CN105367804A - Amphiphilic block polymer for carrying medicine and preparing method and application of amphiphilic block polymer - Google Patents
Amphiphilic block polymer for carrying medicine and preparing method and application of amphiphilic block polymer Download PDFInfo
- Publication number
- CN105367804A CN105367804A CN201510690016.4A CN201510690016A CN105367804A CN 105367804 A CN105367804 A CN 105367804A CN 201510690016 A CN201510690016 A CN 201510690016A CN 105367804 A CN105367804 A CN 105367804A
- Authority
- CN
- China
- Prior art keywords
- block polymer
- drug
- ethylene glycol
- methoxy poly
- polymkeric substance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an amphiphilic block polymer and a preparing method and application of the amphiphilic block polymer in treating tumor diseases. The amphiphilic block polymer comprises a hydrophilic chain segment and a hydrophobic chain segment, wherein polyethylene glycol with the molecular weight ranging from 100 to 6,000 or methoxy polyethylene glycol with the molecular weight ranging from 300 to 6,000 serves as the hydrophilic chain segment, polylactide with the molecular weight ranging from 200 to 6,000 serves as the hydrophobic chain segment, 6-fmoc ethanolamine-2-carbobenzoxy-aminocarproic acid is used for blocking of the hydrophobic chain segment, and the weight ratio of polyethylene glycol or methoxy polyethylene glycol to polylactide is 0.1-30:1. The amphiphilic block polymer can be prepared into a medicine carrying system with anti-tumor drug and medically-acceptable auxiliary materials. The invention further provides the application of the amphiphilic block polymer in preparing tumor treating medicine.
Description
Technical field
The invention provides the preparation method of a kind of block polymer and micella thereof, and the application of its treatment tumour aspect disease, belong to chemical field.
Background technology
Polymer micelle is a kind of stable colloidal dispersion system that development in recent years is got up.Micella is formed by self-assembly by amphiphilic block macromolecular polymkeric substance usually, and its hydrophobic segment is inside, and hydrophilic chain is outside, presents typical " core-shell structure copolymer " structure.Polymer micelle can significantly improve the solubleness of insoluble drug; Hydrophobic pharmaceutical pack is wrapped in the core of micella, can reduce the toxic side effects of medicine; In addition, micella passs release system as a kind of Nano medication, reaches the object of tumor tissues passive target by strengthening osmotic effect (EnhancedPermeabilityandRetentionEffect, EPR effect).
Polymer micelle common vector is general linear Amphipathilic block polymer, hydrophilic section material is usually by polyoxyethylene glycol (Polyethyleneglycol, and its derivative, polyoxyethylene (polyethyleneoxide PEG), PEO), polyvinylpyrrolidone (Polyvinylpyrrolidone, the composition such as PVP), and hydrophobic section material is made up of polyester or poly-acid usually, such as: polylactide (Polylactide, PLA), polycaprolactone, polyglycolic acid (Polyglycolicacid, PGA) etc.Wherein polyoxyethylene glycol polylactide (PEG-PLA) is a kind of common polymer blocks polymkeric substance, carries out vivo medicine-feeding after can being combined with medicine.
In order to effectively play the EPR effect of nano-carrier, improving the tumor tissue targeting of medicine, just requiring that carrier can keep stable in blood, by nano-carrier in blood for a long time circulation improve the probability entering tumor tissues.But, for self-assembling polymers micella, research in recent years finds: in the very short time of micella after entering blood, medicine just discharges, and the medicine of release completes the transhipment (JournalofControlledRelease164 (2012): 108-114) of tissue and tumour essentially by the mode of random diffusion.Occur that the major cause of this situation is that hydrophobic segment in block macromolecular and the reactive force between medicine are more weak, micella is through the dilution of blood after entering blood, and medicine is easy to diffuse out from the core of micella.As can be seen here, the stability of micella be improved, thus the effect of more effective performance passive target, the problem of core increases the reactive force between hydrophobic segment and drug molecule.
Therefore how to improve the reactive force between hydrophobic segment and drug molecule, become the new problem of the new carrier micelle polymkeric substance of exploitation.
For above-mentioned technical problem, contriver is by feasibility in theory demonstration and the collection of many experimental results, provide a kind of novel amphipathic sex-mosaicism polymkeric substance, this polymkeric substance is made up of jointly hydrophilic section and hydrophobic section, hydrophilic section has selected polyoxyethylene glycol (PEG) or methoxy poly (ethylene glycol) (mPEG), these two kinds have polymkeric substance and have good biocompatibility and biodegradability, hydrophobic section then needs with polylactide, thus construct PEG-PLA or mPEG-PLA polymkeric substance, and on the terminal hydroxyl of PEG-PLA or mPEG-PLA, introduce fluorenylmethyloxycarbonyl (Fmoc) group, because in Fmoc group, the delocalization scope of electronic cloud is very large, therefore, it is possible to and containing phenyl ring, very strong conjugation is formed between the medicine of the groups such as double bond, and drug molecule is limited to firmly " in core " not easily stripping of micella, obtain the micelle medicine carrying system that a kind of inside and outside has high stability, the targeting of the tumor tissues of medicine can be improved.
Summary of the invention
According to specification sheets technical background content, technical problem solved by the invention is, improves the reactive force between polymer micelle and medicine, thus makes it, in drug effect process, can high stabilityly to exist, and improves the targeting of medicine for focal zone.
Based on above-mentioned purpose, the invention provides a kind of Amphipathilic block polymer, described Amphipathilic block polymer comprises hydrophilic segment and hydrophobic chain segment, hydrophilic segment is the polyoxyethylene glycol of molecular weight 100-6000 or the methoxy poly (ethylene glycol) of molecular weight 300-6000, hydrophobic chain segment is the polylactide of molecular weight 200-6000, hydrophobic chain carries out end-blocking with 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid, and the part by weight scope of polyoxyethylene glycol or methoxy poly (ethylene glycol) and polylactide is 0.1-30: 1.
Because methoxy poly (ethylene glycol) is different with the molecular weight of polylactide, cause their composition drug-loading system stability variant.
The present invention is preferred, and hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 300-4000, and hydrophobic chain is polylactide and the polymkeric substance thereof of molecular weight 300-5000; Preferred further, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 600-3000, and hydrophobic chain is polylactide and the polymkeric substance thereof of molecular weight 400-4000; Preferred further again, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 1000-3000, and hydrophobic chain is polylactide and the polymkeric substance thereof of molecular weight 500-3000; Preferred further again, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 1500-3000, and hydrophobic chain is polylactide and the polymkeric substance thereof of molecular weight 1000-2000; Most preferably, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 1500-2500, and polylactide is 1200-1500.For obtaining the polymkeric substance of more stable high-quality, preferably the part by weight scope of polyoxyethylene glycol or methoxy poly (ethylene glycol) and polylactide is 0.5-10: 1 further.
Wherein hydrophobic chain carries out end-blocking with 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
The present invention selects the polymer with good biocompatibility and degradation property, can not remain by Cumulate Sum in vivo, has high biological safety.MPEG-PLA end section hydroxyl is with after above-mentioned group modified end-blocking, and hydrophobicity improves greatly, and reduce the micelle-forming concentration forming micella, stability significantly improves.In addition in Fmoc group, the delocalization scope of electronic cloud is very large, therefore, it is possible to form very strong conjugation with the medicine containing the group such as phenyl ring, double bond, the carrier micelle Chinese traditional medicine molecule that according to this prepared by polymer is limited to not easily stripping in the core of micella firmly, thus obtains the micelle medicine carrying system that a kind of inside and outside has high stability.The stability improving micella can prolong drug cycling time in blood, thus utilize EPR effect to improve the targeting of tumor tissues.
Therefore above-mentioned amphipathic nature polyalcohol of the present invention can effectively solve polymer hydrophobic chain and drug interaction power is weak, the technical barrier of drug-loading system poor stability.
Present invention also offers a kind of drug-loading system containing described amphipathic chimeric polymkeric substance, drug-loading system forms by treating the antitumor drug of significant quantity, polymkeric substance and/or pharmaceutically acceptable pharmaceutical excipients.
Drug-loading system of the present invention, directly can be made up of polymkeric substance and medicine completely, can reach beneficial effect of the present invention; But preferably add pharmaceutical excipients in drug-loading system, the drug-loading system obtained more aspect is more excellent.
In an embodiment of the present invention, the drug-loading system of described polymkeric substance, it is made up of polymkeric substance and antitumor drug, and the drug loading of this polymkeric substance is 0.5%-20%, when its drug loading is 0.5%-20%, the weight ratio being equivalent to antitumor drug and polymkeric substance is 1: 4-1000; In a preferred embodiment of the invention, the drug loading of this polymkeric substance is generally 1%-20%, preferred 1%-15%, more preferably 3%-10%.
In another preferred embodiment of the present invention, described drug-loading system, also comprises pharmaceutically acceptable pharmaceutical excipients; That is, this drug-loading system is made up of antitumor drug, polymkeric substance and pharmaceutically acceptable pharmaceutical excipients, and the weight ratio of antitumor drug and polymkeric substance is 1: 4-1000, and the weight ratio of antitumor drug and pharmaceutical excipients is 1: 0.5-30.
The above-mentioned drug-loading system be made up of antitumor drug, polymkeric substance and pharmaceutically acceptable pharmaceutical excipients, described antitumor drug and the weight ratio of polymkeric substance are 1: 4-1000, the amount (drug loading of the present invention) being equivalent to polymer supported tumour medicine is 0.5%-20%, preferred 1%-20%, more preferably 1%-15%, most preferably 3%-10%.
Wherein antitumor drug can be taxol, docetaxel, Cabazitaxel, methotrexate, 5 FU 5 fluorouracil, endoxan, daunorubicin, Zorubicin, pidorubicin, pirarubicin, ipsapirone, fulvestrant, Velcade, Ka Feizuo meter, camptothecin, curcumine and derivative, Artemisinin and derivative thereof, Artemether etc.These medicines are mixed with into preparation with interpolymer with pharmaceutical excipients, and wherein freeze-drying micella becomes form of medication optimum at present.Therefore described pharmaceutical excipients can be freeze-dried excipient, and described freeze-dried excipient can be one or more combinations of lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, sucrose, trehalose, fructose, glucose, sodium alginate or gelatin.
Preferably, this drug-loading system is made up of antitumor drug, polymkeric substance and/or pharmaceutically acceptable pharmaceutical excipients, and the weight ratio of antitumor drug and polymkeric substance is 1: 4-1000, and the weight ratio of antitumor drug and pharmaceutical excipients is 1: 0.5-30.
Present invention also offers a kind of preparation method of amphipathic chimeric polymkeric substance, comprise the following steps:
(1) polyoxyethylene glycol or methoxy poly (ethylene glycol) are joined in polymerization bottle, heat up and stir and vacuumize, rac-Lactide is added after cooling, stannous octoate, reactant high temperature polymerization after product methylene dichloride dissolves, and filters to obtain solid polyethylene glycol or methoxy poly (ethylene glycol) block polymer after precipitation;
(2) triethylamine is added after being dissolved by 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid anhydrous tetrahydro furan, pivalyl chloride is added after cooling, precipitation is had to generate, reactant continues reaction after heating up, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid;
(3) polyoxyethylene glycol or methoxy poly (ethylene glycol) block polymer are dissolved in methylene dichloride, add triethylamine, 4-pyrollidinopyridine, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in methylene dichloride, after join in the dichloromethane solution of polyoxyethylene glycol or methoxy poly (ethylene glycol) block polymer, stir after heat up, continue stirring reaction.Filter solid is polyoxyethylene glycol or the methoxy poly (ethylene glycol)-polylactide block polymer of using 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant precipitation.
Preferably, above-mentioned preparation method comprises the following steps:
(1) 10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, heat up and stir and vacuumize, add rac-Lactide 11g after cooling, stannous octoate 5.5mg, reactant high temperature polymerization after product methylene dichloride dissolves, and filters white solid had both been mPEG-PLA block polymer after ether sedimentation;
(2) 12.5g6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid anhydrous tetrahydro furan adds 3-10mL triethylamine after dissolving, and adds pivalyl chloride 2-5mL after cooling, has precipitation to generate.Continue reaction 1h after reactant intensification, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid;
(3) 20gmPEG-PLA is dissolved in methylene dichloride, add triethylamine 5mL, 4-pyrollidinopyridine 1.0g, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in methylene dichloride, after join in the dichloromethane solution of mPEG-PLA, heat up after stirring reaction 1h, continue stirring reaction.Filter solid had both been the methoxy poly (ethylene glycol)-polylactide block polymer (mPEG-PLA-Lys (Fmoc)) of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant precipitation.
The preparation method of drug-loading system of the present invention, also comprise, described polymkeric substance and medicine dissolution are in organic solvent, and rotary evaporation removes organic solvent, add appropriate ultrapure water and dissolve medicine film, gained solution after filtration membrane filtration adds freeze-dried excipient and obtains drug-loading system micelle freeze-drying powder; Aseptic treatment step is had before described step of freeze drying.
Described freeze-dried excipient comprises one or more combinations of lactose, N.F,USP MANNITOL, Xylitol, sorbyl alcohol, sucrose, trehalose, fructose, glucose, sodium alginate or gelatin.
Present invention also offers a kind of preparation method of amphipathic chimeric polymkeric substance, comprise the following steps:
(1) polyoxyethylene glycol or methoxy poly (ethylene glycol) are joined in polymerization bottle, heat up and stir and vacuumize, polylactide and stannous octoate is added after cooling, reactant high temperature polymerization after product methylene dichloride dissolves, and filters to obtain solid polyethylene glycol or methoxy poly (ethylene glycol) block polymer after precipitation.
(2) triethylamine is added after being dissolved by 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid anhydrous tetrahydro furan, pivalyl chloride is added after cooling, precipitation is had to generate, reactant continues reaction after heating up, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
(3) polyoxyethylene glycol or methoxy poly (ethylene glycol) block polymer are dissolved in methylene dichloride, add triethylamine, 4-pyrollidinopyridine, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in methylene dichloride, after join in the dichloromethane solution of polyoxyethylene glycol or methoxy poly (ethylene glycol) block polymer, stir after heat up, continue stirring reaction; Reactant sedimentation and filtration obtains polyoxyethylene glycol or the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking.
In a preferred embodiment of the invention, provide a kind of preparation method of amphipathic chimeric polymkeric substance, comprise the following steps:
(1) 10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, heat up and stir and vacuumize, add rac-Lactide 11g after cooling, stannous octoate 5.5mg, reactant high temperature polymerization after product methylene dichloride dissolves, and filters white solid is mPEG-PLA block polymer after precipitation.
(2) 12.5g6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid anhydrous tetrahydro furan adds 3-10mL triethylamine after dissolving, and adds pivalyl chloride 2-5mL after cooling, has precipitation to generate; Continue reaction 1h after reactant intensification, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
(3) 20gmPEG-PLA is dissolved in methylene dichloride, add triethylamine 5mL, 4-pyrollidinopyridine 1.0g, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in methylene dichloride, after join in the dichloromethane solution of mPEG-PLA, heat up after stirring reaction 1h, continue stirring reaction; Filter solid is the methoxy poly (ethylene glycol)-polylactide block polymer (mPEG-PLA-Lys (Fmoc)) of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant precipitation.
In another preferred embodiment of the present invention, provide a kind of preparation method of amphipathic chimeric polymkeric substance, comprise the following steps:
(1) synthesis of mPEG-PLA
Polyoxyethylene glycol or methoxy poly (ethylene glycol) are joined in polymerization bottle, heat up and stir and vacuumize, add rac-Lactide after cooling, stannous octoate, reactant dissolves through high temperature polymerization after product methylene dichloride, filters to obtain solid polyethylene glycol or methoxy poly (ethylene glycol) block polymer after precipitation.
(2) acid anhydrides preparation
Triethylamine is added after being dissolved by 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid anhydrous tetrahydro furan, pivalyl chloride is added after cooling, precipitation is had to generate, reactant continues reaction after heating up, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
(3) end capping
Polyoxyethylene glycol or methoxy poly (ethylene glycol) block polymer are dissolved in methylene dichloride, add triethylamine, 4-pyrollidinopyridine, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in methylene dichloride, after join in the dichloromethane solution of polyoxyethylene glycol or methoxy poly (ethylene glycol) block polymer, stir after heat up, continue stirring reaction.Filter solid is polyoxyethylene glycol or the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant precipitation.
According to above-mentioned preparation method, present invention also offers a kind of preferred method, comprise the following steps:
(1) 10g methoxy poly (ethylene glycol) 2000 (mPEG2000) joins in polymerization bottle, heat up and stir and vacuumize, rac-Lactide 11g is added after cooling, stannous octoate 5.5mg, reactant high temperature polymerization after product methylene dichloride dissolves, and filters white solid had both been mPEG-PLA block polymer (mPEG-PLA) after ether sedimentation.
(2) 12.5g6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid (α-Fmoc-ω-Boclysine) adds 5mL triethylamine after dissolving with anhydrous tetrahydro furan, adds pivalyl chloride 3.5mL after cooling, has precipitation to generate.Continue reaction 1h after reactant intensification, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
(3) 20gmPEG-PLA is dissolved in methylene dichloride, add triethylamine 5mL, 4-pyrollidinopyridine 1.0g, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in methylene dichloride, after join in the dichloromethane solution of mPEG-PLA, heat up after stirring reaction 1h, continue stirring reaction.Filter solid had both been the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant precipitation.
Amphipathic chimeric polymkeric substance described in invention is mixed with into micelle freeze-drying preparation with antitumor drug, substantially increase the solubleness of antitumor drug, and the micella particle diameter of preparation is little, encapsulation rate is high, good stability, there is the feature such as passive target and long circulating, wherein methoxy poly (ethylene glycol)-polylactide the block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking has the effect overcoming multidrug resistance, the micella energy significantly increasing medicament be prepared into is in intracellular accumulation, can be applicable to reversing tumor many resistances field, there is good application prospect.
Therefore the invention provides the application of a kind of Amphipathilic block polymer in preparation tumor.
Present invention also offers the application of a kind of drug-loading system containing amphipathic chimeric polymkeric substance in the medicine of preparation treatment tumour.
Embodiment
Ultrapure water described in the present invention is known to the skilled person, namely water for injection.
Contriver verifies practicality and the beneficial effect of the compounds of this invention by following experiment.
Reiterate: following experiment is the exemplary experiment in R&D process of the present invention in numerous experiment, do not contained with limit all experiments that invention people does for the present invention, object is only that setting forth the present invention by those data is provided with features and application.
Embodiment 1
The preparation of methoxy poly (ethylene glycol)-polylactide block polymer
1) mPEG
2000-PLA
1300synthesis
10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, be warming up to 130 DEG C stir and vacuumize 1h, D is added after being cooled to room temperature, L-rac-Lactide 11g, stannous octoate 5.5mg, vacuum seal polymerization bottle, reactant dissolves at 130 DEG C of polymerization 15h after product methylene dichloride, filters white solid had both been mPEG after ice ether sedimentation
2000-PLA
1300block polymer, it is 3300 that nuclear-magnetism calculates polymericular weight, and gel permeation chromatography (GelPermeationChromatography, GPC) measures high molecular molecular weight and molecular weight distribution index is respectively 4596,1.06.(data table related 1).
Table 1 Generalized Relative peak value
2) end capping
12.5g6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid 50mL anhydrous tetrahydro furan adds 3.5mL triethylamine after dissolving, and adds pivalyl chloride 3.05mL after being cooled to-10 DEG C, and adularescent precipitation generates at once.Reactant is warming up to and 0 DEG C of reaction 2h follow-up continuing is warming up to 25 DEG C of reaction 1h, crosses evaporating solvent after filtering insolubles extremely dry that colourless viscous liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
20gmPEG
2000-PLA
1300be dissolved in 100mL methylene dichloride, add triethylamine 3.5mL, 4-pyrollidinopyridine 0.37g, after this solution is cooled to 0 DEG C, join in the dichloromethane solution of mPEG-PLA after new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in 50mL methylene dichloride, be warming up to 25 DEG C after stirring reaction 1h and continue stirring reaction 24h.Filter white solid had both been the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant ice ether sedimentation.
Embodiment 2
1) mPEG
2000-PLA
1000synthesis
10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, be warming up to 130 DEG C stir and vacuumize 1h, D is added after being cooled to room temperature, L-rac-Lactide 7g, stannous octoate 3mg, vacuum seal polymerization bottle, reactant dissolves at 130 DEG C of polymerization 15h after product methylene dichloride, filters white solid had both been mPEG after ice ether sedimentation
2000-PLA
1000block polymer, it is that 3000, GPC measures high molecular molecular weight and molecular weight distribution index is respectively 3943 that nuclear-magnetism calculates polymericular weight, 1.05.
2) end capping
12.5g6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid 50mL anhydrous tetrahydro furan adds 3-10mL triethylamine after dissolving, and adds pivalyl chloride 3.05-3.5mL after being cooled to-10 DEG C, and adularescent precipitation generates.Reactant is warming up to and 0 DEG C of reaction 2h follow-up continuing is warming up to 25 DEG C of reaction 1h, crosses evaporating solvent after filtering insolubles extremely dry that colourless viscous liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
20gmPEG
2000-PLA
1000be dissolved in 100mL methylene dichloride, add triethylamine 3.5mL, 4-pyrollidinopyridine 0.37g, after this solution is cooled to 0 DEG C, join in the dichloromethane solution of mPEG-PLA after new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in 50mL methylene dichloride, be warming up to 25 DEG C after stirring reaction 1h and continue stirring reaction 24h.Filter white solid had both been the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant ice ether sedimentation.
Embodiment 3
1) mPEG
2000-PLA
1500synthesis
10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, be warming up to 130 DEG C stir and vacuumize 1h, D is added after being cooled to room temperature, L-rac-Lactide 13g, stannous octoate 6mg, vacuum seal polymerization bottle, reactant dissolves at 130 DEG C of polymerization 15h after product methylene dichloride, filters white solid had both been mPEG after ice ether sedimentation
2000-PLA
1300block polymer, it is that 3500, GPC measures high molecular molecular weight and molecular weight distribution index is respectively 4746 that nuclear-magnetism calculates polymericular weight, 1.06.
2) end capping
12.5g6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid 50mL anhydrous tetrahydro furan adds 3.5mL triethylamine after dissolving, and adds pivalyl chloride 3.05mL after being cooled to-10 DEG C, and adularescent precipitation generates at once.Reactant is warming up to and 0 DEG C of reaction 2h follow-up continuing is warming up to 25 DEG C of reaction 1h, crosses evaporating solvent after filtering insolubles extremely dry that colourless viscous liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
20gmPEG
2000-PLA
1500be dissolved in 100mL methylene dichloride, add triethylamine 3.5mL, 4-pyrollidinopyridine 0.37g, after this solution is cooled to 0 DEG C, join in the dichloromethane solution of mPEG-PLA after new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in 50mL methylene dichloride, be warming up to 25 DEG C after stirring reaction 1h and continue stirring reaction 24h.Filter white solid had both been the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant ice ether sedimentation.
Embodiment 4
1) mPEG
2000-PLA
1800synthesis
10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, be warming up to 130 DEG C stir and vacuumize 1h, D is added, L-rac-Lactide 15g, stannous octoate 8mg after being cooled to room temperature, vacuum seal polymerization bottle, reactant dissolves at 130 DEG C of polymerization 15h after product methylene dichloride, and filter white solid had been both mPEG2000-PLA1800 block polymer after ice ether sedimentation, it is 3800 that nuclear-magnetism calculates polymericular weight, GPC measures high molecular molecular weight and molecular weight distribution index is respectively 4938, and 1.06.
2) end capping
12.5g6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid 50mL anhydrous tetrahydro furan adds 3.5mL triethylamine after dissolving, and adds pivalyl chloride 3.05mL after being cooled to-10 DEG C, and adularescent precipitation generates at once.Reactant is warming up to and 0 DEG C of reaction 2h follow-up continuing is warming up to 25 DEG C of reaction 1h, crosses evaporating solvent after filtering insolubles extremely dry that colourless viscous liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
20gmPEG
2000-PLA
1800be dissolved in 100mL methylene dichloride, add triethylamine 3.5mL, 4-pyrollidinopyridine 0.37g, after this solution is cooled to 0 DEG C, join in the dichloromethane solution of mPEG-PLA after new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in 50mL methylene dichloride, be warming up to 25 DEG C after stirring reaction 1h and continue stirring reaction 24h.Filter white solid had both been the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant ice ether sedimentation.
Embodiment 5
2mg docetaxel and the methoxy poly (ethylene glycol)-polylactide block polymer 98mg of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking obtained by embodiment 1 are dissolved in 20mL ethanol at 45 DEG C, rotary evaporation adds 2mL ultrapure water and dissolves medicine film after removing ethanol, after gained solution adds 50mg N.F,USP MANNITOL after 0.22um membrane filtration, freeze-drying obtains docetaxel micelle freeze-drying powder, drug loading 2%.
Embodiment 6
100mg docetaxel and the methoxy poly (ethylene glycol)-polylactide block polymer 1900mg of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking obtained by embodiment 1 are dissolved in 20mL ethanol at 45 DEG C, rotary evaporation adds 20mL ultrapure water and dissolves medicine film after removing ethanol, after gained solution adds 500mg N.F,USP MANNITOL after 0.22um membrane filtration, freeze-drying obtains docetaxel micelle freeze-drying powder, drug loading 5%.
Embodiment 7
1mg docetaxel and the methoxy poly (ethylene glycol)-polylactide block polymer 99mg of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking obtained by embodiment 2 are dissolved in 20mL ethanol at 45 DEG C, rotary evaporation adds 2mL ultrapure water and dissolves medicine film after removing ethanol, after adding 10mg N.F,USP MANNITOL, the freeze-drying after 0.22um membrane filtration of gained solution obtains docetaxel micelle freeze-drying powder, drug loading 1%.
Embodiment 8
10mg Cabazitaxel and the methoxy poly (ethylene glycol)-polylactide block polymer 90mg of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking obtained by embodiment 3 are dissolved in 5mL ethanol at 45 DEG C, rotary evaporation adds 10mL ultrapure water and dissolves medicine film after removing ethanol, after gained solution adds 10mg sucrose after 0.22um membrane filtration, freeze-drying obtains docetaxel micelle freeze-drying powder, drug loading 10%.
Embodiment 9
10mg taxol and the methoxy poly (ethylene glycol)-polylactide block polymer 50mg of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking obtained by embodiment 4 are dissolved in 5mL ethanol at 45 DEG C, rotary evaporation adds 5mL ultrapure water and dissolves medicine film after removing ethanol, after gained solution adds 100mg glucose after 0.22um membrane filtration, freeze-drying obtains docetaxel micelle freeze-drying powder, drug loading 16.7%.
Embodiment 10
Prepare mPEG respectively
2000-PLA
1300methoxy poly (ethylene glycol)-polylactide block polymer/docetaxel the micellar solution (drug level is 2mg/mL) of/docetaxel micellar solution and 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking, in two kinds of micellar solution, add foetal calf serum (FBS) respectively and regulate serum-concentration to 50%, adopting the change of size of Dynamic Light Scattering Determination different time micella; The initial particle of two kinds of docetaxel micellas all at about 21nm, then methoxy poly (ethylene glycol)-polylactide block polymer/docetaxel the micella of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking in the blood solution of 50% after 12h particle diameter still there is no considerable change; But mPEG
2000-PLA
1300the micella size distribution that/docetaxel micella records in the serum solution of 50% obviously broadens, and illustrates that micella there occurs gathering.As can be seen here, the methoxy poly (ethylene glycol)-polylactide block polymer/docetaxel micella of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking has very high stability.
The present invention is not limited to above-mentioned embodiment, anyone other any or akin products identical with the present invention drawn under enlightenment of the present invention, is all not precluded within outside protection scope of the present invention.
Claims (16)
1. an Amphipathilic block polymer, it is characterized in that, described Amphipathilic block polymer comprises hydrophilic segment and hydrophobic chain segment, hydrophilic segment is the polyoxyethylene glycol of molecular weight 100-6000 or the methoxy poly (ethylene glycol) of molecular weight 300-6000, hydrophobic chain segment is the polylactide of molecular weight 200-6000, hydrophobic chain 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid carries out end-blocking, and the part by weight of polyoxyethylene glycol or methoxy poly (ethylene glycol) and polylactide is 0.1-30: 1.
2. polymkeric substance according to claim 1, it is characterized in that, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 300-4000, and hydrophobic chain is the polylactide of molecular weight 300-5000.
3. polymkeric substance according to claim 1, it is characterized in that, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 600-3000, and hydrophobic chain is the polylactide of molecular weight 400-4000.
4. polymkeric substance according to claim 1, is characterized in that, the methoxy poly (ethylene glycol) of hydrophilic chain to be molecular weight be 1000-3000, hydrophobic chain is the polylactide of molecular weight 500-3000.
5. polymkeric substance according to claim 1, is characterized in that, the methoxy poly (ethylene glycol) of hydrophilic chain to be molecular weight be 1500-3000, hydrophobic chain is the polylactide of molecular weight 1000-2000.
6. polymkeric substance according to claim 1, it is characterized in that, the part by weight of polyoxyethylene glycol or methoxy poly (ethylene glycol) and polylactide is 0.5-10: 1.
7. the drug-loading system containing polymkeric substance described in claim 1, it is characterized in that, this drug-loading system comprises polymkeric substance and antitumor drug, and the drug loading of this polymkeric substance is 0.5%-20%.
8. drug-loading system according to claim 7, is characterized in that, this drug-loading system also comprises pharmaceutically acceptable pharmaceutical excipients; This drug-loading system is made up of antitumor drug, polymkeric substance and pharmaceutically acceptable pharmaceutical excipients, and the weight ratio of antitumor drug and polymkeric substance is 1: 4-1000, and the weight ratio of antitumor drug and pharmaceutical excipients is 1: 0.5-30.
9. the drug-loading system according to claim 7 or 8, it is characterized in that, described medicine is taxol, docetaxel, Cabazitaxel, methotrexate, 5 FU 5 fluorouracil, endoxan, daunorubicin, Zorubicin, pidorubicin, pirarubicin, ipsapirone, fulvestrant, Velcade, Ka Feizuo meter, camptothecin, curcumine and derivative, Artemisinin, Artemether.
10. a preparation method for polymkeric substance described in claim 1, is characterized in that, comprises the following steps:
(1) polyoxyethylene glycol or methoxy poly (ethylene glycol) are joined in polymerization bottle, heat up and stir and vacuumize, rac-Lactide is added after cooling, stannous octoate, reactant high temperature polymerization after product methylene dichloride dissolves, and filters to obtain solid polyethylene glycol or methoxy poly (ethylene glycol) block polymer after precipitation;
(2) triethylamine is added after being dissolved by the group anhydrous tetrahydro furan containing 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid, pivalyl chloride is added after cooling, precipitation is had to generate, reactant continues reaction after heating up, cross evaporating solvent after filtering impurity and, to dry, obtain thick liquid for containing new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid;
(3) polyoxyethylene glycol or methoxy poly (ethylene glycol) block polymer are dissolved in methylene dichloride, add triethylamine, 4-pyrollidinopyridine, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid that contains of above-mentioned reaction gained is dissolved in methylene dichloride, after join in the dichloromethane solution of polyoxyethylene glycol or methoxy poly (ethylene glycol) block polymer, stir after heat up, continue stirring reaction.Filter solid is polyoxyethylene glycol or the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant precipitation.
11. preparation methods according to claim 13, is characterized in that, comprise the following steps:
(1) 10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, heat up and stir and vacuumize, add rac-Lactide 11g after cooling, stannous octoate 5.5mg, reactant high temperature polymerization after product methylene dichloride dissolves, and filters white solid had both been mPEG-PLA block polymer after precipitation;
(2) 12.5g6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid anhydrous tetrahydro furan adds 3-10mL triethylamine after dissolving, and adds pivalyl chloride 2-5mL after cooling, has precipitation to generate.Continue reaction 1h after reactant intensification, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid;
(3) 20gmPEG-PLA is dissolved in methylene dichloride, add triethylamine 5mL, 4-pyrollidinopyridine 1.0g, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in methylene dichloride, after join in the dichloromethane solution of mPEG-PLA, heat up after stirring reaction 1h, continue stirring reaction.Filter solid had both been the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid end-blocking after reactant precipitation.
The preparation method of drug-loading system described in 12. 1 kinds of claims 10, it is characterized in that, described polymkeric substance and medicine dissolution are in organic solvent, and rotary evaporation removes organic solvent, add appropriate ultrapure water and dissolve medicine film, gained solution after filtration membrane filtration freeze-drying obtains drug-loading system micelle freeze-drying powder.
13. according to the preparation method of drug-loading system described in claim 15, it is characterized in that, described polymkeric substance and medicine dissolution are in organic solvent, rotary evaporation removes organic solvent, add appropriate ultrapure water and dissolve medicine film, gained solution after filtration membrane filtration adds freeze-dried excipient and obtains drug-loading system micelle freeze-drying powder; Aseptic treatment step is had before described step of freeze drying.
14., according to preparation method described in claim 16, is characterized in that, described freeze-dried excipient comprises one or more combinations of lactose, N.F,USP MANNITOL, Xylitol, sorbyl alcohol, sucrose, trehalose, fructose, glucose, sodium alginate or gelatin.
15. 1 kinds of Amphipathilic block polymer according to claim 1 application in preparation tumor.
The application of drug-loading system described in 16. 1 kinds of claims 10 in preparation tumor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510690016.4A CN105367804A (en) | 2015-10-16 | 2015-10-16 | Amphiphilic block polymer for carrying medicine and preparing method and application of amphiphilic block polymer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510690016.4A CN105367804A (en) | 2015-10-16 | 2015-10-16 | Amphiphilic block polymer for carrying medicine and preparing method and application of amphiphilic block polymer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105367804A true CN105367804A (en) | 2016-03-02 |
Family
ID=55370473
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510690016.4A Pending CN105367804A (en) | 2015-10-16 | 2015-10-16 | Amphiphilic block polymer for carrying medicine and preparing method and application of amphiphilic block polymer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105367804A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109010840A (en) * | 2018-09-29 | 2018-12-18 | 清华大学 | A kind of preparation method of amphipathic biodegradable carrier micelle |
| CN111035617A (en) * | 2018-10-11 | 2020-04-21 | 四川大学 | A method for preparing multi-molecule micro-core-loaded artemisinin (DHA, ARM, ARS) for treating cancer and its application |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103172819A (en) * | 2013-03-01 | 2013-06-26 | 中国科学院长春应用化学研究所 | Biodegradable polyurethane with amino on side chain and preparation method and application thereof |
| CN103772686A (en) * | 2012-10-26 | 2014-05-07 | 苏州雷纳药物研发有限公司 | Amphiphilic block copolymer and preparation method thereof, micelle drug delivery system formed by copolymer and anti-tumor drug |
| CN104758255A (en) * | 2014-01-08 | 2015-07-08 | 苏州雷纳药物研发有限公司 | Curcumin micellar drug carrying system and preparation method thereof |
| CN104856950A (en) * | 2014-02-25 | 2015-08-26 | 苏州雷纳药物研发有限公司 | Paclitaxel micelle drug load system and preparation method thereof |
-
2015
- 2015-10-16 CN CN201510690016.4A patent/CN105367804A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772686A (en) * | 2012-10-26 | 2014-05-07 | 苏州雷纳药物研发有限公司 | Amphiphilic block copolymer and preparation method thereof, micelle drug delivery system formed by copolymer and anti-tumor drug |
| CN103172819A (en) * | 2013-03-01 | 2013-06-26 | 中国科学院长春应用化学研究所 | Biodegradable polyurethane with amino on side chain and preparation method and application thereof |
| CN104758255A (en) * | 2014-01-08 | 2015-07-08 | 苏州雷纳药物研发有限公司 | Curcumin micellar drug carrying system and preparation method thereof |
| CN104856950A (en) * | 2014-02-25 | 2015-08-26 | 苏州雷纳药物研发有限公司 | Paclitaxel micelle drug load system and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109010840A (en) * | 2018-09-29 | 2018-12-18 | 清华大学 | A kind of preparation method of amphipathic biodegradable carrier micelle |
| CN111035617A (en) * | 2018-10-11 | 2020-04-21 | 四川大学 | A method for preparing multi-molecule micro-core-loaded artemisinin (DHA, ARM, ARS) for treating cancer and its application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2889518C (en) | An amphiphilic block copolymer, the preparation method thereof, and a micellar drug-loaded system formed by said copolymer and an anti-tumor drug | |
| Zhang et al. | Tumor microenvironment-labile polymer–doxorubicin conjugate thermogel combined with docetaxel for in situ synergistic chemotherapy of hepatoma | |
| Wang et al. | Hyaluronic acid decorated pluronic P85 solid lipid nanoparticles as a potential carrier to overcome multidrug resistance in cervical and breast cancer | |
| KR101024742B1 (en) | Amphiphilic Block Copolymer Micelle Composition Containing Taxane and Manufacturing Process of The Same | |
| JP4049588B2 (en) | Production method of polymer micelle by phase separation of block copolymer | |
| Gong et al. | Efficient inhibition of colorectal peritoneal carcinomatosis by drug loaded micelles in thermosensitive hydrogel composites | |
| Lo et al. | pH-and thermo-sensitive pluronic/poly (acrylic acid) in situ hydrogels for sustained release of an anticancer drug | |
| CN1429120A (en) | Stable polymeric micelle-type drug composition and method for preparation thereof | |
| CN103006539B (en) | A kind of polymeric micelle medicine composition and preparation method thereof | |
| WO2009084801A1 (en) | Amphiphilic block copolymer micelle composition containing taxane and manufacturing process of the same | |
| CN104758255A (en) | Curcumin micellar drug carrying system and preparation method thereof | |
| CN105287377A (en) | Taxol polymer micelle drug-loading system and preparation method and application thereof | |
| US9801818B2 (en) | Method for stabilizing amphiphilic block copolymer micelle composition containing poorly water-soluble drug | |
| CN105399938A (en) | Preparation method and application of amphiphilic block copolymer, and preparation method and application of micelle of copolymer | |
| CN105816427A (en) | Curcumin micelle drug-loaded system and preparation method thereof | |
| CN105399931A (en) | Amphiphilic block copolymer, and preparation method and application thereof | |
| Hu et al. | Stabilization and sustained release of zeylenone, a soft cytotoxic drug, within polymeric micelles for local antitumor drug delivery | |
| CN111978520A (en) | Polyethylene glycol monomethyl ether-polylactic acid segmented copolymer, polymer micelle medicine and preparation method | |
| CN105395481A (en) | Curcumin-containing polymeric micelle drug delivery system and preparation method and application thereof | |
| CN105310981A (en) | Docetaxel micelle drug loading system and preparation method and application thereof | |
| Ho et al. | Preparation, characterisation and in vitro/in vivo anticancer activity of lyophilised artesunate-loaded nanoparticles | |
| CN105367804A (en) | Amphiphilic block polymer for carrying medicine and preparing method and application of amphiphilic block polymer | |
| Lin et al. | A novel drug delivery system of mixed micelles based on poly (ethylene glycol)‐poly (lactide) and poly (ethylene glycol)‐poly (ɛ‐caprolactone) for gambogenic acid | |
| Yang et al. | Preparation, pharmacokinetics and tissue distribution of micelles made of reverse thermo-responsive polymers | |
| CN105367772A (en) | Amphiphilic block copolymer and preparation method of micelle thereof and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20180606 Address after: 226100 688, Hai Lu, Haimen Economic Development Zone, Jiangsu Applicant after: Jiangsu Wangao Pharmaceutical Co., Ltd. Address before: 226100 688, Hai Lu, Haimen Economic Development Zone, Jiangsu Applicant before: Yao Junhua |
|
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160302 |