CN104825441A - EGCG and gamma-aminobutyric acid composition, and preparation method and applications thereof - Google Patents

Abstract

The invention provides a health product composition or a pharmaceutical composition containing EGCG and gamma-aminobutyric acid; a drug dosage form includes any pharmaceutically acceptable drug dosage form, and EGCG and gamma-aminobutyric acid are combined according to the weight ratio of (0.2-3):1; furthermore, the invention provides a preparation method of the composition, an application of the composition in preparation of drugs for prevention and treatment of cerebral ischemia, cerebral arteriosclerosis, cerebral embolism and cerebral apoplexy sequela, and an application of the composition in preparation of drugs for prevention and treatment of cerebral nerve degenerative change or cerebral dysfunction disease.

Description

The composition and method of making the same of EGCG and γ-aminobutyric acid and application

Technical field

The present invention relates to a kind of healthy product compositions, and its preparation method and application, the specifically compositions of EGCG and γ-aminobutyric acid, with and its preparation method and application.Healthy product compositions of the present invention, includes but not limited to medicine, medical food, health food or functional food, bread and cheese etc.

Background technology

EGCG, i.e. epigallocatechin gallate (EGCG), structural formula is as follows,

，

EGCG is a kind of native compound that extracting and developing obtains from green tea; it is the most efficient active monomer component in tea polyphenols; there is good safety and physiological activity widely; research shows; EGCG has antitumor, antiviral, antibacterial, immunity moderation, free radical resisting infringement, antioxidation, anti-oxidation stress, antithrombus formation, arteriosclerosis, neuroprotective system, antiangiogenic, protection cardiovascular and cerebrovascular vessel and antiinflammatory action, very important for health.

But, disadvantageously, on the one hand, EGCG less stable, be vulnerable to the impact of the factors such as temperature, water, pH, especially deposit in liquid environment 7 days, its hydrolysis/degradation rate reaches more than 17%, even if in the solid state, although stability can improve relatively, more responsive for temperature, progressively can degrade under thermal environment, have a strong impact on the exploitation of product quality and EGCG preparation/product, preparation, storage, circulation etc. for product bring serious harmful effect; On the other hand, the taste of EGCG is very pained, limits its application in medicine food, consumer or patient direct oral time be difficult to accept its bitter taste, the compliance making it apply is seriously restricted; 3rd aspect, EGCG is more single in the mechanism of action for the treatment of cardiac and cerebral vascular diseases, lacks the function of omnibearing protection cardiovascular and cerebrovascular vessel or treatment cardiovascular and cerebrovascular disease.

Summary of the invention

Inventor surprisingly finds, the combination of EGCG and γ-aminobutyric acid, can solve the unfavorable factor of above-mentioned three aspects.

γ-aminobutyric acid (GABA) is a kind of active skull cap components, is distributed widely in the non-protein amino acid in animal and plant body, plays irreplaceable effect to the adjustment of organism vital movement; It is a kind of important inhibitory neurotransmitter that research is comparatively deep at present, it participates in multiple metabolic activity, there is very high physiologically active, in cerebrovascular and cranial nerve, have and promote the energy metabolism of brain, activation cerebral blood flow, increase oxygen supply amount, trophic nerve cell, promote brain vigor, recover function of brain cell, improve nervous function, delay cerebral senility and wait for a long time, very important for health.

The object of this invention is to provide a kind of pharmaceutical composition containing EGCG and γ-aminobutyric acid, the dosage form of described medicine is any pharmaceutical dosage form of acceptable on pharmaceutics.

Another object of the present invention is to provide the preparation method of above-mentioned composition;

The invention still further relates to the application of above-mentioned composition in medicine, medical usage.

The present composition comprises two kinds of compound modes:

A kind of compound mode is existed with the form of compound preparation EGCG and γ-aminobutyric acid, and the dosage form of described medicine is any pharmaceutical dosage form of acceptable on pharmaceutics.Use corresponding pharmaceutical carrier or adjuvant, adopt different preparation technologies to can be made into different compound medicinal formulations.Be to be understood that, compound preparation refers to makes independent preparation using EGCG and γ-aminobutyric acid as medicament active composition, can be any pharmaceutical dosage form that pharmaceutics can accept, preferred oral preparation, and such as tablet (comprises dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, effervescent tablet, etc.), hard capsule (comprising enteric coated capsule), soft capsule, granule, powder, dry suspension, pill, pellet (comprising enteric coated micropill), drop pill, dry syrup, powder, oral solution, oral administration mixed suspension, and oral rapid release or the dosage form such as slow release or controlled release, or injection or cutaneous permeable agent, powder ampoule agent for injection (comprises Injectable sterile fill injectable powder, lyophilized injectable powder), aqueous solution injection, injection can also be with glucose, sodium chloride, fructose, Nulomoline, xylitol or maltose etc. use the aqueous solution of (comprising intravenous injection and intravenous drip) as the intravenous injection of osmotic pressure regulator, also comprise the ointment of external preparation for skin, gel, emulsion agent, emulsion agent, patch, etc., also can be the dosage form such as rapid release, slow release, controlled release of above various dosage form, such as oral dispersible tablet, slow releasing tablet, slow releasing capsule, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets, born of the same parents rise granule, etc.Especially, by means known in the art preparation, be preferred for preparing oral solution, tablet (comprising dispersible tablet, slow-release tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets), capsule (comprising gastric solubleness, enteric, slow releasing capsule), injection (comprising powder ampoule agent for injection and injection) that pharmaceutics uses.Preferred combination dosage form is oral formulations, most preferably oral granule, powder, dry suspension, tablet (comprise dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, effervescent tablet, etc.), hard capsule (comprising enteric coated capsule), soft capsule, pill, pellet (comprising enteric coated micropill), drop pill, dry syrup, powder, oral solution, oral administration mixed suspension etc.

Another kind of compound mode is that EGCG and γ-aminobutyric acid are made independent preparation respectively, in use, patient can successively medication successively, also use after the preparation of the EGCG separated can being mixed with the preparation of γ-aminobutyric acid simultaneously, finally to reach the object using composition of medicine of the present invention, necessary, two kinds of independent preparations should be packaged in same drug package assembly by conveniently patient medication and represent the feature of drug regimen, further, when EGCG and γ-aminobutyric acid are independent preparations, both pharmaceutical dosage forms can be identical, also can be different, as EGCG sheet and γ-aminobutyric acid tablet medicament composition, EGCG capsule and γ-aminobutyric acid pharmaceutical capsules compositions, EGCG sheet and γ-aminobutyric acid pharmaceutical capsules compositions, EGCG capsule and γ-aminobutyric acid tablet medicament composition, also can be the rapid release of above various dosage form, slow release, the dosage forms such as controlled release, such as oral dispersible tablet, slow releasing tablet, slow releasing capsule, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets, born of the same parents rise granule, etc..Especially, by means known in the art preparation, be preferred for preparing tablet (comprising dispersible tablet, slow-release tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets), capsule (comprising gastric solubleness, enteric, slow releasing capsule), granule, powder, dry suspension, pill, pellet (comprising enteric coated micropill), drop pill, dry syrup, powder, oral solution, injection (comprising powder ampoule agent for injection and injection) etc. that pharmaceutics uses.

Should be appreciated that or can give the present invention's compound of combination in turn simultaneously, these combination of compounds can be same or different pharmaceutical compositions.If administration in turn, the delay administration of the second active component should not reduce the effect of synergistic therapeutic action between this active ingredient combinations or collaborative drug mechanism.No matter simultaneously or administration in turn it is also understood that, EGCG and γ-aminobutyric acid can with independent or any combining form administrations, preferably by EGCG and γ-aminobutyric acid administration simultaneously or with the administration in turn of independent medicine type, and most preferably administration simultaneously.

Preferably give drug regimen of the present invention with single combination preparation form, such as tablet, special in tablet is double-layer tablet, chewable tablet, capsule, granule, powder, dry suspension, oral solution, liquid preparation, spirituosity pharmaceutical solutions, medicinal tea for another example, etc.

Especially, the pharmaceutical composition containing EGCG and γ-aminobutyric acid provided by the invention, when pharmaceutical dosage form is the solid preparations such as tablet, capsule, granule, powder or dry suspension, wherein EGCG or γ-aminobutyric acid are the compositionss made with micronized form, preferred EGCG and γ-aminobutyric acid are pulverized by low-temperature airflow crushing technology, its powder size is greater than 800 orders, and preferred powder size is at 800 ~ 1000 orders, and even the granularity of preferred powder is greater than 1000 orders.

The present invention that another aspect of the present invention provides EGCG and γ-aminobutyric acid to exist with the ratio of synergistic drug dose combines.

Another aspect of the present invention provides EGCG and γ-aminobutyric acid with the combination of arbitrary proportion, and preferably with the present invention's combination that the ratio of synergistic dosage exists, EGCG and γ-aminobutyric acid are (0.2 ~ 3) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.3 ~ 2.8) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.4 ~ 2.5) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.5 ~ 2.2) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.6 ~ 2) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.7 ~ 1.8) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.7 ~ 1.7) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.8 ~ 1.5) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.8 ~ 1.3) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.8 ~ 1.2) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.2) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.3) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.4) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.5) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.6) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.7) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.8) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 2) with weight ratio: the ratio combination of 1;

Concrete, such as preferably EGCG and γ-aminobutyric acid take weight ratio as 0.2:1,0.3:1,0.4:1,0.5:1,0.6:1,0.7:1,0.8:1,0.9:1,1:1,1.1:1,1.2:1,1.3:1,1.4:1,1.5:1,1.6:1,1.7:1,1.8:1,1.9:1,2:1,2.1:1,2.2:1,2.3:1,2.4:1,2.5:1,2.6:1,2.7:1,2.8:1,2.9:1,3:1, etc.

The oral applicable dosage of EGCG is generally adult's 50 ~ 1000mg level every day and gives this compound, preferred every day 100 ~ 800mg single or give this compound at twice, such as 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, the EGCG of 900mg or 1000mg, and give the γ-aminobutyric acid of effective dose, preferably give the γ-aminobutyric acid of 50 ~ 1000mg, such as 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, the γ-aminobutyric acid of 450mg or 500mg, or give the γ-aminobutyric acid of 50 ~ 5000mg, such as 50mg, 80mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 800mg, the γ-aminobutyric acid of 1000mg, etc..

Be to be understood that, the present invention contains the compositions of EGCG and γ-aminobutyric acid, optionally can also contain other medicines effect or food function composition, such as mannatide, lentinan, oligofructose, oligomeric xylose, Oligomeric manna sugar, etc.

Preferably, the pharmaceutical composition of EGCG and γ-aminobutyric acid, wherein contains 50 ~ 1000mgEGCG and 50 ~ 800mg γ-aminobutyric acid in preferred per unit preparation;

Concrete, containing 50mgEGCG and 50mg γ-aminobutyric acid in per unit preparation,

Or containing 50mgEGCG and 100mg γ-aminobutyric acid in per unit preparation,

Or containing 50mgEGCG and 150mg γ-aminobutyric acid in per unit preparation,

Or containing 50mgEGCG and 200mg γ-aminobutyric acid in per unit preparation,

Or containing 50mgEGCG and 250mg γ-aminobutyric acid in per unit preparation,

Or containing 50mgEGCG and 300mg γ-aminobutyric acid in per unit preparation,

Or containing 50mgEGCG and 350mg γ-aminobutyric acid in per unit preparation,

Or containing 50mgEGCG and 400mg γ-aminobutyric acid in per unit preparation,

Or containing 50mgEGCG and 450mg γ-aminobutyric acid in per unit preparation,

Or containing 50mgEGCG and 500mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 100mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 150mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 160mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 200mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 250mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 300mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 350mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 400mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 450mg γ-aminobutyric acid in per unit preparation,

Or containing 100mgEGCG and 500mg γ-aminobutyric acid in per unit preparation,

Or containing 150mgEGCG and 100mg γ-aminobutyric acid in per unit preparation,

Or containing 150mgEGCG and 150mg γ-aminobutyric acid in per unit preparation,

Or containing 150mgEGCG and 200mg γ-aminobutyric acid in per unit preparation,

Or containing 150mgEGCG and 250mg γ-aminobutyric acid in per unit preparation,

Or containing 150mgEGCG and 300mg γ-aminobutyric acid in per unit preparation,

Or containing 150mgEGCG and 350mg γ-aminobutyric acid in per unit preparation,

Or containing 150mgEGCG and 400mg γ-aminobutyric acid in per unit preparation,

Or containing 150mgEGCG and 450mg γ-aminobutyric acid in per unit preparation,

Or containing 150mgEGCG and 500mg γ-aminobutyric acid in per unit preparation,

Or containing 200mgEGCG and 100mg γ-aminobutyric acid in per unit preparation,

Or containing 200mgEGCG and 150mg γ-aminobutyric acid in per unit preparation,

Or containing 200mgEGCG and 200mg γ-aminobutyric acid in per unit preparation,

Or containing 200mgEGCG and 250mg γ-aminobutyric acid in per unit preparation,

Or containing 200mgEGCG and 300mg γ-aminobutyric acid in per unit preparation,

Or containing 200mgEGCG and 350mg γ-aminobutyric acid in per unit preparation,

Or containing 200mgEGCG and 400mg γ-aminobutyric acid in per unit preparation,

Or containing 200mgEGCG and 450mg γ-aminobutyric acid in per unit preparation,

Or containing 200mgEGCG and 500mg γ-aminobutyric acid in per unit preparation,

Or containing 250mgEGCG and 100mg γ-aminobutyric acid in per unit preparation,

Or containing 250mgEGCG and 150mg γ-aminobutyric acid in per unit preparation,

Or containing 250mgEGCG and 200mg γ-aminobutyric acid in per unit preparation,

Or containing 250mgEGCG and 250mg γ-aminobutyric acid in per unit preparation,

Or containing 250mgEGCG and 300mg γ-aminobutyric acid in per unit preparation,

Or containing 250mgEGCG and 350mg γ-aminobutyric acid in per unit preparation,

Or containing 250mgEGCG and 400mg γ-aminobutyric acid in per unit preparation,

Or containing 250mgEGCG and 450mg γ-aminobutyric acid in per unit preparation,

Or containing 250mgEGCG and 500mg γ-aminobutyric acid in per unit preparation,

Or containing 300mgEGCG and 100mg γ-aminobutyric acid in per unit preparation,

Or containing 300mgEGCG and 150mg γ-aminobutyric acid in per unit preparation,

Or containing 300mgEGCG and 200mg γ-aminobutyric acid in per unit preparation,

Or containing 300mgEGCG and 250mg γ-aminobutyric acid in per unit preparation,

Or containing 300mgEGCG and 300mg γ-aminobutyric acid in per unit preparation,

Or containing 300mgEGCG and 350mg γ-aminobutyric acid in per unit preparation,

Or containing 300mgEGCG and 400mg γ-aminobutyric acid in per unit preparation,

Or containing 300mgEGCG and 450mg γ-aminobutyric acid in per unit preparation,

Or containing 300mgEGCG and 500mg γ-aminobutyric acid in per unit preparation,

Or containing 350mgEGCG and 500mg γ-aminobutyric acid in per unit preparation,

Or containing 400mgEGCG and 500mg γ-aminobutyric acid in per unit preparation,

Or containing 500mgEGCG and 500mg γ-aminobutyric acid in per unit preparation.

Described " per unit preparation " refers to the preparation unit of minimum package or minimum form of medication, comprise each seed lac wafer, each tablet or pill, each bag of granule or powder, each bottle of oral administration solution, each injection or injection, each bottle of injection or injection, each piece of suppository, each bottle of eye drop, each pipe ointment, etc.

Usually can give the active component of drug regimen with chemical raw material form, but preferably give with Pharmaceutical composition form.Pharmaceutical composition of the present invention comprises EGCG and described γ-aminobutyric acid, and the drug regimen of the present invention of one or more pharmaceutically acceptable carriers or excipient.These carriers must be acceptable, can with other component compatibility of formula, and nontoxic to its receiver.When giving separately each component of said composition, they are each form of Pharmaceutical composition naturally generally.Unless otherwise indicated, the compositions of indication of the present invention refers to the drug regimen containing EGCG and γ-aminobutyric acid, or the compositions of the wherein drug regimen of each component of EGCG and γ-aminobutyric acid.

Preferably, the combination of EGCG and γ-aminobutyric acid is generally the Pharmaceutical composition with one or more pharmaceutically acceptable carriers of unit dosage form, the EGCG contained in conventional unit formulation and the dosage of γ-aminobutyric acid clear and definite in the foregoing.

Use corresponding, different pharmaceutical carriers and preparation technology, pharmaceutical composition of the present invention can be made different pharmaceutical dosage forms.What those skilled in the art were appreciated that is, these pharmaceutical carriers be become various dosage form for the ease of production and processing, guarantee medicine safe, effectively with the factor such as to stablize, and to select according to the physicochemical property of different pharmaceutical dosage forms and medicine self.The choice for use of pharmaceutical carrier is that those of skill in the art of the present invention know with apparent.

Be to be understood that, for oral or injection, according to method well known in the art, usually according to the pharmaceutical carrier that different medicaments is selected or combinationally used, optionally comprise excipient or diluent, such as microcrystalline Cellulose, mannitol, non-dairy creamer, lactose, pregelatinized Starch, starch, dextrin, cyclodextrin, maltodextrin, HP-β-CD, calcium phosphate, calcium hydrogen phosphate, hydroxypropyl emthylcellulose, sucrose, dextran, poloxamer, sodium chloride, sorbitol, glucose, oligofructose, oligomeric xylose, polydextrose, Oligomeric manna sugar, solid polyethylene glycol (such as PEG-4000, Polyethylene Glycol-12000, PEG-4000, Polyethylene glycol-2000 etc.), resistant dextrin, fructose, water, propylene glycol, glycerol, coffee, milk powder, vegetable protein powder, etc., for oral solid formulation, optionally can also comprise binding agent, such as polyvidone (polyvinylpyrrolidone), methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, pregelatinized Starch, carboxymethyl starch sodium, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, etc., also comprise lubricant, such as magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate, sodium lauryl sulphate, etc., also optionally comprise disintegrating agent, such as carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium, pregelatinized Starch, etc., also optionally comprise surfactant or cosolvent, such as sodium lauryl sulphate, Tween-80, etc., also can comprise pH value regulator or buffer agent or cosolvent, such as phosphate buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, lactic acid, sodium carbonate, sodium hydroxide, alkaline organic compound, as arginine, lysine, meglumine, trometamol, etc., also optionally comprise antiseptic, such as sodium benzoate, potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, etc., also optionally comprise stabilizing agent and antioxidant, such as metal chelating agent selects ethylenediaminetetraacetic acid and salt (calcium disodium edetate, disodium edetate) etc. thereof, sodium sulfite, sodium pyrosulfite, vitamin C, vitamin E, etc., also optionally comprise taste regulator, such as maltose alcohol, fructose, sucrose, saccharin sodium, flavoring orange essence, strawberry essence, etc., that also can comprise other routine in addition, appropriate additive.It is also understood that agent type be tablet or capsule time, can be film coating.For the material of film coating, comprise applicable coating materials, such as hydroxypropyl methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (enteric-coating material), etc.; Also can comprise plasticizer, such as Polyethylene Glycol, triethyl citrate, etc.; Also optionally comprise suitable solubilizing agent, as Polyoxyethylene Sorbitan Monooleate; Also can comprise suitable pigment, as titanium dioxide, various ferrum oxide, pink pigment, etc.Should be appreciated that above-mentioned " optionally comprising " refers to namely can optionally choice for use, also can not use.

Especially, the compositions of EGCG of the present invention and γ-aminobutyric acid, EGCG can be different on medicament releasing pattern from the chemical composition of γ-aminobutyric acid, such as EGCG can the form of slow release or controlled release occur, and γ-aminobutyric acid also can the form of slow release or controlled release occur, to improve the not synergism of the blood drug level that EGCG and the time difference of γ-aminobutyric acid in onset or metabolism cause.

In the present patent application, " compositions " refers to described EGCG or/and γ-aminobutyric acid, with other chemical composition, such as, on physiology/mixture that formed of pharmaceutically acceptable carrier or excipient, the object of pharmaceutical composition is conducive to the using of medicine, carries, preserves; " administration " mentioned here refer in order to prevent or disease therapy and to organism (comprising patient or healthy population) deliver described in compound, its pharmaceutically useful salt or its solvate; Described " per unit preparation " refers to the preparation unit of minimum package or minimum form of medication, as each bottle of oral administration solution, each capsules, each tablet or pill, each bag of granule or powder, each injection or injection, each bottle of injection or injection, each piece of suppository, each bottle of eye drop, each pipe ointment, etc.

On the other hand, have now found that, when EGCG and γ-aminobutyric acid combinationally use, it demonstrates unexpected advantage, especially this drug regimen demonstrates outstanding, beyond thought in cerebral ischemia, cerebral arteriosclerosis, cerebral embolism, cerebral apoplexy sequela, such as, and in cranial nerve degeneration or disordered brain function disease, Alzheimer, parkinsonism etc. have good synergistic function.Preferably, the pharmaceutical composition of EGCG of the present invention and γ-aminobutyric acid, for the preparation of the application in the medicine of control cerebral ischemia, cerebral arteriosclerosis, cerebral embolism, cerebral apoplexy sequela, the application in the medicine that preparation prevents and treats cranial nerve degeneration or disordered brain function disease, etc.

Therefore, on the other hand, the invention provides a kind of control cerebral ischemia, cerebral arteriosclerosis, cerebral embolism, cerebral apoplexy sequela, or the pharmaceutical composition of control cranial nerve degeneration or disordered brain function disease, it contains EGCG and γ-aminobutyric acid.It will be appreciated by those skilled in the art that, in its pharmaceutical composition, the dosage ratio in the compound mode of EGCG and γ-aminobutyric acid, per unit preparation and content, just the same with the aforesaid content of the present invention.

Further, present invention also offers the preparation method of the pharmaceutical composition of EGCG and γ-aminobutyric acid, it comprises and EGCG and γ-aminobutyric acid is mixed with pharmaceutically acceptable pharmaceutical carrier and make acceptable any pharmaceutical preparation on pharmaceutics, such as EGCG and γ-aminobutyric acid and pharmaceutical carrier dry powder blend, dry granulation mixing (dry granulating machine process), wet granulation mixing (with water or alcoholic solution wet granulation), liquid or semisolid mixes (as the content of soft capsule, drop pill dropping liquid mixes) etc., preferred pharmaceutical dosage form is that tablet (comprises dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, effervescent tablet etc.), hard capsule (comprising enteric coated capsule), granule, dry suspension, oral solution, dry syrup, powder, oral administration mixed suspension, soft capsule, pill, pellet (comprising enteric coated micropill), drop pill, and oral rapid release or the dosage form such as slow release or controlled release, powder ampoule agent for injection (comprises Injectable sterile fill powder, lyophilized injectable powder), aqueous solution injection, injection can also be with glucose, sodium chloride, fructose, Nulomoline, xylitol or maltose etc. use the aqueous solution of (comprising intravenous injection and intravenous drip) as the intravenous injection of osmotic pressure regulator, also can be the rapid releases of above various dosage form, slow release, the dosage forms such as controlled release, such as oral dispersible tablet, slow releasing tablet, slow releasing capsule, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets, born of the same parents rise granule, etc.Especially, by means known in the art preparation, be preferred for preparing tablet (comprising dispersible tablet, slow-release tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets), capsule (comprising gastric solubleness, enteric, slow releasing capsule), oral solution, injection (comprising powder ampoule agent for injection and injection) etc. that pharmaceutics uses; Or

The preparation method of the pharmaceutical composition of the EGCG that the present invention also provides and γ-aminobutyric acid, it comprises EGCG and γ-aminobutyric acid is mixed and made into independent pharmaceutical preparation with pharmaceutically acceptable pharmaceutical carrier respectively, and by two kinds of independent pharmaceutical preparation packages in same medicine box, preferred pharmaceutical dosage form is that tablet (comprises dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, effervescent tablet etc.), hard capsule (comprising enteric coated capsule), granule, dry suspension, dry syrup, powder, soft capsule, oral solution, pill, pellet (comprising enteric coated micropill), drop pill, oral administration mixed suspension, and oral rapid release or the dosage form such as slow release or controlled release, powder ampoule agent for injection (comprises Injectable sterile fill powder, lyophilized injectable powder), aqueous solution injection, injection can also be with glucose, sodium chloride, fructose, Nulomoline, xylitol or maltose etc. use the aqueous solution of (comprising intravenous injection and intravenous drip) as the intravenous injection of osmotic pressure regulator.Also can be the dosage form such as rapid release, slow release, controlled release of above various dosage form, such as oral dispersible tablet, slow releasing tablet, slow releasing capsule, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets, effervescent granule, etc.Especially, by means known in the art preparation, be preferred for preparing tablet (comprising dispersible tablet, slow-release tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets), capsule (comprising gastric solubleness, enteric, slow releasing capsule), oral solution, injection (comprising powder ampoule agent for injection and injection) etc. that pharmaceutics uses.

Preferably, the invention provides a kind of granule containing EGCG and γ-aminobutyric acid, described EGCG and γ-aminobutyric acid are (0.2 ~ 3) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.3 ~ 2.8) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.4 ~ 2.5) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.5 ~ 2.2) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.6 ~ 2) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.7 ~ 1.8) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.7 ~ 1.7) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.8 ~ 1.5) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.8 ~ 1.3) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (0.8 ~ 1.2) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.2) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.3) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.4) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.5) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.6) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.7) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 1.8) with weight ratio: the ratio combination of 1,

Preferred EGCG and γ-aminobutyric acid are (1 ~ 2) with weight ratio: the ratio combination of 1;

Concrete, such as preferably EGCG and γ-aminobutyric acid take weight ratio as 0.2:1,0.3:1,0.4:1,0.5:1,0.6:1,0.7:1,0.8:1,0.9:1,1:1,1.1:1,1.2:1,1.3:1,1.4:1,1.5:1,1.6:1,1.7:1,1.8:1,1.9:1,2:1,2.1:1,2.2:1,2.3:1,2.4:1,2.5:1,2.6:1,2.7:1,2.8:1,2.9:1,3:1, etc.;

Also containing granule adjuvant in described compositions, described granule adjuvant comprises one or more compositions following: fructose, xylitol, oligofructose, oligomeric xylose, polydextrose, mannitol, sucrose, Nulomoline (i.e. the equal amount of mixture of glucose and fructose), glucose, resistant dextrin, Sorbitol, maltose, hydroxyl isomaltulose, Oligomeric manna sugar, solid polyethylene glycol (such as PEG-4000, Polyethylene Glycol-12000, PEG-4000, Polyethylene glycol-2000 etc.), dextrin, cyclodextrin, maltodextrin, HP-β-CD, microcrystalline Cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, pregelatinized Starch, starch, starch sugar, lactose, non-dairy creamer, milk powder, vegetable protein powder, coffee, carboxymethyl starch sodium, protein sugar, sucralose, aspartame, acesulfame potassium, stachyose, neotame, steviol glycosides, wherein the content of granule adjuvant is greater than 60% with mass ratio range,

Further, the invention provides a kind of preparation method containing the granule of EGCG and γ-aminobutyric acid, it comprises: EGCG, γ-aminobutyric acid are mixed homogeneously with granule adjuvant respectively, use ethanol water wet granulation again, dry, granulate, wherein the content of granule adjuvant is greater than 60% with mass ratio range; Especially, the invention provides a kind of preparation method containing EGCG and γ-aminobutyric acid granule, it comprises:

(1) prepare burden: take EGCG, γ-aminobutyric acid by formula, first EGCG is added mix homogeneously in granule adjuvant, then add γ-aminobutyric acid mix homogeneously, preferably adopt equal increments hybrid mode to carry out mix homogeneously;

(2) granulate: by the material 75% alcoholic solution soft material prepared in (1), wet granulation, 45 ~ 70 DEG C of dryings, granulate;

(3) pack, check, obtain the granule that the present invention contains EGCG and γ-aminobutyric acid.

Further, the present invention also provides the compositions application below of EGCG and γ-aminobutyric acid:

Application in the medicine of preparation control cerebral ischemia, cerebral arteriosclerosis, cerebral embolism, cerebral apoplexy sequela;

Application in the medicine that preparation prevents and treats cranial nerve degeneration or disordered brain function disease, etc.

The compositions of EGCG of the present invention and γ-aminobutyric acid, has the advantage of following three aspects:

1, EGCG and γ-aminobutyric acid form the Van der Waals force of intermolecular hydrogen bonding, improve the heat stability of EGCG;

2, γ-aminobutyric acid has special taste, is similar to burnt saline taste, can improve the bitter taste of EGCG well;

3, the compositions of EGCG and γ-aminobutyric acid is preventing and treating cerebral ischemia, cerebral arteriosclerosis, cerebral embolism, cerebral apoplexy sequela, and control cranial nerve degeneration or disordered brain function disease aspect there is good synergistic function.

detailed description of the inventionin implementation process of the present invention, those of ordinary skill in the art are not departing from the scope of the present invention various embodiment that the basis with spirit produces and are modifying apparent and be easily carry out.By the following examples application of the present invention etc. done and illustrate further, but do not represent embodiment limitation of the present invention.

The compound tablet of embodiment 1, EGCG and γ-aminobutyric acid and preparation thereof

Recipe quantity by weight percentage, contains:

EGCG 5% ~ 25%, is preferably 15%,

γ-aminobutyric acid 7% ~ 35%, is preferably 25%,

Mannitol 20% ~ 45%, is preferably 37%,

Calcium hydrogen phosphate 8% ~ 25%, is preferably 15%,

Carboxymethyl starch sodium 1% ~ 10%, is preferably 5%,

2.5% hydroxypropyl cellulose aqueous solution is appropriate, preferably counts 2% with hydroxypropyl cellulose,

Magnesium stearate 0.5% ~ 2%, is preferably 1%;

Its preparation method comprises: by EGCG, γ-aminobutyric acid, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium crosses 80 mesh sieves respectively, preferred mistake 100 order, after taking by recipe quantity, first by EGCG and mannitol mix homogeneously, obtain A mixed-powder, another by γ-aminobutyric acid and calcium hydrogen phosphate mix homogeneously, obtain B mixed-powder, then by A mixed-powder, after B mixed-powder is mixed homogeneously with carboxymethyl starch sodium, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 45 ~ 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, tabletting, obtain.

Stability test: the tablet getting EGCG that the optimizing prescriptions in the present embodiment obtains and γ-aminobutyric acid, separately get the pure powder of EGCG as blank product, often kind of a sample samples 8 (n=8), the data result detected is averaged, by Accelerated stability test (40 DEG C, under humidity 75% condition) place 2 months, sampling detects, HPLC method is adopted to detect the content of EGCG in each sample, and result was compared with 0 day, draw the content drop-out value of 2 months some EGCG, data statistics software processes; Detection method: adopt high effective liquid chromatography for measuring content, using 0.1 phosphoric acid and acetonitrile as mobile phase, sample size 20 μ L, column temperature 28 DEG C, determined wavelength 273nm, retention time is greater than 7min.Result of the test is in table 1.

Table 1 stability test result

Result shows, the present embodiment compositions, and the content drop-out value of its EGCG lower than blank product, and has the significance difference opposite sex, and the compositions embodying EGCG of the present invention and γ-aminobutyric acid has significant stability.

The compound granule of embodiment 2, EGCG and γ-aminobutyric acid and preparation thereof

Recipe quantity by weight percentage, contains:

EGCG 1% ~ 6%, is preferably 3%,

γ-aminobutyric acid 1% ~ 10%, is preferably 5%,

Granule adjuvant 85% ~ 98%, is preferably fructose 92%;

Wherein said granule adjuvant comprises one or more compositions following: fructose, xylitol, oligofructose, oligomeric xylose, polydextrose, mannitol, sucrose, Nulomoline (i.e. the equal amount of mixture of glucose and fructose), glucose, resistant dextrin, Sorbitol, maltose, hydroxyl isomaltulose, Oligomeric manna sugar, solid polyethylene glycol (such as PEG-4000, Polyethylene Glycol-12000, PEG-4000, Polyethylene glycol-2000 etc.), dextrin, cyclodextrin, maltodextrin, HP-β-CD, microcrystalline Cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, pregelatinized Starch, starch, starch sugar, lactose, non-dairy creamer, milk powder, vegetable protein powder, coffee, carboxymethyl starch sodium, protein sugar, sucralose, aspartame, acesulfame potassium, stachyose, neotame, steviol glycosides, most preferably be fructose or/and oligofructose,

Its preparation method comprises: EGCG, γ-aminobutyric acid, granule adjuvant are crossed 80 mesh sieves respectively, preferred mistake 100 order, after taking by recipe quantity, first EGCG is mixed homogeneously with granule adjuvant, then after adding γ-aminobutyric acid mix homogeneously, with 75% alcoholic solution wet granulation, 45 ~ 70 DEG C of dryings, granulate packaging, inspection, to obtain final product.

Stability test: the granule getting EGCG that the optimizing prescriptions in the present embodiment obtains and γ-aminobutyric acid, separately get the pure powder of EGCG as blank product, often kind of a sample samples 8 (n=8), the data result detected is averaged, by Accelerated stability test (40 DEG C, under humidity 75% condition) place 2 months, sampling detects, HPLC method is adopted to detect the content of EGCG in each sample, and result was compared with 0 day, draw the content drop-out value of 2 months some EGCG, data statistics software processes; Detection method: adopt high effective liquid chromatography for measuring content, using 0.1 phosphoric acid and acetonitrile as mobile phase, sample size 20 μ L, column temperature 28 DEG C, determined wavelength 273nm, retention time is greater than 7min.Result of the test is in table 2.

Table 2 stability test result

Result shows, the present embodiment compositions, and the content drop-out value of its EGCG lower than blank product, and has the significance difference opposite sex, and the compositions embodying EGCG of the present invention and γ-aminobutyric acid has significant stability.

The compound capsule of embodiment 3, EGCG and γ-aminobutyric acid and preparation thereof

Recipe quantity by weight percentage, contains:

EGCG 10% ~ 30%, is preferably 15%,

γ-aminobutyric acid 15% ~ 35%, is preferably 30%,

Mannitol 15% ~ 40%, is preferably 36%,

Pregelatinized Starch 8% ~ 25%, is preferably 12%,

Carboxymethyl starch sodium 1% ~ 10%, is preferably 5%,

The alcoholic solution of polyvinylpyrrolidone is appropriate, preferably with polyvinylpyrrolidone for 1%,

Magnesium stearate 0.5% ~ 2%, is preferably 1%;

Its preparation method comprises: EGCG, γ-aminobutyric acid, mannitol, pregelatinized Starch, carboxymethyl starch sodium are crossed 80 mesh sieves respectively, preferred mistake 100 mesh sieve, after taking by recipe quantity, first by EGCG and γ-aminobutyric acid mix homogeneously, obtain A mixed-powder, stand-by; Another by mannitol, pregelatinized Starch, carboxymethyl starch sodium mix homogeneously, obtain B mixed-powder, then A mixed-powder is fully mixed homogeneously with B mixed-powder, the alcoholic solution adding polyvinylpyrrolidone makes soft material, crosses 20 mesh sieves and granulates, 45 ~ 70 DEG C of oven dry, dry granule crosses 18 mesh sieve granulate, add magnesium stearate mix homogeneously, be filled to capsulae vacuus, to obtain final product.

Stability test: the capsule getting EGCG that the optimizing prescriptions in the present embodiment obtains and γ-aminobutyric acid, separately get the pure powder of EGCG as blank product, often kind of a sample samples 8 (n=8), the data result detected is averaged, by Accelerated stability test (40 DEG C, under humidity 75% condition) place 2 months, sampling detects, HPLC method is adopted to detect the content of EGCG in each sample, and result was compared with 0 day, draw the content drop-out value of 2 months some EGCG, data statistics software processes; Detection method: adopt high effective liquid chromatography for measuring content, using 0.1 phosphoric acid and acetonitrile as mobile phase, sample size 20 μ L, column temperature 28 DEG C, determined wavelength 273nm, retention time is greater than 7min.Result of the test is in table 3.

Table 3 stability test result

Result shows, the present embodiment compositions, and the content drop-out value of its EGCG lower than blank product, and has the significance difference opposite sex, and the compositions embodying EGCG of the present invention and γ-aminobutyric acid has significant stability.

The compound granule of embodiment 4, EGCG and γ-aminobutyric acid and preparation thereof

Recipe quantity by weight percentage, contains:

EGCG 1% ~ 6%, is preferably 2%,

γ-aminobutyric acid 1% ~ 10%, is preferably 3%,

Maltodextrin 3% ~ 10%, is preferably 5%,

Other granule adjuvant 75% ~ 95%, is preferably fructose 90%;

Other granule adjuvant wherein said comprises one or more compositions following: fructose, xylitol, oligofructose, oligomeric xylose, polydextrose, mannitol, sucrose, Nulomoline (i.e. the equal amount of mixture of glucose and fructose), glucose, resistant dextrin, Sorbitol, maltose, hydroxyl isomaltulose, Oligomeric manna sugar, solid polyethylene glycol, dextrin, cyclodextrin, HP-β-CD, microcrystalline Cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, pregelatinized Starch, starch, starch sugar, lactose, non-dairy creamer, milk powder, vegetable protein powder, coffee, carboxymethyl starch sodium, protein sugar, sucralose, aspartame, acesulfame potassium, stachyose, neotame, steviol glycosides, most preferably be fructose or/and oligofructose,

Its preparation method comprises: EGCG, γ-aminobutyric acid, maltodextrin, other granule adjuvant are crossed 80 mesh sieves respectively, preferred mistake 100 order, after taking by recipe quantity, first EGCG is mixed homogeneously with maltodextrin, other granule adjuvant successively, then after adding γ-aminobutyric acid mix homogeneously, with 75% alcoholic solution wet granulation, 45 ~ 70 DEG C of dryings, granulate packaging, inspection, to obtain final product.

Stability test: the granule getting EGCG that the optimizing prescriptions in the present embodiment obtains and γ-aminobutyric acid, separately get the pure powder of EGCG as blank product, often kind of a sample samples 8 (n=8), the data result detected is averaged, by Accelerated stability test (40 DEG C, under humidity 75% condition) place 2 months, sampling detects, HPLC method is adopted to detect the content of EGCG in each sample, and result was compared with 0 day, draw the content drop-out value of 2 months some EGCG, data statistics software processes; Detection method: adopt high effective liquid chromatography for measuring content, using 0.1 phosphoric acid and acetonitrile as mobile phase, sample size 20 μ L, column temperature 28 DEG C, determined wavelength 273nm, retention time is greater than 7min.Result of the test is in table 4.

Table 4 stability test result

Sample (n=8 averages)	EGCG content drop-out value
		The present embodiment compositions	0.49%
Blank product	2.39%

Result shows, the present embodiment compositions, and the content drop-out value of its EGCG lower than blank product, and has the significance difference opposite sex, and the compositions embodying EGCG of the present invention and γ-aminobutyric acid has significant stability.

The compositions of embodiment 5, EGCG and γ-aminobutyric acid is to the protective effect of cerebral ischemia-reperfusion neural cell injury

Employing is closed folder middle cerebral artery and is made specific region, local acute cerebral ischemia in rats model; calculate dead neuronal cell number; observe neuronic morphological change, from the compositions of cell and Molecular level study EGCG and γ-aminobutyric acid in neuroprotective unit and the effect preventing and treating cerebral ischemia.

Method: Wistar rat, body weight 150 ~ 200g, male and female half and half, random packet, is divided into the compositions administration group of model group, EGCG administration group, γ-aminobutyric acid administration group, EGCG and γ-aminobutyric acid, often organizes 8.

First to rats underwent 10% chloral hydrate anesthesia (ip, 350mg.Kg ^-1) after, carefully pry open skull with apparatus, expose and close folder middle cerebral artery and cause specific region, local acute cerebral ischemia model, to close folder middle cerebral artery side for ischemia side (experimental group), opposite side does not close folder (matched group) in contrast.

Test group all gives feed medicine in first 5 days at ischemia.All specimen all have drawn from representational relevant range, and fix through 4% neutral formalin rapidly, conventional dehydration, paraffin embedding, HE dyeing and HSP70 dyeing.Occur karyopycnosis with neuronal cell, karyorrhexis after HE dyeing, karyolysis person is judged to neuronal death, gets 5 high power lens visuals field often opening in section, and statistics dead cell accounts for the percentage ratio of total cell, gets its meansigma methods.

HSP70 is the one in HSP family, and molecular weight is 70KDa, and its major function is that protection is various stress caused cell injury and apoptosis, and induction HSP70 high expressed can alleviate the neuronal damage caused by cerebral ischemia.

Experiment grouping:

(1) model group: normal feed, does not give medicine;

(3) EGCG administration group: on the basis of normal feed, gives gavage EGCG aqueous solution, EGCG dosage 10mg/kg;

(4) γ-aminobutyric acid administration group: on the basis of normal feed, gives gavage γ-aminobutyric acid aqueous solution, γ-aminobutyric acid dosage 10mg/kg;

(5) the compositions administration group of EGCG and γ-aminobutyric acid: on the basis of normal feed, gives the aqueous solution of EGCG that weight ratio is 1:1 and γ-aminobutyric acid mixture, EGCG and γ-aminobutyric acid dosage 10mg/kg.

The results are shown in following table 5.

The compositions of table 5 EGCG and γ-aminobutyric acid changes cerebral morphology,

The expression (n=8) of nerve cell death rate and HSP70

As can be seen from Table 5; the compositions of EGCG and γ-aminobutyric acid has good protective effect for rat cerebral ischemia; and protection cerebral tissue, neuroprotective cell, alleviate cerebral tissue edema degree; in nerve cell death rate, HSP70 expression data; compared with EGCG administration group, γ-aminobutyric acid administration group; there is significant difference, p<0.05.Show the present composition in the significance effect protecting cerebrovascular, protect cerebral tissue, improve cerebral ischemia, protect brain cell.

The compositions of embodiment 6, EGCG and γ-aminobutyric acid is to the effect of bitter taste improving EGCG

Get EGCG and γ-aminobutyric acid weight ratio is the compositions of 1:0.5,1:1,1:1.5,1:2, carry out bitter taste and compare.

The preparation of bitter taste reference material: be the former powder of EGCG and the mixed uniformly powder of maltodextrin of 0,10%, 30%, 50%, 70%, 90% respectively with the addition of maltodextrin, respectively get 5g, add 45 DEG C of hot water of 100ml, abundant dissolving, tastes, obtains the bitter taste reference material that bitter taste degree is labeled as 10.0 points, 9.0 points, 7.0 points, 5.0 points, 3.0 points, 1.0 points respectively, be up to 10.0 points, retain an arithmetic point, score value is higher, characterizes bitter taste larger.

Bitter taste comparative approach: based on bitter taste reference material, by the trial test method of 5 people to testing combination bitter taste, compare with bitter taste reference material, differentiate, testing combination bitter taste is given a mark and (is up to 10.0 points, retain an arithmetic point), average, be used for comparing, the bitter taste of compositions relatively more prepared respectively.

Bitter taste compares the following table 6 of data.

Table 6

As can be seen from 6 tables, the compositions of EGCG of the present invention and γ-aminobutyric acid, compare with the former powder of EGCG, bitter taste significantly declines, and along with the increase of γ-aminobutyric acid content in the composition, the decline of its bitter taste is more; EGCG and γ-aminobutyric acid weight ratio are the compositions of 1:0.5, its bitter taste only has about 60 percent (p<0.05) of the former powder of EGCG, EGCG and γ-aminobutyric acid weight ratio are the compositions of 1:1,1:1.5,1:2, and its bitter taste is all less than 50 percent (p<0.01) of the former powder of EGCG; Demonstrate the present composition, to the bitter taste improving EGCG, there is remarkable effect.

The application in following of the compositions of embodiment 7, EGCG described in embodiment 1 to embodiment 4 and γ-aminobutyric acid:

Application in the medicine of preparation control cerebral ischemia, cerebral arteriosclerosis, cerebral embolism, cerebral apoplexy sequela;

Application in the medicine that preparation prevents and treats cranial nerve degeneration or disordered brain function disease.

Claims (10)

1. contain the pharmaceutical composition of EGCG and γ-aminobutyric acid, the dosage form of described medicine is any pharmaceutical dosage form of acceptable on pharmaceutics, the dosage form of described medicine is any pharmaceutical dosage form of acceptable on pharmaceutics, its compound mode comprises: EGCG and γ-aminobutyric acid are made compound preparation, or EGCG and γ-aminobutyric acid are made independent preparation respectively, and two kinds of independent preparations are packaged in same drug package assembly.

2. contain the pharmaceutical composition of EGCG and γ-aminobutyric acid, wherein said EGCG and γ-aminobutyric acid are (0.2 ~ 3) with weight ratio: the ratio combination of 1.

The pharmaceutical composition of 3.EGCG and γ-aminobutyric acid, wherein contain 50 ~ 1000mgEGCG and 50 ~ 800mg γ-aminobutyric acid in per unit preparation, described " per unit preparation " refers to the preparation unit of minimum package or minimum form of medication, comprises each seed lac wafer, each tablet or pill, each bag of granule or powder, each bottle of oral administration solution, each injection or injection, each bottle of injection or injection, each piece of suppository, each bottle of eye drop, each pipe ointment.

4. described in claim 1 to claim 3, any one contains the preparation method of the pharmaceutical composition of EGCG and γ-aminobutyric acid, and it comprises and EGCG and γ-aminobutyric acid is mixed with pharmaceutically acceptable pharmaceutical carrier and make acceptable any pharmaceutical preparation on pharmaceutics.

5. one kind contains the granule of EGCG and γ-aminobutyric acid, described EGCG and γ-aminobutyric acid are (0.2 ~ 3) with weight ratio: the ratio combination of 1, also containing granule adjuvant in described compositions, wherein granule adjuvant comprises one or more compositions following: fructose, xylitol, oligofructose, oligomeric xylose, polydextrose, mannitol, sucrose, Nulomoline, glucose, resistant dextrin, Sorbitol, maltose, hydroxyl isomaltulose, Oligomeric manna sugar, solid polyethylene glycol, dextrin, cyclodextrin, maltodextrin, HP-β-CD, microcrystalline Cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, pregelatinized Starch, starch, starch sugar, lactose, non-dairy creamer, milk powder, vegetable protein powder, coffee, carboxymethyl starch sodium, protein sugar, sucralose, aspartame, acesulfame potassium, stachyose, neotame, steviol glycosides, wherein the content of granule adjuvant is greater than 60% with mass ratio range,

The preparation method of described granule comprises:

(1) prepare burden: take EGCG, γ-aminobutyric acid by formula, first EGCG is added mix homogeneously in granule adjuvant, then add γ-aminobutyric acid mix homogeneously;

(2) granulate: by the material 75% alcoholic solution soft material prepared in (1), wet granulation, 45 ~ 70 DEG C of dryings, granulate;

(3) pack, check, to obtain final product.

6. a compound tablet for EGCG and γ-aminobutyric acid, its recipe quantity by weight percentage, contains:

EGCG 5%～25%，

γ-aminobutyric acid 7% ~ 35%,

Mannitol 20% ~ 45%,

Calcium hydrogen phosphate 8% ~ 25%,

Carboxymethyl starch sodium 1% ~ 10%,

2.5% hydroxypropyl cellulose aqueous solution is appropriate,

Magnesium stearate 0.5% ~ 2%;

Its preparation method comprises: by EGCG, γ-aminobutyric acid, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium crosses 80 mesh sieves respectively, after taking by recipe quantity, first by EGCG and mannitol mix homogeneously, obtain A mixed-powder, another by γ-aminobutyric acid and calcium hydrogen phosphate mix homogeneously, obtain B mixed-powder, then by A mixed-powder, after B mixed-powder is mixed homogeneously with carboxymethyl starch sodium, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 45 ~ 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, tabletting, obtain.

7. a compound granule for EGCG and γ-aminobutyric acid, its recipe quantity by weight percentage, contains:

EGCG 1%～6%，

γ-aminobutyric acid 1% ~ 10%,

Granule adjuvant 85% ~ 98%;

Wherein said granule adjuvant comprises one or more compositions following: fructose, xylitol, oligofructose, oligomeric xylose, polydextrose, mannitol, sucrose, Nulomoline, glucose, resistant dextrin, Sorbitol, maltose, hydroxyl isomaltulose, Oligomeric manna sugar, solid polyethylene glycol, dextrin, cyclodextrin, maltodextrin, HP-β-CD, microcrystalline Cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, pregelatinized Starch, starch, starch sugar, lactose, non-dairy creamer, milk powder, vegetable protein powder, coffee, carboxymethyl starch sodium, protein sugar, sucralose, aspartame, acesulfame potassium, stachyose, neotame, steviol glycosides,

Its preparation method comprises: EGCG, γ-aminobutyric acid, granule adjuvant are crossed 80 mesh sieves respectively, after taking by recipe quantity, first EGCG is mixed homogeneously with granule adjuvant, then after adding γ-aminobutyric acid mix homogeneously, with 75% alcoholic solution wet granulation, 45 ~ 70 DEG C of dryings, granulate packaging, inspection, to obtain final product.

8. a compound capsule for EGCG and γ-aminobutyric acid, its recipe quantity by weight percentage, contains:

EGCG 10%～30%，

γ-aminobutyric acid 15% ~ 35%,

Mannitol 15% ~ 40%,

Pregelatinized Starch 8% ~ 25%,

Carboxymethyl starch sodium 1% ~ 10%,

The alcoholic solution of polyvinylpyrrolidone is appropriate,

Magnesium stearate 0.5% ~ 2%;

Its preparation method comprises: EGCG, γ-aminobutyric acid, mannitol, pregelatinized Starch, carboxymethyl starch sodium are crossed 80 mesh sieves respectively, after taking, first by EGCG and γ-aminobutyric acid mix homogeneously, obtains A mixed-powder by recipe quantity, stand-by; Another by mannitol, pregelatinized Starch, carboxymethyl starch sodium mix homogeneously, obtain B mixed-powder, then A mixed-powder is fully mixed homogeneously with B mixed-powder, the alcoholic solution adding polyvinylpyrrolidone makes soft material, crosses 20 mesh sieves and granulates, 45 ~ 70 DEG C of oven dry, dry granule crosses 18 mesh sieve granulate, add magnesium stearate mix homogeneously, be filled to capsulae vacuus, to obtain final product.

9. a compound granule for EGCG and γ-aminobutyric acid, its recipe quantity by weight percentage, contains:

EGCG 1%～6%，

γ-aminobutyric acid 1% ~ 10%,

Maltodextrin 3% ~ 10%,

Other granule adjuvant 75% ~ 95%;

Other granule adjuvant wherein said comprises one or more compositions following: fructose, xylitol, oligofructose, oligomeric xylose, polydextrose, mannitol, sucrose, Nulomoline, glucose, resistant dextrin, Sorbitol, maltose, hydroxyl isomaltulose, Oligomeric manna sugar, solid polyethylene glycol, dextrin, cyclodextrin, HP-β-CD, microcrystalline Cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, pregelatinized Starch, starch, starch sugar, lactose, non-dairy creamer, milk powder, vegetable protein powder, coffee, carboxymethyl starch sodium, protein sugar, sucralose, aspartame, acesulfame potassium, stachyose, neotame, steviol glycosides,

Its preparation method comprises: EGCG, γ-aminobutyric acid, maltodextrin, other granule adjuvant are crossed 80 mesh sieves respectively, after taking by recipe quantity, first EGCG is mixed homogeneously with maltodextrin, other granule adjuvant successively, then after adding γ-aminobutyric acid mix homogeneously, with 75% alcoholic solution wet granulation, 45 ~ 70 DEG C of dryings, granulate packaging, inspection, to obtain final product.

10. the application of the pharmaceutical composition that contains EGCG and γ-aminobutyric acid of any one described in claim 1 to claim 3, claim 5 to claim 9 in following:

Application in the medicine of preparation control cerebral ischemia, cerebral arteriosclerosis, cerebral embolism, cerebral apoplexy sequela;

Application in the medicine that preparation prevents and treats cranial nerve degeneration or disordered brain function disease.