CN104922143B - The composition and its preparation method and application of EGCG and chitosan oligosaccharide - Google Patents

Abstract

The present invention provides the pharmaceutical composition containing EGCG and chitosan oligosaccharide, and the dosage form of the drug is any pharmaceutical dosage form of acceptable in pharmacy, and the EGCG is with chitosan oligosaccharide with weight ratio for (0.1~2):1 ratio combination, invention further provides the preparation methods of the composition, and the application in preparing reducing blood lipid, protecting the drug of cardiovascular and cerebrovascular, the application in preparing anti-tumor drug.

Description

The composition and its preparation method and application of EGCG and chitosan oligosaccharide

Technical field

The present invention relates to a kind of healthy product composition, and its preparation method and application, the group of specifically EGCG and chitosan oligosaccharide Object is closed, with and its preparation method and application.Health product composition of the present invention, including but not limited to drug, medical food, Health food or functional food, ordinary food etc..

Background technology

EGCG, i.e. Epigallo-catechin gallate (EGCG), structural formula is as follows,

,

EGCG is a kind of native compound that extracting and developing obtains from green tea, is that most efficient activity is single in tea polyphenols Body ingredient has good safety and extensive physiological activity, studies have shown that EGCG has antithrombus formation, resists and move Arteries and veins hardening, Green Tea Extract damage, anti-oxidant, anti-oxidation stress, antiangiogenic, adjusts immune, the protection heart at protection nervous system The cerebrovascular and anti-inflammatory, antitumor, antiviral, antibacterial action, it is particularly significant for health.

Chitosan oligosaccharide:Also referred to as Chitosan poly oligosaccharide, chitosan oligomer are refined into through enzymolysis process using chitosan as raw material, point Sub- amount≤3200Da, is the basic amine group oligosaccharide of unique positively charged cation in nature, and molecular weight is low, water-soluble It gets well, be easily absorbed by the body, bioactivity height, having reducing blood lipid, protection cardiac muscle cell, adjusting immune（Humoral immunity and cell are exempted from Epidemic disease）, protection function of intestinal canal, protection liver function, Green Tea Extract peroxidatic reaction of lipid, it is antitumor, hypoglycemic, promote calcium uptake And the effects that bone health, it is particularly significant for health.

However, disadvantageously, the stability of EGCG is poor, it is vulnerable to the influence of the factors such as temperature, water, pH, especially in liquid It is stored 7 days in body environment, hydrolysis/degradation rate reaches 17% or more, even if in the solid state, can be carried although stability is opposite Height, but more sensitive for temperature can gradually degrade under thermal environment, seriously affect product quality and EGCG preparations/product Exploitation, serious harmful effect is brought for the preparation, storage, circulation etc. of product, to preparation it is safe to use bring it is unfavorable with it is hidden Suffer from；On the other hand, it is acted on the effect of chitosan oligosaccharide relatively weak, it usually needs improve the effect of its curative effect with compound form.

Invention content

The pleasantly surprised discovery of inventor combines EGCG with chitosan oligosaccharide, can significantly improve the stability of EGCG, on the other hand, EGCG is combined with chitosan oligosaccharide, there is good synergistic effect, the especially synergistic effect in reducing blood lipid, antitumor etc..

The pharmaceutical composition containing EGCG and chitosan oligosaccharide that the object of the present invention is to provide a kind of, the dosage form of the drug is medicine Any pharmaceutical dosage form of the upper acceptable of agent.

It is a further object to provide the preparation methods of above-mentioned composition；

The application that the invention further relates to above-mentioned compositions in drug, medical usage.

The present composition includes two kinds of combinations：

A kind of combination is that have EGCG and chitosan oligosaccharide in the form of compound preparation, and the dosage form of the drug is Any pharmaceutical dosage form of acceptable in pharmacy.It, can using different preparation processes using corresponding pharmaceutical carrier or auxiliary material Different compound medicinal formulations is made.It should be appreciated that compound preparation refers to using EGCG and chitosan oligosaccharide as medicament active composition And individual preparation is made, and can be acceptable any pharmaceutical dosage form in pharmacy, preferably oral preparation, such as tablet (including dispersible tablet, enteric coatel tablets, chewable tablets, oral disnitegration tablet, effervescent tablet, etc.), hard capsule (including capsulae enterosolubilis), soft capsule It is agent, granule, pulvis, dry suspensoid agent, pill, micropill preparation (including enteric-coated micro-pill), pill, dry syrup, powder, oral molten Liquor, oral administration mixed suspension and oral quick-release or the dosage forms such as sustained release or controlled release or injection or cutaneous permeable agent, note It penetrates and can also be with powder-injection (including the filling powder-injection of Injectable sterile, freeze drying powder injection), aqueous solution injection, injection Intravenous injection using glucose, sodium chloride, fructose, inverted sugar, xylitol or maltose etc. as osmotic pressure regulator use ( Including intravenous injection and intravenous drip) aqueous solution；Further include the ointment of external preparation for skin, gelling agent, emulsion agent, emulsion agent, Patch, etc.；Can also be the dosage forms such as quick-release, the slow-release controlled-release of any of the above dosage form, for example, oral dispersible tablet, sustained release tablets, Spansule, enteric coatel tablets, effervescent tablet, oral disnitegration tablet, special-shaped tablets, born of the same parents rise particle, etc..Particularly, by side known in the art Method prepare preferably for prepare pharmacy on use oral solution, tablet (including dispersible tablet, slow-release tablet, enteric coatel tablets, Effervescent tablet, oral disnitegration tablet, special-shaped tablets), capsule (including soluble in the stomach, enteric, spansule), injection (including injection powder Injection and injection).Preferred combination dosage form is oral preparation, most preferably oral granule, pulvis, dry suspensoid agent, piece Agent (including dispersible tablet, enteric coatel tablets, chewable tablets, oral disnitegration tablet, effervescent tablet, etc.), hard capsule (including capsulae enterosolubilis), flexible glue Wafer, pill, micropill preparation (including enteric-coated micro-pill), pill, dry syrup, powder, oral solution, oral administration mixed suspension etc..

Another combination is that individual preparation is respectively prepared in EGCG and chitosan oligosaccharide, and when in use, patient can be first Medication successively afterwards uses after can also mixing the preparation of separated EGCG with the preparation of chitosan oligosaccharide, is made with being finally reached simultaneously With the purpose of composition of medicine of the present invention, it is necessary to, it, should in order to facilitate the feature of patient medication and expression pharmaceutical composition Two kinds of individual preparations are packaged in the same pack arrangement；Further, when EGCG and chitosan oligosaccharide are independent preparations, two The pharmaceutical dosage form of person can be identical, can also be different, such as EGCG pieces and chitosan oligosaccharide tablet medicament composition, EGCG capsules and shell Oligosaccharides pharmaceutical capsules composition, EGCG pieces and chitosan oligosaccharide capsule pharmaceutical composition, EGCG capsules and chitosan oligosaccharide tablet medicament composition, Can also be the dosage forms such as quick-release, the slow-release controlled-release of any of the above dosage form, for example, oral dispersible tablet, sustained release tablets, spansule, Enteric coatel tablets, effervescent tablet, oral disnitegration tablet, special-shaped tablets, born of the same parents rise particle, etc..Particularly, it is prepared by means known in the art, it is excellent It is (including dispersible tablet, slow-release tablet, enteric coatel tablets, effervescent tablet, oral disnitegration tablet, different to be selected to prepare the tablet used in pharmacy Matrix), capsule (including soluble in the stomach, enteric, spansule), granule, pulvis, dry suspensoid agent, pill, micropill preparation (including intestines Molten pellet), pill, dry syrup, powder, oral solution, injection (including powder ampoule agent for injection and injection) etc..

It should be appreciated that the present invention compound combined can simultaneously or sequentially be given, these combination of compounds can be same Or different pharmaceutical composition.If be sequentially administered, the delay administration of second of active component should not reduce the active constituent group The effect of the drug mechanism of synergistic therapeutic action or collaboration between conjunction.It is also understood that no matter simultaneously or sequentially giving Medicine, EGCG and chitosan oligosaccharide can be administered in the form of either alone or in any combination, preferably by EGCG and chitosan oligosaccharide be administered simultaneously or with Independent medicine type is sequentially administered, and is most preferably administered simultaneously.

It is preferred that give the pharmaceutical composition of the present invention in the form of compound preparation, such as tablet, in tablet it is special be double-layer tablets, Chewable tablets, for another example capsule, granule, pulvis, dry suspensoid agent, oral solution, liquid preparation, medicinal tea, etc..

Particularly, the pharmaceutical composition provided by the invention containing EGCG and chitosan oligosaccharide, when pharmaceutical dosage form is tablet, capsule When the solid pharmaceutical preparations such as agent, granule, pulvis or dry suspensoid agent, wherein EGCG or chitosan oligosaccharide are to be combined made of micronized form Object, preferably EGCG and chitosan oligosaccharide are crushed by low-temperature airflow crushing technology, and powder size is more than 800 mesh, preferred powder Last granularity is in 800~1000 mesh, or even the granularity of preferably powder is more than 1000 mesh.

Another aspect of the present invention provides EGCG and chitosan oligosaccharide with this hair existing for the ratio of the drug dose to act synergistically Bright combination.

Another aspect of the present invention provides EGCG with chitosan oligosaccharide with the combination of arbitrary proportion, preferably with the dosage of synergistic effect Ratio existing for present invention combination, EGCG and chitosan oligosaccharide are with weight ratio for (0.1~2):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.2~1.9):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.3~1.8):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.4~1.7):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.5~1.6):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.6~1.5):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.7~1.4):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.8~1.3):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.9~1.2):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.3~1.2):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.4~1.1):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.5~1):1 ratio combination；

Specifically, for example preferred EGCG and chitosan oligosaccharide with weight ratio for 0.1:1、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, etc..

The oral applicable dosage of EGCG is generally daily 50~1000mg levels of being grown up and gives the compound, preferably daily 100~800mg singles give the compound at twice, for example, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, The EGCG of 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 900mg or 1000mg, And give the chitosan oligosaccharide of effective dose, preferably give the chitosan oligosaccharide of 50~2000mg, for example, 50mg, 100mg, 150mg, 200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、 800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、 Chitosan oligosaccharide of 1700mg, 1800mg, 1900mg or 2000mg, etc..

It should be appreciated that the present invention contains the composition of EGCG and chitosan oligosaccharide, it can also optionally contain other medicines work( Effect or food function ingredient, such as mannatide, lentinan, oligofructose, polyfructosan, xylo-oligosaccharide, oligomeric sweet dew Sugar, etc..

Preferably, the pharmaceutical composition of EGCG and chitosan oligosaccharide, wherein it is preferred that in per unit preparation containing 50~ 1000mgEGCG and 50~2000mg chitosan oligosaccharides；

Specifically, contain 50mgEGCG and 50mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 60mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 70mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 80mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 90mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 100mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 150mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 200mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 250mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 300mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 350mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 400mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 450mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 500mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 550mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 600mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 650mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 700mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 750mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 800mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 850mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 900mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 950mg chitosan oligosaccharides in per unit preparation,

Or contain 50mgEGCG and 1000mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 50mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 60mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 70mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 80mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 90mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 100mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 150mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 160mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 200mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 250mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 300mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 350mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 400mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 450mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 500mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 550mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 600mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 650mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 700mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 750mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 800mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 850mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 900mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 950mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 1000mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 1200mg chitosan oligosaccharides in per unit preparation,

Or contain 100mgEGCG and 1500mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 50mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 75mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 80mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 100mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 150mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 200mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 250mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 300mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 350mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 400mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 450mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 500mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 550mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 600mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 650mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 700mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 750mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 800mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 850mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 900mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 950mg chitosan oligosaccharides in per unit preparation,

Or contain 150mgEGCG and 1000mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 50mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 80mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 100mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 150mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 200mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 250mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 300mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 350mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 400mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 450mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 500mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 550mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 600mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 650mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 700mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 750mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 800mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 850mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 900mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 950mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1000mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1100mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1200mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1300mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1400mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1500mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1600mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1700mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1800mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 1900mg chitosan oligosaccharides in per unit preparation,

Or contain 200mgEGCG and 2000mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 50mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 75mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 80mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 90mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 100mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 150mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 200mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 250mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 300mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 350mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 400mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 450mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 500mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 600mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 700mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 800mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 900mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1000mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1100mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1200mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1300mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1400mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1500mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1600mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1700mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1800mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 1900mg chitosan oligosaccharides in per unit preparation,

Or contain 250mgEGCG and 2000mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 50mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 80mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 100mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 150mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 200mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 250mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 300mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 350mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 400mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 450mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 500mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 600mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 700mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 800mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 900mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1000mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1100mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1200mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1300mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1400mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1500mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1600mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1700mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1800mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 1900mg chitosan oligosaccharides in per unit preparation,

Or contain 300mgEGCG and 2000mg chitosan oligosaccharides in per unit preparation,

Or contain 350mgEGCG and 500mg chitosan oligosaccharides in per unit preparation,

Or contain 400mgEGCG and 500mg chitosan oligosaccharides in per unit preparation,

Or contain 500mgEGCG and 500mg chitosan oligosaccharides in per unit preparation,

Or contain 500mgEGCG and 550mg chitosan oligosaccharides in per unit preparation,

Or contain 500mgEGCG and 600mg chitosan oligosaccharides in per unit preparation,

Or contain 500mgEGCG and 800mg chitosan oligosaccharides in per unit preparation.

" the per unit preparation " refers to the preparation unit of minimum package or minimum form of medication, including each capsule It is agent, each tablet or pill, each bag of granule or pulvis, each bottle of oral administration solution, each injection or injection, every One bottle of injection or injection, each piece of suppository, each bottle of eye drops, each pipe ointment, etc..

The active component of pharmaceutical composition can be usually given in the form of chemical raw material, but is preferably given in the form of Pharmaceutical composition It gives.Pharmaceutical composition of the present invention includes EGCG and chitosan oligosaccharide and one or more pharmaceutically acceptable carriers or excipient The present invention pharmaceutical composition.These carriers must be acceptable, you can and it is compatible with other components of formula, and it is received Person is nontoxic.When each group of timesharing for individually giving the composition, they are generally individually Pharmaceutical composition form.Except as otherwise saying Bright, the signified composition of the present invention refers to the pharmaceutical composition containing EGCG and chitosan oligosaccharide or in which each group of EGCG and chitosan oligosaccharide The composition of the pharmaceutical composition divided.

Preferably, the combination of EGCG and chitosan oligosaccharide is usually can pharmaceutically being connect with one or more for unit dosage form The Pharmaceutical composition for the carrier received, the dosage of the EGCG and chitosan oligosaccharide that contain in common unit formulation is in the foregoing It is clear.

Using corresponding, different pharmaceutical carrier and preparation process, pharmaceutical composition of the present invention can be made different Pharmaceutical dosage form.Those skilled in the art are it will be appreciated that these pharmaceutical carriers are for the ease of producing and processing at each Kind of dosage form, ensure drug safely, effectively with factors, and the physics and chemistry according to different pharmaceutical dosage forms and drug itself such as stablize Property is selected.The selection of pharmaceutical carrier is using being that technical staff in field of the present invention is known and obvious.

It should be appreciated that being selected generally according to different medicaments according to method well known in the art for oral or injection With or the pharmaceutical carrier that is applied in combination, include optionally excipient or diluent, such as microcrystalline cellulose, mannitol, plant Fat end, lactose, pregelatinized starch, starch, dextrin, cyclodextrin, maltodextrin, hydroxypropyl-β-cyclodextrin, calcium phosphate, phosphoric acid hydrogen Calcium, hydroxypropyl methyl cellulose, sucrose, dextran, poloxamer, sodium chloride, sorbierite, glucose, oligofructose, poly Fructose, xylo-oligosaccharide, polydextrose, Oligomeric manna sugar, solid polyethylene glycol（Such as polyethylene glycol-4000, polyethylene glycol- 12000, polyethylene glycol-6000, Polyethylene glycol-2000 etc.）, resistant dextrin, fructose, water, propylene glycol, glycerine, coffee, milk powder, Plant protein powder, etc.；For oral solid formulation, it is also an option that property includes adhesive, such as povidone (polyethylene Pyrrolidones), methylcellulose, hydroxymethyl cellulose, hypromellose, pregelatinized starch, sodium carboxymethyl starch, hydroxypropyl Base cellulose, hydroxyethyl cellulose, gelatin, guar gum, xanthans, etc.；Further include lubricant, such as magnesium stearate, tristearin Acid, talcum powder, stearyl fumarate, lauryl sodium sulfate, etc.；Also include optionally disintegrant, such as carboxylic first Base sodium starch, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, cross-linked carboxymethyl fiber Plain sodium, crosslinked carboxymethyl fecula sodium, pregelatinized starch, etc.；Also optionally including surfactant or cosolvent, such as Lauryl sodium sulfate, Tween-80, etc.；It may also include pH values conditioning agent or buffer or cosolvent, such as phosphoric acid Salt buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, lactic acid, sodium carbonate, sodium hydroxide, alkalinity organise Object is closed, such as arginine, lysine, meglumine, tromethamine, etc.；Also include optionally preservative, such as benzoic acid Sodium, potassium sorbate, methyl p-hydroxybenzoate, propylparaben, etc.；Also include optionally stabilizer and anti- Oxygen agent, for example, metal chelating agent select ethylenediamine tetra-acetic acid and its salt (mosatil, natrium adetate) etc., sodium sulfite, Sodium pyrosulfite, vitamin C, vitamin E, etc.；Also optionally include taste conditioning agent, such as maltitol, fructose, Sucrose, saccharin sodium, flavoring orange essence, strawberry essence, etc.；It additionally can include other conventional, appropriate additives.Should also Understand, can be film coating when agent type is tablet or capsule.For the material of film coating, including suitable coating agent, Such as hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (enteric Coating material), etc.；It also may include plasticizer, such as polyethylene glycol, triethyl citrate, etc.；Also include optionally Suitable solubilizer, such as Polyoxyethylene Sorbitan Monooleate；It also may include suitable pigment, such as titanium dioxide, various iron oxide, pink Pigment, etc..It should be appreciated that above-mentioned " including optionally " refers to that can optionally select to use, can not also use.

Particularly, the chemical composition of the composition of EGCG and chitosan oligosaccharide of the present invention, EGCG and chitosan oligosaccharide is released in medicament Putting in form can be different, such as EGCG can be sustained or the form of controlled release occurs, and chitosan oligosaccharide can also be sustained or controlled release Form occurs, to improve not cooperateing with for blood concentrations of the EGCG with chitosan oligosaccharide caused by the time difference in terms of action or metabolism Effect.

In the present patent application, " composition " refers to the EGCG or/and chitosan oligosaccharide, and other chemical compositions, such as raw In reason/mixture that is formed of pharmaceutically acceptable carrier or excipient, the purpose of pharmaceutical composition is to be conducive to applying for drug With, carry, preserve；" administration " mentioned here refer in order to prevent or treat disease and to organism（Including patient or it is good for Kang Renqun）Deliver described compound, its pharmaceutical salt or its solvate；" the per unit preparation " refers to minimum package Or the preparation unit of minimum form of medication, such as each bottle of oral administration solution, each capsule, each tablet or pill, each bag Granule or pulvis, each injection or injection, each bottle of injection or injection, each piece of suppository, each bottle of eye drip Liquid, each pipe ointment, etc..

Another aspect, it has been found that when EGCG is applied in combination with chitosan oligosaccharide, show unexpected advantage, especially It is the pharmaceutical composition show it is outstanding, unexpected in reducing blood lipid, antitumor, protection cardiovascular and cerebrovascular etc. collaboration Effect.Preferably, the pharmaceutical composition of EGCG and chitosan oligosaccharide of the present invention is used to prepare reducing blood lipid, antitumor, protection cardiovascular and cerebrovascular Drug in application, etc..

Therefore, another aspect, the present invention provide a kind of reducing blood lipid, antitumor, protection cardiovascular and cerebrovascular pharmaceutical composition, It contains EGCG and chitosan oligosaccharide.It will be appreciated by those skilled in the art that, in pharmaceutical composition, the combination of EGCG and chitosan oligosaccharide Mode, the dosage ratio in per unit preparation and content, it is just the same with present invention content above-mentioned.

Further, the present invention also provides the preparation methods of the pharmaceutical composition of EGCG and chitosan oligosaccharide, it includes will EGCG and chitosan oligosaccharide mix with pharmaceutically acceptable pharmaceutical carrier and acceptable any pharmaceutical preparation in pharmacy are made, example As EGCG and chitosan oligosaccharide mixed with pharmaceutical carrier dry powder blend, dry granulation (dry granulating machine processing), wet granulation mixing (with Water or ethanol solution wet granulation), liquid or semisolid mixing (content of such as soft capsule, the mixing of dripping pill dropping liquid), it is excellent The pharmaceutical dosage form of choosing is tablet (including dispersible tablet, enteric coatel tablets, chewable tablets, oral disnitegration tablet, effervescent tablet etc.), hard capsule (packet Include capsulae enterosolubilis), granule, dry suspensoid agent, oral solution, dry syrup, powder, oral administration mixed suspension, soft capsule, ball Agent, micropill preparation (including enteric-coated micro-pill), pill and oral quick-release or the dosage forms such as sustained release or controlled release, powder ampoule agent for injection (including the filling powder of Injectable sterile, freeze drying powder injection), aqueous solution injection, injection can also be with glucose, chlorination Sodium, fructose, inverted sugar, xylitol or maltose etc. use as the intravenous injection of osmotic pressure regulator (including intravenous injection and Intravenous drip) aqueous solution, can also be the dosage forms such as quick-release, the slow-release controlled-release of any of the above dosage form, such as oral dispersion Piece, sustained release tablets, spansule, enteric coatel tablets, effervescent tablet, oral disnitegration tablet, special-shaped tablets, born of the same parents rise particle, etc..Particularly, this is pressed Prepared by art-known methods preferably for prepare tablet (including dispersible tablet, slow-release tablet, enteric coatel tablets, the bubble used in pharmacy Rise piece, oral disnitegration tablet, special-shaped tablets), capsule (including soluble in the stomach, enteric, spansule), oral solution, injection (including Powder ampoule agent for injection and injection) etc.；Or

The present invention also provides EGCG and chitosan oligosaccharide pharmaceutical composition preparation method, it includes by EGCG and chitosan oligosaccharide It is mixed and made into individual pharmaceutical preparation with pharmaceutically acceptable pharmaceutical carrier respectively, and by two kinds of individual pharmaceutical preparation packets In the same medicine box, preferred pharmaceutical dosage form is tablet (including dispersible tablet, enteric coatel tablets, chewable tablets, oral disnitegration tablet, bubble Rise piece etc.), it is hard capsule (including capsulae enterosolubilis), granule, dry suspensoid agent, dry syrup, powder, soft capsule, oral molten Liquor, pill, micropill preparation (including enteric-coated micro-pill), pill, oral administration mixed suspension and oral quick-release or sustained release or controlled release etc. Dosage form, powder ampoule agent for injection (including the filling powder of Injectable sterile, freeze drying powder injection), aqueous solution injection, injection may be used also Made with being intravenous injection using glucose, sodium chloride, fructose, inverted sugar, xylitol or maltose etc. as osmotic pressure regulator With the aqueous solution of (including intravenous injection and intravenous drip).Can also be the agent such as quick-release, the slow-release controlled-release of any of the above dosage form Type, such as oral dispersible tablet, sustained release tablets, spansule, enteric coatel tablets, effervescent tablet, oral disnitegration tablet, special-shaped tablets, effervescence granular, Etc..Particularly, it is prepared by means known in the art preferably for it is (including dispersible tablet, slow to prepare the tablet used in pharmacy Controlled release tablet, enteric coatel tablets, effervescent tablet, oral disnitegration tablet, special-shaped tablets), it is capsule (including soluble in the stomach, enteric, spansule), oral molten Liquor, injection (including powder ampoule agent for injection and injection) etc..

Preferably, the present invention provides a kind of granule containing EGCG and chitosan oligosaccharide, and the EGCG is with chitosan oligosaccharide with weight Than for (0.1~2):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.2~1.9):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.3~1.8):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.4~1.7):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.5~1.6):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.6~1.5):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.7~1.4):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.8~1.3):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.9~1.2):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.3~1.2):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.4~1.1):1 ratio combination,

It is preferred that EGCG and chitosan oligosaccharide with weight ratio for (0.5~1):1 ratio combination；

Specifically, for example preferred EGCG and chitosan oligosaccharide with weight ratio for 0.1:1、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, etc..

In the granule composite also contain granule auxiliary material, the granule auxiliary material include it is following it is one or more at Point：Fructose, xylitol, oligofructose, polyfructosan, xylo-oligosaccharide, polydextrose, mannitol, sucrose, inverted sugar（That is grape The equal amount of mixture of sugar and fructose）, glucose, resistant dextrin, D-sorbite, maltose, isomalt, oligomeric sweet dew Sugar, solid polyethylene glycol（Such as polyethylene glycol-4000, polyethylene glycol -12000, polyethylene glycol-6000, Polyethylene glycol-2000 Deng）, dextrin, cyclodextrin, maltodextrin, hydroxypropyl-β-cyclodextrin, microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose Element, pregelatinized starch, starch, starch sugar, lactose, vegetable fat powder, milk powder, plant protein powder, coffee, sodium carboxymethyl starch, albumen Sugar, Sucralose, Aspartame, acesulfame potassium, stachyose, neotame, stevioside, wherein the content of granule auxiliary material is with weight ratio Meter is more than 30%, and the preferably content of granule auxiliary material is more than 45% with weight ratio meter, and preferably the content of granule auxiliary material is with weight ratio Meter is more than 60%；

Further, the present invention provides a kind of preparation method of the granule containing EGCG and chitosan oligosaccharide, it includes：It will EGCG, chitosan oligosaccharide are uniformly mixed with granule auxiliary material respectively, then with ethanol water wet granulation, dry, whole grain, wherein particle The content of agent auxiliary material is more than 30% with weight ratio meter；Particularly, the present invention provides a kind of system containing EGCG and chitosan oligosaccharide granule Preparation Method, it includes：

(1) dispensing：EGCG, chitosan oligosaccharide are weighed by formula, first EGCG is added in granule auxiliary material and is uniformly mixed, adds Chitosan oligosaccharide is uniformly mixed, it is preferred to use equal increments hybrid mode is uniformly mixed；

(2) it pelletizes：By 75% ethanol solution softwood of prepared material in (1), wet granulation, 45~70 DEG C of dryings, Whole grain；

(3) it packs, examine to get granule of the present invention containing EGCG and chitosan oligosaccharide.

Further, capsule can be obtained in Capsules shell by above-mentioned granule is filling, or by above-mentioned granule It is tabletted by tablet forming technique.

Further, the present invention also provides the compositions of EGCG and chitosan oligosaccharide in following application：

Application in preparing reducing blood lipid, protecting the drug of cardiovascular and cerebrovascular；

Application in preparing anti-tumor drug, etc..

The composition of EGCG and chitosan oligosaccharide of the present invention have the advantages that following three aspect：

1, the combination of EGCG and chitosan oligosaccharide improves the thermal stability of EGCG；

2, in reducing blood lipid, protection cardiovascular and cerebrovascular, and reducing cardiovascular and cerebrovascular disease occurs for the composition of EGCG and chitosan oligosaccharide Application in the drug of risk caused by disease；And it is antitumor etc. with good synergistic effect.

For specific implementation mode in the implementation process of the present invention, those of ordinary skill in the art are not departing from the present invention's The various embodiments generated on the basis of scope and spirits and modification are obvious and are easy to perform.It is logical The following examples are crossed to be further elaborated with to the application etc. of the present invention, it is not intended that limit of the embodiment to the present invention System.

Embodiment 1, the composite tablet of EGCG and chitosan oligosaccharide and its preparation

Recipe quantity by weight percentage, contains：

EGCG 8%~35%, preferably 30%,

Chitosan oligosaccharide 15%~50%, preferably 50%,

Mannitol 10%~40%, preferably 12%,

Sodium carboxymethyl starch 1%~10%, preferably 5%,

Appropriate hydroxypropyl cellulose aqueous solution, preferably 2.5% hydroxypropyl cellulose aqueous solution, with hydroxypropyl cellulose 2% is calculated as,

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

Preparation method includes：EGCG, chitosan oligosaccharide, mannitol, sodium carboxymethyl starch are crossed to 80 mesh sieve, preferably mistake respectively After being weighed by recipe quantity, EGCG, chitosan oligosaccharide are uniformly mixed for 100 mesh, and mannitol and sodium carboxymethyl starch is added, and are uniformly mixed Afterwards, hydroxypropyl cellulose aqueous solution is added and softwood is made, cross the sieve granulation of 24 mesh, after 45~60 DEG C of dryings, 20 mesh sieves are added The magnesium stearate of recipe quantity, mixing, tabletting to get.

Stability test：The composite tablet for taking EGCG and chitosan oligosaccharide made from the optimizing prescriptions in the present embodiment, separately takes The pure powder of EGCG is as blank control product, and the respectively sampling 8 (n=8) of each sample, the data result of detection is averaged, by steady Qualitative accelerated test (under the conditions of 40 DEG C, humidity 75%) is placed 2 months, sample detection, is detected in each sample using HPLC methods The content of EGCG, and by result compared with 0 day, obtain the content drop-out value of 2 months point EGCG, data statistics software Processing；Detection method：Using high effective liquid chromatography for measuring content, using 0.1 phosphoric acid and acetonitrile as mobile phase, 20 μ of sample size L, 28 DEG C, Detection wavelength 273nm of column temperature, retention time are more than 7min.Test result is shown in Table 1.

1 stability test result of table

The result shows that the present embodiment composition, the content drop-out value of EGCG is less than blank control product, and with notable Otherness, the composition for embodying EGCG and chitosan oligosaccharide of the present invention have significant stability.

Embodiment 2, the compound granule of EGCG and chitosan oligosaccharide and its preparation

Recipe quantity by weight percentage, contains：

EGCG 0.5%~10%, preferably 1%,

Chitosan oligosaccharide 0.5%~20%, preferably 1.5%,

Granule auxiliary material 85%~99%, preferably fructose 97.5%；

The wherein described granule auxiliary material includes following one or more ingredients：Fructose, xylitol, oligofructose, poly fruit Sugar, xylo-oligosaccharide, polydextrose, mannitol, sucrose, inverted sugar（That is the equal amount of mixture of glucose and fructose）, it is glucose, anti- Property dextrin, D-sorbite, maltose, isomalt, Oligomeric manna sugar, solid polyethylene glycol（Such as polyethylene glycol- 4000, polyethylene glycol -12000, polyethylene glycol-6000, Polyethylene glycol-2000 etc.）, dextrin, cyclodextrin, maltodextrin, hydroxypropyl Group-beta-cyclodextrin, microcrystalline cellulose, carboxymethyl cellulose, hypromellose, pregelatinized starch, starch, starch sugar, breast Sugar, vegetable fat powder, milk powder, plant protein powder, coffee, sodium carboxymethyl starch, protein sugar, Sucralose, Aspartame, acesulfame potassium, Stachyose, neotame, stevioside, most preferably fructose or/and oligofructose, polyfructosan；

Preparation method includes：EGCG, chitosan oligosaccharide, granule auxiliary material are crossed to 80 mesh sieve respectively, preferably cross 100 mesh, by place After side's amount weighs, first EGCG is uniformly mixed with granule auxiliary material, chitosan oligosaccharide then is added after mixing, it is molten with 75% ethyl alcohol Liquid wet granulation, 45~70 DEG C of dryings, whole grain packaging, examine to get.It further, can be filling in hollow by above-mentioned granule Capsule is obtained in capsule shells, or above-mentioned granule is tabletted by tablet forming technique.

Stability test：The compound granule for taking EGCG and chitosan oligosaccharide made from the optimizing prescriptions in the present embodiment, separately takes The pure powder of EGCG is as blank control product, and the respectively sampling 8 (n=8) of each sample, the data result of detection is averaged, by steady Qualitative accelerated test (under the conditions of 40 DEG C, humidity 75%) is placed 2 months, sample detection, is detected in each sample using HPLC methods The content of EGCG, and by result compared with 0 day, obtain the content drop-out value of 2 months point EGCG, data statistics software Processing；Detection method：Using high effective liquid chromatography for measuring content, using 0.1 phosphoric acid and acetonitrile as mobile phase, 20 μ of sample size L, 28 DEG C, Detection wavelength 273nm of column temperature, retention time are more than 7min.Test result is shown in Table 2.

2 stability test result of table

The result shows that the present embodiment composition, the content drop-out value of EGCG is less than blank control product, and with notable Otherness, the composition for embodying EGCG and chitosan oligosaccharide of the present invention have significant stability.

Embodiment 3, the compound capsule of EGCG and chitosan oligosaccharide and its preparation

Recipe quantity by weight percentage, contains：

EGCG 10%~30%, preferably 25%,

Chitosan oligosaccharide 15%~45%, preferably 30%,

Mannitol 15%~35%, preferably 23%,

Pregelatinized starch 8%~25%, preferably 15%,

Sodium carboxymethyl starch 1%~15%, preferably 5%,

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

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

Preparation method includes：EGCG, chitosan oligosaccharide, mannitol, pregelatinized starch, sodium carboxymethyl starch are crossed into 80 mesh respectively Sieve, preferably sieves with 100 mesh sieve, after being weighed by recipe quantity, is first uniformly mixed EGCG and chitosan oligosaccharide, obtain A mixed-powders, for use； Separately mannitol, pregelatinized starch, sodium carboxymethyl starch are uniformly mixed, obtain B mixed-powders, then mixes A mixed-powders with B It closes powder and is sufficiently mixed and the ethanol solution of polyvinylpyrrolidone is uniformly added is made softwood, cross 20 mesh sieve and pelletizes, 45~70 DEG C Drying, dry particl cross 18 mesh sieves, and stiffened fatty acid magnesium is uniformly mixed, filling to capsulae vacuus to get.

Stability test：The compound capsule for taking EGCG and chitosan oligosaccharide made from the optimizing prescriptions in the present embodiment, separately takes The pure powder of EGCG is as blank control product, and the respectively sampling 8 (n=8) of each sample, the data result of detection is averaged, by steady Qualitative accelerated test (under the conditions of 40 DEG C, humidity 75%) is placed 2 months, sample detection, is detected in each sample using HPLC methods The content of EGCG, and by result compared with 0 day, obtain the content drop-out value of 2 months point EGCG, data statistics software Processing；Detection method：Using high effective liquid chromatography for measuring content, using 0.1 phosphoric acid and acetonitrile as mobile phase, 20 μ of sample size L, 28 DEG C, Detection wavelength 273nm of column temperature, retention time are more than 7min.Test result is shown in Table 3.

3 stability test result of table

The result shows that the present embodiment composition, the content drop-out value of EGCG is less than blank control product, and with notable Otherness, the composition for embodying EGCG and chitosan oligosaccharide of the present invention have significant stability.

Embodiment 4, the compound granule of EGCG and chitosan oligosaccharide and its preparation

Recipe quantity by weight percentage, contains：

EGCG 0.5%~6%, preferably 3%,

Chitosan oligosaccharide 0.5%~10%, preferably 5%,

Maltodextrin 3%~10%, preferably 5%,

Other granule auxiliary materials 75%~95%, preferably fructose 87%；

Wherein described other granule auxiliary materials include following one or more ingredients：It is fructose, xylitol, oligofructose, more Fructooligosaccharides, xylo-oligosaccharide, polydextrose, mannitol, sucrose, inverted sugar（That is the equal amount of mixture of glucose and fructose）, grape Sugar, resistant dextrin, D-sorbite, maltose, isomalt, Oligomeric manna sugar, solid polyethylene glycol, dextrin, cyclodextrin, Hydroxypropyl-β-cyclodextrin, microcrystalline cellulose, carboxymethyl cellulose, hypromellose, pregelatinized starch, starch, starch Sugar, lactose, vegetable fat powder, milk powder, plant protein powder, coffee, sodium carboxymethyl starch, protein sugar, Sucralose, Aspartame, peace Match honey, stachyose, neotame, stevioside, most preferably fructose or/and oligofructose, polyfructosan；

Preparation method includes：EGCG, chitosan oligosaccharide, maltodextrin, other granule auxiliary materials are crossed to 80 mesh sieve respectively, preferably 100 mesh are crossed, after being weighed by recipe quantity, EGCG, chitosan oligosaccharide, maltodextrin, other granule auxiliary materials are uniformly mixed, with 75% second Alcoholic solution wet granulation, 45~70 DEG C of dryings, whole grain packaging, examine to get.

Stability test：The compound granule for taking EGCG and chitosan oligosaccharide made from the optimizing prescriptions in the present embodiment, separately takes The pure powder of EGCG is as blank control product, and the respectively sampling 8 (n=8) of each sample, the data result of detection is averaged, by steady Qualitative accelerated test (under the conditions of 40 DEG C, humidity 75%) is placed 2 months, sample detection, is detected in each sample using HPLC methods The content of EGCG, and by result compared with 0 day, obtain the content drop-out value of 2 months point EGCG, data statistics software Processing；Detection method：Using high effective liquid chromatography for measuring content, using 0.1 phosphoric acid and acetonitrile as mobile phase, 20 μ of sample size L, 28 DEG C, Detection wavelength 273nm of column temperature, retention time are more than 7min.Test result is shown in Table 4.

4 stability test result of table

Sample（N=8 are averaged）	EGCG content drop-out value
		The present embodiment composition	0.44%
Blank control product	2.39%

The result shows that the present embodiment composition, the content drop-out value of EGCG is less than blank control product, and with notable Otherness, the composition for embodying EGCG and chitosan oligosaccharide of the present invention have significant stability.

Embodiment 5, EGCG and chitosan oligosaccharide are with the stability study of the composition of different weight ratio

Test method：It is respectively 0.2 by weight ratio by EGCG and chitosan oligosaccharide:1、0.4:1、0.6:1、0.8:1、1:1、 1.4:1、1.8:1、2:1 mixing, by mixed-powder according to the preparation method of particle in above-described embodiment, is respectively prepared granule group Object is closed,

Particle separately is made according to identical preparation method in the pure powder of EGCG, respectively by each particle be placed under 45 DEG C of environment into Row accelerates thermal stability to investigate 30d, checks that each particle 0 day and the content of 30 days EGCG, calculates the decline of EGCG content It is worth (degradation rate).

Detection method：Using high effective liquid chromatography for measuring content, using 0.1 phosphoric acid and acetonitrile as mobile phase, sample size 20 μ L, 28 DEG C, Detection wavelength 273nm of column temperature, retention time are more than 7min.

As a result such as the following table 5.

Table 5

As can be seen from Table 5, in the composition of the different ratio of EGCG and chitosan oligosaccharide, the degradation rate of EGCG is far below EGCG Pure powder particles embody in present composition kind, and chitosan oligosaccharide has the function of stablizing EGCG, in the stability for improving composition Aspect has significant difference（p<0.01）.

The composition of embodiment 6, EGCG and chitosan oligosaccharide is in reducing blood lipid and the synergistic effect of protection treating cardiac and cerebral vascular diseases

Method：Using High fat diet rats model, if Normal group (feeding basal feed), model control group (feed feeding high in fat Material), test group (feed high lipid food, and feed EGCG or/and chitosan oligosaccharide respectively daily), be continuously fed with 30d, it is total to measure its serum Cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) are horizontal, and further Atherogenic index (AI) is calculated,

AI=[total cholesterol (TC)-high-density lipoprotein (HDL-C)]/high-density lipoprotein (HDL-C).

Animal：Cleaning grade SD male rats 40,200~250g of weight, every group of 8 rats.

High lipid food：Including 80% normal diet, 2% cholesterol, 8% yolk powder, 10% lard.

Statistical procedures:Data using SPSS17.0 statistical softwares analyze, all data withIt indicates.

Experiment packet：

(1) Normal group：Arm's length basis feed is fed with；

(2) model control group:High lipid food is fed with；

(3) EGCG groups:High lipid food is fed with, and gavages the EGCG of 0.6g/KG daily；

(4) chitosan oligosaccharide group:High lipid food is fed with, and gavages the chitosan oligosaccharide of 0.6g/KG daily；

(5) the composition group of EGCG and chitosan oligosaccharide:High lipid food is fed with, and gavages the composition of EGCG and chitosan oligosaccharide daily The weight ratio of 0.6g/KG, the wherein chitosan oligosaccharide of the EGCG of 0.3g/KG and 0.3g/KG, i.e. EGCG and chitosan oligosaccharide is 1:1.

It the results are shown in Table 6.

The composition of 6 EGCG of table and chitosan oligosaccharide in terms of reducing blood lipid synergistic effect (n=8, mmol/L,)

*：The p compared with EGCG groups, chitosan oligosaccharide group<0.05；

##：The p compared with EGCG groups, chitosan oligosaccharide group<0.01.

Conclusion：For the composition of EGCG and chitosan oligosaccharide of the present invention in the experiment of SD rat hyperlipidemia models, having significantly reduces blood Fat and the effect for promoting high-density lipoprotein cholesterol compared with EGCG groups, chitosan oligosaccharide group, have aobvious in terms of reducing TC, TG Write difference, p<0.05；In terms of reducing LDL-C and promoting HDL-C, compared with EGCG groups, chitosan oligosaccharide group, there is very significance difference It is different, p<0.01；On the other hand, atherogenic index AI values are a fingers of the measurement Degree of arteriosclerosis that international medical community is formulated Mark, reflects the degree of atherosclerosis, and numerical value is smaller to illustrate that the degree of artery sclerosis is lighter, causes cardiovascular and cerebrovascular diseases Danger it is lower, the AI values of the composition of EGCG and chitosan oligosaccharide are with EGCG groups, chitosan oligosaccharide group compared with, with very significance difference It is different, p<0.01.

Show good action of the composition in reducing blood lipid and inhibition artery artery sclerosis of EGCG and chitosan oligosaccharide of the present invention, I.e. the present composition has outstanding reducing blood lipid, protection cardiovascular and cerebrovascular, reduces risk caused by cardiovascular and cerebrovascular disease occurs The synergistic effect of aspect.

Effect of the composition of embodiment 7, EGCG and chitosan oligosaccharide in anti-tumor aspect

It is used as experimental animal model by establishing H22 liver cancer mice with tumor, studies the composition of EGCG and chitosan oligosaccharide to tumour Inhibiting effect.

Experimental animal：Kunming mouse, half male and half female, 18~22g of weight.

Method：Cell strain H22 liver cancer cells come from kunming mice, are inoculated in mouse peritoneal after the recovery of H22 liver cancer cells, 7~10 days mouse row cervical dislocations are put to death after passing on 1 time.It is fixed on mimeograph stencil, sterilizes skin of abdomen, cut off and peel off abdomen Skin aspirates ascites with sterile empty needle, puts in people's sterile test tube, dilutes tumor cell suspension to viable count with Hanks working solutions It is 1 × 10⁸/ mL, it is spare.

Experiment packet and dosage regimen：40 mouse are randomly divided into 4 groups, every group 10, respectively control group, EGCG groups, shell The composition group of oligosaccharides group, EGCG and chitosan oligosaccharide；It tests the 1st day to the 7th day each group mouse peritoneal and injects drug or physiology respectively Brine 0.2ml (control group) extracts H22 liver cancer cells (1 × 10 on the 8th day⁸/ mL) to be inoculated in every mouse back subcutaneous by 0.2ml, Each group mouse weight is recorded after 24 hours.Inject the drug or physiology salt of 1 0.2ml respectively to each group mouse peritoneal daily later Water, successive administration 10 days, next day after drug withdrawal take off neck and put to death, remove tumor mass, weigh, calculate tumour inhibiting rate, tumour inhibiting rate=(control group Knurl weight-experimental group knurl weight)/control group knurl weight × 100%.

Control group:Injecting normal saline；

EGCG groups:The 40mg/KG based on EGCG, is dissolved in physiological saline；

Chitosan oligosaccharide group:The 40mg/KG based on chitosan oligosaccharide, is dissolved in physiological saline；

The composition group of EGCG and chitosan oligosaccharide:By 40mg/KG based on the composition of EGCG and chitosan oligosaccharide, wherein EGCG is few with shell The weight ratio of sugar is 0.6:1, it is dissolved in physiological saline.

Statistical procedures:Data using SPSS15.0 statistical softwares analyze, all data withIt indicates, variance analysis Compare group difference, with P<0.05 is statistically significant for difference.

It the results are shown in Table 7.

The composition of 7 EGCG of table and chitosan oligosaccharide anti-tumor aspect synergistic effect (n=10, mmol/L,)

*：The p compared with EGCG groups, chitosan oligosaccharide group<0.05；

Conclusion：The composition of EGCG and chitosan oligosaccharide of the present invention have significantly suppression in the experiment of mice with tumor experimental animal model The effect of tumour growth processed has significant difference, p compared with EGCG groups, chitosan oligosaccharide group<0.05；Show EGCG and chitosan oligosaccharide Composition anti-tumor aspect have good synergistic effect.

The application of the composition of EGCG and chitosan oligosaccharide described in embodiment 8, embodiment 1 to embodiment 4 in the following aspects：

Application in preparing reducing blood lipid, protecting the drug of cardiovascular and cerebrovascular；

Preparing the application reduced during the drug of risk caused by cardiovascular and cerebrovascular disease occurs；

Application in preparing anti-tumor drug.

Claims (4)

1. the composite tablet of a kind of EGCG and chitosan oligosaccharide, recipe quantity by weight percentage, contains：

EGCG 30%,

Chitosan oligosaccharide 50%,

Mannitol 12%,

Sodium carboxymethyl starch 5%,

Appropriate hydroxypropyl cellulose aqueous solution,

Magnesium stearate 1%；

Preparation method includes：EGCG, chitosan oligosaccharide, mannitol, sodium carboxymethyl starch are crossed to 80 mesh sieve respectively, weighed by recipe quantity Afterwards, EGCG, chitosan oligosaccharide are uniformly mixed, mannitol and sodium carboxymethyl starch is added, after mixing, hydroxypropyl cellulose is added Softwood is made in aqueous solution, crosses the sieve granulation of 24 mesh, after 45~60 DEG C of dryings, the magnesium stearate of recipe quantity is added in 20 mesh sieves, mixes It is even, tabletting to get.

2. the compound granule of a kind of EGCG and chitosan oligosaccharide, recipe quantity by weight percentage, contains：

EGCG 1%,

Chitosan oligosaccharide 1.5%,

Fructose 97.5%；

Preparation method includes：EGCG, chitosan oligosaccharide, fructose are crossed to 80 mesh sieve respectively, after being weighed by recipe quantity, first by EGCG and fruit Sugar is uniformly mixed, and chitosan oligosaccharide then is added after mixing, with 75% ethanol solution wet granulation, 45~70 DEG C of dryings, whole grain packet Dress, examine to get.

3. the compound capsule of a kind of EGCG and chitosan oligosaccharide, recipe quantity by weight percentage, contains：

EGCG 25%,

Chitosan oligosaccharide 30%,

Mannitol 23%,

Pregelatinized starch 15%,

Sodium carboxymethyl starch 5%,

The ethanol solution of polyvinylpyrrolidone is appropriate,

Magnesium stearate 1%；

Preparation method includes：EGCG, chitosan oligosaccharide, mannitol, pregelatinized starch, sodium carboxymethyl starch are crossed to 80 mesh sieve respectively, After being weighed by recipe quantity, first EGCG and chitosan oligosaccharide are uniformly mixed, obtain A mixed-powders, for use；Separately by mannitol, pregelatinated Starch, sodium carboxymethyl starch are uniformly mixed, and obtain B mixed-powders, are then sufficiently mixed A mixed-powders and B mixed-powders Even, softwood is made in the ethanol solution that polyvinylpyrrolidone is added, and crosses the sieve granulation of 20 mesh, 45~70 DEG C of drying, and dry particl crosses 18 Mesh sieve, stiffened fatty acid magnesium be uniformly mixed, filling to capsulae vacuus to get.

4. the compound granule of a kind of EGCG and chitosan oligosaccharide, recipe quantity by weight percentage, contains：

EGCG 3%,

Chitosan oligosaccharide 5%,

Maltodextrin 5%,

Fructose 87%；

Preparation method includes：EGCG, chitosan oligosaccharide, maltodextrin, fructose are crossed to 80 mesh sieve respectively, it, will after being weighed by recipe quantity EGCG, chitosan oligosaccharide, maltodextrin, fructose are uniformly mixed, with 75% ethanol solution wet granulation, 45~70 DEG C of dryings, whole grain packet Dress, examine to get.