or less, 30 mg/kg/day or less, or 10 mg/kg/day or less.
In one embodiment, the composition may be for enhancing Blood Brain Barrier (BBB) permeability of one or more of GCG and EGCG.
In another embodiment, the present invention relates to the use of said composition for the preparation of a composition for enhancing the permeability of the Blood Brain Barrier (BBB).
In one embodiment, the composition may be for improving cognitive function decline.
In another embodiment, the present invention relates to the use of said composition for the preparation of a composition for improving cognitive function decline.
In an embodiment, the decline in cognitive function may be due to any one selected from the group consisting of neurotransmitter degradation, reduced neurotransmitter production, and reduced neurotransmitter receptors.
In one embodiment, the neurotransmitter may be acetylcholine.
Dementia is classified into Alzheimer's disease, vascular dementia, and dementia due to other diseases, and dementia patients generally show clinically significant impairment in the aspects of mental, emotional, and behavioral changes, and thereafter show severe signs of cerebral cortical dysfunction such as loss of directional sensation, memory impairment, aphasia, and the like. As a pathological mechanism proposed as a result of the research of alzheimer's disease, an abnormal protein called β -amyloid (β -amyloid) is first accumulated in the brain outside nerve cells, and then tau protein is accumulated inside nerve cells to cause synaptic damage, which finally leads to nerve dysfunction and brain cell death. In addition, in dementia, neurobiochemical disorders of the cholinergic nervous system of the hippocampus and temporal lobe, which are directly or indirectly associated with memory impairment, are particularly prominent. The biochemical decline of the cholinergic nervous system of the basal forebrain pathway (basal forebrain pathway) and neuronal loss are facts consistently disclosed by dementia researchers. In fact, it has been confirmed that in dementia patients, the uptake of choline (choline uptake) and the synthesis of acetylcholine in hippocampus and cerebral cortex are reduced, and on the contrary, it is disclosed that the expression of acetylcholinesterase (AChE), which is an enzyme degrading acetylcholine, is high. In addition, it has been confirmed that the activity of choline acetyltransferase (ChAT), which is an enzyme synthesizing acetylcholine, is sharply decreased, being greatest in the hippocampus, and the number of nicotinic and/or muscarinic acetylcholine receptors (nAChR and/or mAChR) in the brain is decreased.
According to the composition, the blood brain barrier permeability of more than one of GCG and EGCG is greatly increased, the effective concentration of more than one of GCG and EGCG in brain tissues is remarkably increased, so that the cognitive function reduction and improvement activity of GCG and/or EGCG can be greatly improved, and great help can be provided for improving the life quality and improving the disease conditions and treating patients with reduced cognitive function such as dementia patients, memory impairment patients, amnesia patients and the like.
In one embodiment, the cognitive function decline may be one or more selected from the group consisting of weakness, memory deterioration, amnesia, cognitive decline, learning disorders, attention decline, depression, hearing decline, analgesia, anhidrosis, and discrimination decline.
In one embodiment, the decline in cognitive function may result from a neurodegenerative disease.
In one embodiment, the neurodegenerative disease may be one or more of the group consisting of alzheimer's disease, dementia, parkinson's disease, huntington's disease, autosomal dominant cerebellar ataxia (autosomal-dominant cerebellar ataxia), hypersomnia, alcoholism, drug intoxication, and Hereditary sensory and autonomic neuropathy.
In one embodiment, the composition may be a food or pharmaceutical composition.
The food composition may be a health functional food composition, and the dosage form thereof is not particularly limited, and for example, it may be formulated into tablets, granules, pills, powders, liquid formulations such as drinks, caramel, gels, sticks, tea bags, and the like. The food composition of each dosage form can be appropriately selected and configured by those skilled in the art without difficulty according to the dosage form or the purpose of use, in addition to the effective ingredient, the ingredients generally used in the art, and can produce a synergistic effect when applied simultaneously with other raw materials. In addition, the food can also be a health functional food.
The composition can be administered by various methods such as simple ingestion, drinking, injection administration, spray administration, or extrusion administration.
In the food composition according to an aspect of the present invention, the determination of the dosage of the effective ingredient is within the ability of those skilled in the art, and the amount to be administered may vary depending on various factors such as age, health condition, complications, and the like.
The food composition according to an aspect of the present invention may be various foods including, for example, chewing gum, caramel products, candies, ice cream, cookies, etc., various beverage products including, for example, cooling drinks, mineral water, alcoholic drinks, etc., health functional foods including, for example, vitamins or minerals, etc.
In addition to the above, the food composition according to an aspect of the present invention may include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like. Further, the food composition according to an aspect of the present invention may include pulp for preparing natural juice, juice beverages, and vegetable beverages. These components may be used alone or in combination. The proportions of these additives are not so critical, but are generally included in the range of 0 to about 60 parts by weight per 100 parts by weight of the composition according to an aspect of the invention.
The pharmaceutical composition according to an aspect of the present invention may be administered orally, parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, etc. The dosage form for oral administration may be tablets, pills, soft and hard capsules, granules, powders, fine granules, liquids, emulsions or pellets, but is not limited thereto. The preparation for parenteral administration may be a solution, a suspension, an emulsion, a gel, an injection, a drop, a suppository, a patch or a spray, but is not limited thereto. The dosage form can be easily prepared according to a conventional method in the art, and may additionally include a surfactant, an excipient, a wetting agent, an emulsification promoter, a suspending agent, a salt or buffer for controlling osmotic pressure, a colorant, a perfume, a stabilizer, a preservative, or other commonly used adjuvants.
The pharmaceutical composition according to an aspect of the present invention may also comprise pharmaceutically acceptable salts, which may comprise (1) salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an acid addition salt (acid addition salt) formed from an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2, 2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, or the like; or (2) a salt formed when an acidic proton present in the parent compound is replaced.
The appropriate amount or dose of the pharmaceutical composition according to an aspect of the present invention may vary according to the age, sex, body weight, pathological condition and severity thereof of the subject to be administered, administration route or judgment of the prescriber. It is within the ability of the person skilled in the art to determine the dosage of the active ingredient based on these factors.
The present invention will be described in more detail below with reference to examples, test examples, and dosage form examples. However, these examples and test examples are only provided for understanding the contents of the present invention, and the scope of the present invention is not limited to these examples and test examples, and modifications, substitutions, and insertions, which are generally known in the art, may be performed, and are also included in the scope of the present invention.
Example 1 preparation of Green tea extract with varied content of ingredients
Adding 1000ml 50% ethanol into 100g green tea (Camellia sinensis, osulloc farm, jizhou), stirring at 60 deg.C under reflux for 1 hr, filtering, distilling under reduced pressure to obtain first green tea extract, concentrating, and concentrating at 1.2kgf/cm 2 ~1.5kgf/cm 2 Stirring in steam for 1-7 hr. Thereafter, the temperature was lowered to room temperature, insoluble matter was filtered, concentrated under reduced pressure, and 60g of green tea extract was harvested with the content of ingredients changed so as to contain epicatechin epimer. In this case, the change in the content of EGCG and GCG was measured for the green tea extracts obtained in the above-mentioned stirring period (1 to 7 hours), and each green tea extract was used as samples 1 to 5.
In addition, 1200ml of 50% ethanol was added to 1000g of green tea (tea tree (Camellia sinensis), japan Osulloc farm), and the mixture was stirred twice under reflux at 60 ℃ for 3 hours, filtered and distilled under reduced pressure to obtain the first green tea extract (255 g), and then the first green tea extract was dissolved in 1L of water, sterilized at 121 ℃ for 90 minutes, and concentrated under vacuum using a rotary evaporator (Buchi R200, flawil, switzerland) to obtain 250g of green tea extract (sample 6).
After 50% (v/v) methanol aqueous solution was added to each sample and sonication (sonication) was performed, the content measurement of EGCG and GCG was analyzed using UPLC-PDA, the detailed conditions are shown in table 1 below, and the analysis results are shown in table 2 below. In this case, the quantitative analysis utilizes a standard test curve prepared for each concentration of the standard solution.
[ TABLE 1]
[ TABLE 2]
EGCG(mg/g) | GCG(mg/g) | Catechin (8 kinds) (mg/g) | |
Sample No. 1 | 110±22 | 10±2 | 260±20 |
Sample No. 2 | 90±18 | 30±6 | 228±20 |
Sample No. 3 | 80±16 | 40±8 | 230±20 |
Test specimen4 | 60±12 | 60±12 | 224±20 |
Sample No. 5 | 40±10 | 80±16 | 200±20 |
Sample No. 6 | 104±10 | 76±16 | 290±20 |
[ test example 1] measurement of p-glycoprotein (Pgp) Activity
The p-glycoprotein present in the cerebral blood vessels is a protein that functions to move substances entered into brain cells outward again, and the higher the activity thereof, the lower the concentration of substances in brain tissues becomes. Thus, the relative p-glycoprotein activities of the treated samples 1 to 6 were measured.
Using Pgp-Glo TM Specifically, a reaction solution to which a p-glycoprotein membrane and verapamil (verapamil) were added was treated with 10. Mu.g/ml samples 1 to 6, 1. Mu.M and 3. Mu.M EGCG, 1. Mu.M and 3. Mu.M GCG, 1.5. Mu.M EGCG + 1.5. Mu.M GCG, 1.7. Mu.M EGCG + 1.3. Mu.M GCG, 2. Mu.M EGCG +1. Mu.M GCG, and 1. Mu.M EGCG + 2. Mu.M GCG, and then reacted at 37 ℃ for 40 minutes, an ATP detection reagent (detection reagent) was added thereto, and a luminescence amount (luminorescent) was measured after 20 minutes. The results are shown in Table 3 below.
[ TABLE 3]
From the results of table 3, it was confirmed that the p-glycoprotein activity was decreased in the case of the treatment with mixed EGCG and GCG as compared with the treatment with EGCG or GCG alone, and it was confirmed that, particularly, the p-glycoprotein activity was decreased in the range of 1:1 weight ratio of EGCG to GCG, the p-glycoprotein activity decreased by nearly half. Furthermore, it was confirmed that the activity of p-glycoprotein was greatly reduced when the green tea extracts of samples 3 to 5 were used, and particularly, the activity of p-glycoprotein was reduced by almost half when the green tea extract of sample 4 was used. From this, it was found that in the case of the treatment with a mixture of EGCG and GCG or with a green tea extract containing all of EGCG and GCG, the p-glycoprotein activity was greatly reduced, and the concentration of EGCG in brain tissue was maintained at a high level, as compared with the case of the treatment with EGCG and GCG alone.
Further, it was confirmed that, in comparison with the case of 1.7:1.3 weight ratio of EGCG and GCG mixed in the ratio of 1:1, the activity of p-glycoprotein is significantly reduced in the case of treatment with EGCG and GCG mixed. Furthermore, it was confirmed that the activity of p-glycoprotein significantly decreased when the sample 4 was treated with the green tea extract, as compared with the sample 6. From this, it is found that the ratio of 1:1 by weight ratio of EGCG and GCG or 1:1 weight ratio of green tea extract containing EGCG and GCG, compared to a weight ratio of green tea extract treated at 1.7:1.3 weight ratio of EGCG and GCG treated or treated with a 1.7:1.3 weight ratio of the green tea extract containing EGCG and GCG, the p-glycoprotein activity was greatly reduced, so that the concentration of EGCG in brain tissue was maintained at a high level.
Test example 2 measurement of Blood Brain Barrier (BBB) Permeability
1. Culturing Human Brain Microvascular Endothelial Cells (Human Brain Microvascular Endothelial Cells, HBMECs)
Will be 1 × 10 5 The HBMEC of (a) was inoculated in a Collagen-coated transwell chamber (Collagen-coated transwell insert) and cultured in DMEM/F-12 (ThermoFisher) containing 10% FBS for 3 days.
2. Determination of Blood Brain Barrier (BBB) Permeability
The hardness of the cells cultured in the above item 1 was measured by using a cell TEER value (STX 2 electrode, world Precision Instruments), and only cells having a resistance value exceeding 100 Ω (ohm) were used in the test. Samples 1 to 6, 100. Mu.M EGCG, 100. Mu.M GCG, 50. Mu.M EGCG + 50. Mu.M GCG, 57. Mu.M EGCG + 43. Mu.M GCG, 25. Mu.M EGCG + 75. Mu.M GCG, 75. Mu.M EGCG + 25. Mu.M GCG, each at 1000. Mu.g/ml, were applied to the upper side of the corresponding cells, and after 30 minutes, the medium was collected, and the cell culture solution and methanol 1: after 1 (v/v) dilution and then sonication (sonication) for 20 minutes, the amounts of EGCG and GCG were measured using UPLC-PDA in the same manner as described in example 1. The results are shown in Table 4 below.
[ TABLE 4 ]
From the results of table 4, it was confirmed that the relative permeation amount of each component was much higher when EGCG and GCG were mixed or treated with a green tea extract containing both EGCG and GCG, compared to the case of treating with EGCG and GCG alone.
It was confirmed that, in the case of a 1:1 case of mixed EGCG and GCG, compared to 1.3: 1. 1:3 and 3:1, the relative permeation rate is high, and particularly in the case of the treatment with the green tea extracts of samples 4 and 5, the relative permeation rate of EGCG and GCG is significantly increased compared to the case of the treatment with simple mixture of EGCG and GCG and the case of the treatment with the green tea extract of sample 6.
[ test example 3] measurement of EGCG concentration in brain tissue
The concentration of EGCG in brain tissue was measured by treatment with samples 1-5 according to an embodiment of the present invention. Specifically, 2g/kg of each of samples 1 to 6, 100mg/kg of EGCG, 100mg/kg of GCG, 50mg/kg of EGCG +50mg/kg of GCG, 57mg/kg of EGCG +43mg/kg of GCG, 25mg/kg of EGCG +75mg/kg of GCG, and 75mg/kg of EGCG +25mg/kg of GCG were orally administered to 7-week-old ICR mice (mice), and plasma and brain tissues were separated at 1 hour. After the separated brain tissue was homogenized by adding PBS (phosphate buffer), centrifuged, EGCG and GCG were quantitatively analyzed using the supernatant, and the amounts of EGCG and GCG in plasma and brain tissue were measured by the same method as in example 1 using UPLC-PDA. The results are shown in Table 5 below.
[ TABLE 5 ]
From the results of table 5, it was confirmed that the amount in brain tissue was very small compared to plasma in the case of treatment with EGCG and GCG alone, and on the contrary, in the case of treatment with EGCG and GCG mixed, the ratio of the amount in brain tissue was particularly 1:1, the amount of EGCG in brain tissue increased significantly when treated in combination with a treatment at a weight ratio of 1.3: the weight ratio of 1 was also significantly increased in the amount of EGCG in brain tissue compared to the treatment with the blend.
Meanwhile, in the case of the treatment with the green tea extracts of samples 4 and 5, the amounts of EGCG and GCG in the brain tissue were greatly increased compared to plasma and the concentrations of EGCG and GCG in the brain tissue were the highest, as compared to the case of the treatment with the simple mixture of EGCG and GCG and the case of the treatment with the green tea extract of sample 6.
From the results of the test examples 1 to 3, it was confirmed that, according to the examples of the present invention, the content ratio in the specific content range, particularly 1:1, the activity of p-glycoprotein is reduced, and the blood brain barrier permeability of EGCG and GCG is greatly increased, so that the concentration of GCG and EGCG in brain tissue can be kept at a high level, and accordingly, the cognitive function reduction and improvement activity of GCG and EGCG in brain tissue can be greatly improved.
[ dosage form example 1] Soft capsules
150mg of sample 4 according to example 1 was prepared, and 440mg of lactose, 430mg of corn starch and 2mg of magnesium stearate were mixed to prepare a soft capsule filling solution. In addition, soft capsule tablets were prepared separately from the above in a ratio of 66 parts by weight of gelatin, 24 parts by weight of glycerin and 10 parts by weight of sorbitol solution, and the filling solution was filled to prepare soft capsules.
[ dosage form example 2] tablets
150mg of sample 4 according to the above-mentioned example was prepared, and 15mg of vitamin E, 15mg of vitamin C, 250mg of galactooligosaccharide, 60mg of lactose and 140mg of maltose were mixed, and then granulated by a fluidized bed dryer, and 8mg of sugar ester (sugar ester) was added. The composition is tableted by a conventional method to prepare tablets.
[ dosage form example 3] drink
80mg of sample 4 according to the above example 1 was prepared, and 9mg of vitamin E, 9mg of vitamin C, 10g of glucose, 0.6g of citric acid and 25g of liquid oligosaccharide were mixed, and then 400ml of purified water was added to fill the mixture. Bottling, and sterilizing at 30 deg.C for 4-5 s to obtain beverage.
[ dosage form example 4 ] granules
150mg of sample 4 according to example 1 was prepared, and 9mg of vitamin E, 9mg of vitamin C, 250mg of anhydrous crystalline glucose and 550mg of starch were mixed, and then the mixture was molded into granules by a fluidized bed granulator, and the granules were packed to prepare granules.
[ dosage form example 5 ] health food
150mg of sample 4 according to said example 1 was prepared, combining a vitamin mixture (70. Mu.g of vitamin A acetate, 1.0mg of vitamin E, 0.13mg of vitamin B1, 0.15mg of vitamin B2, 0.5mg of vitamin B6, 0.2. Mu.g of vitamin B12, 10mg of vitamin C, 10. Mu.g of biotin, 1.7mg of nicotinamide, 50. Mu.g of folic acid) and an inorganic substance mixture (1.75 mg of ferrous sulfate, 0.82mg of zinc oxide, 25.3mg of magnesium carbonate, 15mg of monopotassium phosphate, 55mg of dibasic calcium phosphate, 90mg of potassium citrate, 100mg of calcium carbonate, 24.8mg of magnesium chloride) to prepare a health food.
[ dosage form example 6 ] A health beverage
A 900mL health drink was prepared by preparing 150mg of sample 4 according to example 1, and adding 1000mg of citric acid, 100g of oligosaccharide, 2g of green plum concentrate, 1g of taurine, and the balance purified water.
While certain portions of this specification have been described in detail above, it will be apparent to those skilled in the art that these specific techniques are merely preferred embodiments, and thus, it is not intended that the scope of this specification be limited thereto. Accordingly, the substantial scope of the present specification will be defined by the appended claims and equivalents thereof.
The present invention may provide the following embodiments as an example.
A first embodiment may provide a green tea extract having enhanced Blood Brain Barrier (BBB) permeability of more than one of GCG and EGCG, comprising 3% to 10% by weight (-) -epigallocatechin gallate ((-) -galloatechin gate, GCG) and 3% to 10% by weight (-) -epigallocatechin gallate ((-) -epigalloatechin gate, EGCG) based on the total weight of the extract.
A second embodiment may provide the green tea extract according to the first embodiment, wherein the ratio of GCG: the weight ratio of EGCG is 1:0.5 to 1:2.
a third embodiment may provide the green tea extract according to any one or more of the first and second embodiments, wherein the extract is extracted once or more with any one or more of water and C1 to C4 alcohols.
A fourth embodiment may provide the green tea extract according to any one or more of the first to third embodiments, wherein the blood-brain barrier permeability of one or more of GCG and EGCG is 30% or more relative to the initial dose.
The fifth embodiment may provide a composition comprising one or more of the green tea extracts of the first to fourth embodiments as an active ingredient.
A sixth embodiment may provide the composition according to one or more of the first to fifth embodiments, wherein the green tea extract is included in an amount of 1 to 100 wt% with respect to the total weight of the composition.
A seventh embodiment may provide the composition of one or more of the first to sixth embodiments, wherein the dose of the active ingredient is 5 mg/kg/day to 1000 mg/kg/day.
An eighth embodiment may provide the composition of one or more of the first to seventh embodiments, wherein the composition is a food product or a pharmaceutical composition.
The ninth embodiment may provide a use of the green tea extract of one or more of the first to eighth embodiments for preparing a composition for improving blood brain barrier permeability of one or more of GCG and EGCG.
The tenth embodiment may provide a use of one or more of the green tea extracts of the first to eighth embodiments for preparing a composition for improving cognitive function decline.
An eleventh embodiment may provide the use of one or more of the first to tenth embodiments, wherein the decline in cognitive function results from any one selected from the group consisting of neurotransmitter degradation, neurotransmitter production reduction, and neurotransmitter receptor reduction.
A twelfth embodiment may provide the use of one or more of the first to eleventh embodiments, wherein the neurotransmitter is acetylcholine.
A thirteenth embodiment may provide the use of one or more of the first to twelfth embodiments, wherein the cognitive function decline is one or more selected from the group consisting of weakness, memory decline, amnesia, cognitive decline, learning disorders, attention decline, depression, hearing decline, analgesia, anhidrosis, and discriminability decline.
A fourteenth embodiment may provide the use of one or more of the first to thirteenth embodiments, wherein the decreased cognitive function is due to a neurodegenerative disease.
A fifteenth embodiment may provide the use of one or more of the first to fourteenth embodiments, wherein the neurodegenerative disease is one or more selected from the group consisting of alzheimer's disease, dementia, parkinson's disease, huntington's disease, autosomal dominant cerebellar ataxia (autosomal-dominant cerebellar ataxia), narcolepsy, alcoholism, drug intoxication, and Hereditary sensory and autonomic neuropathy.
Claims (15)
1. A green tea extract with improved blood brain barrier permeability of more than one of (-) -epigallocatechin gallate (GCG) and (-) -epigallocatechin gallate (EGCG) comprises 3-10 wt% of GCG and 3-10 wt% of EGCG based on the total weight of the extract.
2. The green tea extract according to claim 1,
the extract has a GCG: the weight ratio of EGCG is 1:0.5 to 1:2.
3. the green tea extract according to claim 1, wherein,
the extract is obtained by extracting with at least one of water and C1-C4 alcohol.
4. The green tea extract according to claim 1, wherein,
the blood brain barrier permeability of one or more of said GCG and said EGCG is more than 30% relative to the initial dose.
5. A composition comprising the green tea extract of any one of claims 1 to 4 as an active ingredient.
6. The composition of claim 5, wherein,
the green tea extract is included in an amount of 1 to 100 wt% relative to the total weight of the composition.
7. The composition of claim 5, wherein,
the dosage of the effective components is 5 mg/kg/day to 1000 mg/kg/day.
8. The composition of claim 5, wherein,
the composition is a food or pharmaceutical composition.
9. Use of the green tea extract of any one of claims 1 to 4 for the preparation of a composition for enhancing blood brain barrier permeability of one or more of GCG and EGCG.
10. Use of the green tea extract according to any one of claims 1 to 4 for the preparation of a composition for improving cognitive function decline.
11. The use according to claim 10, wherein,
the cognitive function decline is due to any one selected from the group consisting of neurotransmitter degradation, neurotransmitter production reduction, and neurotransmitter receptor reduction.
12. The use according to claim 11, wherein,
the neurotransmitter is acetylcholine.
13. The use according to claim 10, wherein,
the cognitive function decline is one or more selected from the group consisting of weakness, memory deterioration, amnesia, cognitive deterioration, learning disabilities, attention decline, depression, hearing deterioration, analgesia, anhidrosis, and discrimination deterioration.
14. The use according to claim 10, wherein,
the decline in cognitive function is due to a neurodegenerative disease.
15. The use according to claim 14, wherein,
the neurodegenerative disease is at least one selected from the group consisting of Alzheimer's disease, dementia, parkinson's disease, huntington's disease, autosomal dominant hereditary cerebellar ataxia, lethargy, alcoholism, drug intoxication, and hereditary sensory and autonomic neuropathy.
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KR1020220074142A KR20230032864A (en) | 2021-08-31 | 2022-06-17 | Green tea extract with improved blood brain barrier permeability of egcg or gcg, and composition comprising the same |
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KR20150001107A (en) | 2013-06-26 | 2015-01-06 | 계명대학교 산학협력단 | A composition for improving memory and preventing or treating cognitive dysfunction comprising epigallocatechin-3-gallate and luteolin |
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