CN1417242A - Polyglycol grafted and modified cyanoacrylate copolymer and its prepn - Google Patents
Polyglycol grafted and modified cyanoacrylate copolymer and its prepn Download PDFInfo
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- CN1417242A CN1417242A CN 02148633 CN02148633A CN1417242A CN 1417242 A CN1417242 A CN 1417242A CN 02148633 CN02148633 CN 02148633 CN 02148633 A CN02148633 A CN 02148633A CN 1417242 A CN1417242 A CN 1417242A
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Abstract
The polyethyleneglycol (PEG) grafted polycyanoacrylate (PACA) copolymer (PEG-g-PACA) is the copolymer of cyanoacrylate (ACA) and PEG macromolecular monomer with double bond. The PEG macromolecular monomer is either PEG macromolecular monomer with maleic unit in the end group and prepared through reaction of PEG monoalkyl ether and maleic anhydride or PEG macromolecular monomer prepared through grafting methacrylic-beta-hydroxyalkyl ester to the end hydroxyl position of PEG monoalkyl ether. The PEG-g-PACA grafted copolymer is prepared using the PEG macromolecular monomer and ACA as raw material and toluene as solvent and through free radical solvent polymerization in the action of initiator. The polymer is used in preparing nanometer water-dispersed medicine particle of hydropohobic medicine.
Description
Technical field
The present invention relates to polybutylcyanoacrylate (PACA) multipolymer (PEG-g-PACA) of polyoxyethylene glycol (PEG) grafting and modifying and preparation method thereof.Belong to amphipathic graft copolymer and technology of preparing thereof.
Background technology
The polybutylcyanoacrylate multipolymer (PEG-g-PACA) of polyoxyethylene glycol grafting and modifying is biodegradable, and is a kind of amphipathic polymkeric substance.PEG-g-PACA can be self-assembled into nanoparticle or micella in water, wherein hydrophobic polybutylcyanoacrylate main chain is assembled nucleation, PEG props up the hydrophilic shell of chain formation, making the nanoparticle stable existence and hydrophobic drug is had the ability of wrapping up preferably, is a kind of good medicine sustained release solid support material.
The preparation method of the PEG-g-PACA amphipathic graft copolymer of document and patent report is under the condition that is added with formaldehyde solution and dimethylamine solution, carries out the polycondensation preparation by cyanoacetic acid macrogol ester and cyan-acetic ester in ethanol.The preparation method's of this PEG-g-PACA technological process mainly comprises processes such as esterification, polycondensation, purification.Detailed process is at first by synthetic cyanoacetic acid poly glycol monomethyl ether ester of esterification and cyan-acetic ester.Esterification is a very complicated process, is about to the potassium cyanide aqueous solution and chloracetic acid sodium water solution and adds by a certain percentage in the reactor, is heated to 90 ℃ of constant temperature 1 hour, regulate pH value to 2 down for 0 ℃, use the ethyl acetate extraction reaction solution, the extract dried over mgso obtains cyanoacetic acid.Cyanoacetic acid is dissolved in ethyl acetate, the dichloromethane solution that adds a certain amount of Fatty Alcohol(C12-C14 and C12-C18) and 4-Dimethylamino pyridine, add n then, n-two ring carbodiimides, after stirring 12 hours under 20 ℃, filter crude product with sintered glass funnel then, the decompress filter concentrated filtrate separates the cyan-acetic ester of purifying out with silica gel chromatographic column at last; Prepare cyanoacetic acid poly glycol monomethyl ether ester with same method.Second step was preparation PEG-g-PACA, add cyanoacetic acid poly glycol monomethyl ether ester and cyan-acetic ester in the reactor by a certain percentage, add 1: 1 ethanol/dichloromethane mixing solutions of an amount of volume ratio, add a certain amount of 37% formaldehyde solution and 40% diformazan ammonia soln, stirred 20 hours down at 20 ℃, concentrating under reduced pressure, enriched material is dissolved in methylene dichloride, with distilled water wash three times to remove unreacted cyanoacetic acid poly glycol monomethyl ether ester, dewater with dried over mgso, drying under reduced pressure gets PEG-g-PACA again.
The structure of the PEG-g-PACA of above-mentioned preparation method's preparation is as follows:
R is a low-carbon alkyl in the formula, and x, y are integer.
Above-mentioned technological process is quite complicated, and the control difficulty is difficult to realize suitability for industrialized production, and in monomeric preparation process, has used deadly poisonous compound-potassium cyanide, has certain hazardness.
Summary of the invention
The object of the present invention is to provide polybutylcyanoacrylate graft copolymer (PEG-g-PACA) and a kind of better simply preparation method of polyoxyethylene glycol grafting and modifying; this class PEG-g-PACA graft copolymer is the amphipathic graft copolymer that has the polyoxyethylene glycol side chain that is formed by cyanoacrylate and the polyoxyethylene glycol macromonomer copolymerization that has two keys; this quasi-graft copolymer can be self-assembled into stabilized nano grain or micella in water, hydrophobic drug is had good parcel performance.
The molecular structure of the PEG-g-PACA graft copolymer among the present invention is formula I:
R in the formula
1, R
2Be alkyl; A=
Or
Wherein R ' is aromatic series or aliphatics alkane, R " be H or the alkyl that contains 1～5 carbon, R
3Be alkyl with 1～5 carbon, better with methyl, R
4Be the alkylidene group of 1-8 carbon, with-CH
2CH
2-,-CH
2CH
2CH
2-, CH
2(CH
3) CH
2-better, n, m, o, p, p ', q are integer.Formula II and formula III are respectively the structural units of two kinds of polyoxyethylene glycol macromonomers, and these two kinds of polyoxyethylene glycol macromonomers are respectively: (1) maleic anhydride and PEG reaction synthetic polyoxyethylene glycol macromonomer (PEGA), and structure is formula IV:
O and R in the formula
3The same; (2) with the macromonomer (PEGH) of vulcabond conjugated polyethylene glycol and senecioate-hydroxyl ethyl ester or senecioate-hydroxypropyl acrylate formation, structure is formula V:
R ', R in the formula ", R
3, R
4The same with p.
PEG-g-PACA graft copolymer of the present invention, realized by following technical proposals:
The preparation method of polyoxyethylene glycol macromonomer (PEGA) is: the end capped polyoxyethylene glycol of a certain amount of list is added reactor, dewatered 2～4 hours 100～160 ℃ of following fusion decompressions, be lower than 65 ℃, under the normal pressure, by maleic anhydride/polyoxyethylene glycol is that 1～1.1 feed ratio (mol ratio) adds maleic anhydride, be lower than 30mmHg then, reaction made crude product in 2～8 hours under 65～120 ℃, use chloroform, organic solvent dissolutions such as methylene dichloride, join precipitating in 10～30 parts 4～10 ℃ the ether then, centrifugation or decompress filter, throw out vacuum-drying obtains PEGA.
The preparation method of polyoxyethylene glycol macromonomer (PEGH) is: the end capped polyoxyethylene glycol of a certain amount of list is added reactor, dewatered 2～4 hours 100～160 ℃ of following fusion decompressions, at 45～60 ℃, the toluene dissolving polyoxyethylene glycol that adds 3～5 parts, be that 1～1.1 feed ratio (mol ratio) adds vulcabond by vulcabond/polyoxyethylene glycol then, slowly be warming up to 70～90 ℃ of reactions 2～5 hours, at 30 ℃, methacrylic acid-β-the hydroxy alkyl ester that adds 1～1.1 times of end capped polyoxyethylene glycol mole number of list, reacted 3～8 hours, concentrating under reduced pressure reaction solution then, concentrated solution is with organic solvent dissolutions such as chloroforms, join precipitating in 4～10 ℃ of ether of 10～30 parts then, centrifugation or decompress filter obtain PEGH with throw out vacuum-drying.
The preparation method of amphipathic graft copolymer: adopting relative molecular mass is that the PEGA of 500-20000 or PEGH and cyanoacrylate are raw material, the toluene solution of PEGA or PEGH is added in the polymeric kettle, under 50～70 ℃, adding quality is the alkyl cyanoacrylate of 0.25～5 times of polyoxyethylene glycol macromonomer, drip the Diisopropyl azodicarboxylate that concentration is 1-3% or the toluene solution of 2,2'-Azobis(2,4-dimethylvaleronitrile) initiator then, reacted 2～8 hours, add micro-cuprous chloride or Resorcinol termination reaction afterwards, reaction solution joined precipitating in 0～10 ℃ of ether of 10～30 parts, filter, throw out vacuum-drying must contain the crude product of PEG-g-PACA, crude product is dissolved in the solvent that dissolves each other with water, be dispersed in the water then, PEG-g-PACA is scattered in the water with the nano-micelle form, the homopolymer of alkyl cyanoacrylate is precipitated out, and isolates throw out, obtains the PEG-g-PACA amphipathic graft copolymer after the clear liquid lyophilize.
Used cyanoacrylate is cyanacrylate, alpha-cyanoacrylate propyl ester, alpha-cyanoacrylate isopropyl ester, the positive butyl ester of alpha-cyanoacrylate, isobutylcyanoacrylate in the preparation of amphipathic graft copolymer.
When the mass content of hydrophilic polyglycol side chain is 30-80% in the amphipathic graft copolymer, polymkeric substance can be self-assembled into nano-micelle in water, particle diameter is at 20～1000nm, as taxol, Zorubicin, teniposide, Etoposide, daunomycin, Rheumatrex, ametycin, indomethacin, Ibuprofen BP/EP, ciclosporin, the carrier of drugs of low aqueous solubility such as biphenyl dimethyl dicarboxylic ester, packaging medicine can form the water dispersible nano-micelle of load drugs of low aqueous solubility, drug loading is 0.001～30% of a polymer quality, entrapment efficiency is more than 70%, after the freeze-drying of this drug-carrying polymer nano-micelle aqueous dispersions, form meal, can be scattered in certainly in the water that to form concentration be 0.0001～40% medicament nano micella aqueous dispersions, can be used for target administration and medicine sustained release to organism, this medicine micella can increase the water-soluble of drugs of low aqueous solubility, effectively hide the absorption of organism internal protein and engulfing of reticuloendothelial cell, improve bioavailability of medicament.
The PEG-g-PACA biological degradation in vivo of the present invention's preparation, degraded product is nontoxic, is a kind of good pharmaceutical carrier, is the good auxiliary material of exploitation drugs of low aqueous solubility nanometer formulation.Preparation method's technology of the present invention is simple, preparation process is reliable and stable, and can regulate the master of PEG-g-PACA, the ratio and the molecular weight of side chain according to service requirements, and the particle diameter of control PEG-g-PACA nanoparticle, is easy to get at the abundant raw material of employing.
Embodiment
With embodiment the present invention further is illustrated again below.
Embodiment 1:
The poly glycol monomethyl ether 20g that in a round-bottomed flask, adds relative molecular mass 2000, the sealing back is at 120 ℃, and logical nitrogen dewatered 2 hours.At 65 ℃, under the normal pressure, add maleic anhydride 1.1g, at 80 ℃, be lower than 30mmHg, reaction is 6 hours under the condition of logical nitrogen, crude product dissolves with chloroform under 20～30 ℃, join precipitating in 10～30 parts the cold diethyl ether, centrifugation or decompress filter obtain PEGA behind 30 ℃ of vacuum-drying throw outs.
Embodiment 2:
Device and operation add the poly glycol monomethyl ether 20g of relative molecular mass 5000 with embodiment 1 in round-bottomed flask, the sealing back is at 120 ℃, and logical nitrogen dewatered 2 hours.At 65 ℃, under the normal pressure, add maleic anhydride 0.41g, at 80 ℃, be lower than 30mmHg, reaction is 6 hours under the condition of logical nitrogen, crude product dissolves with chloroform under 20～30 ℃, join precipitating in 10～30 parts the cold diethyl ether, centrifugation or decompress filter obtain PEGA behind 30 ℃ of following vacuum-drying throw outs.
Embodiment 3:
The poly glycol monomethyl ether 20g that in a round-bottomed flask, adds relative molecular mass 2000, dewatered 2 hours 120 ℃ of following fusion decompressions,, add the toluene dissolving polyoxyethylene glycol of 40mL at 5 ℃, add tolylene diisocyanate 1.8g, slowly be warming up to 80 ℃ of reactions 3 hours, be cooled to 30 ℃ then, add methacrylic acid-beta-hydroxy ethyl ester 1.4g, reacted 8 hours, reaction solution joins precipitating in 10～30 parts the cold diethyl ether, and centrifugation or decompress filter will obtain PEGH after the throw out vacuum-drying.
Embodiment 4:
Device and operation are with embodiment 3, the poly glycol monomethyl ether 20g that in a round-bottomed flask, adds relative molecular mass 5000, dewatered 2 hours 120 ℃ of following fusion decompressions, at 50 ℃, the toluene dissolving poly glycol monomethyl ether that adds 40mL, add tolylene diisocyanate 0.72g, slowly be warming up to 80 ℃ of reactions and cool to 30 ℃ after 3 hours, add methacrylic acid-beta-hydroxy ethyl ester 0.54g, reacted 8 hours, reaction solution joins precipitating in 10～30 parts the cold diethyl ether, and centrifugation or decompress filter obtain PEGH after the throw out vacuum-drying.
Embodiment 5:
Device and operation are with embodiment 3, the poly glycol monomethyl ether 20g that in round-bottomed flask, adds relative molecular mass 2000, dewatered 2 hours 120 ℃ of following fusion decompressions, at 50 ℃, the toluene dissolving poly glycol monomethyl ether that adds 40mL, add isoflurane chalcone diisocyanate 2.3g, slowly be warming up to 80 ℃ of reactions 5 hours, cool to 30 ℃ then, add methacrylic acid-beta-hydroxy ethyl ester 1.4g again, reacted 8 hours, reaction solution joins precipitating in 10～30 parts the cold diethyl ether, centrifugation or decompress filter obtain PEGH after the throw out vacuum-drying.
Embodiment 6:
(concentration is 2.5% to the toluene solution of the polyoxyethylene glycol macromonomer (PEGA or PEGH) of adding 1g in a round-bottomed flask, wt) 40mL, under 70 ℃, the cyanacrylate that adds 1g, drip concentration and be the toluene solution 1mL of 1% Diisopropyl azodicarboxylate, carry out free radical solution polymerization reaction 6 hours, add 1mg terminator cuprous chloride then, reaction solution joins precipitating in 10～30 parts the cold diethyl ether, filters, and throw out vacuum-drying must contain the crude product of PEG-g-PACA, crude product is dissolved in the solvent that dissolves each other with water, be dispersed in then in the water, filter out throw out, obtain the PEG-g-PACA amphipathic graft copolymer after the filtrate lyophilize.
Embodiment 7:
Device and operation are with embodiment 6, (concentration is 2.5% to the toluene solution of the polyoxyethylene glycol macromonomer (PEGA or PEGH) of adding 1g in round-bottomed flask, wt) 40mL, under 60 ℃, the cyanacrylate that adds 4g, drip concentration then and be the toluene solution 1mL of 3% Diisopropyl azodicarboxylate, carry out free radical solution polymerization reaction 6h, add 1mg terminator cuprous chloride then, reaction solution joins precipitating in 10～30 parts the cold diethyl ether, filter, throw out vacuum-drying must contain the crude product of PEG-g-PACA, crude product is dissolved in the solvent that dissolves each other with water, is dispersed in the water then, filter out throw out, obtain the PEG-g-PACA amphipathic graft copolymer after the filtrate lyophilize.
Embodiment 8:
Device and operation are with embodiment 6, (concentration is 2.5% to the toluene solution of the polyoxyethylene glycol macromonomer (PEGA or PEGH) of adding 1g in a round-bottomed flask, wt) 40mL, under 60 ℃, the positive butyl ester of alpha-cyanoacrylate that adds 1g, drip concentration then and be the toluene solution 1mL of 1% Diisopropyl azodicarboxylate, carry out free radical solution polymerization reaction 6h, add 1mg terminator cuprous chloride then, reaction solution joins precipitating in 10～30 parts the cold diethyl ether, filter, throw out vacuum-drying must contain the crude product of PEG-g-PACA, crude product is dissolved in the solvent that dissolves each other with water, is dispersed in the water then, filter out throw out, obtain the PEG-g-PACA amphipathic graft copolymer after the filtrate lyophilize.
Embodiment 9:
Device and operation are with embodiment 6, (concentration is 2.5% to the toluene solution of the polyoxyethylene glycol macromonomer (PEGA or PEGH) of adding 1g in a round-bottomed flask, wt) 40mL, under 60 ℃, the cyanacrylate that adds 1g, drip concentration then and be the toluene solution 1mL of 1% Diisopropyl azodicarboxylate, carry out free radical solution polymerization reaction 6h, add 1mg terminator Resorcinol then, reaction solution joins precipitating in 10～30 parts the cold diethyl ether, filter, throw out vacuum-drying must contain the crude product of PEG-g-PACA, crude product is dissolved in the solvent that dissolves each other with water, is dispersed in the water then, filter out throw out, obtain the PEG-g-PACA amphipathic graft copolymer after the filtrate lyophilize.
Embodiment 10:
Device and operation are with embodiment 6, (concentration is 2.5% to the toluene solution of the polyoxyethylene glycol macromonomer (PEGA or PEGH) of adding 1g in a round-bottomed flask, wt) 40mL, under 60 ℃, the cyanacrylate that adds 1g, drip concentration then and be the toluene solution 1mL of 1% 2,2'-Azobis(2,4-dimethylvaleronitrile), carry out free radical solution polymerization reaction 6h, add 1mg terminator cuprous chloride then, reaction solution joins precipitating in 10～30 parts the cold diethyl ether, filter, throw out vacuum-drying must contain the crude product of PEG-g-PACA, crude product is dissolved in the solvent that dissolves each other with water, is dispersed in the water then, filter out throw out, obtain the PEG-g-PACA amphipathic graft copolymer after the filtrate lyophilize.
Embodiment 11:
The PEACA of embodiment 8 preparations of 10mg Ibuprofen BP/EP and 90mg is dissolved in 8mL acetone or the methylene dichloride, under magnetic agitation, slowly be added drop-wise in the 300mL distilled water, along with acetone spreads to water ground, the PEG segment progresses into water, the PACA segment is separated out from water, assemble, form the solubilising micella of parcel Ibuprofen BP/EP, up to the acetone volatilization fully, the micella kernel is solidified into ball and forms the polymer nanoparticle that is loaded with Ibuprofen BP/EP, median size is 20～500nm, centrifugation, supernatant liquor gets the PEACA nano freeze-dried powder of load Ibuprofen BP/EP through lyophilize, and the PEACA nano freeze-dried powder of this load Ibuprofen BP/EP can be scattered in the water certainly, is the nanoparticle aqueous dispersions of 20～500nm thereby form particle diameter.
Embodiment 12:
Device and operation have just replaced Ibuprofen BP/EP with taxol with embodiment 11, prepare paclitaxel loaded PEACA nanoparticle.
Claims (8)
1. the polybutylcyanoacrylate graft copolymer of a class polyoxyethylene glycol grafting and modifying is characterized in that polybutylcyanoacrylate (PACA) graft copolymer (PEG-g-PACA) of this class polyoxyethylene glycol (PEG) grafting and modifying has the structure shown in the formula I:
R in the formula
1, R
2For containing the alkyl of 2～10 carbon; A is the chain unit shown in formula II or the formula III,
R wherein
3Be alkyl with 1～5 carbon, better with methyl, R
4Be the alkylidene group of 1～8 carbon, with-CH
2CH
2--CH
2CH
2CH
2-CH
2(CH
3) CH
2-better, R ' is aromatic series or aliphatics alkane, " be the alkyl of H or 1～5 carbon, n, m, o, p, p ', q are integer to R.
2. a polyoxyethylene glycol macromonomer PEGA who prepares by the used formula that the is used to provide II chain unit of the described polymkeric substance of claim 1 is characterized in that having the structure shown in the formula IV,
R wherein
3, o is the same.
3. one kind prepares by the used polyoxyethylene glycol macromonomer PEGH that is used to provide the formula III chain unit of the described polymkeric substance of claim 1, it is characterized in that having the structure shown in the formula V.
R wherein
3, R
4, R ', R ", q is the same.
4. preparation method by the described polyoxyethylene glycol macromonomer of claim 2 PEGA, it is characterized in that with single end capped polyoxyethylene glycol and maleic anhydride being that raw material carries out the ring-opening reaction preparation, method is that the end capped polyoxyethylene glycol of a certain amount of list is added reactor, dewatered 2-4 hour 100～160 ℃ of following fusion decompressions, be lower than under 65 ℃, by maleic anhydride/polyoxyethylene glycol is that 1～1.1 feed ratio (mol ratio) adds maleic anhydride, be lower than 30mmHg then, reaction got crude product in 2～8 hours under 65～120 ℃, crude product joins precipitating in 10～30 parts 0～10 ℃ the ether after dissolution with solvents, isolate throw out, throw out vacuum-drying is obtained PEGA.
5. preparation method by the described polyoxyethylene glycol macromonomer of claim 3 PEGH, it is characterized in that with the vulcabond being coupling agent, with single end capped polyoxyethylene glycol and senecioate-hydroxy alkyl ester is feedstock production, method is that the end capped polyoxyethylene glycol of a certain amount of list is added reactor, dewatered 2～4 hours 100～160 ℃ of following fusion decompressions, be lower than under 60 ℃, the toluene that adds 3～5 parts, the feed ratio (mol ratio) of pressing vulcabond/polyoxyethylene glycol 1～1.1 then adds vulcabond, slowly be warming up to 70～90 ℃ of reactions 2～5 hours, below 50 ℃, methacrylic acid-β-the hydroxy alkyl ester that adds 1～1.1 times of end capped polyoxyethylene glycol mole number of list, reacted 3～8 hours, at 20～30 ℃ of concentrating under reduced pressure reaction solutions, the concentrated solution organic solvent dissolution joins then in 10～30 parts 0～10 ℃ the ether and carries out precipitating, isolate throw out, throw out vacuum-drying is obtained PEGH.
6. an employing prepares the method for the described polymkeric substance of claim 1 by claim 2 and 3 described single end-blocking polyoxyethylene glycol macromonomer PEGA or PEGH, it is characterized in that adopting relative molecular mass is that the PEGA of 500-20000 or PEGH and cyanoacrylate are raw material, the toluene solution of PEGA or PEGH is added in the reactor, under 50～70 ℃, adding quality is the alkyl cyanoacrylate of 0.25～5 times of polyoxyethylene glycol macromonomer, drip the Diisopropyl azodicarboxylate that concentration is 1-3% or the toluene solution of 2,2'-Azobis(2,4-dimethylvaleronitrile) initiator then, reacted 2～8 hours, add micro-cuprous chloride or Resorcinol termination reaction afterwards, reaction solution joined precipitating in 0～10 ℃ of ether of 10～30 parts, filter, throw out vacuum-drying must contain the crude product of PEG-g-PACA, crude product is dissolved in the solvent that dissolves each other with water, be dispersed in the water then, isolate throw out, obtain the PEG-g-PACA amphipathic graft copolymer after the clear liquid lyophilize.
7. by the preparation method of the described PEG-g-PACA of claim 6, it is characterized in that used cyanoacrylate is cyanacrylate, alpha-cyanoacrylate propyl ester, alpha-cyanoacrylate isopropyl ester, the positive butyl ester of alpha-cyanoacrylate, isobutylcyanoacrylate.
8. purposes by the polybutylcyanoacrylate graft copolymer (PEG-g-PACA) of the described polyoxyethylene glycol grafting and modifying of claim 1, the mass content that it is characterized in that hydrophilic polyglycol side chain in this PEG-g-PACA polymkeric substance is 30-80%, PEG-g-PACA can be self-assembled into nano-micelle in water, particle diameter is at 20～1000nm, as taxol, Zorubicin, teniposide, Etoposide, daunomycin, Rheumatrex, ametycin, indomethacin, Ibuprofen BP/EP, ciclosporin, the carrier of drugs of low aqueous solubility such as biphenyl dimethyl dicarboxylic ester, packaging medicine is in micella, form the nano-micelle of load drugs of low aqueous solubility, drug loading is 0.001～30% of a polymer quality, encapsulation rate is more than 70%, this drug-carrying polymer nano-micelle aqueous dispersions lyophilized powder can be scattered in the water certainly, formation concentration is 0.0001～40% nanoparticle aqueous dispersions, is used for target administration and medicine sustained release to organism.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2872703A1 (en) * | 2004-07-07 | 2006-01-13 | Ethypharm Sa | COMPOSITE POLYMERIC NANOPARTICLES |
| WO2006015519A1 (en) * | 2004-08-11 | 2006-02-16 | Yangde Zhang | A method of preparation of cetyltriethyl ammonium bromide-midified polybutylcyanoacrylate nanoparticles |
| CN100374477C (en) * | 2005-07-07 | 2008-03-12 | 复旦大学 | Nano granules adhesive to mucous membrane, preparation method and application |
| CN100586479C (en) * | 2006-07-27 | 2010-02-03 | 中国医学科学院生物医学工程研究所 | Application of cyanoacrylate glycol ester in preparing medicine carrier |
| CN101084882B (en) * | 2007-06-21 | 2011-03-23 | 复旦大学 | Polyalkylcyanoacrylate nano-capsule and preparation method and application thereof |
| CN104829845A (en) * | 2015-05-30 | 2015-08-12 | 山东汇盈新材料科技有限公司 | Biodegradable amphiphilic multi- block copolymer and method for preparing same |
| CN105878187A (en) * | 2016-04-19 | 2016-08-24 | 浙江工业大学 | Paclitaxel self-assembly polymer nanoparticle drug delivery system and preparation method thereof |
| CN108779340A (en) * | 2016-01-22 | 2018-11-09 | 巴斯夫欧洲公司 | Dispersant composition |
| CN118184991A (en) * | 2024-05-16 | 2024-06-14 | 浙江月旭材料科技有限公司 | Size exclusion chromatographic packing and preparation method and application thereof |
-
2002
- 2002-11-14 CN CN 02148633 patent/CN1417242A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2872703A1 (en) * | 2004-07-07 | 2006-01-13 | Ethypharm Sa | COMPOSITE POLYMERIC NANOPARTICLES |
| WO2006016020A3 (en) * | 2004-07-07 | 2006-07-13 | Ethypharm Sa | Nanoparticles comprising a core essentially consisting of a cyanoacrylic polymer and a shell of an amphiphilic polymer and, optionally, an active principle, preferably bisulfan |
| WO2006015519A1 (en) * | 2004-08-11 | 2006-02-16 | Yangde Zhang | A method of preparation of cetyltriethyl ammonium bromide-midified polybutylcyanoacrylate nanoparticles |
| CN100374477C (en) * | 2005-07-07 | 2008-03-12 | 复旦大学 | Nano granules adhesive to mucous membrane, preparation method and application |
| CN100586479C (en) * | 2006-07-27 | 2010-02-03 | 中国医学科学院生物医学工程研究所 | Application of cyanoacrylate glycol ester in preparing medicine carrier |
| CN101084882B (en) * | 2007-06-21 | 2011-03-23 | 复旦大学 | Polyalkylcyanoacrylate nano-capsule and preparation method and application thereof |
| CN104829845A (en) * | 2015-05-30 | 2015-08-12 | 山东汇盈新材料科技有限公司 | Biodegradable amphiphilic multi- block copolymer and method for preparing same |
| CN108779340A (en) * | 2016-01-22 | 2018-11-09 | 巴斯夫欧洲公司 | Dispersant composition |
| CN108779340B (en) * | 2016-01-22 | 2021-05-11 | 巴斯夫欧洲公司 | Dispersant composition |
| CN105878187A (en) * | 2016-04-19 | 2016-08-24 | 浙江工业大学 | Paclitaxel self-assembly polymer nanoparticle drug delivery system and preparation method thereof |
| CN118184991A (en) * | 2024-05-16 | 2024-06-14 | 浙江月旭材料科技有限公司 | Size exclusion chromatographic packing and preparation method and application thereof |
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