CN108420793A

CN108420793A - A kind of blank mixed micelle and its preparation method and application

Info

Publication number: CN108420793A
Application number: CN201711432287.5A
Authority: CN
Inventors: 王丹; 李翀; 王亚华; 詹华杏
Original assignee: Xiamen Ben Su Pharmaceutical Co Ltd
Current assignee: Xiamen Ben Su Pharmaceutical Co Ltd
Priority date: 2017-12-26
Filing date: 2017-12-26
Publication date: 2018-08-21
Anticipated expiration: 2037-12-26
Also published as: CN108420793B; WO2019128608A1

Abstract

The invention discloses a kind of blank mixed micelles and its preparation method and application.The blank mixed micelle of the present invention includes amphipathic copolymer and ginsenoside shown in formula I.The blank mixed micelle of the present invention has many advantages, such as that efficient, safe and stable, targeting is strong, homogeneity is good, stable quality, preparation process are easy, and can be used for one or more in the active material in entrapped drug, cosmetics and substance with health role, form the mixed micelle of carrying active substance.Compared with traditional nano-micelle, the mixed micelle of carrying active substance is more prominent in terms of druggability and anti-multidrug resistance, and stablizes, homogeneity is good, safe, grain size is small, for mdr cell with more preferable curative effect after supported active drug.

Description

A kind of blank mixed micelle and its preparation method and application

Technical field

The present invention relates to a kind of blank mixed micelles and its preparation method and application.

Background technology

The general features of polymer micelle be have it is amphiphilic, i.e., simultaneously have hydrophilic group and hydrophobic group, hydrophobic group general Kernel is formed in centre, hydrophilic group is generally arranged in outside and forms shell.Fat-soluble medicine can be wrapped in it by polymer micelle Hydrophobic centers form the polymer micelle for being loaded with drug, and can be dissolved in water or alcohol with its water-wet side.Polymer micelle can be by medicine Inside object package to micella, extend the circulation time and biological half-life of drug in blood, or drug can be increased in lesion The accumulation of position reduces adverse reaction, or can connect special carrier, antibody or ligand, can be with the receptor knot of target cell It closes, improves therapeutic effect.

The Genexol-PM of Samyang companies of South Korea research and development is with methoxy polyethylene glycol-polylactic acid copolymer (mPEG- PDLLA it is) that membrane material prepares paclitaxel freeze drying nano-micelle, the water solubility of taxol can be increased, reduce the toxic side effect of drug. CN201110105540.2 disclose methoxy poly (ethylene glycol) 2000- polyester block copolymers (mPEG-PDLLA) by molecule from Assembling forms micella, then contains slightly solubility tumour medicine in the hydrophobic cores that polyester is formed and polymer micelle is made, and carries High drug maximum tolerated dose simultaneously reduces toxic side effect.CN201611083457.9 is carried by micella of PEO-PCL copolymers Body has prepared Florfenicol micellar preparation, improves the bioavilability of Florfenicol.CN201611054732.4 is provided A kind of amphiphilic triblock copolymer inclusion adriamycin with pH and reduction Dual Sensitive, the drug embody good biofacies Capacitive reduces the toxicity of anticancer drug, reduces the injury of normal tissue.CN201610847822.2 discloses a kind of PEG- The nanoparticle of the mixed polymer inclusion taxol of PLA or PEG-PLA and folate-PEG-PLA.CN201110367315.6 It discloses a kind of using the block copolymer of polyethers and polyester as the preparation method of the taxol micella of auxiliary material.

Such as China Medicine University Zhang Zhen sea《The progress of drug-carrying polymer micelle preparation method》It is described, polymer micelle Two problems will be solved by actually entering application, one is the stability problem of polymer micelle, the second is polymer micelle is low Concentration problems.Such as seedling elder generation of China Medicine University beacon《The micellization mechanism of block polymer micelle and physically stable Journal of Sex Research》Institute It states, the stability of polymer micelle is the important indicator of preparation.At the same time, amphipathic nature polyalcohol material is biodegradable Property, the problems such as genotoxic potential, high cost, organic synthesis difficulty are big, polymer molecular weight does not have unicity still remains.Cause This, find a kind of good Drug loading capacity, structure and in vivo it is stable, nontoxic, molecule is single, of low cost, the good micella film of drug effect Material is always the important research direction of drug delivery technologies.

According to patent CN201310155639.2, CN201380026612.1, US20150297727A1, PCT/CN2013/ 088558, JP2015-514348 etc., part Hydrolizates (such as Rg5, Rk1 etc.) can self-contained micellas under certain condition And the medicament active compositions such as taxol can be contained.But pass through further investigation revealed that, Hydrolizates nano-micelle is molten It is courageous and upright stronger, limit the use as intravenous injection.

Therefore, research and develop that novel, Drug loading capacity is stronger, bio-compatibility higher, the better micella of safety, or drop The shortcomings of dosage of low existing amphipathic nature polyalcohol is to reduce biocompatibility is the field urgent problem.

Invention content

The technical problem to be solved by the present invention is in order to overcome existing ginsenoside nano-micelle drug-loading system haemolysis Property too strong, animal body in it is unstable the defects of, while in order to solve high molecular polymer micella membrane material biodegradability it is insufficient, The problems such as membrane material molecular structural components are not single, grain size is larger, membrane material easily causes genotoxic potential, membrane material is expensive, and carry A kind of blank mixed micelle and its preparation method and application is supplied.The blank mixed micelle of the present invention has efficient, safe, steady It is fixed, targeting is strong, homogeneity is good, stable quality and it is reliable, preparation process is easy the advantages that, and can be used for entrapped drug, makeup It is one or more in active material and substance with health role in product, form the mixed micelle of carrying active substance. When the active material of the mixed micelle of present invention encapsulating is antitumor drug, the mixed micelle tool of the carrying active substance of gained There are the targeting to tumour cell, the effect of anti-multidrug resistance, Synergy and attenuation and drug synergism.Specifically, with it is traditional Nano-micelle is compared, and the mixed micelle of carrying active substance is more prominent in terms of druggability and anti-multidrug resistance, and stability Well, homogeneity is good, safe, grain size is small, has more preferable curative effect for mdr cell after supported active drug.

The present invention provides a kind of blank mixed micelle, the blank mixed micelle includes amphipathic copolymer and such as formula Ginsenoside shown in I：

Wherein, R¹And R²It is each independently H ,-OH, R¹⁰、R¹¹、R¹²Or R¹³, but R¹And R²It is asynchronously H or-OH；

R³For

R⁴For H ,-OH, ketone (=O), methoxyl group (- OCH₃), ethyoxyl (- OEt), acetoxyl group (- OAc), positive propoxy (n-propoxy), isopropoxy (iso-propoxy), positive propionyloxy (n-propionyloxy), isopropenoxy (iso- Propionyloxy), n-butoxy (n-butoxy), isobutoxy (iso-butoxy), positive bytyry (n-butyryl), different Bytyry (iso-butyryl), benzoyl (- OBz), fluorine (- F), chlorine (- Cl), bromine (- Br), iodine (- I), amino (- NH₂) or Sulfenyl (- SH)；

R⁵For H ,-OH, ketone (=O), methoxyl group (- OCH3) or acetoxyl group (- OAc)；

R⁶For-OH, methoxyl group (- OCH3), hydrop (- OOH), acetoxyl group (- OAc) or benzoyl (- OBz)；

R⁷And R⁸It independently is H ,-OH ,-OCH₃,-OCHO ,-OAc or-OBz；

R¹⁰For any one of following radicals：-O-Glc、-O-Rha、-O-Lyx、-O-Xyl、-O-Ara(p)、-O-Ara (f) ,-O-Glc (2 → 1) Glc (digital representation carbon potential, → indicate connection relation, similarly hereinafter) ,-O-Glc (6 → 1) Glc ,-O-Glc (2→1)Rha、-O-Glc(2→1)Xyl、-O-Glc(6→1)Xyl、-O-Glc(6→1)Rha、-O-Glc(2→1)Ara (p)、-O-Glc(6→1)Ara(p)、-O-Glc(2→1)Ara(f)、-O-Glc(6→1)Ara(f)、-O-Glc(2→1)Glc (2→1)Glc、-O-Glc(2→1)Glc(2→1)Xyl、-O-Glc(6→1)Glc(6→1)Xyl、-O-Glc(2→1)Glc(4 →1)Xyl、-O-Glc(2→1)Lyx、-O-Glc(6→1)Lyx、-O-Glc(2→1)Glc(2→1)Rha、-O-Glc(2→1) Glc(2→1)Lyx、-O-Glc(2→1)Glc(2→1)Ara(f)、-O-Glc(2→1)Glc(2→1)Ara(p)、-O-Glc(2 →1)Glc(6→1)Glc、-O-Glc(2→1)Glc(6→1)Rha、-O-Glc(2→1)Glc(6→1)Xyl、-O-Glc(2→ 1)Glc(6→1)Lyx、-O-Glc(2→1)Glc(6→1)Ara(f)、-O-Glc(2→1)Glc(6→1)Ara(p)、-O-Glc (6→1)Glc(2→1)Glc、-O-Glc(6→1)Glc(2→1)Rha、-O-Glc(6→1)Glc(2→1)Xyl、-O-Glc(6 →1)Glc(2→1)Lyx、-O-Glc(6→1)Glc(2→1)Ara(f)、-O-Glc(6→1)Glc(2→1)Ara(p)、-O- Glc(6→1)Glc(6→1)Glc、-O-Glc(6→1)Glc(6→1)Rha、-O-Glc(6→1)Glc(6→1)Lyx、-O- Glc (6 → 1) Glc (6 → 1) Ara (f) or-O-Glc (6 → 1) Glc (6 → 1) Ara (p)；

R¹¹For R¹⁰In more than one hydroxyl by R¹⁰Replaced, each R¹⁰(when having more than two) is respectively independent Ground is identical or different；

R¹²For any one of following radicals；

I)-mPEG ,-Z-mPEG ,-mPEO ,-Z-PEO ,-mPVP ,-Z-PVP ,-mEPEG or-Z-EPEG；Wherein, m H, Alkyl or acyl group, Z are-CO (CH₂)_aCO-、-NH(CH₂)_aCO-、-NH(CH₂)_bX- or-CO-Ar-CH₂-；Wherein, X O, S or NH, Ar are aryl, a 1,2,3,4,5,6,7 or 8, b 1,2,3,4,5,6,7,8,9 or 10；

II)C₄-C₂₂Fatty acyl group, phosphate-based, succinic acid ester group, n-butyric acie ester group, sulfonate group, malic acid ester group Or sodium sulfate salt；

III) Boc- glycine, Boc- alanine, Boc- arginine, Boc- lysines, Boc- serines, the third ammonia of acetophenone Acid, acetyl proline, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, bright ammonia It is formed by after carboxyl dehydrogenation in acid, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine or valine Group；

IV)-O-PEO ,-O-PVP ,-O-PEG ,-O-MPEG ,-O-EPEG ,-O-Glc (2 → 1) Glc (6 → 1) Mal or-O- Glc(2→1)Glc(6→1)Ac；

R¹³For any one of following radicals；(N, N- dimethyl aminoethyl)-carbamoyl (abbreviation DC, molecule knot Structure formula is(abbreviation DMAPA, molecular structural formula are (N, N- dimethylaminopropyl)-carbamoyl(molecular structural formula is N- (N ', N '-dimethyl) ethyl succinic acid monoamides Or (molecular structural formula is N- (N ', N '-dimethyl) propyl succinic acid monoamides

In a preferred embodiment of the invention, R¹Preferably-OH,

In a preferred embodiment of the invention, R²Preferably H ,-OH,

In a preferred embodiment of the invention, R³Preferably Further preferably More preferably

In a preferred embodiment of the invention, R⁴Preferably-OH ,-OAc or=O.

In a preferred embodiment of the invention, R⁵Preferably H or-OH.

In an of the invention preferred embodiment, more than one hydroxyl in ginsenoside shown in formula I optionally by R¹¹Replaced；Each R¹¹(when there are two or more) are identical or different each independently.

In an of the invention preferred embodiment, more than one hydroxyl in ginsenoside shown in formula I optionally by R¹²Replaced；Each R¹²(when having more than two) is identical or different each independently.

Wherein, Glc is glucopyranosyl, and Xyl is xylopyranosyl, and Rha is rhamnopyranosyl, and Ara (p) is pyrans Aralino, Ara (f) are arabinofuranosyl, and Lyx is lysol glycosyl.

Wherein, Mal is malonyl, and Ac is acetyl group, and PEG is polyethylene glycol, and PEO is polyoxyethylene, and MPEG is single first The polyethylene glycol of oxygroup sealing end, EPEG are epoxy-capped polyethylene glycol, and PVP is povidone.

Wherein, in-O-Glc, the structural formula of Glc is：In-O-Ara (p), the structural formula of Ara (p) For：In-O-Lyx, the structural formula of Lyx is：In-O-Ara (f), the structural formula of Ara (f) ForIn-O-Rha, the structural formula of Rha isIn-O-Xyl, the structural formula of Xyl is The structural formula of Mal is

Wherein, the number-average molecular weight of described PEG, PEO, PVP and EPEG are preferably separately 200~20000.

Wherein, the fatty acyl group can be naturally occurring saturation or the acyl group of unsaturated fatty acid and artificial synthesized Saturated or undersaturated aliphatic acid acyl group, preferably stearyl or palmityl.

In a preferred embodiment of the invention, the ginsenoside shown in formula I is preferably in 1 compound of table It is one or more, more preferably 20 (S)-ginseng sapoglycoside Rg 3s, 20 (S)-ginseng saponin Rh 2s, protopanoxadiol, protopanaxatriol, Ginsenoside Rg 5, ginsenoside Rk1, ginsenoside Rh 3, ginsenoside Rg2, ginsenoside Rg 4, Ginsenoside Rh4, ginseng Saponin(e Rh1, up to female woods A, ginsenoside Rg 5H, ginsenoside Rg 5H1 (E), ginsenoside Rg 5H1 (Z), ginsenoside Rk1H, Ginsenoside Rh 3H, ginsenoside Rh 3H1 (E), ginsenoside Rh 3H1 (Z), ginsenoside Rp1,25- methyl-different ginsenoside Rg3, different ginseng sapoglycoside Rg 3 (E), different ginseng sapoglycoside Rg 3 (Z), different ginsenoside Rg3H, different ginseng saponin Rh 2 (E), Yi Rencan Saponin(e Rh2 (Z), ginsenoside Rp2, ginsenoside Rp3, Pseudo-ginsenoside GQ, pseudoginsenoside HQ, ginsenoside SC-Rp1 and It is one or more in ginsenoside DC-Rp1.

Table 1

In the blank mixed micelle, the HPLC purity of the ginsenoside shown in formula I is preferably greater than or waits In 90%, more preferably 95% or more, the percentage refers to the quality of the ginsenoside shown in formula I described Blank mixed micelle gross mass in accounting percentage.

The amphipathic copolymer can be common di-block copolymer and/or triblock copolymer in common nano-micelle Object.The amphipathic copolymer preferably refers to the polymer that hydrophilic radical and hydrophobic grouping connect together, wherein the parent Water base group be preferably polyethylene glycol (PEG), mono methoxy polyethylene glycol (mPEG), polyethylene pyrrole alkanone (PVP), polyoxyethylene (PEO), polyvinyl alcohol (PVA), chitosan and its derivative (such as chitosan-cholic acid), imitative cell membrane Phosphorylcholine (PC) and It is one or more in water soluble cyclodextrin derivant；The hydrophobic grouping is preferably polylactic acid (PLA, such as, poly- D-ALPHA-Hydroxypropionic acid (PDLA), Poly-L-lactide (PLLA), poly- D, Pfansteihl (PDLLA), polylactide-glycolide (PLGA), poly-epsilon-caprolactone (PCL), poly- benzyl asparatate (PBLA), poly benzyl glutamate (PBLG), polystyrene (Pst), poly- isopropyl acrylamide Amine (PIPAA), polylysine (Plys), poly-aspartate (Pasp), polyhistidyl (Phis), phosphatide, phosphatidyl-ethanolamine (PE), in Distearoyl Phosphatidylethanolamine (DSPE), cholesterol (CHO) and hydrophobic cyclodextrin derivative (ethyl-β-CD) It is one or more.

In a preferred embodiment of the invention, in the blank mixed micelle, the amphipathic copolymer is preferred For mPEG-DSPE, mPEG-PDLLA, mPEG-PLA, PVP-PNIPAM (the poly- n-isopropyl acrylamide of PNIPA=), mPEG- PAsp、PEG-DSPE、PEG-DSPE-NH2、PEG-PAsp、PEG-Phis、PEG-PLGA、PEG-PBLG、PEG-PLA、PEG- PBLA、PEG-PCL、PEG-PCLLA、PEO-PAsp、PEO-PGlu、PNIPPA-PAA、PCLLA-PEG-PCLLA、PEO-PPO- PEO, PEO-PLA-PEO, PEG-PLGA-PEG, phosphatidyl-ethanolamine-polyethylene glycol (DMPE-PEG), two palmityl phosphatidyls Ethanol amine-polyethylene glycol (DPPE-PEG), distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), dioleoyl phosphorus Acyl ethanol amine-polyethylene glycol (DOPE-PEG), C8 ceramides-polyethylene glycol (C8Ceramide-PEG), C16 nerve acyls Amine-polyethylene glycol (C16Ceramide-PEG), distearoylphosphatidylethanolamine-polyethylene glycol-succinyl (DSPE-PEG Succinyl), distearoylphosphatidylethanolamine-polyethylene glycol-carboxyl (DSPE-PEG) Carboxylic Acid), it is two hard Fatty acyl group phosphatidyl-ethanolamine-polyethylene glycol-dimaleoyl imino (DSPE-PEG Maleimide), distearyl acyl group phosphatidyl The poly- second of the double mercaptopyridine (DSPE-PEG PDP) of ethanol amine-polyethylene glycol-propionamide, distearoylphosphatidylethanolamine-two Alcohol-Cyanuric Chloride (DSPE-PEG Cyanur), distearoylphosphatidylethanolamine-polyethylene glycol-amino (DSPE-PEG Amine), distearoylphosphatidylethanolamine-polyethylene glycol-biotin (DSPE-PEG Biotin), distearyl acyl group phosphatide Acyl ethanol amine-polyethylene glycol-folic acid (DSPE-PEG Folate), distearoylphosphatidylethanolamine-polyethylene glycol-folic acid (DSPE-PEG Folate), dilauroyl phosphatidyl-ethanolamine-polyethylene glycol (DLPE-PEG), distearyl acyl group phosphatidyl Ethanol amine-polyethylene glycol-active ester (DSPE-PEG-NHS), phosphatidyl-ethanolamine-polyethylene glycol-active ester (DMPE-PEG- NHS), dipalmitoylphosphatidylethanolamine-polyethylene glycol-active ester (DPPE-PEG-NHS), dilauroyl phosphatidyl second Hydramine-polyethylene glycol-active ester (DLPE-PEG-NHS), distearoylphosphatidylethanolamine-polyethylene glycol-maleimide Base (DSPE-PEG-Maleimide), phosphatidyl-ethanolamine-polyethylene glycol-dimaleoyl imino (DMPE-PEG- Maleimide), dipalmitoylphosphatidylethanolamine-polyethylene glycol-dimaleoyl imino (DPPE-PEG-Maleimide), Dilauroyl phosphatidyl-ethanolamine-polyethylene glycol-dimaleoyl imino (DLPE-PEG-Maleimide), distearyl acyl group phosphorus Acyl ethanol amine-polyethylene glycol-biotin (DSPE-PEG-Biotin), distearoylphosphatidylethanolamine-polyethylene glycol- Fluorescein (DSPE-PEG-FITC), distearoylphosphatidylethanolamine-polyethylene glycol-hydroxyl (DSPE-PEG-OH), two are firmly Fatty acyl group phosphatidyl-ethanolamine-polyethylene glycol-amino (DSPE-PEG-NH₂), phosphatidyl-ethanolamine-polyethylene glycol-amino (DMPE-PEG-NH₂), dipalmitoylphosphatidylethanolamine-polyethylene glycol-amino (DPPE-PEG-NH₂), dilauroyl phosphorus Acyl ethanol amine-polyethylene glycol-amino (DLPE-PEG-NH₂), distearoylphosphatidylethanolamine-polyethylene glycol-carboxyl (DSPE-PEG-COOH), phosphatidyl-ethanolamine-polyethylene glycol-carboxyl (DMPE-PEG-COOH), two palmityl phosphatidyl second Hydramine-polyethylene glycol-carboxyl (DPPE-PEG-COOH), dilauroyl phosphatidyl-ethanolamine-polyethylene glycol-carboxyl (DLPE- PEG-COOH), distearoylphosphatidylethanolamine-polyethylene glycol-sulfenyl (DSPE-PEG-SH), distearyl acyl group phosphatidyl Ethanol amine-polyethylene glycol-silane (DSPE-PEG-Silane), distearoylphosphatidylethanolamine-polyethylene glycol-nitrine (DSPE-PEG-N₃), cholesterol-polyethylene glycol (Cholesterol PEG), methoxypolyethylene glycol-cholesterol (mPEG- CLS), cholesterol-polyethylene glycol-active ester (Cholesterol PEG NHS ester), cholesterol-polyethylene glycol-Malaysia acyl Imines (CLS-PEG-Mal), cholesterol-polyethylene glycol-biotin (Cholesterol PEG Biotin), the poly- second of cholesterol- Glycol-fluorescein (Cholesterol PEG fluorescein), cholesterol-polyethylene glycol-carboxyl (Cholesterol PEG COOH), cholesterol-polyethylene glycol-amino (Cholesterol PEG NH₂) and cholesterol-polyethylene glycol-sulfenyl It is one or more in (Cholesterol PEG SH), more preferably mPEG-DSPE, mPEG-PDLLA, mPEG-PLA, PEG- DSPE、PEG-DSPE-NH2、PEG-PAsp、PEG-PBLA、PEG-PBLG、PEG-PCL、PEG-Phis、PEG-PLGA、PEO- It is one or more in PAsp and PEO-PPO-PEO.Wherein, the number-average molecular weight of the polyethylene glycol is preferably 300- 50000, more preferably 500-10000, for example, 300,350,500,550,1000,2000,3400,5000,10000,20000, 30000,40000 or 50000.

In the present invention, the number-average molecular weight of the mPEG-DSPE is preferably 2000.The number of the mPEG-PDLLA is equal Molecular weight is preferably 2000 or 4000, more preferably 2000.The number-average molecular weight of the mPEG-PLA is preferably 2400.It is described The number-average molecular weight of PEG-DSPE be preferably 2000 or 4000.The number-average molecular weight of the PEG-DSPE-NH2 is preferably 4000.The number-average molecular weight of the PEG-PAsp is preferably 4800.The number-average molecular weight of the PEG-PBLA is preferably 2000.The number-average molecular weight of the PEG-PBLG is preferably 4000.The number-average molecular weight of the PEG-PCL is preferably 2000.The number-average molecular weight of the PEG-Phis is preferably 4000.The number-average molecular weight of the PEG-PLGA is preferably 2000.The number-average molecular weight of the PEO-PAsp is preferably 4800.The number-average molecular weight of the PEO-PPO-PEO is preferably 4800.The number-average molecular weight of the DMPE-PEG is preferably 350,550,750,1000,2000,3000 or 5000.Described The number-average molecular weight of DPPE-PEG is preferably 350,550,750,1000,2000,3000 or 5000.The number of the DSPE-PEG Average molecular weight is preferably 350,550,750,1000,2000,3000,5000,10000,20000,30000 or 40000.Described The number-average molecular weight of DOPE-PEG is preferably 350,550,750,1000,2000,3000 or 5000.The C8Ceramide- The number-average molecular weight of PEG is preferably 750,2000 or 5000.The number-average molecular weight of the C16Ceramide-PEG is preferably 750,2000 or 5000.The number-average molecular weight of the DLPE-PEG is preferably 2000 or 5000.The DSPE-PEG-NHS Number-average molecular weight be preferably 1000,2000,5000,10000,20000,30000 or 40000.The DMPE-PEG-NHS Number-average molecular weight be preferably 3400 or 5000.The number-average molecular weight of the DPPE-PEG-NHS is preferably 3400 or 5000. The number-average molecular weight of the DLPE-PEG-NHS is preferably 3400 or 5000.The number of the DSPE-PEG-Maleimide is equal Molecular weight is preferably 1000,2000,3400,5000 or 10000.The number-average molecular weight of the DMPE-PEG-Maleimide is excellent It is selected as 1000,2000,3400,5000 or 10000.The number-average molecular weight of the DPPE-PEG-Maleimide is preferably 1000,2000,3400,5000 or 10000.The number-average molecular weight of the DLPE-PEG-Maleimid is preferably 1000, 2000,3400,5000 or 10000.The number-average molecular weight of the DSPE-PEG-Biotin is preferably 1000,2000,3400, 5000 or 10000.The number-average molecular weight of the DSPE-PEG-FITC is preferably 1000,2000,3400,5000 or 10000. The number-average molecular weight of the DSPE-PEG-OH is preferably 2000,3400 or 5000.The number of the DSPE-PEG-NH2 is divided equally Son amount preferably 2000,3400 or 5000.The number-average molecular weight of the DMPE-PEG-NH2 be preferably 2000,3400 or 5000.The number-average molecular weight of the DPPE-PEG-NH2 is preferably 2000,3400 or 5000.The DLPE-PEG-NH2's Number-average molecular weight is preferably 2000,3400 or 5000.The number-average molecular weight of the DSPE-PEG-COOH is preferably 2000, 3400 or 5000.The number-average molecular weight of the DMPE-PEG-COOH is preferably 2000,3400 or 5000.The DPPE- The number-average molecular weight of PEG-COOH is preferably 2000,3400 or 5000.The number-average molecular weight of the DLPE-PEG-COOH is preferred It is 2000,3400 or 5000.The number-average molecular weight of the DSPE-PEG-SH is preferably 5000.The DSPE-PEG- The number-average molecular weight of Silane is preferably 3400.The number-average molecular weight of the DSPE-PEG-N3 be preferably 2000,3400 or 5000.The number-average molecular weight of the mPEG-CLS is preferably 1000,2000,5000,10000 or 20000.Described The number-average molecular weight of Cholesterol PEG NHS ester is preferably 1000,2000,3400,5000 or 10000.Described The number-average molecular weight of CLS-PEG-Mal is preferably 2000,3400,5000 or 10000.The number of the CLS-PEG-Biotin is equal Molecular weight is preferably 2000,3400 or 5000.The number-average molecular weight of the CLS-PEG-FITC be preferably 2000,3400 or 5000.The number-average molecular weight of the Cholesterol PEG COOH is preferably 3400.The Cholesterol PEG The number-average molecular weight of amine is preferably 3400.The equal molecule of number of the Cholesterol PEG Thiol/Sulfhydril Amount preferably 3400.

In a preferred embodiment of the invention, the di-block copolymer is preferably mPEG-DSPE, mPEG- PDLLA、mPEG-PLA、PEG-DSPE、PEG-DSPE-NH2、PEG-PAsp、PEG-PBLA、PEG-PBLG、PEG-PCL、PEG- It is one or more in Phis, PEG-PLGA, PEO-PAsp and PEO-PPO-PEO.

In a preferred embodiment of the invention, the triblock copolymer is preferably poloxamer (PEO-PPO- PEO), one or more in PEG-PLGA-PEG, PCLLA-PEG-PCLLA, PEO-PLA-PEO and PCL-PEG-PCL.Its In, PEG number-average molecular weights require between 200-20000, between preferably 1000-15000, the number-average molecular weight of hydrophobic grouping Ratio with the number-average molecular weight of hydrophilic radical is preferably 1:1~0.8:1.

In a preferred embodiment of the invention, the amphipathic copolymer and the ginseng shown in formula I The mass ratio of saponin(e is preferably 100:1-0.01:1, preferably 10:1-0.1:1, more preferably 10:1-0.25:1, such as 4:1、 3:1、2:1、1.67:1、0.67:1、0.5:1、0.25:1。

In a preferred embodiment of the invention, the blank mixed micelle also can further include antioxidant, freeze It is one or more in dry protective agent, emulsifier and assistant for emulsifying agent.

In the present invention, the antioxidant can be the antioxidant of this field routine, preferably sodium pyrosulfite, thio Sodium sulphate, propylgallate, alpha-tocopherol, 'alpha '-hydroxy acids, flavone compound, Phenylpropanoid glycoside, vitamin E (VE), vitamin C (VC), fumaric acid, cysteine, methionine, butyl anisole (BHA), butyl hydroxy toluene (BHT), thio-2 acid, sulphite (such as sodium sulfite), bisulfites (such as sodium hydrogensulfite), dithiocarbamates benzene first Acid compounds, citric acid, malic acid, sorbierite, glycerine, propylene glycol, quinhydrones, Hydroxycoumarin, ethanol amine, phosphoric acid and phosphorous It is one or more in acid.Content of the antioxidant in blank mixed micelle, which is generally less than, is equal to 25%, preferably 0.001%-15%, for example, 3%, 6%, 14%, 0.01%-10%, 0.01%-5% or 0.1%-1%；The percentage (%) refers to the percentage of the quality and the gross mass of the blank mixed micelle of antioxidant.

In a preferred embodiment of the invention, the antioxidant is vitamin E and/or vitamin C.

In the present invention, the freeze drying protectant can be this field routine freeze drying protectant, generally sugar, polyalcohol, It is one or more in amino acid and buffer.Wherein, the sugar is preferably one kind or more in monosaccharide and disaccharide and polysaccharide Kind.The monosaccharide is preferably one or more in glucose, mannitol, xylitol and sorbierite.The disaccharide is preferred It is one or more in sucrose, lactose, galactolipin and maltose.The polysaccharide is preferably trehalose.The polyalcohol Preferably propylene glycol and/or glycerine.The amino acid is preferably a-amino acid, for example, threonine, glycine, glutamic acid, It is one or more in arginine and histidine.The buffer generally refers to buffer solution.The buffer solution can be The buffer solution of this field routine, preferably its pH value is between 3-10, more preferably between 5-7.The buffer solution is preferred It is slow for physiological saline, ethyl alcohol-hac buffer, trishydroxymethylaminomethane buffer solution, barbital buffer solution, sodium formate Rush solution, phthalic acid salt buffer solution, citrate buffer solution, citric acid-disodium hydrogen phosphate buffer solution, ammonia-chlorine Change ammonium buffer solution, borax-calcium chloride buffer solution, acetate buffer solution, acetic acid-lithium salts buffer solution, Acetic acid-sodium acetate Buffer solution, acetic acid-ammonium acetate buffer solution, phosphoric acid-triethylamine buffer solution or phosphate buffer solution.The freeze-drying is protected It protects content of the agent in blank mixed micelle to be generally less than equal to 80%, such as 61.73~75.76%, in another example 61.73%, 65.36%, 65.57%, 74.07%, 75.19%, 75.76%, 0.5%-60%, 5%-60% or 30%-60%；Described Percentage (%) refers to the percentage that the quality of freeze drying protectant accounts for the blank mixed micelle gross mass.

In an of the invention preferred embodiment, the freeze drying protectant be 5% glucose solution, physiological saline and It is one or more in phosphate buffer solution.

In the present invention, the emulsifier is preferably Arabic gum, western twelve month yam glue, gelatin, albumin, casein, soybean Phosphatide, lecithin, cholesterol, fatty acid sorbitan (lipophile), polysorbate (20,40,60,80), polyoxyethylene ester fat acid Ester (hydrophily), polyoxyethylene aliphatic alcohol ether class, poloxalkol class, sucrose-fatty lipid and single tristearin It is one or more in acid glyceride etc., such as cholesterol.Content of the emulsifier in blank mixed micelle is generally small In equal to 10%, such as 0.01%-10%, 0.1%-5% or 1%-5%；The percentage (%) refers to the matter of emulsifier Amount accounts for the percentage of the blank mixed micelle gross mass.

In the present invention, the assistant for emulsifying agent is preferably n-butanol, ethylene glycol, ethyl alcohol, propylene glycol, glycerine and polyglycerol ester In it is one or more.Content of the assistant for emulsifying agent in blank mixed micelle is generally less than equal to 10%, such as 0.01%-10%, 0.1%-5% or 1%-5%；The percentage (%) refers to that the quality of assistant for emulsifying agent accounts for the blank The percentage of mixed micelle gross mass.

In an of the invention preferred embodiment, the blank mixed micelle includes amphipathic copolymer and such as Formulas I institute The ginsenoside shown.

In an of the invention preferred embodiment, the blank mixed micelle includes that (number-average molecular weight is PEG-DSPE And ginsenoside Rk1 2000).

In a preferred embodiment of the invention, the blank mixed micelle includes mPEG-PDLLA (number-average molecular weights 2000) and protopanaxatriol PPT for.

In an of the invention preferred embodiment, the blank mixed micelle includes amphipathic copolymer, shown in formula I Ginsenoside, antioxidant and freeze drying protectant.

In an of the invention preferred embodiment, the blank mixed micelle includes that (number-average molecular weight is mPEG-DSPE 2000) mother woods A, VE and 5% glucose solution, are reached.

In an of the invention preferred embodiment, the blank mixed micelle includes that (number-average molecular weight is PEG-DSPE 4000), protopanoxadiol PPD, VC and 5% glucose solution.

In the present invention, the preparation method that this field routine can be used in the blank mixed micelle is prepared, usually, Direct dissolution method or dialysis can be used.The present invention preferably uses following method one or method two：

Method one includes the following steps：

(1) water, amphipathic copolymer and ginsenoside shown in formula I are mixed, is optionally added into antioxidant, emulsification It is one or more in agent and assistant for emulsifying agent, obtain a clear solution；

(2) film forming or self-contained micella are optionally added into anti-oxidant then with water or the aqueous solution containing freeze drying protectant mixes It is one or more in agent, emulsifier and assistant for emulsifying agent, a solution is obtained, is filtered, is freeze-dried to get the blank epoxy glue Beam；

Method two includes the following steps：

(1) by organic solvent or the mixed solvent of water and organic solvent, with amphipathic copolymer, people shown in formula I Join saponin(e mixing, is optionally added into one or more in antioxidant, emulsifier and assistant for emulsifying agent, obtains a clear solution；

(2) organic solvent of gained clear solution in step (1), film forming, then with water or containing freeze drying protectant are removed Aqueous solution mixes, and is optionally added into one or more in antioxidant, emulsifier and assistant for emulsifying agent, obtains a solution, filtering, Freeze-drying is to get the blank mixed micelle.

It is the amphipathic copolymer, the ginsenoside shown in formula I, described in method one or method two Antioxidant, the freeze drying protectant, the emulsifier and the assistant for emulsifying agent definition as described above.

In step (1) in method two, the organic solvent can be conventional in the mixed micelle preparation method of this field In organic solvent, preferably nitrile solvents, the alcohols solvent of C1-C4, ketones solvent, ether solvent and halogenated hydrocarbon solvent It is one or more, more preferably in the alcohols solvent of C1-C4, nitrile solvents, ether solvent and halogenated hydrocarbon solvent one kind or It is a variety of.The nitrile solvents are preferably acetonitrile.The C1-C4 alcohols solvents be preferably methanol, ethyl alcohol, isopropanol and It is one or more in n-butanol.The ether solvent is preferably ether, tetrahydrofuran.The halogenated hydrocarbon solvent compared with It is chloroform and/or dichloromethane goodly.The ketones solvent is preferably acetone and/or butanone.The organic solvent Dosage can be conventional dosage in the mixed micelle preparation method of this field, can be not especially limited, generally require organic solvent and Clear solution can be obtained after all components mixing, preferably, the organic solvent and the institute in two step of method (1) It is 4-10mL/g to have the volume mass ratio of component.

In method one or method two, in step (1), the temperature of the mixing can be the temperature of this field routine, generally It is 0-80 DEG C, preferably 10-80 DEG C, more preferably 30-60 DEG C (such as 30,37,40,45,50,55,60 DEG C).According to this field Common sense to make mixing temperature reach 80 DEG C, needs to be performed under heating conditions in some cases；Or it is protected when except freeze-drying Protecting in all raw material components of agent has thermally sensitive substance such as protein substance, is typically chosen at 0 DEG C and mixes.

In the step of method two (2), the operation of the organic solvent of clear solution can be ability in the removing step (1) Domain routine operation generally uses rotary evaporator, film evaporator or film dialysis to remove organic solvent.Wherein, the removing The organic solvent progress conventional selection that the temperature of organic solvent removes as needed, generally 25-80 DEG C.

In step (2) in method one or method two, the method for the film forming can be decompression spin concentration.

In step (2) in method one or method two, the operation of the filtering can be this field mixed micelle preparation side Conventional operation in method, the purpose is to remove degerm, solid particle etc..In the present invention, the filtering is preferably miillpore filter Filtering.The aperture of the miillpore filter is preferably 0.22 micron.

In method one or method two, when what is mixed with the film in the step (2) is the aqueous solution of freeze drying protectant, The aqueous solution of the freeze drying protectant refers to the aqueous solution that the freeze drying protectant is mixed to form with water.Wherein, described The aqueous solution of freeze drying protectant is preferably the aqueous solution of the freeze drying protectant of 5%-10%, and the percentage refers to that freeze-drying is protected The quality of shield agent accounts for the percentage of freeze drying protectant aqueous solution gross mass.The freeze drying protectant is preferably that 5% glucose is water-soluble Liquid, physiological saline or phosphate buffer.The dosage of the aqueous solution of the freeze drying protectant can be not especially limited, as long as not The formation of mixed micelle is influenced, it is preferably identical as the dosage of step (1) organic solvent.

In a preferred embodiment of the invention, in method two, when the aqueous solution of the freeze drying protectant is buffer When, after the middle operation to form a film of step (2), directly mixed with the freeze drying protectant.

In method one or method two, in step (2), the operation of the drying can be the operation of this field routine, preferably For freeze-drying, generally it is freeze-dried using freeze drier.The temperature and time of the freeze-drying is this field Conventional temperature and time, can be not especially limited.

The present invention also provides a kind of blank mixed micelles in the mixed micelle for preparing carrying active substance Using the active material in the mixed micelle of the carrying active substance is drug, the active material in cosmetics and has It is one or more in the substance of healthcare function.Therefore, the present invention also provides a kind of mixed micelles of carrying active substance.Institute The mixed micelle for the carrying active substance stated is typically referred to one or more (active materials) in the active material in drug It is wrapped in the blank mixed micelle.

In the present invention, when the active material loaded is a variety of, in addition to drug combination mode used in clinic, as long as It does not react to each other between the active material loaded, pharmacological activity is not caused to reduce or occur adverse reaction.

In the mixed micelle of the carrying active substance, the ginsenoside shown in formula I and amphipathic copolymerization The mass ratio of object and the drug is preferably 100:1-1:1 (such as 20:1、16.7:1、16:1、12:1、10:1、8.3:1、 6:1、4:1), more preferably 25:1-5:1 (such as 20:1、16.7:1、16:1、12:1、10:1、8.3:1、6:1), most preferably 15:1-5:1 (such as 12:1、10:1、8.3:1、6:1).

In the active material, the drug can be the drug of this field routine, preferably antitumor drug, anti-inflammatory Drug, antibacterials, sedative hypnotic drug, antipsychotics, hormone medicine, antibiotics, calcium ion antagonist, Antiviral drugs, immunosuppressor, anesthetic, cardiovascular and cerebrovascular and blood vessel dilatation drug, polynucleotide and oligonucleotides (including Ribonucleotide and deoxyribonucleotide) in it is one or more.

In the active material, the antitumor drug can be the drug of the anti-malignant tumor of this field routine, excellent It is selected as taxol, docetaxel, Cabazitaxel, irinotecan hydrochloride, camptothecine, hydroxycamptothecin, amino camptothecin, 7- second Base -10-hydroxycamptothecine, topotecan hydrochloride, Lurtotecan (Lurtotecan), Hycamtin, Belotecan, cis-platinum, card Platinum, oxaliplatin, Nedaplatin (Nedaplatin), network platinum (Lobaplatin), satraplatin (Satraplatin), Miboplatin, penta Platinum, Aroplatin (L-NDDP), carmustine, Chlorambucil, melphalan, harringtonine, homoharringtonine, tripterygium wilfordii A prime, tacrolimus, daunorubicin, bleomycin A5, doxorubicin hydrochloride, idarubicin, fluorouracil, cytarabine, first ammonia Pterin, Etoposide phosphate, deoxypodophyllotoxin, vinorelbine tartrate, vincristine sulphate, vinblastine sulfate, different Changchun Flower alkali, vindesine sulfate, Temozolomide, Tegafur, cyclophosphamide, ifosfamide, Dacarbazine, ebomycin A, Ai Bo Mycin B, epothilones C, Epothilone D, Epothilones E, Epothilones F, bortezomib, gemcitabine hydrochloride, phosphoric acid fluorine reach Draw shore, capecitabine, Decitabine, pemetrexed disodium, recombinant human interferon alpha 2 a2b, Arabinoside cytimidine, total trans dimension Formic acid, proleulzin, etoposide, thymidylate synthase inhibitor, mitoxantrone, minoxidil, azithromycin, hydrochloric acid table are soft Than star, doxorubicin hydrochloride (adriamycin), Amrubicin Hydrochloride, KRN-5500, tamoxifen, tamoxifen, 5- amino ketones penta It is one or more in sour (5-ALA), 3 ', 5 '-dipalmitoyl cyclocytidines and rcumenol.

In a preferred embodiment of the invention, the antitumor drug is taxol, docetaxel, camptothecine, height One kind in harringtonine, adriamycin, cis-platinum, oxaliplatin, angstrom primycin C, irinotecan hydrochloride and all-trans retinoic acid Or it is a variety of.

In the active material, the anti-inflammatory drug be preferably Indomethacin, naproxen, ketone chromic acid, aspirin, One kind or more in paracetamol, Diclofenac, brufen, bifendate, aulin, rofecoxib and celecoxib Kind.

In a preferred embodiment of the invention, the anti-inflammatory drug is in Indomethacin, naproxen and bifendate It is one or more.

In the active material, the antibacterials are preferably amphotericin B, gentamicin, benzyl penicillin, nitric acid Econazole, Flucytosine, Fluconazole, Itraconazole, voriconazole, posaconazole, ravuconazole, Caspofungin, mikafen, Anidulafungin, CefPiramide Sodium, Cefotaxime Sodium, ceftriaxone, cefoperazone, Cefditoren pivoxil Cephalosporins, cefoxitin sodium, cephalo Ammonia benzyl, Cefuroxime Sodium, Cefixime, Cefpodoxime, Cefmenoxime, Cefodizime, Cefsulodin, Cefuzonam, cephalo azoles Oxime, Cefetamet Pivoxil, Cefteram Pivoxil, ceftibuten, Cefdinir, Cefamandole, Cefotiam, ceforanide, cephalo Buddhist nun West, cefotaxime, Cefradine, Cefprozil, Cefazolin sodium, cefadroxil, cefoxitin, cefathiamidine, cephalo thiophene Pyridine, cephalosporin, ceftezole, cefapirin, Cefpirome, Cefclidin, Cefepime, sodium fusidate, Florfenicol With it is one or more in tigecycline.

In a preferred embodiment of the invention, the antibacterials are amphotericin B.

In the active material, the anti-sedative hypnotic drug is preferably Clonazepam, diazepam, nitrazepam, Chinese mugwort It takes charge of one or more in azoles logical sequence, alprazolam, barbital, phenobarbital, amytal, secobarbital sodium and pentothal.

In a preferred embodiment of the invention, the anti-sedative hypnotic drug is Clonazepam.

In the active material, the antipsychotics be preferably haloperidol, chlorpromazine, Li Paili ketone, Ah Ge Meilating, Prozac, Paxil, Duloxetine, Sertraline, Fluvoxamine, Citalopram, escitalopram, Wen La Method is pungent, Mirtazapine, imipramine, amitriptyline, chlorimipramine, doxepin, Remeron, venlafaxin, nardil, Isocarboxazid and It is one or more in parnitene.

In a preferred embodiment of the invention, the antipsychotics is haloperidol.

In the active material, the hormone medicine is preferably dihydrotestosterone and/or progesterone.

In a preferred embodiment of the invention, the hormone medicine is dihydrotestosterone.

In the active material, the antibiotic be preferably cyclosporin A, Nysfungin, penicillin, ospen, Ah Amdinocillin, ampicillin, oxacillin, Cloxacillin, procaine penicillin, tardocillin, Piperacillin, Mei Luoxi Woods, Ticarcillin, azlocillin, Mecillinam, Carbenicillin, sulbenicillin, Furbucillin, naphthlazole, dicloxacillin, ammonia XiLin, apalcillin, aspoxicillin, Pivmecillinam, methicillin, Lenampicillin, fomidacillin, flucloxacillin, kanamycins, Natamycin, mitomycin, amikacin, tylosin, Verteporfin (Verteporfin), CefPiramide Sodium, sulfuric acid Netilmicin, azithromycin, Ofloxacin, Ciprofloxacin, Enoxacin, Lomefloxacin, pefloxacin, Rufloxacin, department's fluorine Sha Xing, fleraxacin, Moxifloxacin, Grepafloxacin, trovafloxacin, linxacin, gemifloxacin, gatifloxacin, tosufloxacin, pa Pearl sand star, Sparfloxacin, clarithromycin, clindamycin, polymyxins, tobramycin, vancomycin, azithromycin, how western ring How element tetracycline, terramycin, minocycline, aureomycin, guamecycline, demeclocycline, metacycline, Etimicin, replaces rice Star, sisomicin, amikacin, Arbekacin, dibekacin, aztreonam, Meropenem, Imipenem, thiomycin, Pa Nipei It is one or more in south, ertapenem, neomycin, paromomycin and spectinomycin.

In a preferred embodiment of the invention, the antibiotic is cyclosporin A.

In the active material, the calcium ion antagonist be preferably fenofibrate, Nimodipine, nifedipine, Nicardipine, nitrendipine, Verapamil, Amlodipine, diltiazem, flunarizine, prenylamine, Gallopamil and thiophene pa It is one or more in rice.

In a preferred embodiment of the invention, the calcium ion antagonist is fenofibrate.

In the active material, the anesthetic is preferably Desflurane, sevoflurane, isoflurane, enflurane, the third pool Phenol, fentanyl, urethane, lidocaine, procaine, totokaine, Bupivacaine, yellow Jackets, chloraldurate, chloramines It is one or more in ketone, chloralose and morphine.

In a preferred embodiment of the invention, the anesthetic is Propofol.

In the active material, the cardiovascular and cerebrovascular and blood vessel dilatation drug are preferably dabigatran etcxilate, A Gelie Spit of fland, sodium alginate, ginkgolides, GINKGO BILOBA EXTRACT, ginkgo biloba extract, asarone, olmesartan medoxomil, Repaglinide, lipoic acid, Breviscapinun, Urapidil, niacin, captopril, Losartan, Puerarin, tanshinone IIA, sarpogrelate hydrochloride, tropoyl Amine, Fluvastatin, Pravastatin, Simvastatin, Lovastatin, Simvastatin, mevastatin, cerivastatin, rosuvastatin, It is one or more in Atorvastatin calcium and Rosuvastatine calcium.

In a preferred embodiment of the invention, the cardiovascular and cerebrovascular and blood vessel dilatation drug are Puerarin.

In the active material, the polynucleotide or oligonucleotides preferably refer to by base A, T, C, G and U Several compositions the segment with the functions such as heredity, such as SiRNA, antisense nucleic acid or microglia NLRP3 genes RNAi sequences.

In a preferred embodiment of the invention, the polynucleotide or oligonucleotides are SiRNA.

In the active material, the active material in the cosmetics generally refers to have nutrition in cosmetics, change The active material of the effect of kind skin and prevention skin disease, preferably ursolic acid, superoxide dismutase (SOD), life One in object albumen T4N5, calciferol, Vitamin K3, methyl nicotinate, refined snake oil, hyaluronic acid, essential oil and ceramide Kind is a variety of.

In a preferred embodiment of the invention, the active material in the cosmetics is Vitamin K3.

In a preferred embodiment of the invention, the mixed micelle includes amphipathic copolymer, people shown in formula I Join saponin(e and active material.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is mPEG-PDLLA 4000), ginsenoside Rg 5H and docetaxel.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-DSPE 2000), the different Rg3Me of ginsenoside and Propofol.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is mPEG-PDLLA 4000), chitosan-cholic acid, ginsenoside Rg 4 and homoharringtonine.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is mPEG-PLA 2400), Ginsenoside Rh4 and adriamycin.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-PBLG 4000), different ginsenoside Rg2 (Z) and all-trans retinoic acid.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-PAsp 4800), different ginsenoside Rg3H and cis-platinum.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-PBLA 2000), different ginsenoside Rg3E and irinotecan hydrochloride.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-Phis 4000), ginsenoside Rg2 and Ai primycin C.

In a preferred embodiment of the invention, the mixed micelle includes amphipathic copolymer, people shown in formula I Join saponin(e, active material and antioxidant.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-DSPE 2000), ginsenoside Rg 5, taxol and vitamin E (VE).

In a preferred embodiment of the invention, the mixed micelle includes amphipathic copolymer, people shown in formula I Join saponin(e, active material and freeze drying protectant.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEO-PAsp 4800), ginsenoside Rh 1, camptothecine and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-PLGA 2000), ginseng saponin Rh 2, oxaliplatin and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is mPEG-PDLLA 4000), ginseng sapoglycoside Rg 3, Indomethacin and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-Phis 4000), Rh3, naproxen and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle include PEG-PCL (number-average molecular weight 2000), Different ginseng saponin Rh 2 (E), haloperidol and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-PBLA 2000), different ginseng sapoglycoside Rg 3 (Z), dihydrotestosterone and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-PAsp 4800), Pseudo-ginsenoside GQ, Vitamin K3 and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-PBLG 4000), ginsenoside Rp2, bifendate and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-DSPE-NH2 4000), pseudoginsenoside HQ, Puerarin and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle include PEG-PCL (number-average molecular weight 2000), Ginsenoside Rp3, cyclosporin A and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle include PEG-PCL (number-average molecular weight 2000), Different ginseng saponin Rh 2 (Z), fenofibrate and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle include PEG-PCL (number-average molecular weight 2000), Different ginsenoside SC-Rp1, amphotericin B and 5% glucose solution.

In an of the invention preferred embodiment, the mixed micelle include PEG-PCL (number-average molecular weight 2000), Ginsenoside DC-Rp1, SiRNA and 5% glucose solution.

In a preferred embodiment of the invention, the mixed micelle includes PLURONICS F87 (PEO-PPO-PEO) (number-average molecular weight 4800), different ginsenoside Rg2 (E), adriamycin and 5% glucose solution.

In a preferred embodiment of the invention, the mixed micelle includes amphipathic copolymer, people shown in formula I Join saponin(e, active material, antioxidant, freeze drying protectant and emulsifier.

In an of the invention preferred embodiment, the mixed micelle includes that (number-average molecular weight is PEG-DSPE 4000), ginsenoside Rp1, Clonazepam, vitamin E, saturation phosphate buffer solution and cholesterol.

In a preferred embodiment of the invention, other auxiliary materials can be also further comprised in the mixed micelle and are encapsulated In film.Other described auxiliary materials can be this field prepare routinely added when micella in addition to antioxidant and freeze drying protectant Other auxiliary materials, such as it is one or more in emulsifier or assistant for emulsifying agent.

The present invention also provides a kind of people shown in formula I of the amphipathic copolymer of carrying active substance modification Join the preparation method of saponin(e mixed micelle.

In the present invention, the preparation method of the mixed micelle of the carrying active substance can be tied with the conventional chemistry in this field Legal and physically encapsulation method (such as solvent evaporated method, dialysis, emulsion process).The present invention is preferably following either method：

Method A (solvent evaporated method) includes the following steps：

Amphipathic copolymer, ginsenoside shown in formula I, active material and organic solvent are mixed, are optionally added into It is one or more in antioxidant, emulsifier and assistant for emulsifying agent, organic solvent is removed, is formed a film, then with water or containing frozen-dried protective The aqueous solution of agent mixes, and is optionally added into one or more in antioxidant, emulsifier and assistant for emulsifying agent, formation supported active To get the mixed micelle solution of carrying active substance, filtering, after freeze-drying after the mixed micelle of substance；

Method B (dialysis) includes the following steps：

Amphipathic copolymer, ginsenoside shown in formula I and organic solvent are mixed, then is mixed with active material, used Water or aqueous solution containing freeze drying protectant are dialysed to get the mixed micelle solution of carrying active substance, are optionally added into anti-oxidant It is one or more in agent, emulsifier and assistant for emulsifying agent, filtering, dialyzate freeze-drying；

Method C (emulsion process) includes the following steps：

Active material is mixed to obtain to mixture A with organic solvent, by amphipathic copolymer and ginsenoside shown in formula I Mixture B is mixed to obtain with water or buffer solution, mixture A is added drop-wise to formation oil/water (O/W) mixed type emulsion in mixture B, It is optionally added into one or more in antioxidant, freeze drying protectant, emulsifier and assistant for emulsifying agent, removing organic solvent, mistake Filter, after freeze-drying；

Method D (chemical bonding processes) includes the following steps：

Active material, amphipathic copolymer, ginsenoside shown in formula I and solvent are mixed, the active material, Covalent bond occurs with the active group on, amphipathic copolymer or ginsenoside shown in formula I, is optionally added into anti-oxidant It is one or more in agent, freeze drying protectant, emulsifier and assistant for emulsifying agent, it is organic when needing to remove containing organic solvent in solvent Solvent, filtering, after freeze-drying.

Method E (direct dissolution method) includes the following steps：

When active material is soluble easily in water, in active material, amphipathic copolymer, ginsenoside and water shown in formula I Mixing is optionally added into one or more in antioxidant, emulsifier and assistant for emulsifying agent, filtering, after freeze-drying.

In method A, B, C, D, E, each condition and parameter with reference to the blank mixed micelle preparation method in method One or method two.

In method B, the operation of the dialysis can be operation conventional in the mixed micelle preparation method of this field, the present invention Preferably the mixed micelle solution is placed in glucose solution (such as 0.15mol/L) or is dialysed in pure water.Institute The time for the dialysis stated can be conventional time in the mixed micelle preparation method of this field, preferably 5-20 hours, more preferably 12 hours.

In above-mentioned each method, the organic solvent or solvent are preferably dichloromethane, chloroform, methanol, ethyl alcohol, second Ether, acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMAc), It is one or more in dimethyl sulfoxide (DMSO) (DMSO) and pyridine.

In above-mentioned each method, according to the fat-soluble or water-soluble of the active material, the active material is preferably It can be to be used in the form of the organic solution of the aqueous solution of the active material or the active material.The active material Aqueous solution or the mass fraction of organic solution of the active material can be not especially limited, preferably mass body integrates Number is the aqueous solution or organic solution of 1%-20%, and the percentage refers to the quality (g) of the active material, accounts for the work Property substance aqueous solution or the percentage of the active material organic solution total volume (mL).The active material organic solution In organic solvent can be organic solvent conventional in the art, as long as can be good at dissolving the active material, you can. In the present invention, the organic solvent is preferably sulfoxide type solvents, such as dimethyl sulfoxide (DMSO) (DMSO).

In above-mentioned each method, the amphipathic copolymer, the ginsenoside shown in formula I, the antioxygen Agent, the freeze drying protectant, the emulsifier and the assistant for emulsifying agent definition as described above, the use of each ingredient Amount and ratio are also as described above.

Mono- preferred embodiments of method D can be that PEO-PPO-PEO and adriamycin are dissolved in DMSO, at 30-50 DEG C, DMAP (lutidines) is added and stirs 3-4hrs, the conjugate of micella and adriamycin is made, pH=7.4 is added dissolved with such as Formulas I Shown in ginsenoside PBS buffer solutions after, decompression concentration removes organic solvent, up to carrying active substance after freeze-drying Mixed micelle.

The mixed micelle of the blank mixed micelle and the carrying active substance, grain size are preferably 10-200nm (such as 24.5,40.9,24.5,28.6,16.7,24.5,33.4,35.5,66,27.3,18.8,26.9,23.9,22.5, 20.7,46.5,32.9,18.3,23.6,27,26.2,29.6,28.2,21.1,30.7,42.2,28.3,24.7), more preferably 16.7-30.7nm。

The encapsulation rate of the mixed micelle of the carrying active substance is preferably 80% or more, and more preferably 90% or more, Most preferably 95% or more.

Active material described in the mixed micelle of the carrying active substance for drug and/or has healthcare function Substance when, the administration route of the mixed micelle of the carrying active substance can be the administration route of this field routine, preferably For drug administration by injection, oral medication or cutaneous penetration, it to be used for the treatment and/or health care of disease.Therefore, the supported active The mixed micelle of substance is generally prepared as injection, freeze dried injection, oral solid formulation, oral solution, liniment, paste, tincture Or the form of aerosol.The mode of the wherein described drug administration by injection is preferably intravenous injection, intramuscular injection, intraperitoneal injection, intradermal Injection is subcutaneously injected.Usually, the mixed micelle of the carrying active substance is added to physiological saline, phosphate-buffered Solution or 5% glucose solution are configured to injection, are used for drug administration by injection.

It is described when the active material is antitumor drug in the mixed micelle of the carrying active substance The mixed micelle of carrying active substance generally all has to the targeting of tumour cell, anti-multidrug resistance effect, Synergy and attenuation And drug synergism.

In the present invention, described " including ... " can also be expressed as " by ... form ".

Such as：In a preferred embodiment of the invention, the mixed micelle includes amphipathic copolymer, such as Formulas I institute Ginsenoside, active material, antioxidant, freeze drying protectant and the emulsifier shown.

It can also be expressed as：In an of the invention preferred embodiment, the mixed micelle by amphipathic copolymer, such as formula Ginsenoside, active material, antioxidant, freeze drying protectant shown in I and emulsifier composition.

Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined arbitrarily each preferably to get the present invention Example.

In the present invention, room temperature refers to 10-30 DEG C.

In the present invention, the density of the aqueous solution of the aqueous solution of the freeze drying protectant or the active material according to 1g/mL calculates (i.e. the density of water), therefore, the aqueous solution of the aqueous solution of the freeze drying protectant or the active material Gross mass m=ρ * V.

In the present invention, the density of the organic solution of the active material is calculated according to the type of organic solvent, such as when When organic solvent is DMSO, the density of the organic solution of the active material is 1.1g/mL.

The reagents and materials used in the present invention are commercially available.

The positive effect of the present invention is that：

(1) blank mixed micelle of the invention is with efficient, safe and stable, homogeneity is good, reliable, preparation process is easy The advantages that, and can be used for it is one or more in the active material in entrapped drug, cosmetics and substance with health role, Form the blank mixed micelle of carrying active substance.When the active material of the blank mixed micelle encapsulating of the present invention is antineoplastic When object, the mixed micelle of the carrying active substance of gained has to the targeting of tumour cell, anti-multidrug resistance effect, synergy Attenuation and drug synergism.Specifically, compared with traditional mixed micelle, indices are more outstanding, especially in patent medicine Property, anti-multidrug resistance, Synergy and attenuation, drug synergism etc..

(2) mixed micelle of the invention can effectively improve ginsenoside into the hemolytic after micella, epoxy glue of the invention Beam has no haemolysis in 1mg/ml.

(3) mixed micelle of the invention can effectively improve the stability of micella, place 8~12 hours even 24 hours or more Just see muddiness, for grain size in 15~66nm, performance is significantly better than ginsenoside nano-micelle or amphipathic copolymer nano micella.

(4) mixed micelle of the invention has antibody-resistant bacterium such as human lung cancer taxol resistance strain (A549/T) preferable Activity, action concentration is low, good drug efficacy.

Description of the drawings

Fig. 1 is to mix sky, Genexol-PM, taxol mixed micelle to the cell survival rate of human lung carcinoma cell (A549) song Line chart.Wherein, upper X-axis statement ginsenoside concentration (ngmL^-1) logarithm, lower X-axis indicates paclitaxel concentration (ngmL^-1) logarithm.

Fig. 2 is that mixing sky, Genexol-PM, taxol mixed micelle are thin to human lung cancer taxol resistance strain (A549/T) The curve graph of born of the same parents' survival rate.Wherein, upper X-axis statement ginsenoside concentration (ngmL^-1) logarithm, lower X-axis indicates taxol Concentration (ngmL^-1) logarithm.

Fig. 3 is Control groups, Genexol-PM groups, taxol mixed micelle group are bent to the tumor suppression of human lung cancer cell A549 Line chart.

Fig. 4 is Control groups, Genexol-PM groups, taxol mixed micelle group to human lung cancer taxol resistance strain (A549/T) tumor suppression curve graph.

Specific implementation mode

It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient Product specification selects.

1, experimental drug：20 (S)-ginseng sapoglycoside Rg 3s, 20 (S)-ginseng saponin Rh 2s, protopanoxadiol, protopanaxatriol, Ginsenoside Rg 5, ginsenoside Rk1, ginsenoside Rh 3, ginsenoside Rg2, ginsenoside Rg 4, Ginsenoside Rh4, ginseng Saponin(e Rh1, female woods A, ginsenoside Rp1,25- methyl-different ginseng sapoglycoside Rg 3, different ginseng sapoglycoside Rg 3 (E), different ginsenoside are reached Rg3 (Z), different ginseng saponin Rh 2 (E), different ginseng saponin Rh 2 (Z), different ginsenoside Rg2 (E), different ginsenoside Rg2 (Z), people Join saponin(e Rp2, ginsenoside Rp3, Pseudo-ginsenoside GQ, pseudoginsenoside HQ, ginsenoside SC-Rp1, ginsenoside DC- Rp1, taxol, docetaxel, cis-platinum, camptothecine, all-trans retinoic acid, irinotecan hydrochloride, oxaliplatin, angstrom primycin C, Amphotericin B, Indomethacin, naproxen, homoharringtonine, adriamycin, Clonazepam, haloperidol, dihydrotestosterone, ring spore Rhzomorph A, fenofibrate, bifendate, Propofol, Puerarin, Vitamin K3, which are this field conventional commercial, to be obtained, such as Shanghai sheet Plain Pharmaceutical Technology Co., Ltd.

Ginsenoside Rg 5H, different ginsenoside Rg3H can be prepared by embodiment is prepared in the application.

PEG-DSPE, mPEG-PDLLA, mPEG-PLA, PEO-PAsp, PEG-DSPE-NH2, PLURONICS F87 (PEO- PPO-PEO), PEG-PCL, PEG-PLGA, PEG-PBLA, PEG-PBLG, PEG-PAsp, PEG-PHis, vitamin E are this field Conventional commercial can obtain, such as the Xi'an bio tech ltd Rui Xi.

Conventional SiRNA is purchased from sharp rich biology.

Genexol-PM, polyethylene glycol-polylactic acid copolymer (mPEG-PDLLA) are that membrane material prepares paclitaxel freeze drying nanometer Micella is purchased from Samyang Biopharmaceuticals Corporation companies of South Korea.

2, the instrument used in following embodiments and Application Example is that pharmaceutical college of Southwestern University has instrument and equipment by oneself, Unit type and source-information are as follows：

High performance liquid chromatograph (Agilent 1100)；

Electronic balance (TB-215, U.S. Denver Instrument)；

Supersonic wave cleaning machine (SB3200DT, NingBo XinZhi Biology Science Co., Ltd)；

Nitrogen evaporator (HGC-12A, Tianjin Hengao Technology Development Co., Ltd.)；

Rotary evaporator (RE-2000A, Shanghai Yarong Biochemical Instrument Plant)；

Hyperpure water manufacturing systems (ULUP-IV-10T, Sichuan UP Hyperpure Technology Co., Ltd.)；

Constant temperature oscillator (SHA-C, Changzhou Ao Hua Instrument Ltd.)；

Ultrasonic cell disruptor (JY92-II, NingBo XinZhi Biology Science Co., Ltd)；

High pressure homogenizer (B15, Canadian AVESTIN)；

Laser particle size analyzer (Nano ZS, Malvern instrument company of Britain)；

Miniature extruder (Mini-extruder, Avanti Polar Lipids Inc)；

Photoelectric microscope (XDS-1B, Chongqing Optical ＆ Electrical Instrument Co., Ltd.)；

Clean bench (SW-CJ-1FD, SuZhou Antai Air Tech Co., Ltd.)；

Cell incubator (CCL-170B-8, Singapore ESCO)；

Fluorescence inverted microscope (IX-73, Japanese Olympus)；

Small animal living body imaging system (FX PRO, Bruker companies of the U.S.)；

3, experimental cell strain：

A549 human lung carcinoma cells (Nanjing Keygen Biotech)；

A549/T human lung cancer taxol resistance strain method for building up：

Human lung cancer medicine-resistant cell line A549/ is established using low concentration dosage successive induction method induction parent's A549 cells Taxol.2 generations or 3 generations will be cultivated under the conditions of the A549 cell routines newly recovered, cell growth is made to stablize.Wait for that cell dissociation passes on When second day update culture medium, with Taxol to parent A549IC₅₀1/10 for initial concentration be added taxol.Dosing second day Culture medium is updated, and maintains the concentration routine passage culture of taxol.It is carried again after the growth of each paclitaxel concentration cytotostatic High drug concentration continues to cultivate, and until cell can stablize growth in the culture medium of the taxol containing 2.5mg/L, lasts 12 Month.

4, hemolysis test：

The preparation of 2% red blood cell suspension：Healthy rabbits blood is taken, is put into the conical flask containing bead and shakes 10 points Clock, or make into defibrinated blood with glass bar agitation blood to remove fibrinogen.About 10 times of 0.9% sodium chloride solution is added Amount, shakes up, and per minute 1000~1500 leave the heart 15 minutes, removes supernatant, and the red blood cell of precipitation is molten with 0.9% sodium chloride again Liquid washs 2~3 times as stated above, until the not aobvious red of supernatant.Gained red blood cell is made of 0.9% sodium chloride solution 2% suspension, is for experiment.

Inspection technique：Take 5, cleaned glass test tube, 1, No. 2 pipe of number is test sample pipe, and No. 3 pipes are negative control pipe, No. 4 Pipe is positive control pipe, and No. 5 pipes are test sample control tube.2% red cell suspension, 0.9% chlorination are sequentially added shown according to the form below Sodium solution, purified water after mixing, are set in 37 ± 0.5 DEG C of insulating box and are incubated immediately.Haemolysis and cohesion are observed after 3 hours Reaction.

Test tube is numbered	1、2	3	4	5
					2% red cell suspension/ml	2.5	2.5	2.5	/
0.9% sodium chloride solution/ml	2.2	2.5	/	4.7
					Purified water/ml	/	/	2.5	/
Test solution/ml	0.3	/	/	0.3

If the solution in test tube is in clear and bright red, residual that tube bottom is acellular shows there is haemolysis；Under red blood cell whole Heavy, though supernatant water white transparency or supernatant are coloured clear and bright, 1, No. 2 pipe and No. 5 pipes visually observe no significant difference, then table Bright no haemolysis occurs.

If having brownish red or rufous flocculent deposit in solution, gently reverses 3 times and throw away and do not disperse, show there may be red blood cell Cohesion occurs, and should further set microscopically observation, and such as visible erythrocyte aggregation is cohesion.

As a result judge：When negative control pipe occurs without haemolysis or cohesion, positive control pipe has haemolysis, if 2 for examination Haemolysis and cohesion do not occur in 3 hours for the solution in quality control, and judgement test sample meets regulation；If there is 1 test sample pipe Haemolysis and (or) cohesion occur in 3 hours for solution, should set 4 test sample pipes and carry out retrial, the solution of test sample pipe is small 3 When it is interior haemolysis and (or) cohesion must not occur, otherwise judge test sample it is against regulation.

In specific experiment, test sample (ginsenoside) concentration can be according to practical adjustments.

5, experimental animal：Kunming mice (or normal mouse) is purchased from Third Military Medical University's animal center；

BALB/C-nu/nu mouse (or nude mouse) are purchased from Shanghai Slac Experimental Animal Co., Ltd..

6, cell culture processes：The cell strain being related to is placed in containing 5%CO₂37 DEG C of incubators in, with DMEM or RPMI1640 complete mediums (containing 10% fetal calf serum, 100U/ml penicillin, 100 μ g/ml streptomysins) culture, 0.25% pancreas Enzyme-EDTA had digestive transfer cultures pass on 2-3 times weekly.

7, it is administered：For testing every time, setting negative control group (mixing blank micella referred to as mixes empty), positive control Group (Genexol-PM), mixed micelle group.6 concentrations above gradients, sesquialter or five times of dilutions, each concentration three wells are set.

8, inhibiting tumour cells concentration IC₅₀Experimental method：It is prepared after the tumour cell of exponential phase is digested with pancreatin At certain density cell liquid, 96 orifice plates are inoculated in by 5000/hole, add 100 μ l per hole.Sample containing various concentration is added in next day And the fresh culture of coordinative solvent control, add 100 μ l (DMSO final concentrations per hole<0.5%) 10 dosage groups, are set per sample, Every group sets three parallel holes, after 37 DEG C of incubators continue to cultivate 72h, abandons supernatant, adds the PBS's and 10 μ l of 100 μ l per hole CCK-8 shakes mixing with microoscillator, continues to cultivate 3h, with microplate reader in reference wavelength 630nm, Detection wavelength 450nm items OD value (OD) is measured under part, the tumour cell handled using solvent control is control group, by middle effect equation calculation IC₅₀。

9, In vitro cell experiment method：The tumour cell for collecting exponential phase, cell is resuspended to DMEM and is cultivated completely In base (containing 10% fetal calf serum, 100U/mL penicillin, 100 μ g/mL streptomysins), final concentration of 4 × 10⁴A/mL.In 96 holes In tissue culture plate, the above-mentioned cell suspensions of 200 μ l (8 × 10 are added per hole³A cells/well), it is placed in 37 DEG C, 5%CO₂Cell 48h is cultivated in incubator, is changed DMEM complete mediums into 200 antitumor drugs of the μ l containing various concentration respectively, is made drug Ultimate density is set as 6 groups or more, and using DMEM complete mediums as negative control group, each concentration sets 4 multiple holes, and experiment repeats 3 times.Cell is in 37 DEG C, 5%CO₂Cell incubator in after culture 72h, the 20 μ l of MTT solution of 5mg/mL are added per hole, set thin Continue in born of the same parents' incubator after cultivating 4h, abandon supernatant, 150 μ l DMSO are added per hole, after shaking 10min, with the more work(of continuous spectrum Energy microplate reader (Tecan infinite M 200, TECAN, Switzerland) measures the OD values at 490nm, and cell is calculated as follows and deposits Motility rate：(cell survival rate (%)=OD_Drug/OD_Control× 100%).

Cell survival rate (%)=OD_{490 (samples)}/OD_{490 (controls)}× 100%；

Wherein, OD_{490 (samples)}For the OD values of experimental group, OD_{490 (controls)}For the OD values of blank control group.

10, internal effect experiment method：Take 1 × 10⁷-10×10⁷The tumour cell of a/mL exponential phases, is noted with 1mL The nude mouse right side oxter that emitter is slowly injected to 18-20g is subcutaneous, and every nude mouse injects 100 μ l, and observation tumor mass is grown, directly To tumor mass, the bulk grows to about 100mm³.Animal is grouped at random and starts to be administered.It weighs every three days and measures gross tumor volume, be used in combination Vernier caliper measurement tumour longest diameter and most short diameter put to death nude mouse, measure tumor mass volume, calculate relative tumour volume (RTV), Relative tumor proliferation rate (T/C) and tumor suppression percentage, do statistical analysis.

Gross tumor volume calculation formula：V=abh/2.Wherein, a is diameter of tumor, and b is tumour transverse diameter, and h is tumour height.

Relative tumour volume RTV calculation formula：RTV=Vt/V0.Wherein Vt is gross tumor volume sometime, and V0 is to open Gross tumor volume when beginning to be administered.

The calculation formula of Relative tumor proliferation rate：T/C (%)=TRTV/CRTV × 100%.Wherein TRTV is treatment group RTV, CRTV are solvent control group RTV.

The calculation formula of tumor suppression percentage：Tumor suppression percentage=(solvent control group knurl weight-administration group knurl weight)/ Solvent control group knurl weight × 100%.

The standard of curative effect evaluation：T/C (%)>60 be invalid；T/C ()≤60 %, and compared with solvent control group, knurl product It is statistically analyzed P<0.05 is effective.

C (μM) refers to concentration in following Application Examples, wherein the concentration of Taxol+Rg5 refers to Japanese yew in mixed micelle The concentration of the concentration and ginsenoside Rg 5 of alcohol, such as 5+30 refer to the dense of taxol in 5 taxol mixed micelle of ginsenoside Rg Degree is 5 μM, a concentration of 30 μM of ginsenoside Rg 5；Time (d) refers to time (day).

In following Application Examples, when there is 5 blank mixed micelle of ginsenoside Rg, such as it is not specifically noted, is Refer to the blank mixed micelle (referred to as mixing empty) formed by PEG-DSPE made from 1 method of embodiment and ginsenoside Rg 5；When going out When existing 5 taxol mixed micelle of ginsenoside Rg, such as it is not specifically noted, each means by PEG- made from 5 method of embodiment The taxol mixed micelle (abbreviation Taxol+Rg5) that DSPE and ginsenoside Rg 5 are formed.

In following embodiments, for operation temperature and pressure, such as it is not specifically noted, generally refers to room temperature and normal pressure.Its In, room temperature refers to 10-30 DEG C；Normal pressure refers to a standard atmospheric pressure.

One, the preparation of ginsenoside compound shown in formula I

Prepare the preparation of 1 ginsenoside Rg 5H of embodiment

10g 20 (R)-ginseng sapoglycoside Rg 3 is dissolved in 20mL pyridines, 10mL acetic anhydride is added dropwise under ice-water bath, is then added again Enter appropriate (generally catalytic amount, such as 1g) catalyst DMAP, is to slowly warm up to room temperature, reacts 10 hours, TLC is detected to raw material Point disappears, and is concentrated under reduced pressure and removes organic solvent, and 200mL/ ethyl acetate extracts 3 times, merging organic phase, 2M salt acid elution 3 times, Saturated sodium bicarbonate washs 3 times, and anhydrous sodium sulfate drying is concentrated to dryness, obtains Rg3 acetylates.

It takes 10g Rg3 acetylates to be dissolved in 50mL dichloromethane, under ice-water bath, sequentially adds 1g boron trifluoride second Ether and 1g triethylsilanes, are to slowly warm up to room temperature, the reaction was continued at room temperature 5-10min, then are cooled to 0 DEG C, and ice water is added Essence is gone out reaction, is washed 3 times with 100mL/ saturated sodium bicarbonate solution, and anhydrous sodium sulfate drying is concentrated to dryness, obtains Rg5H acetylates.

The Rg5H acetylates for taking 10g, are dissolved in 50mL methanol and dioxane 1：In 1 mixed solution, 2g is added Potassium hydroxide, stirring and dissolving, heating reflux reaction 10 hours, TLC, which is detected to raw material point, to disappear, in saturated lemon aqueous solution It with to pH=7, is extracted 3 times with 100mL/ ethyl acetate, merges organic phase, appropriate anhydrous sodium sulfate drying is concentrated under reduced pressure into Dry, through high pressure chromatography, with C18 chromatographies, methanol-water gradient elution, evaporative light-scattering device (ELSD) detects, product Section is concentrated to dryness, and obtains ginsenoside Rg 5H.

Ginsenoside Rg 5H：

¹H NMR(δ,500M):5.37 (1H, d, J=7.5Hz), 5.30 (1H, t, J=6.0Hz), 4.91 (1H, d, J= 7.5Hz),4.55(1H,m),4.45-4.49(2H,m),4.23-4.33(5H,m),4.12-4.14(2H,m),3.90-3.92 (3H, m), 3.27 (1H, m), 2.28-2.59 (2H, m), 2.17 (1H, m), 1.99-2.02 (3H, m), 1.80-1.89 (2H, m), 1.64 (3H, s), 1.61 (3H, s), 1.41 (3H, d, J=2.8), 1.35-1.50 (8H, m), 1.28 (3H, s), 1.20 (1H, m),1.09(3H,s),1.03(1H,m),0.94(3H,s),0.95(3H,s),0.78(3H,s),0.73(1H,m).

¹³C NMR(δ,125M):130.8,126.4,106.1,105.1,89.0,83.4,78.4,78.2,78.3,78.0, 71.7,71.0,62.9,62.8,77.2,56.4,54.8,51.7,50.4,49.2,48.6,40.0,39.7,39.2,36.9,9, 35.2,32.1,31.4,28.2,27.1,26.9,26.8,25.8,23.0,18.5,17.7,17.0,16.6,16.4,15.9.

ESI:770.13(M+H)⁺,HR-ESI-MS:792.0215(C₄₂H₇₂NaO₁₂),Cal 792.0230.

Prepare the preparation of embodiment 2 ginsenoside Rg 5H1 (E), Rg5H1 (Z), Rk1H

10g 20 (R)-Rg3 acetylates are weighed, are dissolved in 50mL methanol, 1g palladium carbons are added, under normal temperature and pressure, are led to Enter hydrogen, stirring does not inhale hydrogen in 4-6 hours to reaction solution, and TLC, which is detected to raw material point, to disappear, and filters out palladium carbon, and decompression concentration removes Methanol, drying, obtains the 20 acetylated hydrogenated products of (R)-Rg3.

The acetylated hydrogenated products of 10g 20 (R)-Rg3 are weighed, are dissolved in 50mL toluene, 10g p-methyl benzenesulfonic acid are added, slowly It is slow to be warming up to 90 DEG C of reflux, it reacts 4 hours, TLC, which is detected to raw material point, to disappear, cooling, 100mL/ saturated sodium bicarbonate solution Washing 3 times, anhydrous sodium sulfate drying, is concentrated to dryness, obtains acetylate crude mixture (Rg5H1 (E types), Rg5H1 The acetylate mixture of (Z-type) and Rk1H).

5g acetylate crude mixtures are weighed, are dissolved in 20mL methanol, 5g sodium methoxides are added, it is small to react 10 at room temperature When, TLC, which is detected to raw material point, to disappear, and is concentrated to dryness, is re-dissolved with ethyl acetate, 100mL/ washing 3 times, anhydrous sulphur Sour sodium drying, is concentrated to dryness, obtains the crude mixture (mixing of Rg5H1 (E types), Rg5H1 (Z-type) and Rk1H of product Object).

The crude mixture of the product of 5g is weighed, then through high pressure chromatography, using C18 as filler, methanol-water gradient elution, Evaporative light-scattering device (ELSD), product section is concentrated to dryness, and respectively obtains Rg5H1 (E of the 1.8g HPLC purity 98% or more Type), Rg5H1 (Z-type) and 0.8g HPLC purity Rk1H 98% or more of the 0.2g HPLC purity 98% or more.

Ginsenoside Rg 5H1 (Z)

¹H NMR(δ,500M):5.38 (1H, d, J=7.5Hz), 5.10 (1H, t, J=6.6Hz), 4.91 (1H, d, J= 7.5Hz),4.55(1H,m),4.45-4.49(2H,m),4.23-4.33(5H,m),4.12-4.14(2H,m),3.90-3.92 (3H, m), 3.27 (1H, m), 2.28-2.59 (2H, m), 2.17 (1H, m), 1.99-2.02 (3H, m), 1.80-1.89 (2H, m), 1.64(3H,s),1.61(3H,s),1.41(3H,s),1.35-1.50(8H,m),1.28(3H,s),1.20(1H,m),1.09 (3H, d, J=2.8Hz), 1.02 (1H, m), 0.97 (3H, s), 0.96 (3H, d, J=2.8Hz), 0.79 (3H, s), 0.74 (1H, m).

¹³C NMR(δ,125M):138.79,125.86,106.3,105.3,89.2,83.6,78.6,78.4,78.2, 78.0,71.9,71.2,63.1,63.0,77.4,56.6,55.0,51.9,50.6,49.4,48.8,40.2,39.9,39.4, 37.1,35.4,32.3,31.6,28.4,27.3,26.9,26.9,25.9,23.2,18.7,17.9,17.2,16.8,16.6, 16.3.

ESI:770.13(M+H)⁺,HR-ESI-MS:770.0321(C₄₂H₇₃O₁₂),Cal 770.0315.

Ginsenoside Rg 5H1 (E)

¹H NMR(δ,500M):5.37 (1H, d, J=7.5Hz), 5.11 (1H, t, J=7.0Hz), 4.91 (1H, d, J= 7.5Hz),4.55(1H,m),4.45-4.49(2H,m),4.23-4.33(5H,m),4.12-4.14(2H,m),3.90-3.92 (3H, m), 3.27 (1H, m), 2.28-2.59 (2H, m), 2.17 (1H, m), 1.99-2.02 (3H, m), 1.80-1.89 (2H, m), 1.64(3H,s),1.61(3H,s),1.41(3H,s),1.35-1.50(8H,m),1.28(3H,s),1.20(1H,m),1.09 (3H, d, J=2.8Hz), 1.02 (1H, m), 0.97 (3H, s), 0.96 (3H, d, J=2.8Hz), 0.79 (3H, s), 0.74 (1H, m).

¹³C NMR(δ,125M):138.81,126.55,106.3,105.3,89.2,83.6,78.6,78.4,78.2, 78.0,71.9,71.2,63.1,63.0,77.4,56.6,55.0,51.9,50.6,49.4,48.8,40.2,39.9,39.4, 37.1,35.4,32.3,31.6,28.4,27.3,26.9,26.9,25.9,23.2,18.7,17.9,17.2,16.8,16.6, 16.3.

ESI:770.13(M+H)⁺,HR-ESI-MS:770.0321(C₄₂H₇₃O₁₂),Cal 770.0315.

Ginsenoside Rk1H

¹H NMR(δ,500M):5.37 (1H, d, J=7.5Hz), 5.04 (1H, br.s), 4.91 (1H, d, J=7.5Hz), 4.80(1H,m),4.55(1H,m),4.45-4.49(2H,m),4.23-4.33(5H,m),4.12-4.14(2H,m),3.90- 3.92(3H,m),3.27(1H,m),2.28-2.59(2H,m),2.17(1H,m),1.99-2.02(3H,m),1.80-1.89 (2H,m),1.64(3H,s),1.61(3H,s),1.35-1.50(8H,m),1.28(3H,s),1.20(1H,m),1.09(3H,d, ), J=2.8Hz 1.02 (1H, m), 0.97 (3H, s), 0.96 (3H, d, J=2.8Hz), 0.79 (3H, s), 0.74 (1H, m)

¹³C NMR(δ,125M):155.6,108.2,106.3,105.3,89.2,83.6,78.6,78.4,78.2,78.0, 71.9,71.2,63.1,63.0,77.4,56.6,55.0,51.9,50.6,49.4,48.8,40.2,39.9,39.4,37.1, 35.4,32.3,31.6,28.4,27.3,26.9,26.9,25.9,23.2,18.7,17.9,17.2,16.8,16.6,16.3.

ESI:770.13(M+H)⁺,HR-ESI-MS:770.0321(C₄₂H₇₃O₁₂),Cal 770.0315.

Prepare the preparation of 3 ginsenoside Rh 3H of embodiment

Using 1 same procedure of embodiment is prepared, raw material is respectively 20 (R)-Rh2 and 20 (S)-Rh2, obtains ginsenoside Rh3H。

Ginsenoside Rh 3H,

¹H NMR(δ,500M):5.11 (1H, t, J=7.0Hz), 4.95 (1H, d, J=8.0Hz), 4.40 (1H, d, J= 11.5Hz),4.40(1H,m),4.24(1H,m),4.21(1H,m),4.05(1H,m),4.02(1H,m),3.93(1H,m), 3.38 (1H, dd, J=11.5,4.5Hz), 2.46-2.53 (2H, m), 2.40 (1H, dd, J=21.5,10.5Hz), 2.21 (1H, m),1.95(1H,m),2.03(2H,m),1.82(1H,m),1.72(2H,m),1.71(3H,s),1.69(3H,s),1.65(3H, s),1.59(1H,m),1.52(2H,m),1.49(2H,m),1.43(2H,m),1.36(1H,m),1.32(3H,s),1.24(1H, m),1.06(1H,m),1.01(3H,s),1.00(H,s),0.99(3H,s),0.81(3H,s),0.76(1,m),0.74(1H,d, J=10.5Hz)

¹³C NMR(δ,125M):131.7,127.0,107.9,89.7,79.7,79.3,76.8,72.8,71.8,64.0, 57.3,52.7,51.6,51.3,50.1,44.2,41.0,40.6,40.1,37.9,36.1,33.1,32.4,29.1,27.7, 27.6,26.8,23.7,23.6,19.4,18.7,18.3,17.7,17.4,16.8,

ESI:607.83(M+H)⁺,HR-ESI-MS:607.8921(C₃₆H₆₇O₇),[M+H]⁺,Cal 607.8915.

Prepare the preparation of embodiment 4 ginsenoside Rh 3H1 (E), ginsenoside Rh 3H1 (Z) and ginsenoside Rk_2 H

Using 2 same procedure of embodiment is prepared, raw material is that 20 (R)-Rh2 acetylates or 20 (S)-Rh2 acetylations are produced Object respectively obtains ginsenoside Rh 3H1 (E), ginsenoside Rh 3H1 (Z) and ginsenoside of the HPLC purity 98% or more Rk2H。

Ginsenoside Rh 3H1 (E),

¹H NMR(δ,500M):5.04 (1H, br.s), 4.95 (1H, d, J=8.0Hz), 4.80 (1H, m), 4.40 (1H, D, J=11.5Hz), 4.40 (1H, m), 4.24 (1H, m), 4.21 (1H, m), 4.05 (1H, m), 4.02 (1H, m), 3.93 (1H, M), 3.38 (1H, dd, J=11.5,4.5Hz), 2.46-2.53 (2H, m), 2.40 (1H, dd, J=21.5,10.5Hz), 2.21 (1H,m),1.95(1H,m),2.03(2H,m),1.82(1H,m),1.72(2H,m),1.69(3H,s),1.65(3H,s),1.59 (1H,m),1.52(2H,m),1.49(2H,m),1.43(2H,m),1.39(3H,m),1.36(1H,m),1.32(3H,s),1.24 (1H, m), 1.06 (1H, m), 1.01 (3H, d, J=2.8Hz), 1.00 (H, s), 0.99 (3H, d, J=2.8Hz), 0.81 (3H, S), 0.76 (1, m), 0.74 (1H, d, J=10.5Hz)

¹³C NMR(δ,125M):138.7,125.9,107.9,89.7,79.7,79.3,76.8,72.8,71.8,64.0, 57.3,52.7,51.6,51.3,50.1,44.2,41.0,40.6,40.1,37.9,36.1,33.1,32.4,29.1,27.7, 27.6,26.8,23.7,23.6,19.4,18.7,18.3,17.7,17.4,16.8,

Ginsenoside Rh 3H1 (Z),

¹H NMR(δ,500M):5.32 (1H, t, J=7.0Hz), 4.95 (1H, d, J=8.0Hz), 4.40 (1H, d, J= 11.5Hz),4.40(1H,m),4.24(1H,m),4.21(1H,m),4.05(1H,m),4.02(1H,m),3.93(1H,m), 3.38 (1H, dd, J=11.5,4.5Hz), 2.46-2.53 (2H, m), 2.40 (1H, dd, J=21.5,10.5Hz), 2.21 (1H, m),1.95(1H,m),2.03(2H,m),1.82(1H,m),1.72(2H,m),1.70(3H,s),1.69(3H,s),1.59(1H, m),1.52(2H,m),1.49(2H,m),1.43(2H,m),1.39(3H,m),1.36(1H,m),1.32(3H,s),1.24(1H, M), 1.06 (1H, m), 1.01 (3H, d, J=2.8Hz), 1.00 (H, s), 0.99 (3H, d, J=2.8Hz), 0.81 (3H, s), 0.76 (1, m), 0.74 (1H, d, J=10.5Hz)

Ginsenoside Rk_2 H

¹H NMR(δ,500M):4.95 (1H, d, J=8.0Hz), 4.40 (1H, d, J=11.5Hz), 4.40 (1H, m), 4.24 (1H, m), 4.21 (1H, m), 4.05 (1H, m), 4.02 (1H, m), 3.93 (1H, m), 3.38 (1H, dd, J=11.5, 4.5Hz), 2.46-2.53 (2H, m), 2.40 (1H, dd, J=21.5,10.5Hz), 2.21 (1H, m), 1.95 (1H, m), 2.03 (2H,m),1.82(1H,m),1.72(2H,m),1.70(3H,s),1.69(3H,s),1.59(1H,m),1.52(2H,m),1.49 (2H,m),1.43(2H,m),1.39(3H,m),1.36(1H,m),1.32(3H,s),1.24(1H,m),1.06(1H,m),1.01 (3H, d, J=2.8Hz), 1.00 (H, s), 0.99 (3H, d, J=2.8Hz), 0.81 (3H, s), 0.76 (1, m), 0.74 (1H, d, J=10.5Hz)

¹³C NMR(δ,125M):155.6,108.2,107.9,89.7,79.7,79.3,76.8,72.8,71.8,64.0, 57.3,52.7,51.6,51.3,50.1,44.2,41.0,40.6,40.1,37.9,36.1,33.1,32.4,29.1,27.7, 27.6,26.8,23.7,23.6,19.4,18.7,18.3,17.7,17.4,16.8,

Prepare the preparation of 5 ginsenoside Rk4H of embodiment

Using 1 same procedure of embodiment is prepared, raw material is respectively 20 (R)-Rg2 and 20 (S)-Rg2, obtains ginsenoside Rk4H。

Ginsenoside Rk4H,

¹H NMR(δ,500M):6.46 (1H, brs), 5.33 (1H, t, J=8.3), 5.25 (1H, d, J=7.2), 4.92 (1H, m), 4.77 (1H, m), 4.66 (1H, m), 4.52 (1H, d, J=9.8), 4.69 (1H, m), 4.34 (1H, m), 4.37 (1H, M), 4.28 (1H, m), 4.20 (1H, m), 3.96 (1H, m), 3.90 (1H, m), 3.47 (1H, dd, J=4.1,11.6), 2.59 (1H,m),2.30(1H,m),2.26(1H,m),2.26(3H,m),2.10(3H,s),2.01(1H,m),1.98(2H,m),1.86 (1H, m), 1.79 (3H, m), 1.78 (3H, d, J=5.7), 1.67 (3H, s), 1.63 (3H, s), 1.64 (2H, m), 1.53 (3H, M), 1.41 (3H, d, J=2.8Hz), 1.39 (1H, m), 1.35 (3H, s), 1.29 (2H, m), 1.20 (3H, s), 0.98 (3H, s),0.95(3H,s),0.96(3H,m).

¹³C NMR(δ,125M):130.8,126.4,102.0,101.9,79.5,78.7,78.4,75.9,78.9,71.3, 67.3,74.4,73.1,71.1,63.0,60.9,54.7,51.8,49.7,39.7,48.3,46.1,41.2,40.1,39.4, 32.1,35.9,32.2,31.4,27.1,26.7,27.8,25.9,23.0,17.7,17.0,17.2.

ESI:770.23(M+H)⁺,HR-ESI-MS:770.0341(C₃₆H₆₇O₇),[M+H]⁺,Cal 770.0328.

Prepare the preparation of embodiment 6 ginsenoside Rk4H1 (E), ginsenoside Rk4H1 (Z) and DELTA.-20(22)-Ginsenoside Rg6 H

Using 2 same procedure of embodiment is prepared, raw material is 20 (R)-Rg2 acetylates, 20 (S)-Rg2 acetylations production Object respectively obtains HPLC purity in 98% or more ginsenoside Rk4H1 (E), ginsenoside Rk4H1 (Z), ginsenoside Rg6H。

Ginsenoside Rk4H1E,

¹H NMR(δ,500M):6.46 (1H, brs), 5.40 (1H, t, J=8.3), 5.25 (1H, d, J=7.2), 4.92 (1H, m), 4.77 (1H, m), 4.66 (1H, m), 4.52 (1H, d, J=9.8), 4.69 (1H, m), 4.34 (1H, m), 4.37 (1H, M), 4.28 (1H, m), 4.20 (1H, m), 3.96 (1H, m), 3.90 (1H, m), 3.47 (1H, dd, J=4.1,11.6), 2.59 (1H,m),2.30(1H,m),2.26(1H,m),2.26(3H,m),2.10(3H,s),2.01(1H,m),1.98(2H,m),1.86 (1H, m), 1.79 (3H, m), 1.78 (3H, d, J=5.7), 1.71 (3H, s), 1.67 (3H, s), 1.63 (3H, s), 1.64 (2H, M), 1.53 (3H, d, J=10.5Hz), 1.41 (3H, d, J=2.8Hz), 1.39 (1H, m), 1.29 (2H, m), 1.20 (3H, s), 0.98 (3H, s), 0.95 (3H, s), 0.83 (3H, d, J=10.5Hz)

¹³C NMR(δ,125M):140.2,123.6,102.0,101.9,79.5,78.7,78.4,75.9,78.9,71.3, 67.3,74.4,73.1,71.1,63.0,60.9,54.7,51.8,49.7,39.7,48.3,46.1,41.2,40.1,39.4, 32.1,35.9,32.2,31.4,27.1,26.7,27.8,25.9,23.0,17.7,17.0,17.2.

Ginsenoside Rk4H1Z,

¹H NMR(δ,500M):6.46 (1H, brs), 5.42 (1H, t, J=8.3), 5.25 (1H, d, J=7.2), 4.92 (1H, m), 4.77 (1H, m), 4.66 (1H, m), 4.52 (1H, d, J=9.8), 4.69 (1H, m), 4.34 (1H, m), 4.37 (1H, M), 4.28 (1H, m), 4.20 (1H, m), 3.96 (1H, m), 3.90 (1H, m), 3.47 (1H, dd, J=4.1,11.6), 2.59 (1H,m),2.30(1H,m),2.26(1H,m),2.26(3H,m),2.10(3H,s),2.01(1H,m),1.98(2H,m),1.86 (1H, m), 1.79 (3H, m), 1.78 (3H, d, J=5.7), 1.67 (3H, s), 1.65 (3H, s), 1.64 (2H, m), 1.53 (3H, D, J=10.5Hz), 1.41 (3H, d, J=2.8Hz), 1.39 (1H, m), 1.29 (2H, m), 1.20 (3H, s), 0.98 (3H, s), 0.95 (3H, s), 0.83 (3H, d, J=10.5Hz)

¹³C NMR(δ,125M):140.2,120.4,102.0,101.9,79.5,78.7,78.4,75.9,78.9,71.3, 67.3,74.4,73.1,71.1,63.0,60.9,54.7,51.8,49.7,39.7,48.3,46.1,41.2,40.1,39.4, 32.1,35.9,32.2,31.4,27.1,26.7,27.8,25.9,23.0,17.7,17.0,17.2.

DELTA.-20(22)-Ginsenoside Rg6 H

¹H NMR(δ,500M):6.46 (1H, brs), 5.25 (1H, d, J=7.2), 5.04 (1H, br.s), 4.92 (1H, M), 4.80 (1H, m), 4.77 (1H, m), 4.66 (1H, m), 4.52 (1H, d, J=9.8), 4.69 (1H, m), 4.34 (1H, m), 4.37 (1H, m), 4.28 (1H, m), 4.20 (1H, m), 3.96 (1H, m), 3.90 (1H, m), 3.47 (1H, dd, J=4.1, 11.6),2.5(1H,m),2.30(1H,m),2.26(1H,m),2.26(3H,m),2.10(3H,s),2.01(1H,m),1.98 (2H, m), 1.86 (1H, m), 1.79 (3H, m), 1.78 (3H, d, J=5.7), 1.63 (3H, s), 1.64 (2H, m), 1.53 (3H, D, J=10.5Hz), 1.41 (3H, d, J=2.8Hz), 1.39 (1H, m), 1.35 (3H, s), 1.29 (2H, m), 1.20 (3H, s), 0.98 (3H, s), 0.95 (3H, s), 0.83 (3H, d, J=10.5Hz)

¹³C NMR(δ,125M):155.6,108.2,102.0,101.9,79.5,78.7,78.4,75.9,78.9,71.3, 67.3,74.4,73.1,71.1,63.0,60.9,54.7,51.8,49.7,39.7,48.3,46.1,41.2,40.1,39.4, 32.1,35.9,32.2,31.4,27.1,26.7,27.8,25.9,23.0,17.7,17.0,17.2.

Prepare the preparation of 7 different ginsenoside Rg3H of embodiment

The different ginseng sapoglycoside Rg 3 acetylate for taking 1.5g, is dissolved in the ethyl alcohol of 150mL, the 5% of 300mg is added Palladium carbon, stirring are passed through hydrogen under the conditions of 40 DEG C, react 6 hours.After reaction, palladium carbon, filtrate acetic acid second are filtered to remove Ester extracts 3 times, merges organic phase, is concentrated to dryness to obtain the different ginsenoside Rg3H of crude product.Again through high pressure chromatography, with C18 is filler, methanol-water gradient elution, and evaporative light-scattering device (ELSD) detection, product section is concentrated to dryness, and obtains 0.36g+ Different ginsenoside Rg3H of the 0.55g HPLC purity 98% or more.

Different ginsenoside Rg3H,

¹H NMR(δ,500M):5.37 (1H, d, J=7.5Hz), 4.91 (1H, d, J=7.5Hz), 4.55 (1H, m), 4.45-4.49(2H,m),4.23-4.33(5H,m),4.12-4.14(2H,m),3.90-3.92(3H,m),3.27(1H,m), 2.28-2.59 (2H, m), 2.17 (1H, m), 1.99-2.02 (3H, m), 1.80-1.89 (3H, m), 1.78 (3H, d, J=5.7), 1.67-1.71(3H,m),1.64(3H,s),1.61(3H,s),1.41(6H,s),1.35-1.50(10H,m),1.28(3H,s), 1.20(1H,m),1.09(3H,m),1.02(1H,m),0.97(3H,s),0.96(3H,m),0.79(3H,s),0.74(1H,m).

¹³C NMR(δ,125M):106.3,105.3,89.2,83.6,82.3,78.6,78.4,78.2,78.0,71.9, 71.2,63.1,63.0,77.4,56.6,55.0,51.9,50.6,49.4,48.8,40.2,39.9,39.4,37.1,35.4, 32.3,31.6,30.0,29.8,27.3,26.9,26.9,25.9,23.2,18.7,17.9,17.2,16.8.

ESI:788.05(M+H)⁺,HR-ESI-MS:788.0721(M+H)⁺,(C₄₂H₇₃O₁₃),Cal 788.0728.

Prepare the preparation of 8 3- sodium sulphate of embodiment-ginsenoside Rg 5H (SC-Rg5H)

10g ginsenoside Rg 5H are taken, are dissolved in 50mL ethyl alcohol, 1g NaOH are added, 80 DEG C of reflux is heated to, is passed through sky Gas reacts 5 days, and TLC, which is detected to raw material point, to disappear.After reaction, 100mL/ extracting n-butyl alcohol 3 times merges organic phase, subtracts Pressure is concentrated to dryness, alcohol crystal 3 times, and drying obtains 2.6g HPLC purity in 98% or more ginsenoside Rg's 5H parent nucleus.

10g Rg5H parent nucleus is weighed, is dissolved in 100mL pyridines, reaction bulb is placed in brine-ice bath, is cooled to 0 DEG C, Chlorosulfonic acid 30mL is slowly added dropwise, after then reacting 2 hours at room temperature, TLC, which is detected to raw material point, to disappear.After reaction, add Enter 0.1M NaOH and adjust pH=7.0, extracting n-butyl alcohol 3 times merges organic phase, is concentrated to dryness.Again through high pressure chromatography point From using C18 as filler, methanol-water gradient elution, evaporative light-scattering device (ELSD), product section is concentrated to dryness, and obtains 11.4g Rg5H parent nucleus of the HPLC purity 98% or more.

¹H NMR(δ,500M):5.30 (1H, t, J=6.0Hz), 3.96 (1H, m), 3.80 (1H, m), 2.28-2.59 (2H,m),2.17(1H,m),1.99-2.02(3H,m),1.80-1.89(2H,m),1.64(3H,s),1.61(3H,s),1.41 (3H, d, J=2.8), 1.35-1.50 (8H, m), 1.28 (3H, s), 1.20 (1H, m), 1.09 (3H, s), 1.03 (1H, m), 0.94(3H,s),0.95(3H,s),0.78(3H,s),0.73(1H,m).

¹³C NMR(δ,125M):139.7,125.7,78.2,78.3,72.8,69.7,56.6,51.7,51.1,51.0, 44.4,40.4,39.7,37.6,35.6,32.8,32.4,30.2,29.0,28.9,28.4,23.8,18.9,17.2,16.7, 16.5,16.0,13.2.

LRMS(ESI):523.7916[C₃₀H₅₁O₆S])；HRMS(ESI):found 523.7923,[C₃₀H₅₁O₆S]).

Prepare the preparation of 9 3- sodium sulphate of embodiment-different protopanoxadiol PPD (E) (the different PPD of SC- (E))

The different protopanoxadiol PPD of 10g (E types) are weighed, are dissolved in 100mL pyridines, reaction bulb is placed in brine-ice bath In, it is cooled to 0 DEG C, chlorosulfonic acid 30mL is slowly added dropwise, then removes ice bath, after reacting 2 hours at room temperature, TLC is detected to original Shots disappear.After reaction, 0.1M NaOH are added and adjust pH=7.0, extracting n-butyl alcohol 3 times merges organic phase, and decompression is dense It is reduced to dry.Again through high pressure chromatography, using C18 as filler, methanol-water gradient elution, evaporative light-scattering device (ELSD), product section It is concentrated to dryness, obtains 3- sodium sulphate-different protopanoxadiol PPD (E type) of the 11.4g HPLC purity 98% or more.

¹H NMR(δ,500M):5.40 (1H, t, J=6.0Hz), 3.96 (1H, m), 3.80 (1H, m), 2.28-2.59 (2H,m),2.17(1H,m),1.99-2.02(3H,m),1.80-1.89(2H,m),1.71(3H,s),1.57(3H,s),1.51 (3H,s),1.35-1.50(8H,m),1.20(1H,m),1.09(3H,s),1.03(1H,m),0.94(3H,s),0.95(3H, s),0.78(3H,s),0.73(1H,m).

¹³C NMR(δ,125M):123.8,123.6,78.2,72.8,70.7,56.6,51.7,51.1,51.0,44.4, 40.4,39.7,37.6,35.6,32.8,32.4,30.2,29.0,28.9,28.4,23.8,18.9,17.2,16.7,16.5, 16.0,13.2.

ESI-MS:539.79[M-Na]^-.

Prepare embodiment 10 3- (N, N- dimethyl aminoethyl)-carbamoyl-ginsenoside Rg 5H (DC-Rg5H) Preparation

Using 23 same procedure of embodiment, raw material is Rg5H parent nucleus to get DC- ginsenoside Rgs 5H.

10g Rg5H parent nucleus is weighed, the dichloromethane of 200mL dryings is dissolved in, 10g DMAP are added, as cold in ice bath But to 0 DEG C, 50mL being added dropwise and is dissolved in the triphosgene (10g) in dichloromethane, 0~5 DEG C of controlling reaction temperature is reacted 2 hours, TLC, which is detected to raw material point, to disappear.Purified water is added and terminates reaction, ethyl acetate extracts 3 times, merges organic phase, is concentrated under reduced pressure into Dry, alcohol crystal 2 times, drying obtains 6.5g 3- chloroformyls-ginsenoside Rg 5H.

5g 3- chloroformyls-ginsenoside Rg 5H is weighed, is dissolved in 50mL dichloromethane, 0 DEG C is cooled in ice bath, is delayed Slow that the chloroformic solution 15mL containing 5mL N, N- dimethyl-ethylenediamines is added dropwise, controlling reaction temperature is reacted 4 hours at 0~5 DEG C, TLC, which is detected to raw material point, to disappear.Purified water is added and terminates reaction, chloroform extracts 3 times, merges organic phase, is concentrated to dryness, second Alcohol crystallizes 3 times, and drying obtains 3.6g 3- (N, N- dimethyl aminoethyl)-carbamoyl-ginsenoside Rg 5H.

¹H NMR(δ,500M):5.20 (1H, t, J=6.9Hz), 3.80 (1H, m), 3.75 (4H, m), 3.42 (6H, s), 2.70(1H,m),2.20-2.28(4H,m),2.08(1H,m),1.98(2H,m),1.95(1H,m),1.72(1H,m),1.60 (1H,m),1.57(3H,s),1.51(3H,s),1.45(3H,m),1.38(1H,m),1.32(3H,m),1.19(1H,m),0.98 (1H, m), 0.92 (3H, s), 0.92 (3H, d, J=6.5Hz), 0.72 (3H, s), 0.68 (1H, m), 0.63 (1H, m)

¹³C NMR(δ,125M):156.1,131.2,125.3,89.0,72.5,60.3,56.5,52.5,51.2,50.8, 48.2,46.1,40.2,39.8,39.3,37.1,35.4,33.9,32.6,30.7,28.1,27.1,26.7,25.7,18.5, 17.7,17.0,16.6,16.4,15.8.

ESI:559.90(M+H)⁺,HR-ESI-MS:559.9011(C₃₅H₆₃N2O₃),Cal 559.9020.

Prepare the preparation of 11 pseudoginsenoside GP of embodiment

It takes 10g ginsenoside GQ acetylates to be dissolved in 200mL toluene, 1.5g boron trifluoride ether is added, is heated to 90 DEG C are flowed back 4 hours, and TLC, which is detected to raw material point, to disappear, cooling, is washed 3 times with 100mL/ saturated sodium bicarbonate solution, anhydrous Sodium sulphate is dried, and is concentrated to dryness, is obtained GP acetylates.

The GP acetylates for taking 10g, are dissolved in 50mL methanol, and 2g sodium methoxides are added, and stirring and dissolving is reacted at room temperature 10 hours, TLC, which is detected to raw material point, to disappear, and is extracted 3 times with 100mL/ ethyl acetate, merges organic phase, appropriate anhydrous slufuric acid Sodium is dried, and is concentrated to dryness, and proper amount of methanol crystallizes 2 times, and drying obtains pseudo- ginseng soap of the 2.2g HPLC purity 98% or more Glycosides GP.

¹H NMR(δ,500M):5.25 (1H, d, J=7.8Hz), 4.81 (1H, d, J=7.8Hz), 4.45 (1H, d, J= 10.2Hz), 4.36 (2H, m), 4.21-4.24 (3H, m), 4.09-4.14 (2H, dd, J=19.2,9.6Hz), 3.99-4.05 (2H, m), 3.79-3.83 (3H, m), 3.59 (1H, td, J=10.2,4.8Hz), 3.16 (1H, dd, J=12.0,4.2Hz), 1.33 (3H, d, J=6.5Hz), 1.15 (s, 6H), 1.13 (3H, d, J=6.5Hz) 1.08 (s, 3H), 0.96 (s, 3H), 0.84 (s,3H),0.78(s,3H),0.64(s,3H).

¹³C NMR(C₅D₅N,150MHz)d:106.2,105.2,88.9,86.8,85.7,83.6,78.4,78.3,78.2, 78.1,77.3,71.8,71.7,71.2,70.4,62.9,62.8,56.5,52.2,50.8,49.8,48.5,40.0,39.8, 39.3,37.0,35.2,32.9,32.5,31.7,28.9,28.1,27.7,27.3,27.0,26.8,25.5,18.5,18.4, 16.6,16.6,15.6.

ESI-MS:m/z 786.03[M+1]⁺.

Two, the preparation of mixed micelle

The preparation of ginsenoside Rk1 blank mixed micelle of the embodiment 1 containing PEG-DSPE

The PEG-DSPE (number-average molecular weight 2000) of the 100mg and ginsenoside Rk1 of 200mg is taken, 20ml ethyl alcohol is dissolved in In, rotation film forming is concentrated under reduced pressure in 37 DEG C, then proceedes to be evaporated to dryness, 20ml purified waters are added, aquation, dissolving are stirred at 37 DEG C 0.22 μm of filter membrane is crossed afterwards, obtains blank nanometer mixed micelle solution.After after testing, average grain diameter 24.5nm.

The preparation of protopanaxatriol PPT blank mixed micelle of the embodiment 2 containing mPEG-PDLLA

The mPEG-PDLLA (number-average molecular weight 2000) of the 200mg and protopanaxatriol PPT of 100mg is taken, 20ml is dissolved in In methanol, film forming is concentrated under reduced pressure in 50 DEG C, then proceedes to be evaporated to dryness, 20ml purified waters are added, aquation, dissolving are stirred at 50 DEG C 0.22 μm of filter membrane is crossed afterwards, obtains blank mixed micelle solution.After after testing, average grain diameter 40.9nm.

Preparation up to female woods A blank mixed micelle of the embodiment 3 containing mPEG-DSPE

It takes the mPEG-DSPE's (number-average molecular weight 2000) and 400mg of 200mg to reach female woods A, 20mg VE, is dissolved in 20ml In ethyl alcohol, rotation film forming is concentrated under reduced pressure in 60 DEG C, then proceedes to be evaporated to dryness, 5% glucose solutions of 20ml are added, 60 DEG C stirring aquation, after dissolving cross 0.22 μm of filter membrane, obtain blank nanometer mixed micelle solution.After after testing, average grain diameter is 24.5nm。

The preparation of protopanoxadiol PPD blank mixed micelle of the embodiment 4 containing PEG-DSPE

Protopanoxadiol PPD, 20mg VC of the PEG-DSPE (number-average molecular weight 4000) and 200mg of 100mg are taken, it is molten In 20ml acetonitriles, rotation film forming is concentrated under reduced pressure in 50 DEG C, then proceedes to be evaporated to dryness, it is water-soluble that 5% glucose of 20ml is added Liquid stirs aquation at 50 DEG C, and 0.22 μm of filter membrane is crossed after dissolving, obtains blank nanometer mixed micelle solution.After after testing, average grain Diameter is 28.6nm.

The preparation of taxol ginsenoside Rg 5 mixed micelle of the embodiment 5 containing PEG-DSPE

Take the PEG-DSPE (number-average molecular weight 2000) of 200mg, the ginsenoside Rg 5 of 400mg, 100mg taxols, 100mg VE are dissolved in 200ml methanol：Chloroform=1：In the mixed solution of 1 (volume ratio), spin concentration film forming is depressurized in 60 DEG C, It then proceedes to be evaporated to dryness, 20ml purified waters is added, aquation is stirred at 60 DEG C, dissolving obtains clear micellar solution.Through 0.22 μm Membrane filtration is freeze-dried to obtain the final product.After redissolving and detecting, average grain diameter 16.7nm, Bao Feng Shuai≤95%.

The preparation of docetaxel ginsenoside Rg 5H mixed micelle of the embodiment 6 containing mPEG-PDLLA

Take the ginsenoside Rg 5H and 50mg of the mPEG-PDLLA (number-average molecular weight 4000) and 400mg of 200mg how western He matches, and is dissolved in 20ml chloroforms, and spin concentration film forming is depressurized in 45 DEG C, then proceedes to be evaporated to dryness, 20ml purified waters are added, 45 DEG C of stirring aquations, dissolving obtain clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.After redissolving and detecting, Average grain diameter is 24.5nm, Bao Feng Shuai≤95%.

Embodiment 7：The preparation of camptothecine ginsenoside Rh 1 mixed micelle containing PEO-PAsp

The ginsenoside Rh 1 and 25mg camptothecines of the PEO-PAsp (number-average molecular weight 4800) and 100mg of 400mg are taken, It is dissolved in 20ml dichloromethane, spin concentration film forming is depressurized in 40 DEG C, then proceedes to be evaporated to dryness, 20ml5% glucose is added Aqueous solution, aquation is stirred at 40 DEG C, and dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.Through multiple After molten detection, average grain diameter 33.4nm, Bao Feng Shuai≤95%.

Embodiment 8：The system of Propofol 25- methyl-different ginseng sapoglycoside Rg 3 (different Rg3Me) mixed micelle containing PEG-DSPE It is standby

The PEG-DSPE (number-average molecular weight 2000) of 100mg, the different Rg3Me and 25mg Propofols of 400mg are taken, is dissolved in In 20ml ethyl alcohol, spin concentration film forming is depressurized in 60 DEG C, then proceedes to be evaporated to dryness, 20ml purified waters are added, stirred at 40 DEG C Aquation, dissolving obtain clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.After redissolving and detecting, average grain diameter For 35.5nm, Bao Feng Shuai≤95%.

The system of homoharringtonine ginsenoside Rg 4 mixed micelle of the embodiment 9 containing mPEG-PDLLA and chitosan-cholic acid It is standby

Take mPEG-PDLLA (number-average molecular weight 4000), chitosan-cholic acid of 100mg and the ginseng of 300mg of 500mg Saponin(e Rg4 and 50mg homoharringtonine, is dissolved in 20ml ether, and spin concentration film forming is depressurized in 30 DEG C, then proceedes to evaporate To dry, addition 20ml purified waters, aquation is stirred at 30 DEG C, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, freezing It is drying to obtain.After redissolving and detecting, average grain diameter 66nm, Bao Feng Shuai≤90%.

The preparation of adriamycin Ginsenoside Rh4 mixed micelle of the embodiment 10 containing mPEG-PLA

The mPEG-PLA (number-average molecular weight 2400) of 100mg, the Ginsenoside Rh4 of 400mg and 50mg adriamycins are taken, it is molten In 20ml methanol, spin concentration film forming is depressurized in 50 DEG C, then proceedes to be evaporated to dryness, 20ml purified waters are added, are stirred at 40 DEG C Aquation is mixed, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.After redissolving and detecting, average grain Diameter is 27.3nm, Bao Feng Shuai≤95%.

The preparation of oxaliplatin ginseng saponin Rh 2 mixed micelle of the embodiment 11 containing PEG-PLGA

The PEG-PLGA (number-average molecular weight 2000) of 100mg, the ginseng saponin Rh 2 and 50mg oxaliplatins of 200mg are taken, It is dissolved in 20ml THF, spin concentration film forming is depressurized in 55 DEG C, then proceedes to be evaporated to dryness, it is water-soluble that 20ml5% glucose is added Liquid, aquation is stirred at 55 DEG C, and dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is examined through redissolving After survey, average grain diameter 18.8nm, Bao Feng Shuai≤95%.

The preparation of Clonazepam ginsenoside Rp1 mixed micelle of the embodiment 12 containing PEG-DSPE

Take the PEG-DSPE (number-average molecular weight 4000) of 100mg, ginsenoside Rp1,10mg vitamin E of 400mg, 10mg cholesterol and 50mg Clonazepams, are dissolved in 20ml tetrahydrofurans, and rotation film forming is concentrated under reduced pressure in 60 DEG C, then proceedes to steam It is sent to dry, 20ml is added and is saturated phosphate buffer solution, in 40 DEG C of aquations, dissolving obtains clear micellar solution.It is filtered through 0.22 μm Membrane filtration is freeze-dried to obtain the final product.After redissolving and detecting, average grain diameter 26.9nm, Bao Feng Shuai≤90%.

The preparation of Indomethacin ginseng sapoglycoside Rg 3 mixed micelle of the embodiment 13 containing mPEG-PDLLA

Take the mPEG-PDLLA (number-average molecular weight 4000) of 100mg, the ginseng sapoglycoside Rg 3 of 400mg and 30mg indoles beautiful It is pungent, 20ml chloroforms are dissolved in, rotation film forming is concentrated under reduced pressure in 45 DEG C, then proceedes to be evaporated to dryness, it is water-soluble that 20ml5% glucose is added Liquid, in 30 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 23.9nm, Bao Feng Shuai≤95%.

The preparation of naproxen ginsenoside Rh 3 mixed micelle of the embodiment 14 containing PEG-PHis

Ginsenoside Rh 3 and the 30mg naproxens of the PEG-Phis (number-average molecular weight 4000) and 200mg of 100mg are taken, It is dissolved in 20ml methanol, rotation film forming is concentrated under reduced pressure in 50 DEG C, then proceedes to be evaporated to dryness, it is water-soluble that 5% glucose of 20ml is added Liquid, in 30 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 22.5nm, Bao Feng Shuai≤90%.

The preparation of the different ginseng saponin Rh 2 of haloperidol of the embodiment 15 containing PEG-PCL (E) mixed micelle

Take the PEG-PCL (number-average molecular weight 2000) of 400mg, the different ginseng saponin Rh 2 (E) of 100mg and 30mg fluorine piperazines Pyridine alcohol is dissolved in 20ml chloroforms, and rotation film forming is concentrated under reduced pressure in 45 DEG C, then proceedes to be evaporated to dryness, 20ml5% glucose waters are added Solution, in 30 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 20.7nm, Bao Feng Shuai≤95%.

The preparation of the mixed micelle of the different ginseng sapoglycoside Rg 3 of dihydrotestosterone of the embodiment 16 containing PEG-PBLA (Z)

Take the PEG-PBLA (number-average molecular weight 2000) of 400mg, the different ginseng sapoglycoside Rg 3 (Z) of 100mg and 30mg dihydros Testosterone is dissolved in 20ml chloroforms, and rotation film forming is concentrated under reduced pressure in 40 DEG C, then proceedes to be evaporated to dryness, 20ml5% glucose waters are added Solution, in 30 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 46.5nm, Bao Feng Shuai≤90%.

The preparation of Vitamin K3 Pseudo-ginsenoside GQ mixed micelle of the embodiment 17 containing PEG-PAsp

Take the Pseudo-ginsenoside GQ and 30mg vitamins of the PEG-PAsp (number-average molecular weight 4800) and 100mg of 400mg K3 is dissolved in 20ml chloroforms, and rotation film forming is concentrated under reduced pressure in 45 DEG C, then proceedes to be evaporated to dryness, it is water-soluble that 20ml5% glucose is added Liquid, in 45 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 32.9nm, Bao Feng Shuai≤90%.

The preparation of bifendate ginsenoside Rp2 mixed micelle of the embodiment 18 containing PEG-PBLG

The PEG-PBLG (number-average molecular weight 4000) of 400mg, ginsenoside Rp2 and the 30mg bifendate of 100mg are taken, 20ml chloroforms are dissolved in, rotation film forming is concentrated under reduced pressure in 40 DEG C, then proceedes to be evaporated to dryness, it is water-soluble that 5% glucose of 20ml is added Liquid, in 40 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 18.3nm, Bao Feng Shuai≤95%.

The preparation of Puerarin pseudoginsenoside HQ mixed micelle of the embodiment 19 containing PEG-DSPE-NH2

Take the PEG-DSPE-NH2 (number-average molecular weight 4000) of 400mg, pseudoginsenoside's HQ and 30mg pueraria lobata of 100mg Element is dissolved in 20ml chloroforms, and rotation film forming is concentrated under reduced pressure in 45 DEG C, then proceedes to be evaporated to dryness, 5% glucose waters of 20ml are added Solution, in 45 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 23.6nm, Bao Feng Shuai≤90%.

The preparation of cyclosporin A ginsenoside Rp3 mixed micelle of the embodiment 20 containing PEG-PCL

The PEG-PCL (number-average molecular weight 2000) of 400mg, ginsenoside Rp3 and the 30mg cyclosporin A of 100mg are taken, It is dissolved in 20ml ethyl alcohol, rotation film forming is concentrated under reduced pressure in 60 DEG C, then proceedes to be evaporated to dryness, it is water-soluble that 5% glucose of 20ml is added Liquid, in 30 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 27nm, Bao Feng Shuai≤90%.

The preparation of the different ginseng saponin Rh 2 of fenofibrate of the embodiment 21 containing PEG-PCL (Z) mixed micelle

Take the PEG-PCL (number-average molecular weight 2000) of 400mg, the different ginseng saponin Rh 2 (Z) of 100mg and the non-promises of 30mg Bei Te is dissolved in 20ml chloroforms, and rotation film forming is concentrated under reduced pressure in 45 DEG C, then proceedes to be evaporated to dryness, 20ml5% glucose waters are added Solution, in 45 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 26.2nm, Bao Feng Shuai≤90%.

The preparation of amphotericin B ginsenoside SC-Rp1 mixed micelle of the embodiment 22 containing PEG-PCL

Take the PEG-PCL (number-average molecular weight 2000) of 400mg, ginsenoside SC-Rp1, the 20mg deoxycholic acid of 200mg Sodium and 30mg amphotericin Bs, are dissolved in 100ml purified waters, and rotation film forming is concentrated under reduced pressure in 60 DEG C, then proceedes to be evaporated to dryness, 5% glucose solutions of 20ml are added, in 50 DEG C of aquations, dissolving obtains clear micellar solution.It is cold through 0.22 μm of membrane filtration Jelly is drying to obtain.After redissolving and detecting, average grain diameter 29.6nm, Bao Feng Shuai≤90%.

The preparation of siRNA ginsenoside DC-Rp1 mixed micelle of the embodiment 23 containing PEG-PCL

The PEG-PCL (number-average molecular weight 2000) of 400mg, ginsenoside DC-Rp1 and the 30mg SiRNA of 100mg are taken, It is dissolved in 50ml physiological saline, at room temperature, stirs 12 hours, through 0.22 μm of membrane filtration, be freeze-dried to obtain the final product.It is examined through redissolving After survey, average grain diameter 28.2nm, Bao Feng Shuai≤90%.

Embodiment 24：The preparation of the different ginsenoside Rg2 of adriamycin (E) mixed micelle containing PEO-PPO-PEO

Take the adriamycin dissolving of the PLURONICS F87 (PEO-PPO-PEO) (number-average molecular weight 4800), 100mg of 300mg It in DMSO, at 30-50 DEG C, is added in the lutidines dissolved with the DMAP of 20mg of 10ml, stirs 3-4 hours, glue is made PBS buffer solutions of the pH=7.4 dissolved with the different ginsenoside Rg2s of 2mg/ml (E) of 50ml is added in the conjugate of beam and adriamycin Afterwards, decompression concentration removes organic solvent, crosses 0.22 μm of membrane filtration, after freeze-drying to obtain the final product.After redissolving and detecting, average grain diameter For 21.1nm, Bao Feng Shuai≤90%.After testing, which stablizes in pH 7.4, but can discharge adriamycin in pH 6.6-7.2.

The preparation of the different ginsenoside Rg2 of all-trans retinoic acid of the embodiment 25 containing PEG-PBLG (Z) mixed micelle

The PEG-PBLG (number-average molecular weight 4000) of 200mg, the different ginsenoside Rg2 (Z) of 300mg are taken, 20ml is dissolved in In dimethylformamide (DMF), in 30 DEG C of stirring and dissolvings.The all-trans retinoic acid of 50mg is added, is stirred 12 hours at room temperature. Then mixed solution is placed in bag filter, is dialysed 8 hours with purified water, dialyzate crosses 0.22 μm of membrane filtration, freeze-drying To obtain the final product.After redissolving and detecting, average grain diameter 30.7nm, Bao Feng Shuai≤90%.

The preparation of the different ginsenoside Rg3H mixed micelles of cis-platinum of the embodiment 26 containing PEG-PAsp

The cis-platinum for taking PEG-PAsp (number-average molecular weight 4800) and 30mg of 200mg, is dissolved in 50ml purified waters, It stirs 8 hours at room temperature so that cis-platinum forms coordination mi-celle with PEG-PAsp.The different ginsenoside Rg3H of 50mg is added, 60 DEG C of stirring and dissolvings.It crosses 0.22 μm of membrane filtration, is freeze-dried to obtain the final product.After redissolving and detecting, average grain diameter 42.2nm, encapsulating Shuai≤90%.

Embodiment 27：The preparation of the different ginsenoside Rg3E mixed micelles of irinotecan hydrochloride containing PEG-PBLA

The PEG-PBLA (number-average molecular weight 2000) of 200mg and the different ginseng sapoglycoside Rg 3 of 400mg are taken, with 50ml's 50% ethanol water dissolves, and obtains blank micella solution.The irinotecan hydrochloride of 50mg is dissolved in the chloroform of 10ml, room temperature Under high degree of agitation, liquid is added drop-wise in the blank micella solution of 50ml, forms oil mixing with water solution【Or mixed solution high speed Shearing 10 minutes or 2-4 times high-pressure homogeneous, or shearing and homogeneous are used in combination】, continue stirring 2 hours.Then at 60 DEG C, Rotary evaporation removes organic solvent, crosses 0.22 μm of membrane filtration, is freeze-dried to obtain the final product.After redissolving and detecting, average grain diameter is 28.3nm, Bao Feng Shuai≤90%.

Embodiment 28：The preparation of angstrom primycin C ginsenoside Rg2's mixed micelles containing PEG-PHis

The ginsenoside Rg2 for taking PEG-Phis (number-average molecular weight 4000) and 200mg of 400mg, is dissolved in 20ml diformazans In base formamide (DMF), dissolving is stirred at room temperature.Angstrom primycin C of 50mg is added, is stirred 12 hours at room temperature.Then will Mixed solution is placed in bag filter, is dialysed 8 hours with purified water, dialyzate crosses 0.22 μm of membrane filtration, is freeze-dried to obtain the final product.Through After redissolving detection, average grain diameter 24.7nm, Bao Feng Shuai≤90%.

Homoharringtonine ginsenoside Rg 5H1 (E) epoxy glue of embodiment 29 containing mPEG-PDLLA and chitosan-cholic acid The preparation of beam

Take the mPEG-PDLLA (number-average molecular weight 4000) of 500mg, chitosan-cholic acid of 100mg and 300mg Rg5H1 (E) and 50mg homoharringtonines, are dissolved in 20ml ether, and spin concentration film forming is depressurized in 30 DEG C, then proceedes to evaporate To dry, addition 20ml purified waters, aquation is stirred at 30 DEG C, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, freezing It is drying to obtain.After redissolving and detecting, average grain diameter 66nm, Bao Feng Shuai≤90%.

The preparation of adriamycin ginsenoside Rg 5H1 (Z) mixed micelle of embodiment 30 containing mPEG-PLA

Take the mPEG-PLA (number-average molecular weight 2400) of 100mg, the ginsenoside Rg 5H1 (Z) of 400mg and 50mg Ah mould Element is dissolved in 20ml methanol, and spin concentration film forming is depressurized in 50 DEG C, then proceedes to be evaporated to dryness, 20ml purified waters are added, 40 DEG C stirring aquation, dissolving obtain clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.After redissolving and detecting, put down Equal grain size is 27.3nm, Bao Feng Shuai≤95%.

The preparation of cis-platinum ginsenoside Rk1H mixed micelle of the embodiment 31 containing PEG-PLGA

The PEG-PLGA (number-average molecular weight 2000) of 100mg, ginsenoside Rk1H and the 50mg cis-platinum of 200mg are taken, it is molten In 20ml THF, spin concentration film forming is depressurized in 55 DEG C, then proceedes to be evaporated to dryness, it is water-soluble that 5% glucose of 20ml is added Liquid, aquation is stirred at 55 DEG C, and dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is examined through redissolving After survey, average grain diameter 18.8nm, Bao Feng Shuai≤95%.

The preparation of naproxen ginsenoside Rh 3H mixed micelle of the embodiment 32 containing PEG-PHis

20 (the R)-Rh3H and 30mg naproxens of the PEG-Phis (number-average molecular weight 4000) and 200mg of 100mg are taken, it is molten In 20ml methanol, rotation film forming is concentrated under reduced pressure in 50 DEG C, then proceedes to be evaporated to dryness, it is water-soluble that 5% glucose of 20ml is added Liquid, in 30 DEG C of aquations, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.It is detected through redissolving Afterwards, average grain diameter 22.5nm, Bao Feng Shuai≤90%.

Homoharringtonine ginseng sapoglycoside Rg 3 H1 (E) epoxy glue of embodiment 33 containing mPEG-PDLLA and chitosan-cholic acid The preparation of beam

Take the mPEG-PDLLA (number-average molecular weight 4000) of 500mg, chitosan-cholic acid of 100mg and 300mg Rg3H1 (E) and 50mg homoharringtonines, are dissolved in 20ml ether, and spin concentration film forming is depressurized in 30 DEG C, then proceedes to evaporate To dry, addition 20ml purified waters, aquation is stirred at 30 DEG C, dissolving obtains clear micellar solution.Through 0.22 μm of membrane filtration, freezing It is drying to obtain.After redissolving and detecting, average grain diameter 35.5nm, Bao Feng Shuai≤90%.

The preparation of adriamycin ginseng sapoglycoside Rg 3 H1 (Z) mixed micelle of embodiment 34 containing mPEG-PLA

Take the mPEG-PLA (number-average molecular weight 2400) of 100mg, the ginseng sapoglycoside Rg 3 H1 (Z) of 400mg and 50mg Ah mould Element is dissolved in 20ml methanol, and spin concentration film forming is depressurized in 50 DEG C, then proceedes to be evaporated to dryness, 20ml purified waters are added, 40 DEG C stirring aquation, dissolving obtain clear micellar solution.Through 0.22 μm of membrane filtration, it is freeze-dried to obtain the final product.After redissolving and detecting, put down Equal grain size is 24.5nm, Bao Feng Shuai≤95%.

The haemolysis Journal of Sex Research of 1 ginsenoside nano-micelle of application examples and mixed micelle

Ginsenoside (12 total)：Ginsenoside Rg 5,20 (R)-Rg5H, 20 (S)-Rg5H, Rg5H1 (E), Rg5H1 (Z), Rk1H, S-Rp1, R-Rp1, R-Rh3H, S-Rh3H, Rh3H1 (E), Rh3H1 (Z) etc. 12.

The preparation of ginsenoside nano-micelle：With reference to the method for the preparation Examples 1 to 4 of aforementioned mixed micelle, it is added without Amphipathic copolymer replaces different ginsenosides.

The preparation of mixed micelle：With reference to the preparation method of ginsenoside nano-micelle in the application example, different people is replaced Join saponin(e and amphipathic nature polyalcohol.

Table 2

Number	Hemolytic (HD50)	Number	Hemolytic (HD50)
				Rg5 nano-micelles	45-50ug/ml	Rg5+PEG-DSPE mixed micelles	1mg/ml has no haemolysis
Rg5H nano-micelles	120-130ug/ml	Rg5H+PEG-DSPE mixed micelles	1mg/ml has no haemolysis
				Rg5H1 (E) nano-micelle	70-80ug/ml	Rg5H1 (E)+mPEG-PDLLA mixed micelles	1mg/ml has no haemolysis
Rg5H1 (Z) nano-micelle	70-80ug/ml	Rg5H1 (Z)+mPEG-PLA mixed micelles	1mg/ml has no haemolysis
				Rk1H nano-micelles	70-80ug/ml	Rk1H+PEO-PAsp mixed micelles	1mg/ml has no haemolysis
Rp1 nano-micelles	≤0.5ug/ml	Rp1+PEG-PCL mixed micelles	1mg/ml has no haemolysis
				Rh3H nano-micelles	35-40ug/ml	Rh3H+PEG-PAsp mixed micelles	1mg/ml has no haemolysis
Rh3H1 (E) nano-micelle	35-40ug/ml	Rh3H1 (E)+PEG-PHis mixed micelles	1mg/ml has no haemolysis
				Rh3H1 (Z) nano-micelle	35-40ug/ml	Rh3H1 (Z)+PEG-PHis mixed micelles	1mg/ml has no haemolysis

Conclusion：Ginsenoside itself has stronger hemolytic, and after ginsenoside is at nano-micelle, HD50 generally exists 50ug/ml or so, hemolytic are stronger if Rp1 is even in 0.5ug/ml hereinafter, be dfficult to apply to drug-loading system；And mixed micelle Haemolysis is had no in 1mg/ml.

Mixed micelle considerably reduces the hemolytic of ginsenoside nano-micelle compared to ginsenoside nano-micelle.

The nanometer particle size of 2 mixed micelle of application examples is studied

The preparation of nano-micelle：With reference to the preparation Examples 1 to 4 method of aforementioned mixed micelle, but it is added without ginseng respectively Saponin(e or amphipathic copolymer, and amphipathic nature polyalcohol nano-micelle or ginsenoside nano-micelle is made.Each sample detection 3 It is secondary, obtain 3 particle size ranges.

Mixed micelle：With reference to the preparation method of nano-micelle in the application example, different saponin(es and amphipathic nature polyalcohol are replaced, Each sample detection 3 times, obtains 3 particle size ranges.

Table 3

Conclusion：Under identical conditions, the grain size of ginsenoside nano-micelle is generally in 60~100nm；Amphipathic copolymer Nano-micelle has been even up to a μm rank, it is difficult to compatible well with organism generally in 300~800nm；And mixed micelle Grain size is generally in 15~60nm.

It follows that mixed micelle, compared to ginsenoside nano-micelle, amphipathic nature polyalcohol nano-micelle, grain size obtains Significantly reduce.

The preparation stabilization Journal of Sex Research of 3 mixed micelle of application examples

The preparation of mixed micelle：Take the amphipathic copolymer of 200mg, the ginsenoside of 400mg, 50mg taxols, 50mg VE is dissolved in 20ml methanol：Chloroform=1：In the mixed solution of 1 (volume ratio), spin concentration film forming is depressurized in 60 DEG C, is then proceeded to It is evaporated to dryness, 5% glucose solutions of 20ml is added, aquation is stirred at 60 DEG C, dissolving obtains clear micellar solution.By micella As in 4 DEG C of refrigerators, observation solution presents muddy or solid required time is precipitated solution, and experiment is terminated after 24 hours.

The preparation of ginsenoside nano-micelle：With reference to the preparation method of mixed micelle in the application example, it is added without amphipathic Copolymer.

The preparation of amphipathic copolymer nano micella：With reference to the preparation method of mixed micelle in the application example, it is added without people Join saponin(e.

Table 4

Conclusion：Under under identical conditions, ginsenoside nano-micelle, which is placed 2~4 hours, there is muddy, amphipathic copolymerization Object nano-micelle, which is placed 3~4 hours, there is muddiness, and mixed micelle just occurred up to 8~12 hours or even 24 hours or more It is muddy.

It follows that the preparation stability of mixed micelle obtains significantly than the stability of saponin(e or polymer nano micelle Promotion.

4 In vitro cell experiment of application examples and interior animal experiment

Ginsenoside Rg's 5+mPEG-DSPE blank mixed micelle is (referred to as：Mixing is empty), taxol polymer micelle (referred to as： Genexol-PM), taxol ginsenoside Rg 5 and PEG-DSPE mixed micelles (abbreviation：Taxol mixed micelle) to human lung cancer The effect experiment of cell (A549)/human lung cancer taxol resistance strain (A549/T).

Remarks：Because in preliminary experiment, 5 micella of taxol ginsenoside Rg is unstable in Mice, causes small white mouse Death, therefore, comparative study in the non-receptosome of taxol ginsenoside nano-micelle.

The preparation of taxol mixed micelle：The method for preparing embodiment 5 with reference to aforementioned mixed micelle.

Mix empty preparation：With reference to the method that aforementioned mixed micelle prepares embodiment 5, it is added without active material taxol.

Taxol polymer micelle is purchased from South Korea Samyang Biopharmaceuticals Corporation (Seoul,Korea)。

1, cell in vitro viability experiment

According to In vitro cell experiment method, ginsenoside Rg's 5+mPEG-DSPE blank mixed micelle is measured (referred to as：Mixing It is empty), the taxol polymer micelles of South Korea Samyang productions (referred to as：Genexol-PM), taxol ginsenoside Rg 5 with PEG-DSPE mixed micelles are (referred to as：Taxol mixed micelle) processing human lung carcinoma cell (A549) and human lung cancer taxol are resistance to respectively The survival rate of medicine strain (A549/T) cell afterwards.

By 7 drug concentrations are arranged in table 5 and table 6, specific experiment data are shown in Table 5 and table 6 and Fig. 1 and Fig. 2.

Table 5

From table 5 and Fig. 1：The empty activity to human lung carcinoma cell (A549) of mixing is weaker；When taxol high concentration (200ng/mL), Genexol-PM are suitable to the activity of human lung carcinoma cell (A549) with taxol mixed micelle；With taxol Drug level reduce (100,50,25,12.5,6.5ng/mL), taxol mixed micelle to human lung carcinoma cell (A549) compare Genexol-PM embodies better activity.

Table 6

From table 6 and Fig. 2：Mixing is empty and Genexol-PM to the activity of the human lung carcinoma cell of resistance to taxol (A549/T) compared with Weak, when taxol high concentration (100 μ g/mL), Genexol-PM is with taxol mixed micelle to human lung carcinoma cell (A549/T) It is active suitable；As taxol Drug level reduces (50,25,12.5,6.5,3.125,1.5625 μ g/mL), taxol mixing Micella embodies better activity to human lung cancer taxol resistance strain (A549/T) than Genexol-PM.

2, cell in vitro IC₅₀Experiment

According to IC₅₀Experimental method measures mixing sky, Genexol-PM, taxol mixed micelle respectively to human lung carcinoma cell (A549), the IC of human lung cancer taxol resistance strain (A549/T)₅₀Value, experimental data such as table 7：

Table 7

Project	A549 cell strains (ng/mL)	A549/T cell strains (μ g/mL)
			Mixing is empty	/	/
Genexol-PM	62.49	22.20
			Taxol mixed micelle	60.66	12.08

As shown in Table 7：Taxol mixed micelle ratio Genexol-PM is lower to the IC50 of A549, taxol mixed micelle pair The IC50 ratios Genexol-PM of resistance to taxol human lung cancer persister (A549/T) is also lower, compared with cell strain, taxol mixing 3% and 46% has been respectively increased in the cell drug effect ratio Genexol-PM groups of micella group, illustrates the mixed micelle of the present invention to drug resistance Bacterial strain is more effective.

3, internal effect experiment

According to internal effect experiment method, 27 subcutaneous tumor bearing nude mices are randomly divided into 3 groups (every group 9), are set to Blank control group (Control groups, 0.9%NaCl), Genexol-PM groups, taxol mixed micelle group.By corresponding preparations through tail Intravenous injection is (according to 25mgkg^-1Dosage administration).The changes of weight for recording every group of mouse every three days, is used in combination vernier caliper Tumour longest diameter and most short diameter are measured, knurl product is calculated by following formula：V=(dmax × dmin²)/2, wherein dmin and Dmax is respectively the minor axis and major diameter (mm) of tumour；Relative tumour volume (relative tumor are calculated according to the result of measurement Volume, RTV), calculation formula is：RTV=Vt/V0.Wherein V0 is the gross tumor volume measured when administration, and Vt is to survey every three days The gross tumor volume of amount.

3.1, Control groups, Genexol-PM groups, taxol mixed micelle group make the tumor suppression of human lung carcinoma cell (A549) Comparison (drug effect), specific experiment data are shown in Table 8 and Fig. 3.

Table 8

From table 8 and Fig. 3：Under same time, the gross tumor volume of Control groups is maximum, and taxol mixed micelle group Secondly minimum is Genexol-PM groups.Genexol-PM group tumour inhibiting rates are 80%, taxol mixed micelle group tumour inhibiting rate is 95%, it compares, tumour inhibiting rate improves 1.19 times.

3.2, Control groups, Genexol-PM groups, taxol mixed micelle group are to human lung cancer taxol resistance strain (A549/ T the comparison (drug effect) of tumor-inhibiting action), specific experiment data are shown in Table 9 and Fig. 4.

Table 9

From table 9 and Fig. 4：Under same time, the gross tumor volume of Control groups is maximum, and taxol mixed micelle group Secondly minimum is Genexol-PM groups.Genexol-PM group tumour inhibiting rates are 58%, taxol mixed micelle group tumour inhibiting rate is 90%, it compares, tumour inhibiting rate improves 1.55 times.

Claims

1. a kind of blank mixed micelle, which is characterized in that the blank mixed micelle includes amphipathic copolymer and such as Formulas I institute The ginsenoside shown：

R³For

R⁴For H ,-OH ,=O ,-OCH₃,-OEt ,-OAc, positive propoxy, isopropoxy, positive propionyloxy, isopropenoxy, positive fourth Oxygroup, isobutoxy, positive bytyry, isobutyryl ,-OBz ,-F ,-Cl ,-Br ,-I ,-NH₂Or-SH；

R⁵For H ,-OH ,=O ,-OCH3 or-OAc；

R⁶For-OH ,-OCH3 ,-OOH ,-OAc or-OBz；

R⁷And R⁸It independently is H ,-OH ,-OCH₃,-OCHO ,-OAc or-OBz；

R¹⁰For any one of following radicals：-O-Glc、-O-Rha、-O-Lyx、-O-Xyl、-O-Ara(p)、-O-Ara(f)、- O-Glc (2 → 1) Glc (digital representation carbon potential, → indicate connection relation, similarly hereinafter) ,-O-Glc (6 → 1) Glc ,-O-Glc (2 → 1) Rha、-O-Glc(2→1)Xyl、-O-Glc(6→1)Xyl、-O-Glc(6→1)Rha、-O-Glc(2→1)Ara(p)、-O-Glc (6→1)Ara(p)、-O-Glc(2→1)Ara(f)、-O-Glc(6→1)Ara(f)、-O-Glc(2→1)Glc(2→1)Glc、- O-Glc(2→1)Glc(2→1)Xyl、-O-Glc(6→1)Glc(6→1)Xyl、-O-Glc(2→1)Glc(4→1)Xyl、-O- Glc(2→1)Lyx、-O-Glc(6→1)Lyx、-O-Glc(2→1)Glc(2→1)Rha、-O-Glc(2→1)Glc(2→1) Lyx、-O-Glc(2→1)Glc(2→1)Ara(f)、-O-Glc(2→1)Glc(2→1)Ara(p)、-O-Glc(2→1)Glc(6 →1)Glc、-O-Glc(2→1)Glc(6→1)Rha、-O-Glc(2→1)Glc(6→1)Xyl、-O-Glc(2→1)Glc(6→ 1)Lyx、-O-Glc(2→1)Glc(6→1)Ara(f)、-O-Glc(2→1)Glc(6→1)Ara(p)、-O-Glc(6→1)Glc (2→1)Glc、-O-Glc(6→1)Glc(2→1)Rha、-O-Glc(6→1)Glc(2→1)Xyl、-O-Glc(6→1)Glc(2 →1)Lyx、-O-Glc(6→1)Glc(2→1)Ara(f)、-O-Glc(6→1)Glc(2→1)Ara(p)、-O-Glc(6→1) Glc(6→1)Glc、-O-Glc(6→1)Glc(6→1)Rha、-O-Glc(6→1)Glc(6→1)Lyx、-O-Glc(6→1) Glc (6 → 1) Ara (f) or-O-Glc (6 → 1) Glc (6 → 1) Ara (p)；

R¹¹For R¹⁰In more than one hydroxyl by R¹⁰Replaced, each R¹⁰(when having more than two) phase each independently It is same or different；

R¹²For any one of following radicals；

I)-mPEG ,-Z-mPEG ,-mPEO ,-Z-PEO ,-mPVP ,-Z-PVP ,-mEPEG or-Z-EPEG；Wherein, m H, alkyl Or acyl group, Z are-CO (CH₂)_aCO-、-NH(CH₂)_aCO-、-NH(CH₂)_bX- or-CO-Ar-CH₂-；Wherein, X O, S or NH, Ar For aryl, a 1,2,3,4,5,6,7 or 8, b 1,2,3,4,5,6,7,8,9 or 10；

II)C₄-C₂₂Fatty acyl group, phosphate-based, succinic acid ester group, n-butyric acie ester group, sulfonate group, malic acid ester group or sulphur Acid sodium-salt；

III) Boc- glycine, Boc- alanine, Boc- arginine, Boc- lysines, Boc- serines, acetylphenylalanine, Acetyl proline, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, leucine, It is formed by base after carboxyl dehydrogenation in methionine, phenylalanine, proline, threonine, tryptophan, tyrosine or valine Group；

IV)-O-PEO ,-O-PVP ,-O-PEG ,-O-MPEG ,-O-EPEG ,-O-Glc (2 → 1) Glc (6 → 1) Mal or-O-Glc (2→1)Glc(6→1)Ac；

R¹³For any one of following radicals；

2. blank mixed micelle as described in claim 1, which is characterized in that the amphipathic copolymer and described such as formula The mass ratio of ginsenoside shown in I is 100:1-0.01:1, preferably 10:1-0.1:1, more preferably 10:1-0.25:1；

And/or the R¹For-OH,

And/or the R²For H ,-OH,

And/or the R³For Preferably More preferably

And/or the R⁴For-OH ,-OAc or=O；

And/or the R⁵For H or-OH；

And/or more than one hydroxyl in the ginsenoside shown in formula I is optionally by one or more R¹¹Replaced； Each R¹¹It is identical or different each independently；

And/or more than one hydroxyl in the ginsenoside shown in formula I is optionally by R¹²Replaced；Each R¹²Respectively It is independently identical or different；

And/or the number-average molecular weight of described PEG, PEO, PVP and EPEG are separately 200~20000；

And/or the fatty acyl group is naturally occurring saturation or acyl group and the artificial synthesized saturation of unsaturated fatty acid Or the acyl group of undersaturated aliphatic acid, preferably stearyl or palmityl.

3. blank mixed micelle as described in claim 1, which is characterized in that under the ginsenoside shown in formula I is It is one or more in row compound：

,

Preferably 20 (S)-ginseng sapoglycoside Rg 3s, 20 (S)-ginseng saponin Rh 2s, protopanoxadiol, protopanaxatriol, ginsenoside Rg5, ginsenoside Rk1, ginsenoside Rh 3, ginsenoside Rg2, ginsenoside Rg 4, Ginsenoside Rh4, ginsenoside Rh 1, Up to female woods A, ginsenoside Rg 5H, ginsenoside Rg 5H1 (E), ginsenoside Rg 5H1 (Z), ginsenoside Rk1H, ginsenoside Rh3H, ginsenoside Rh 3H1 (E), ginsenoside Rh 3H1 (Z), ginsenoside Rp1,25- methyl-different ginseng sapoglycoside Rg 3, an extraordinary person Join saponin(e Rg3 (E), different ginseng sapoglycoside Rg 3 (Z), different ginsenoside Rg3H, different ginseng saponin Rh 2 (E), different ginseng saponin Rh 2 (Z), ginsenoside Rp2, ginsenoside Rp3, Pseudo-ginsenoside GQ, pseudoginsenoside HQ, ginsenoside SC-Rp1 and ginseng soap It is one or more in glycosides DC-Rp1.

4. blank mixed micelle as described in claim 1, which is characterized in that the amphipathic copolymer is two block copolymerizations Object and/or triblock copolymer；

Hydrophilic radical in the amphipathic copolymer is preferably polyethylene glycol, mono methoxy polyethylene glycol, polyethylene pyrrole Alkanone, polyoxyethylene, polyvinyl alcohol, chitosan and its derivative, imitative cell membrane Phosphorylcholine and water soluble cyclodextrin derivant In it is one or more；The number-average molecular weight of the polyethylene glycol is preferably 300-50000, more preferably 500-10000, example Such as 300,350,500,550,1000,2000,3400,5000,10000,20000,30000,40000 or 50000；

Hydrophobic grouping in the amphipathic copolymer is preferably polylactic acid, Poly-L-lactide, poly- D, and Pfansteihl, poly- third are handed over Ester-glycolide, poly-epsilon-caprolactone, poly- benzyl asparatate, poly benzyl glutamate, polystyrene, polyisopropyl acrylamide, Polylysine, poly-aspartate, polyhistidyl, phosphatide, phosphatidyl-ethanolamine, Distearoyl Phosphatidylethanolamine, cholesterol and It is one or more in hydrophobic cyclodextrin derivative.

5. blank mixed micelle as claimed in claim 4, which is characterized in that the amphipathic copolymer be mPEG-DSPE, mPEG-PDLLA、mPEG-PLA、PVP-PNIPAM、mPEG-PAsp、PEG-DSPE、PEG-DSPE-NH2、PEG-PAsp、PEG- Phis、PEG-PLGA、PEG-PBLG、PEG-PLA、PEG-PBLA、PEG-PCL、PEG-PCLLA、PEO-PAsp、PEO-PGlu、 PNIPPA-PAA, PCLLA-PEG-PCLLA, PEO-PPO-PEO, PEO-PLA-PEO, PEG-PLGA-PEG, phosphatidyl-ethanolamine- Polyethylene glycol, dipalmitoylphosphatidylethanolamine-polyethylene glycol, distearoylphosphatidylethanolamine-polyethylene glycol, two oil Acyl phosphatidyl-ethanolamine-polyethylene glycol, C8 ceramides-polyethylene glycol, C16 ceramides-polyethylene glycol, distearyl acyl group phosphorus Acyl ethanol amine-polyethylene glycol-succinyl, distearoylphosphatidylethanolamine-polyethylene glycol-carboxyl, distearyl acyl group phosphorus The double sulfydryls of acyl ethanol amine-polyethylene glycol-dimaleoyl imino, distearoylphosphatidylethanolamine-polyethylene glycol-propionamide The poly- second of pyridine, distearoylphosphatidylethanolamine-polyethylene glycol-Cyanuric Chloride, distearoylphosphatidylethanolamine-two The poly- second of alcohol-amino, distearoylphosphatidylethanolamine-polyethylene glycol-biotin, distearoylphosphatidylethanolamine-two Alcohol-folic acid, distearoylphosphatidylethanolamine-polyethylene glycol-folic acid, dilauroyl phosphatidyl-ethanolamine-polyethylene glycol, Distearoylphosphatidylethanolamine-polyethylene glycol-active ester, phosphatidyl-ethanolamine-polyethylene glycol-active ester, two palmityls Base phosphatidyl-ethanolamine-polyethylene glycol-active ester, dilauroyl phosphatidyl-ethanolamine-polyethylene glycol-active ester, distearyl Acylphosphatidyl ethanolamine-polyethylene glycol-dimaleoyl imino, phosphatidyl-ethanolamine-polyethylene glycol-dimaleoyl imino, two Palmityl phosphatidyl-ethanolamine-polyethylene glycol-dimaleoyl imino, dilauroyl phosphatidyl-ethanolamine-polyethylene glycol-horse Come imide, distearoylphosphatidylethanolamine-polyethylene glycol-biotin, the poly- second of distearoylphosphatidylethanolamine- Glycol-fluorescein, distearoylphosphatidylethanolamine-polyethylene glycol-hydroxyl, the poly- second of distearoylphosphatidylethanolamine- Glycol-amino, phosphatidyl-ethanolamine-polyethylene glycol-amino, dipalmitoylphosphatidylethanolamine-polyethylene glycol-amino, two Lauroyl phosphatidyl-ethanolamine-polyethylene glycol-amino, distearoylphosphatidylethanolamine-polyethylene glycol-carboxyl, phosphatide Acyl ethanol amine-polyethylene glycol-carboxyl, dipalmitoylphosphatidylethanolamine-polyethylene glycol-carboxyl, dilauroyl phosphatidyl Ethanol amine-polyethylene glycol-carboxyl, distearoylphosphatidylethanolamine-polyethylene glycol-sulfenyl, distearyl acyl group phosphatidyl second Hydramine-polyethylene glycol-silane, distearoylphosphatidylethanolamine-polyethylene glycol-nitrine, cholesterol-polyethylene glycol, methoxy Base-polyethylene glycol-cholesterol, cholesterol-polyethylene glycol-active ester, cholesterol-polyethylene glycol-maleimide, cholesterol- Polyethylene glycol-biotin, cholesterol-polyethylene glycol-fluorescein, cholesterol-polyethylene glycol-carboxyl, cholesterol-polyethylene glycol- It is one or more in amino and cholesterol-polyethylene glycol-sulfenyl, preferably mPEG-DSPE, mPEG-PDLLA, mPEG-PLA, PEG-DSPE、PEG-DSPE-NH2、PEG-PAsp、PEG-PBLA、PEG-PBLG、PEG-PCL、PEG-Phis、PEG-PLGA、 It is one or more in PEO-PAsp and PEO-PPO-PEO；

The number-average molecular weight of the mPEG-DSPE is preferably 2000；

The number-average molecular weight of the mPEG-PDLLA preferably 2000 or 4000, more preferably 2000；

The number-average molecular weight of the mPEG-PLA is preferably 2400；

The number-average molecular weight of the PEG-DSPE is preferably 2000 or 4000；

The number-average molecular weight of the PEG-DSPE-NH2 is preferably 4000；

The number-average molecular weight of the PEG-PAsp is preferably 4800；

The number-average molecular weight of the PEG-PBLA is preferably 2000；

The number-average molecular weight of the PEG-PBLG is preferably 4000；

The number-average molecular weight of the PEG-PCL is preferably 2000；

The number-average molecular weight of the PEG-Phis is preferably 4000；

The number-average molecular weight of the PEG-PLGA is preferably 2000；

The number-average molecular weight of the PEO-PAsp is preferably 4800；

The number-average molecular weight of the PEO-PPO-PEO is preferably 4800；

The number-average molecular weight of the DMPE-PEG is preferably 350,550,750,1000,2000,3000 or 5000；

The number-average molecular weight of the DPPE-PEG is preferably 350,550,750,1000,2000,3000 or 5000；

The number-average molecular weight of the DSPE-PEG is preferably 350,550,750,1000,2000,3000,5000,10000, 20000,30000 or 40000

The number-average molecular weight of the DOPE-PEG is preferably 350,550,750,1000,2000,3000 or 5000；

The number-average molecular weight of the C8Ceramide-PEG is preferably 750,2000 or 5000；

The number-average molecular weight of the C16Ceramide-PEG is preferably 750,2000 or 5000；

The number-average molecular weight of the DLPE-PEG is preferably 2000 or 5000；

The number-average molecular weight of the DSPE-PEG-NHS be preferably 1000,2000,5000,10000,20000,30000 or 40000；

The number-average molecular weight of the DMPE-PEG-NHS is preferably 3400 or 5000；

The number-average molecular weight of the DPPE-PEG-NHS is preferably 3400 or 5000；

The number-average molecular weight of the DLPE-PEG-NHS is preferably 3400 or 5000；

The number-average molecular weight of the DSPE-PEG-Maleimide is preferably 1000,2000,3400,5000 or 10000；

The number-average molecular weight of the DMPE-PEG-Maleimide is preferably 1000,2000,3400,5000 or 10000；

The number-average molecular weight of the DPPE-PEG-Maleimide is preferably 1000,2000,3400,5000 or 10000；

The number-average molecular weight of the DLPE-PEG-Maleimid is preferably 1000,2000,3400,5000 or 10000；

The number-average molecular weight of the DSPE-PEG-Biotin is preferably 1000,2000,3400,5000 or 10000；

The number-average molecular weight of the DSPE-PEG-FITC is preferably 1000,2000,3400,5000 or 10000；

The number-average molecular weight of the DSPE-PEG-OH is preferably 2000,3400 or 5000；

The number-average molecular weight of the DSPE-PEG-NH2 is preferably 2000,3400 or 5000；

The number-average molecular weight of the DMPE-PEG-NH2 is preferably 2000,3400 or 5000；

The number-average molecular weight of the DPPE-PEG-NH2 is preferably 2000,3400 or 5000；

The number-average molecular weight of the DLPE-PEG-NH2 is preferably 2000,3400 or 5000；

The number-average molecular weight of the DSPE-PEG-COOH is preferably 2000,3400 or 5000；

The number-average molecular weight of the DMPE-PEG-COOH is preferably 2000,3400 or 5000；

The number-average molecular weight of the DPPE-PEG-COOH is preferably 2000,3400 or 5000；

The number-average molecular weight of the DLPE-PEG-COOH is preferably 2000,3400 or 5000；

The number-average molecular weight of the DSPE-PEG-SH is preferably 5000；

The number-average molecular weight of the DSPE-PEG-Silane is preferably 3400；

The number-average molecular weight of the DSPE-PEG-N3 is preferably 2000,3400 or 5000；

The number-average molecular weight of the mPEG-CLS is preferably 1000,2000,5000,10000 or 20000；

The number-average molecular weight of the Cholesterol PEG NHS ester be preferably 1000,2000,3400,5000 or 10000；

The number-average molecular weight of the CLS-PEG-Mal is preferably 2000,3400,5000 or 10000；

The number-average molecular weight of the CLS-PEG-Biotin is preferably 2000,3400 or 5000；

The number-average molecular weight of the CLS-PEG-FITC is preferably 2000,3400 or 5000；

The number-average molecular weight of the Cholesterol PEG COOH is preferably 3400；

The number-average molecular weight of the Cholesterol PEG amine is preferably 3400；

The number-average molecular weight of the Cholesterol PEG Thiol/Sulfhydril is preferably 3400；

The di-block copolymer is preferably mPEG-DSPE, mPEG-PDLLA, mPEG-PLA, PEG-DSPE, PEG-DSPE- NH2, PEG-PAsp, PEG-PBLA, PEG-PBLG, PEG-PCL, PEG-Phis, PEG-PLGA, PEO-PAsp and PEO-PPO- It is one or more in PEO；

The triblock copolymer is preferably PEO-PPO-PEO, PEG-PLGA-PEG, PCLLA-PEG-PCLLA, PEO-PLA- It is one or more in PEO and PCL-PEG-PCL.

6. blank mixed micelle as described in claim 1, which is characterized in that the blank mixed micelle also may include antioxygen It is one or more in agent, freeze drying protectant, emulsifier and assistant for emulsifying agent；

The antioxidant be preferably sodium pyrosulfite, sodium thiosulfate, propylgallate, vitamin C, alpha-tocopherol, 'alpha '-hydroxy acids, flavone compound, Phenylpropanoid glycoside, vitamin E, fumaric acid, cysteine, methionine, fourth Hydroxyanisole, butyl hydroxy toluene, thio-2 acid, sulphite, bisulfites, dithiocarbamates benzoic acids chemical combination One in object, citric acid, malic acid, sorbierite, glycerine, propylene glycol, quinhydrones, Hydroxycoumarin, ethanol amine, phosphoric acid and phosphorous acid Kind is a variety of, more preferably vitamin E and/or vitamin C；

Content of the antioxidant in blank mixed micelle is preferably smaller than equal to 25%, more preferably 0.001%- 15%, for example, 3%, 6%, 14%, 0.01%-10%, 0.01%-5% or 0.1%-1%；The percentage refers to antioxygen The percentage of the quality of agent and the gross mass of the blank mixed micelle；

It is one or more in the freeze drying protectant preferably sugar, polyalcohol, amino acid and buffer, more preferably 5% It is one or more in glucose solution, physiological saline and phosphate buffer solution；The sugar be preferably monosaccharide and disaccharide and It is one or more in polysaccharide；The monosaccharide is preferably one kind or more in glucose, mannitol, xylitol and sorbierite Kind；The disaccharide is preferably one or more in sucrose, lactose, galactolipin and maltose；The polysaccharide is preferably sea Algae sugar；The polyalcohol is preferably propylene glycol and/or glycerine；The amino acid is preferably a-amino acid, such as ammonia of reviving It is one or more in acid, glycine, glutamic acid, arginine and histidine；

The buffer solution is preferably buffer solution of the pH value between 3-10, and buffering of the more preferable pH value between 5-7 is molten Liquid；The buffer solution be preferably physiological saline, ethyl alcohol-hac buffer, trishydroxymethylaminomethane buffer solution, bar Than appropriate buffer solution, sodium formate buffer solution, phthalic acid salt buffer solution, citrate buffer solution, citric acid-phosphoric acid Disodium hydrogen buffer solution, ammonia-ammonium chloride buffer solution, borax-calcium chloride buffer solution, acetate buffer solution, acetic acid-lithium salts Buffer solution, NaAc_HAc buffer solution, acetic acid-ammonium acetate buffer solution, phosphoric acid-triethylamine buffer solution or phosphate Buffer solution；

Content of the freeze drying protectant in blank mixed micelle is preferably smaller than equal to 80%, such as 61.73~ 75.76%, in another example 61.73%, 65.36%, 65.57%, 74.07%, 75.19%, 75.76%, 0.5%-60%, 5%- 60% or 30%-60%；The percentage refers to that the quality of freeze drying protectant accounts for the blank mixed micelle gross mass Percentage；

The emulsifier is preferably Arabic gum, western twelve month yam glue, gelatin, albumin, casein, soybean lecithin, lecithin, courage Sterol, fatty acid sorbitan, polysorbate, polyoxyethylene ester fat acid ester, polyoxyethylene aliphatic alcohol ether class, polyoxyethylene polyoxy third It is one or more in alkene copolymer class, sucrose-fatty lipid and glycerin monostearate etc., such as cholesterol；

Content of the emulsifier in blank mixed micelle is preferably smaller than equal to 10%, such as 0.01%-10%, 0.1%- 5% or 1%-5%；；The percentage refers to the percentage that the quality of emulsifier accounts for the blank mixed micelle gross mass；

The assistant for emulsifying agent is preferably one kind or more in n-butanol, ethylene glycol, ethyl alcohol, propylene glycol, glycerine and polyglycerol ester Kind；

Content of the assistant for emulsifying agent in blank mixed micelle is preferably smaller than equal to 10%, such as 0.01%-10%, 0.1%-5% or 1%-5%；The percentage refers to that the quality of assistant for emulsifying agent accounts for the blank mixed micelle gross mass Percentage.

7. a kind of preparation method of blank mixed micelle as claimed in any one of claims 1 to 6, wherein it includes following method One or method two：

Method one includes the following steps：

(1) by water, amphipathic copolymer and ginsenoside shown in formula I mix, be optionally added into antioxidant, emulsifier and It is one or more in assistant for emulsifying agent, obtain a clear solution；

(2) film forming or self-contained micella, then with water or the aqueous solution containing freeze drying protectant mixes, be optionally added into antioxidant, It is one or more in emulsifier and assistant for emulsifying agent, a solution is obtained, is filtered, is freeze-dried to get the blank mixed micelle；

Method two includes the following steps：

(1) by organic solvent or the mixed solvent of water and organic solvent, with amphipathic copolymer, ginseng soap shown in formula I Glycosides mixes, and is optionally added into one or more in antioxidant, emulsifier and assistant for emulsifying agent, obtains a clear solution；

(2) organic solvent of gained clear solution in step (1), film forming, then with water or containing the water-soluble of freeze drying protectant are removed Liquid mixes, and is optionally added into one or more in antioxidant, emulsifier and assistant for emulsifying agent, obtains a solution, filtering, freezing Drying is to get the blank mixed micelle；

In method one or method two, the amphipathic copolymer is described such as Formulas I as described in claim 1,4 or 5 any one Shown in ginsenoside as described in claim any one of 1-3, it is the antioxidant, the freeze drying protectant, described Emulsifier and the assistant for emulsifying agent are as claimed in claim 6.

8. preparation method as claimed in claim 7, which is characterized in that

In step (1) in method two, the organic solvent can be nitrile solvents, C₁-C₄Alcohols solvent, ketones solvent, ether It is one or more in class solvent and halogenated hydrocarbon solvent, preferably C₁-C₄Alcohols solvent, nitrile solvents, ether solvent and It is one or more in halogenated hydrocarbon solvent；The nitrile solvents are preferably acetonitrile；The C₁-C₄Alcohols solvent is preferable Ground is one or more in methanol, ethyl alcohol, isopropanol and n-butanol；The ether solvent is preferably ether, tetrahydrochysene furan It mutters；The halogenated hydrocarbon solvent is preferably chloroform and/or dichloromethane；The ketones solvent be preferably acetone and/ Or butanone；The volume mass ratio of the organic solvent and all components in two step of method (1) is 4-10mL/g；

And/or in method one or method two, in step (1), the temperature of the mixing is 0-80 DEG C, preferably 10-80 DEG C, Preferably 30-60 DEG C；

And/or in the step of method two (2), the operation of the organic solvent of clear solution is to use in the removing step (1) Rotary evaporator, film evaporator or film dialysis remove organic solvent；The temperature of the removing organic solvent is 25-80 DEG C；

And/or in the step (2) in method one or method two, the method for the film forming is decompression spin concentration；

And/or in the step (2) in method one or method two, described is filtered into filtering with microporous membrane；The miillpore filter Aperture be preferably 0.22 micron；

And/or in method one or method two, when mixed with the film in the step (2) be freeze drying protectant aqueous solution When, the aqueous solution of the freeze drying protectant is the aqueous solution of the freeze drying protectant of 5%-10%, and the percentage refers to freezing Do the percentage that protectant quality accounts for freeze drying protectant aqueous solution gross mass；

And/or in method one or method two, in step (2), the drying is freeze-drying.

9. a kind of blank mixed micelle as claimed in any one of claims 1 to 6 is in the mixed micelle for preparing carrying active substance Application, the active material in the mixed micelle of the carrying active substance is drug, active material and tool in cosmetics Have one or more in the substance of healthcare function.

10. a kind of mixed micelle of carrying active substance, which is characterized in that the mixed micelle of the carrying active substance refers to One or more in active material and substance with health role in drug, cosmetics are encapsulated in such as claim 1- In 6 any one of them blank mixed micelles.

11. the mixed micelle of application as claimed in claim 9 or carrying active substance as claimed in claim 10, feature It is, the ginsenoside and the mass ratio of amphipathic copolymer and the drug shown in formula I is 100:1-1: 1, such as 20:1、16.7:1、16:1、12:1、10:1、8.3:1、6:1、4:1；Preferably 25:1-5:1, such as 20:1、16.7: 1、16:1、12:1、10:1、8.3:1、6:1；More preferably 15:1-5:1, such as 12:1、10:1、8.3:1、6:1；

And/or the drug be antitumor drug, anti-inflammatory drug, antibacterials, sedative hypnotic drug, antipsychotics, Hormone medicine, antibiotics, calcium ion antagonist, antiviral drugs, immunosuppressor, anesthetic, cardiovascular and cerebrovascular and It is one or more in blood vessel dilatation drug, polynucleotide and oligonucleotides；

The antitumor drug is preferably taxol, docetaxel, Cabazitaxel, irinotecan hydrochloride, camptothecine, hydroxyl happiness Set alkali, amino camptothecin, 7-Ethyl-10-hydroxycamptothecin, topotecan hydrochloride, Lurtotecan, Hycamtin, Belotecan, Cis-platinum, carboplatin, oxaliplatin, Nedaplatin, network platinum, satraplatin, Miboplatin, penta platinum, Aroplatin, carmustine, Chlorambucil, How soft melphalan, harringtonine, homoharringtonine, triptolide, tacrolimus, daunorubicin, bleomycin A5, hydrochloric acid is Than star, idarubicin, fluorouracil, cytarabine, methotrexate (MTX), Etoposide phosphate, deoxypodophyllotoxin, tartaric acid Changchun Rui Bin, vincristine sulphate, vinblastine sulfate, vinorelbine, vindesine sulfate, Temozolomide, Tegafur, ring phosphinylidyne Amine, ifosfamide, Dacarbazine, ebomycin A, epothilone B, epothilones C, Epothilone D, Epothilones E, Ai Bo Mycin F, bortezomib, gemcitabine hydrochloride, fludarabine phosphate, capecitabine, Decitabine, pemetrexed disodium, recombination Human interferon a2b, Arabinoside cytimidine, all-trans retinoic acid, proleulzin, etoposide, thymidylate synthase inhibit Agent, mitoxantrone, minoxidil, azithromycin, epirubicin hydrochloride, doxorubicin hydrochloride, Amrubicin Hydrochloride, KRN- 5500, tamoxifen, tamoxifen, 5-ALA, 3 ', 5 '-dipalmitoyl cyclocytidines and one kind in rcumenol or It is a variety of；More preferably taxol, docetaxel, camptothecine, homoharringtonine, adriamycin, cis-platinum, oxaliplatin, angstrom uncle are mould It is one or more in plain C, irinotecan hydrochloride and all-trans retinoic acid；

The anti-inflammatory drug is preferably Indomethacin, naproxen, ketone chromic acid, aspirin, paracetamol, double chlorine sweet smell One or more in acid, brufen, bifendate, aulin, rofecoxib and celecoxib, more preferably indoles is beautiful It is one or more in pungent, naproxen and bifendate；

The antibacterials are preferably amphotericin B, gentamicin, benzyl penicillin, econazole nitrate, Flucytosine, fluorine health Azoles, Itraconazole, voriconazole, posaconazole, ravuconazole, Caspofungin, mikafen, anidulafungin, CefPiramide Sodium, Cefotaxime Sodium, ceftriaxone, cefoperazone, Cefditoren pivoxil Cephalosporins, cefoxitin sodium, cefalexin, Cefuroxime Sodium, cephalo Gram oxime, Cefpodoxime, Cefmenoxime, Cefodizime, Cefsulodin, Cefuzonam, Ceftizoxime, Cefetamet Pivoxil, cephalo are special Logical sequence ester, ceftibuten, Cefdinir, Cefamandole, Cefotiam, ceforanide, cefonicid, cefotaxime, Cefradine, Cefprozil, Cefazolin sodium, cefadroxil, cefoxitin, cefathiamidine, cefaloridine, cephalosporin, ceftezole, One kind or more in cefapirin, Cefpirome, Cefclidin, Cefepime, sodium fusidate, Florfenicol and tigecycline Kind, more preferably amphotericin B；

The anti-sedative hypnotic drug is preferably Clonazepam, diazepam, nitrazepam, estazolam, alprazolam, bar ratio It is one or more in appropriate, phenobarbital, amytal, secobarbital sodium and pentothal, more preferably Clonazepam；

The antipsychotics is preferably haloperidol, chlorpromazine, Li Paili ketone, agomelatine, Prozac, Paro west Spit of fland, Duloxetine, Sertraline, Fluvoxamine, Citalopram, escitalopram, Venlafaxine, Mirtazapine, imipramine, Ah meter For one kind in woods, chlorimipramine, doxepin, Remeron, venlafaxin, nardil, Isocarboxazid and parnitene or more Kind；More preferably haloperidol；

The hormone medicine is preferably dihydrotestosterone and/or progesterone, more preferably dihydrotestosterone；

The antibiotic is preferably cyclosporin A, Nysfungin, penicillin, ospen, Amoxicillin, ampicillin, benzene azoles XiLin, Cloxacillin, procaine penicillin, tardocillin, Piperacillin, mezlocillin, Ticarcillin, azlocillin, Mecillinam, Carbenicillin, sulbenicillin, Furbucillin, naphthlazole, dicloxacillin, Pivampicillin, apalcillin, Ah flutterring west Woods, Pivmecillinam, methicillin, Lenampicillin, fomidacillin, flucloxacillin, kanamycins, Natamycin, mitomycin, fourth Amine kanamycins, tylosin, Verteporfin, CefPiramide Sodium, netilmicin sulfate, azithromycin, Ofloxacin, ring third are husky Star, Enoxacin, Lomefloxacin, pefloxacin, Rufloxacin, Sparfloxacin, fleraxacin, Moxifloxacin, Grepafloxacin, song Cut down Sha Xing, linxacin, gemifloxacin, gatifloxacin, tosufloxacin, Pazufloxacin, Sparfloxacin, clarithromycin, clindamycin, Polymyxins, tobramycin, vancomycin, azithromycin, Doxycycline, tetracycline, terramycin, minocycline, aureomycin, guanidine First ring element, demeclocycline, metacycline, Etimicin, Netilmicin, sisomicin, amikacin, Arbekacin, Bekaa Star, aztreonam, Meropenem, Imipenem, thiomycin, Panipenem, ertapenem, neomycin, paromomycin and grand sight are mould It is one or more in element, more preferably cyclosporin A；

The calcium ion antagonist is preferably fenofibrate, Nimodipine, nifedipine, nicardipine, nitrendipine, Wella It is one or more in pa rice, Amlodipine, diltiazem, flunarizine, prenylamine, Gallopamil and tiapamil, it is more excellent It is selected as fenofibrate；

The anesthetic is preferably Desflurane, sevoflurane, isoflurane, enflurane, Propofol, fentanyl, urethane, benefit card One kind in cause, procaine, totokaine, Bupivacaine, yellow Jackets, chloraldurate, ketamine, chloralose and morphine or It is a variety of, more preferably Propofol；

The cardiovascular and cerebrovascular and blood vessel dilatation drug be preferably dabigatran etcxilate, Egelieting, sodium alginate, in ginkgo Ester, GINKGO BILOBA EXTRACT, ginkgo biloba extract, asarone, olmesartan medoxomil, Repaglinide, lipoic acid, Breviscapinun, Urapidil, cigarette Acid, captopril, Losartan, Puerarin, tanshinone IIA, sarpogrelate hydrochloride, tropicamide, Fluvastatin, Pravastatin, Simvastatin, Lovastatin, Simvastatin, mevastatin, cerivastatin, rosuvastatin, Atorvastatin calcium and Rui Su are cut down It is one or more in statin calcium, more preferably Puerarin；

The polynucleotide or oligonucleotides preferably refers to having heredity by what several in base A, T, C, G and U formed Etc. functions segment, such as SiRNA, antisense nucleic acid or microglia NLRP3 genes RNAi sequences, more preferably SiRNA；

Active material in the cosmetics is preferably ursolic acid, superoxide dismutase, bioprotein T4N5, vitamin It is one or more in D2, Vitamin K3, methyl nicotinate, refined snake oil, hyaluronic acid, essential oil and ceramide, more preferably Vitamin K3.

12. a kind of preparation method of the mixed micelle of carrying active substance as described in claim 9 or 10, which is characterized in that It includes following either method

Method A includes the following steps：

Amphipathic copolymer, ginsenoside shown in formula I, active material and organic solvent are mixed, antioxygen is optionally added into It is one or more in agent, emulsifier and assistant for emulsifying agent, organic solvent is removed, is formed a film, then with water or containing freeze drying protectant Aqueous solution mixes, and is optionally added into one or more in antioxidant, emulsifier and assistant for emulsifying agent, formation carrying active substance Mixed micelle after to get carrying active substance mixed micelle solution, filtering, after freeze-drying；

Method B includes the following steps：

Amphipathic copolymer, ginsenoside shown in formula I and organic solvent are mixed, then mixed with active material, with water or Aqueous solution containing freeze drying protectant is dialysed to get the mixed micelle solution of carrying active substance, and antioxidant, breast are optionally added into It is one or more in agent and assistant for emulsifying agent, filtering, dialyzate freeze-drying；

Method C includes the following steps：

Active material is mixed to obtain to mixture A with organic solvent, by amphipathic copolymer and ginsenoside and water shown in formula I Or buffer solution mixes to obtain mixture B, mixture A is added drop-wise to formation oil/water mixed type emulsion in mixture B, optionally One or more in antioxidant, freeze drying protectant, emulsifier and assistant for emulsifying agent, removing organic solvent, filtering, freezing is added After drying；

Method D includes the following steps：

By active material, amphipathic copolymer, ginsenoside shown in formula I and solvent mix, the active material, with, Covalent bond occurs for active group on amphipathic copolymer or ginsenoside shown in formula I, be optionally added into antioxidant, It is one or more in freeze drying protectant, emulsifier and assistant for emulsifying agent, it is organic molten when needing to remove containing organic solvent in solvent Agent, filtering, after freeze-drying；

Method E includes the following steps：

When active material is soluble easily in water, mixed in active material, amphipathic copolymer, ginsenoside and water shown in formula I, It is optionally added into one or more in antioxidant, emulsifier and assistant for emulsifying agent, filtering, after freeze-drying；

Amphipathic copolymer described in method A, B, C, D or E is described such as Formulas I as described in claim 1,4 or 5 any one Shown in ginsenoside as described in claim any one of 1-3, it is the antioxidant, the freeze drying protectant, described Emulsifier and the assistant for emulsifying agent are as claimed in claim 6.

13. preparation method according to claim 12, which is characterized in that

In method B, the operation of the dialysis includes the following steps：The mixed micelle solution is placed in glucose solution In or pure water in dialyse；The time of the dialysis is 5-20 hours, preferably 12 hours；

And/or the organic solvent or solvent is dichloromethane, chloroform, methanol, ethyl alcohol, ether, acetonitrile, acetone, second It is one or more in acetoacetic ester, tetrahydrofuran, dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO) and pyridine；

And/or in method A, B, C, D or E, according to the fat-soluble or water-soluble of the active material, the active material with The form of the organic solution of the aqueous solution of the active material or the active material uses；The active material it is water-soluble The organic solution preferred mass volume fraction of liquid or the active material is the aqueous solution or organic solution of 1%-20%, described Percentage refer to that the quality of the active material accounts for the active material aqueous solution or the active material organic solution is total The percentage of volume.