CN102453244A - Temperature sensitive biodegradable poly(poly ether-ester diacid)anhydride multiblock copolymer, and hydrogel system and application thereof - Google Patents
Temperature sensitive biodegradable poly(poly ether-ester diacid)anhydride multiblock copolymer, and hydrogel system and application thereof Download PDFInfo
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Abstract
The invention relates to a temperature sensitive biodegradable poly(poly ether-ester diacid)anhydride multiblock copolymer, and a hydrogel system and application thereof. The copolymer is an (ABA)n type amphiphilic multiblock copolymer prepared by maleating and polymerizing poly ether-ester diacid, wherein A is a hydrophobic block, B is a polyethylene glycol block, n ranges from 1 to 60, the polyethylene glycol content is 27 to 73 mass percent, and the mean relative molecular mass of the polyethylene glycol block is 200-800. The hydrogel formed by the amphiphilic multiblock copolymer in an aqueous medium has a reversible conversion property from a solution state to a gel state along with the temperature change, so the poly(poly ether-ester diacid)anhydride is widely applied.
Description
Technical field
What the present invention relates to a kind of thermo-sensitive biodegradable gathers (polyether ester diacid) anhydride copolymer and aquogel system and application.
Technical background
The application in the pharmaceutical carrier field in recent years of thermo-sensitive biodegradable amphipathic nature polyalcohol has obtained paying close attention to widely, and wherein the aqueous solution can present application promise in clinical practice with the situ-gel material of temperature variation generation solution-gel conversion.Situ-gel (in situ gel) is meant the solution system of a family macromolecule material, and the change of envrionment conditionss such as this system Yin Wendu, ionic strength or pH and spontaneously take place to change mutually changes semisolid gel state into by flow state.Aqueous solutions of polymers or aqueous humour situ-gel system possess hydrophilic property three-dimensional net structure, favorable tissue consistency, drug loading and good control Release Performance; Simultaneously; Unique solution-gel conversion character make its have preparation simple, easy to use, with agents area advantages such as particularly mucous membrane tissue avidity is strong, the residence time is long; Therefore, the situ-gel drug delivery system has become a research focus in pharmaceutics field.Polymkeric substance temperature sensing in situ gel rubber with amphipathic block structure has received attention, and that reports at present only limits to two types, and the one, Prist (poloxamer), i.e. T 46155 (PEO) and polyoxypropylene (PPO) segmented copolymer, i.e. PEO-PPO-PEO; The 2nd, be hydrophilic section with polyoxyethylene glycol (PEG), degradable polyester is the amphipathic nature block polymer of hydrophobic section.Patent US5702717, US6004573, US6117949, US6201072, US7018645, US2003003074, US200276431 and the US2006034889 of U.S. MacroMed Inc company discloses about polyester-polyethylene glycol-ester, polyethylene glycol-ester-polyoxyethylene glycol, and the temperature-sensitive situ hydrogel and the related preparations compsn of the segmented copolymer that forms of polyester-polyoxyethylene glycol in succession; Wherein polyester block is polyhydroxy acid and alcohol acid multipolymer and polyethylene glycol carbonates; Polyhydroxy acid comprises the homopolymer of lactic acid, oxyacetic acid, hydroxybutyric acid, caprolactone, GBL, valerolactone, Malic acid, D-, lactic acid-hydroxybutyric acid multipolymer, caprolactone-lactic acid-hydroxybutyric acid multipolymer.US2004185104 is disclosed to be that two kinds and above above-mentioned segmented copolymer are mixed for the situ-gel drug delivery system.US2002076441, US6287588, US2002015737 disclose the drug delivery system about PLGA-PEG-PLGA situ-gel and medicine carrying microgranule composition.US2003228366 and US2004001872 disclose molecular weight at 150～1100 the PEG and the co-mixing system of verivate and above-mentioned segmented copolymer thereof, and purpose is to promote dispersion and the freeze-drying redispersion performance of segmented copolymer in water.US2003068377 adds biodegradable hydrophobicity polyester oligomer in above-mentioned situ-gel system, purpose is to promote dissolving and the dispersion of hydrophobic drug in gel.
The EP1091761 of U.S. Amgen Inc house journal; WO200038651; US6451346; US2003099709 has reported employing PLGA-PEG, PLGA-PEG or the original position hydrogel of the temperature sensitive dual sensitivity of PLGA-PEG-PLGA pH/ and the application in preparation thereof of the pharmaceutical prepn of PLGA-PEG-PLGA amphipathic nature polyalcohol situ-gel and end carboxyl.PEG segment molecule amount is 200～2000, PLGA molecular weight 400～5000, and PEG content is greater than 50%.WO200141735 is disclosed to be PLGA-pluronics-PLGA triblock copolymer original position thermo-sensitive gel, and wherein pluronics is the addition polymer of W 166 and oxyethane; WO200226215 is disclosed to be grafting Biodegradable polyester (polyhydroxy acid, polycaprolactone and multipolymer thereof) on the main chain that forms of polyoxyethylene glycol block, can form temperature sensing in situ gel rubber.And temperature sensitive property is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer and situ-gel system does not appear in the newspapers as yet.
Summary of the invention
What the object of the present invention is to provide a kind of thermo-sensitive biodegradable gathers (polyether ester diacid) anhydride copolymer and aquogel system and application.It is (polyether ester diacid) the acid anhydride amphipathic multi-block multipolymer of biodegradable gathering that the aqueous solution has temperature-sensitive situ hydrogel character.This gathering the hydrogel that in water medium, forms of (polyether ester diacid) acid anhydride, have with the reversible transition character of temperature variation from the solution state to the gel state, therefore (polyether ester diacid) acid anhydride has widely and uses this gathering.
Thermo-sensitive biodegradable provided by the invention gathers (polyether ester diacid) anhydride copolymer and obtains (ABA) by the polyether ester diacid through acid anhydridesization and polymerization
nType amphipathic multi-block multipolymer, wherein A is a hydrophobic section, and B is the polyoxyethylene glycol block, and n is between 1～60, and the mass content of polyoxyethylene glycol block is 27% to 73%, the number average relative molecular mass of polyoxyethylene glycol block is 200 to 800.
Polyether ester diacid of the present invention is that wherein aliphatic dibasic acid is fumaric acid, pentanedioic acid, hexanodioic acid, pimelic acid, suberic acid, nonane diacid, sebacic acid, SL-AH, tridecanyldicarboxylic acid, ten four-carbon dicarboxylic acids, 15 carbon dicarboxylic acids, 16-dicarboxylic acid, 18 carbon dicarboxylic acids by a kind of diprotic acid of polyoxyethylene glycol and aliphatic dibasic acid or the generation of aromatic dicarboxylic acid-respons; Aromatic acid is two (to the carboxyl phenoxy) methane, 1, two (to the carboxyl phenoxy) propane, 1 of 3-, two (to the carboxyl phenoxy) hexanes of 3-, to the carboxyl phenylium, to the positive valeric acid of carboxyl phenoxy or to carboxyl phenoxy pelargonic acid.
Polyether ester diacid of the present invention is a kind of diprotic acid that is generated by polyether ester divalent alcohol and maleic anhydride, succinyl oxide, Tetra hydro Phthalic anhydride or Pyroglutaric acid reaction.
Above-mentioned polyether ester divalent alcohol is polyoxyethylene glycol and D-lactic acid, L-lactic acid, D; L-lactic acid, oxyacetic acid, 3-hydroxybutyric acid, hydroxypentanoic acid or hydroxycaproic acid carry out the polyether ester divalent alcohol that polycondensation generates; Or by polyoxyethylene glycol initiation D-rac-Lactide, L-rac-Lactide, D, the polyether ester divalent alcohol that L-rac-Lactide, NSC 403079, GBL, valerolactone or 6-caprolactone ring-opening polymerization generate.
Described polyoxyethylene glycol block comes from polyoxyethylene glycol, T 46155 and polyoxypropylene block copolymers.
The aquogel system that the thermo-sensitive biodegradable that provides of the present invention gathers (polyether ester diacid) anhydride copolymer is with gathering (polyether ester diacid) anhydride copolymer homodisperse or being dissolved in the water medium; The water solution system of the flow state of gathering (polyether ester diacid) anhydride copolymer that forms forms immobilising gel state through temperature variation again.
Described water medium is aqueous liquid system, is the aqueous solution, water miscible liquid or the aqueous dispersions of pure water, organic or inorganic thing; The body fluid of various damping fluids, animal or human's body.
The water gel that above-mentioned thermo-sensitive biodegradable gathers (polyether ester diacid) anhydride copolymer ties up between 0～80 ℃ the character that has solution-gel phase co-conversion with temperature variation; Gathering (polyether ester diacid) anhydride copolymer content in the aquogel system is 10%～50%, and the content of water is no less than 30%.
The application that thermo-sensitive biodegradable provided by the invention gathers the aquogel system of (polyether ester diacid) anhydride copolymer is: said aquogel system and medicine, protein, polypeptide, polysaccharide, enzyme, cell are combined to form the liquid state compsn; Form gel through temperature variation; Be used to control the release of medicine, enzyme and contained material, or cell, enzyme fixing, cultivate.
" thermo-sensitive biodegradable gathers (polyether ester diacid) anhydride copolymer " among the present invention, its " temperature sensitive property " is meant that this biodegradable gathering aqueous solution of (polyether ester diacid) anhydride copolymer has with temperature variation generation solution-gel conversion character.
" situ-gel " among the present invention refers to have aqueous solutions of polymers or the aqueous humour with temperature variation generation solution-gel conversion character, and described " solution " is represented flowable liquid.
The logical finger of " aquogel system " among the present invention contains the system of gathering (polyether ester diacid) anhydride copolymer and water; Can be liquid or gel state; This system has the character with temperature variation generation solution-gel or gel-solution phase co-conversion, promptly has a critical solution-gel transition temperature at least.Except gathering (polyether ester diacid) anhydride copolymer and water, can also contain other material in this hydrogel, like salt, medicine, photographic developer, enzyme, cell etc.
Above-mentioned biodegradable gathering, (polyether ester diacid) anhydride copolymer temperature-sensitive hydrogel system was under differing temps, to exist with flowable liquid state and gel state respectively, took place by liquid state to gel state or by the transformation of gel state to liquid state with the variation of system or envrionment temperature.
Contained other material such as salt, medicine, macromolecular substance etc. have relation in the solution-gel transition temperature of anhydride copolymer temperature-sensitive hydrogel system that the present invention is biodegradable to be gathered (polyether ester diacid) and molecular structure, relative molecular mass, copolymer concentration and the aquogel system of gelling properties and segmented copolymer; Can form through regulating said structure factor, copolymer concentration and water medium, regulate the solution-gel transition temperature and the gel-strength of aquogel system.Larger molecular weight gather (polyether ester diacid) anhydride copolymer, (aqueous solution as 1%) just has solution-gel conversion character under lower aq, but gel-strength a little less than.In general, concentration is big more, and molecular weight is high more, and easy more formation gel and intensity are bigger.
Amphipathic multi-block of the present invention gathers (polyether ester diacid) anhydride copolymer degradation speed in vivo can be regulated through the kind and the factors such as chemical constitution and segmental length of gathering (polyether ester diacid) acid anhydride.
The amphipathic multi-block that proposes among the present invention gather (polyether ester diacid) anhydride copolymer can with other situ-gel material such as mixing application such as Prist, POLYACTIC ACID and polyethyleneglycol block copolymer, polycaprolactone and polyethyleneglycol block copolymer; Preparation combination copolymer situ-gel is to regulate release rate of drugs and gelling temp.
The amphipathic multi-block that proposes among the present invention gathers the biological degradation in vivo of (polyether ester diacid) anhydride copolymer; Degraded product is nontoxic; Its hydrogel has water-absorbent, permeability and biocompatibility; Be the polymer temperature-sensitive hydrogel material of one type of novel synthetic, simple to operation, have widely the purposes of biomedical and others.The injection site-specific delivery of drugs preparation and the controlled delivery of pharmaceutical agents release that can be medicine provide suitable drug delivery system and medication; Can be also that enzyme is fixed, cell cultures, organizational project etc. provide gel matrix and effective means, and suitable material and technology are provided for the various aqueous solution in fields such as food, healthcare products or the gelation of aqueous humour system.
Description of drawings
Fig. 1 gathers (polyether ester diacid) anhydride copolymer (ABA) by embodiment 3 preparation
nThe infrared spectrum of-S α 3.(A) polyether ester diacid; (B) gather (polyether ester diacid) acid anhydride prepolymer; (C) gather (polyether ester diacid) acid anhydride.
Fig. 2 gathers (polyether ester diacid) anhydride copolymer (ABA) by embodiment 3 preparation
nThe nmr spectrum of-S α 3.(A) polyether ester diacid; (B) gather (polyether ester diacid) acid anhydride.
Fig. 3 gathers (polyether ester diacid) anhydride copolymer (ABA) by embodiment 16 methods preparations
nThe solution of-S α 3 aquogel systems-gel conversion phasor.Gather (polyether ester diacid) (ABA)
n-S α 3 solution-gel conversion. (a) flowable state 25 ℃ the time; (b) gel state 37 ℃ the time; (c) phasor of solution-gel conversion.
Fig. 4 gathers (polyether ester diacid) anhydride copolymer (ABA) by 25% concentration of embodiment 16 methods preparations
n-S α 3 aquogel systems are to the sustained release curve of the taxol (initial content is 3%) of load.Gather (polyether ester diacid) (ABA)
n-S α 3 hydrogels are to taxol sustained release curve.
Embodiment
With embodiment the present invention is further explained again below, but be not that the present invention is done any restriction.
Embodiment 1:
PEG (M with 5g
n=200) join in the reaction vessel with the sebacic acid (mol ratio=1: 2.5) of 12.6g, add a certain amount of dry toluene (dry toluene and sebacic acid, volume/mass=16: 1, mL/g), at 120 ℃ of backflow 1h.Steam toluene then, be warming up to above (180 ℃) the vacuum fusion polycondensation 2h of melt temperature.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester diprotic acid; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 8: 1 (mol ratio); At 140 ℃ of backflow 40min; Remove excessive acetic anhydride via then; Add the toluene dissolving-recrystallization, with ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA) under the room temperature
n-S α 1, the n value is 1, sees table 1.
Embodiment 2:
PEG (M with 5g
n=200) join in the reaction vessel with the sebacic acid (mol ratio=1: 2.5) of 12.6g, add a certain amount of dry toluene (dry toluene and sebacic acid, volume/mass=16: 1, mL/g), at 120 ℃ of backflow 1h.Steam toluene then, be warming up to above (180 ℃) the vacuum fusion polycondensation 2h of melt temperature.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of vacuum-drying obtains the polyether ester diprotic acid under the room temperature; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel in 8: 1 (mol ratio) ratios; At 140 ℃ of backflow 40min; Remove excessive acetic anhydride via then; Add the toluene dissolving-recrystallization, with ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 0.5h, add the trichloromethane dissolving, the ether recrystallization 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, the about 48h of room temperature vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA)
n-S α 2, the n value is 5, sees table 1.
Embodiment 3:
PEG (M with 5g
n=200) join in the reaction vessel with the sebacic acid (mol ratio=1: 2.5) of 12.6g, add a certain amount of dry toluene (dry toluene and sebacic acid, volume/mass=16: 1, mL/g), at 120 ℃ of backflow 1h.Steam toluene then, be warming up to above (180 ℃) the vacuum fusion polycondensation 2h of melt temperature.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of vacuum-drying obtains the polyether ester diprotic acid under the room temperature; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 8: 1 (mol ratio); At 140 ℃ of backflow 40min, remove excessive acetic anhydride via then, add the toluene dissolving-recrystallization; With ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 1.5h, add the trichloromethane dissolving, the ether recrystallization 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, the about 48h of room temperature vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA)
n-S α 3.Ir spectra and NMR spectrum carry out structural characterization, and be as depicted in figs. 1 and 2.Absorption peak (the 1810cm that has presented anhydride group among Fig. 1
-1About), the absorption peak (1735cm of ester carbonyl group
-1About) and the polyoxyethylene glycol block in C-O-C ehter bond vibration peak (1000cm
-1About); Also can observe the absorption peak of each hydrogen proton in the nuclear magnetic resonance spectrum of Fig. 2, Fig. 1 and Fig. 2 result have proved the structure of segmented copolymer, and the n value is 20, sees table 1.
Embodiment 4:
PEG (M with 5g
n=200) join in the reaction vessel with the sebacic acid (mol ratio=1: 2.5) of 12.6g, add a certain amount of dry toluene (dry toluene and sebacic acid, volume/mass=16: 1, mL/g), at 120 ℃ of backflow 1h.Steam toluene then, be warming up to above (180 ℃) the vacuum fusion polycondensation 2h of melt temperature.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of vacuum-drying obtains the polyether ester diprotic acid under the room temperature; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 8: 1 (mol ratio); At 140 ℃ of backflow 40min, remove excessive acetic anhydride via then, add the toluene dissolving-recrystallization; With ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 2.5h, add the trichloromethane dissolving, the ether recrystallization 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, the about 48h of room temperature vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA)
n-S α 4, the n value is 35, sees table 1.
Embodiment 5:
PEG (M with 5g
n=200) join in the reaction vessel with the sebacic acid (mol ratio=1: 2.5) of 12.6g, add a certain amount of dry toluene (dry toluene and sebacic acid, volume/mass=16: 1, mL/g), at 120 ℃ of backflow 1h.Steam toluene then, be warming up to above (180 ℃) the vacuum fusion polycondensation 2h of melt temperature.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of vacuum-drying obtains the polyether ester diprotic acid under the room temperature; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 8: 1 (mol ratio); At 140 ℃ of backflow 40min, remove excessive acetic anhydride via then, add the toluene dissolving-recrystallization; With ether, the washing of sherwood oil mixed solvent, room temperature vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 5h, add the methylene dichloride dissolving, the ether recrystallization 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, the about 48h of vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA) under the room temperature
n-S α 5, the n value is 60, sees table 1.
With the polyoxyethylene glycol of different relative molecular masses and polyoxyethylene glycol and the diprotic acid in the diprotic acid alternative embodiment 1～5, reaction times and vacuum tightness that control gathers (polyether ester diacid) acid anhydride can get different sorts, block (ABA) than, different n values
n-S α type segmented copolymer, as shown in table 1.
Table 1 (ABA)
n-S α type gathers (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer
Embodiment 6:
PEG (M with 5g
n=200) with the D of 5.6g, L-lactic acid (mol ratio=1: 2.5) joins in the reaction vessel, under 0.025MPa vacuum tightness, 110 ℃, dewaters behind the 2h, is warmed up to 160 ℃, decompression frit reaction 5h.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol, succinyl oxide and DMAP (mol ratio=1: 4: 4) are added reaction vessel; Add a certain amount of anhydrous dioxane (anhydrous dioxane and polyether ester divalent alcohol then; Volume/mass=10: 1; ML/g) dissolving drips a certain amount of triethylamine (TEA) (polyether ester divalent alcohol and triethylamine mol ratio 1: 4), in 30 ℃ of nitrogen atmospheres, stirs 48h.After reaction finished, filtering reacting liquid got crude product with the normal hexane precipitating.Use methylene dichloride (DCM) fully to dissolve thick product then, (10%, V/V) the washing extraction is three times, and with saturated NaCl solution washing extraction three times, isolating organic phase is used anhydrous MgSO again with HCl solution earlier
4Drying, the normal hexane precipitating obtains the polyether ester diprotic acid at 40 ℃ of about 48h of vacuum-drying; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 8: 1 (mol ratio); At 140 ℃ of backflow 40min; Remove excessive acetic anhydride via then; Add the toluene dissolving-recrystallization, with ether, the washing of sherwood oil mixed solvent, vacuum-drying obtains amphipathic (polyether ester diacid) anhydride copolymer (ABA) under the room temperature
n-S β 1, the n value is 1, sees table 2.
Embodiment 7:
PEG (M with 5g
n=200) with the D of 5.6g, L-lactic acid (mol ratio=1: 2.5) joins in the reaction vessel, under 0.025MPa vacuum tightness, 110 ℃, dewaters behind the 2h, is warmed up to 160 ℃, decompression frit reaction 5h.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol, succinyl oxide and DMAP (mol ratio=1: 4: 4) are added reaction vessel; Add a certain amount of anhydrous dioxane (anhydrous dioxane and polyether ester divalent alcohol then; Volume/mass=10: 1; ML/g) dissolving drips a certain amount of triethylamine (TEA) (polyether ester divalent alcohol and triethylamine mol ratio 1: 4), in 30 ℃ of nitrogen atmospheres, stirs 48h.After reaction finished, filtering reacting liquid got crude product with the normal hexane precipitating.Use methylene dichloride (DCM) fully to dissolve thick product then, (10%, V/V) the washing extraction is three times, and with saturated NaCl solution washing extraction three times, isolating organic phase is used anhydrous MgSO again with HCl solution earlier
4Drying, the normal hexane precipitating obtains the polyether ester diprotic acid at 40 ℃ of about 48h of vacuum-drying; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 8: 1 (mol ratio); At 140 ℃ of backflow 40min, remove excessive acetic anhydride via then, add the toluene dissolving-recrystallization; With ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 1h, add the trichloromethane dissolving, precipitating in the ether 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, room temperature vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA)
n-S β 2, the n value is 8, sees table 2.
Embodiment 8:
PEG (M with 5g
n=200) with the D of 5.6g, L-lactic acid (mol ratio=1: 2.5) joins in the reaction vessel, under 0.025MPa vacuum tightness, 110 ℃, dewaters behind the 2h, is warmed up to 160 ℃, decompression frit reaction 5h.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol, succinyl oxide and DMAP (mol ratio=1: 4: 4) are added reaction vessel; Add a certain amount of anhydrous dioxane (anhydrous dioxane and polyether ester divalent alcohol then; Volume/mass=10: 1; ML/g) dissolving drips a certain amount of triethylamine (TEA) (polyether ester divalent alcohol and triethylamine mol ratio 1: 4), in 30 ℃ of nitrogen atmospheres, stirs 48h.After reaction finished, filtering reacting liquid got crude product with the normal hexane precipitating.Use methylene dichloride (DCM) fully to dissolve thick product then, (10%, V/V) the washing extraction is three times, and with saturated NaCl solution washing extraction three times, isolating organic phase is used anhydrous MgSO again with HCl solution earlier
4Drying, the normal hexane precipitating obtains the polyether ester diprotic acid at 40 ℃ of about 48h of vacuum-drying; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 8: 1 (mol ratio); At 140 ℃ of backflow 40min, remove excessive acetic anhydride via then, add the toluene dissolving-recrystallization; With ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 2h, add the trichloromethane dissolving, precipitating in the ether 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, room temperature vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA)
n-S β 3, the n value is 22, sees table 2.
Embodiment 9:
PEG (M with 5g
n=200) with the D of 5.6g, L-lactic acid (mol ratio=1: 2.5) joins in the reaction vessel, under 0.025MPa vacuum tightness, 110 ℃, dewaters behind the 2h, is warmed up to 160 ℃, decompression frit reaction 5h.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol, succinyl oxide and DMAP (mol ratio=1: 4: 4) are added reaction vessel; Add a certain amount of anhydrous dioxane (anhydrous dioxane and polyether ester divalent alcohol then; Volume/mass=10: 1; ML/g) dissolving drips a certain amount of triethylamine (TEA) (polyether ester divalent alcohol and triethylamine mol ratio 1: 4), in 30 ℃ of nitrogen atmospheres, stirs 48h.After reaction finished, filtering reacting liquid got crude product with the normal hexane precipitating.Use methylene dichloride (DCM) fully to dissolve thick product then, (10%, V/V) the washing extraction is three times, and with saturated NaCl solution washing extraction three times, isolating organic phase is used anhydrous MgSO again with HCl solution earlier
4Drying, the normal hexane precipitating obtains the polyether ester diprotic acid at 40 ℃ of about 48h of vacuum-drying; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 8: 1 (mol ratio); At 140 ℃ of backflow 40min, remove excessive acetic anhydride via then, add the toluene dissolving-recrystallization; With ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 3h, add the trichloromethane dissolving, precipitating in the ether 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, room temperature vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA)
n-S β 4, the n value is 35, sees table 2.
Embodiment 10:
PEG (M with 5g
n=200) with the D of 5.6g, L-lactic acid (mol ratio=1: 2.5) joins in the reaction vessel, under 0.025MPa vacuum tightness, 110 ℃, dewaters behind the 2h, is warmed up to 160 ℃, decompression frit reaction 5h.Add the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol, succinyl oxide and DMAP (mol ratio=1: 4: 4) are added reaction vessel; Add a certain amount of anhydrous dioxane (anhydrous dioxane and polyether ester divalent alcohol then; Volume/mass=10: 1; ML/g) dissolving drips a certain amount of triethylamine (TEA) (polyether ester divalent alcohol and triethylamine mol ratio 1: 4), in 30 ℃ of nitrogen atmospheres, stirs 48h.After reaction finished, filtering reacting liquid got crude product with the normal hexane precipitating.Use methylene dichloride (DCM) fully to dissolve thick product then, (10%, V/V) the washing extraction is three times, and with saturated NaCl solution washing extraction three times, isolating organic phase is used anhydrous MgSO again with HCl solution earlier
4Drying, the normal hexane precipitating obtains the polyether ester diprotic acid at 40 ℃ of about 48h of vacuum-drying; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 8: 1 (mol ratio); At 140 ℃ of backflow 40min, remove excessive acetic anhydride via then, add the toluene dissolving-recrystallization; With ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 5h, add the trichloromethane dissolving, precipitating in the ether 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, room temperature vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA)
n-S β 5, the n value is 60, sees table 2.
With polyoxyethylene glycol, alcohol acid and the dicarboxylic anhydride in polyoxyethylene glycol, alcohol acid and the dicarboxylic anhydride alternative embodiment 6～10 of different relative molecular masses; Reaction times and vacuum tightness that control gathers (polyether ester diacid) acid anhydride can get different sorts, block (ABA) than, different n values
n-S β type segmented copolymer, as shown in table 2.
Table 2 (ABA)
n-S β type gathers (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer
Embodiment 11:
PEG (M with 4g
n=200), the 6-caprolactone (mol ratio=1: 3) of 9.1g and the stannous octoate of 32.3mg join in the Schlenk reaction tubes, under the nitrogen atmosphere in 140 ℃ of reaction 15h.After reaction finishes, with the methylene dichloride dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol and succinyl oxide (mol ratio=1: 4) are joined in the reaction vessel, and add a certain amount of dry toluene (dry toluene and polyether ester divalent alcohol, volume/mass=10: 1; ML/g); At 120 ℃ of backflow 1h, steam toluene then, be warming up to 140 ℃ of vacuum fusion polycondensation 4h.Reaction finishes, and adds the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of vacuum-drying obtains the polyether ester diprotic acid under the room temperature; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 10: 1 (mol ratio); At 140 ℃ of backflow 40min; Remove excessive acetic anhydride via then; Add the toluene dissolving-recrystallization, wash with ether, sherwood oil mixed solvent, vacuum-drying obtains amphipathic multi-block and gathers (polyether ester diacid) anhydride copolymer (ABA) under the room temperature
n-S γ 1, the n value is 1, sees table 3.
Embodiment 12:
PEG (M with 4g
n=200), the 6-caprolactone (mol ratio=1: 3) of 9.1g and the stannous octoate of 32.3mg join in the Schlenk reaction tubes, under the nitrogen atmosphere in 140 ℃ of reaction 15h.After reaction finishes, with the methylene dichloride dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol and succinyl oxide (mol ratio=1: 4) are joined in the reaction vessel, and add a certain amount of dry toluene (dry toluene and polyether ester divalent alcohol, volume/mass=10: 1; ML/g); At 120 ℃ of backflow 1h, steam toluene then, be warming up to 140 ℃ of vacuum fusion polycondensation 4h.Reaction finishes, and adds the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of vacuum-drying obtains the polyether ester diprotic acid under the room temperature; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 10: 1 (mol ratio); At 140 ℃ of backflow 40min; Remove excessive acetic anhydride via then; Add the toluene dissolving-recrystallization, with ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 1h, add the trichloromethane lysate, precipitating in the ether 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA) under the room temperature
n-S γ 2, the n value is 10, sees table 3.
Embodiment 13:
PEG (M with 4g
n=200), the 6-caprolactone (mol ratio=1: 3) of 9.1g and the stannous octoate of 32.3mg join in the Schlenk reaction tubes, under the nitrogen atmosphere in 140 ℃ of reaction 15h.After reaction finishes, with the methylene dichloride dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol and succinyl oxide (mol ratio=1: 4) are joined in the reaction vessel, and add a certain amount of dry toluene (dry toluene and polyether ester divalent alcohol, volume/mass=10: 1; ML/g); At 120 ℃ of backflow 1h, steam toluene then, be warming up to 140 ℃ of vacuum fusion polycondensation 4h.Reaction finishes, and adds the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of vacuum-drying obtains the polyether ester diprotic acid under the room temperature; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 10: 1 (mol ratio); At 140 ℃ of backflow 40min; Remove excessive acetic anhydride via then; Add the toluene dissolving-recrystallization, with ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 2h, add the trichloromethane lysate, precipitating in the ether 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA) under the room temperature
n-S γ 3, the n value is 26, sees table 3.
Embodiment 14:
PEG (M with 4g
n=200), the 6-caprolactone (mol ratio=1: 3) of 9.1g and the stannous octoate of 32.3mg join in the Schlenk reaction tubes, under the nitrogen atmosphere in 140 ℃ of reaction 15h.After reaction finishes, with the methylene dichloride dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol and succinyl oxide (mol ratio=1: 4) are joined in the reaction vessel, and add a certain amount of dry toluene (dry toluene and polyether ester divalent alcohol, volume/mass=10: 1; ML/g); At 120 ℃ of backflow 1h, steam toluene then, be warming up to 140 ℃ of vacuum fusion polycondensation 4h.Reaction finishes, and adds the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of vacuum-drying obtains the polyether ester diprotic acid under the room temperature; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 10: 1 (mol ratio); At 140 ℃ of backflow 40min; Remove excessive acetic anhydride via then; Add the toluene dissolving-recrystallization, with ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 3h, add the trichloromethane lysate, precipitating in the ether 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA) under the room temperature
n-S γ 4, the n value is 36, sees table 3.
Embodiment 15:
PEG (M with 4g
n=200), the 6-caprolactone (mol ratio=1: 3) of 9.1g and the stannous octoate of 32.3mg join in the Schlenk reaction tubes, under the nitrogen atmosphere in 140 ℃ of reaction 15h.After reaction finishes, with the methylene dichloride dissolving, the ether recrystallization, and with the ether washing, the about 48h of room temperature vacuum-drying obtains the polyether ester divalent alcohol; Polyether ester divalent alcohol and succinyl oxide (mol ratio=1: 4) are joined in the reaction vessel, and add a certain amount of dry toluene (dry toluene and polyether ester divalent alcohol, volume/mass=10: 1; ML/g); At 120 ℃ of backflow 1h, steam toluene then, be warming up to 140 ℃ of vacuum fusion polycondensation 4h.Reaction finishes, and adds the trichloromethane dissolving, the ether recrystallization, and with the ether washing, the about 48h of vacuum-drying obtains the polyether ester diprotic acid under the room temperature; Diacetyl oxide and polyether ester diprotic acid are joined in the reaction vessel by 10: 1 (mol ratio); At 140 ℃ of backflow 40min; Remove excessive acetic anhydride via then; Add the toluene dissolving-recrystallization, with ether, the washing of sherwood oil mixed solvent, vacuum-drying is gathered (polyether ester diacid) acid anhydride prepolymer under the room temperature; To gather (polyether ester diacid) acid anhydride prepolymer and add reaction vessel; Down behind the reaction 5h, add the trichloromethane lysate, precipitating in the ether 0.1MPa vacuum tightness, 180 ℃; And with the ether washing, vacuum-drying is gathered (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer (ABA) under the room temperature
n-S γ 5, the n value is 60, sees table 3.
With polyoxyethylene glycol, lactone and the dicarboxylic anhydride in polyoxyethylene glycol, lactone and the dicarboxylic anhydride alternative embodiment 11～15 of different relative molecular masses; Reaction times and vacuum tightness that control gathers (polyether ester diacid) acid anhydride can get different sorts, block (ABA) than, different n values
n-S γ type segmented copolymer, as shown in table 3.
Table 3 (ABA)
n-S γ type gathers (polyether ester diacid) acid anhydride amphipathic multi-block multipolymer
Embodiment 16:
The segmented copolymer (ABA) of preparation among the embodiment 3
n-S α 3 is under induction stirring, and dispersing and dissolving is prepared concentration and be the aquogel system under 15～40% the liquid state under the room temperature in zero(ppm) water, slowly heats up after being cooled to 4 ℃, observes the formation of gel.As shown in Figure 3, in above-mentioned concentration range, this water gel ties up to and forms gel in (35 ± 5) ℃～(50 ± 5) ℃ TR, and this gelation process is reversible, promptly is solution under the low temperature, and heating up becomes gel, and cooling becomes solution again.And under comparatively high temps, the precipitated and separated phenomenon then appears in gelling system, dissolving again after the cooling.
Embodiment 17:
Replace the zero(ppm) water among the embodiment 16 with saline water, pH damping fluid, photographic developer, blood plasma, glucose injection, tissue culture medium, sodium chloride injection, 1～20% water phase surfactant mixture, the solution-gel transition temperature of 15～40% aquogel system of preparation is still in (35 ± 5) ℃～(50 ± 5) ℃ scope.
Embodiment 18:
Prist 127 with 10～40% or 188 the aqueous solution replace the zero(ppm) water among the embodiment 16,15～40% (ABA) of preparation
nSolution-the gel transition temperature of the liquid water gelling system of-S α 3 samples is in (15 ± 5) ℃～(50 ± 5) ℃ scope.
Embodiment 19:
Prepare the aquogel system under the liquid state of the segmented copolymer described in table 1, table 2 and the table 3 by embodiment 16 methods, the solution of the aquogel system of gained-gel transition temperature scope is seen table 4.
Table 4 (ABA)
nType gathers the solution-gel transition temperature of (polyether ester diacid) anhydride copolymer temperature-sensitive hydrogel
All there is at least one solution-gel transition temperature in 15～40% aqueous solution of the polyanhydride copolymer of embodiment 1～5, embodiment 6～10 and embodiment 11～15 preparations between 4～80 ℃.
Embodiment 20:
Contain 60% (ABA) by the preparation of embodiment 16 methods
nThe liquid water gelling system of-S α 3 is got this aquogel system 1g, adds the ethanol of 1g, mixes, and forms new aquogel system, and the solution-gel conversion of this aquogel system occurs between 15～50 ℃.
Embodiment 21:
The external degradation behavior of the segmented copolymer in the phosphate buffered saline buffer of pH7.4 among the research embodiment 3, temperature is 37 ℃, degraded product is diprotic acid, polyoxyethylene glycol.
Embodiment 22:
Prepare 25% (ABA) by embodiment 16 methods
nThe liquid water gelling system of the phosphate buffered saline buffer of the pH7.4 of-S α 3; Regular Insulin at 20 ℃ following 5% is dissolved in this gelling system; Slowly be warming up to 37 ℃ and form gel; The 1g gel is put in the dialysis tubing, and is put in 37 ℃ the phosphate buffered saline buffer of pH7.4, Regular Insulin can slowly discharge and reach 12h.
The liquid water gelling system of the insulin-containing of embodiment 16 preparation is subcutaneously injected into the belly of rat, and water gel ties up to and forms gel the rat temperature environment under, controls the release of Regular Insulin.
Embodiment 23:
With 1g (ABA)
n-S α 3 is dissolved in the 2ml acetone with the 30mg taxol, and dispersing and dissolving volatilizees acetone in the phosphate buffered saline buffer of 4ml pH7.4 fully then, prepares (ABA) of pastille
n-S α 3 liquid water gelling systems are warming up to 37 ℃ and form gel, are put in the dialysis tubing; And be put in 37 ℃ the phosphate buffered saline buffer of pH7.4; Taxol can slowly discharge and reach more than the 48h, and as shown in Figure 4, taxol slowly releases from gel; Basic not dashing forward released generation, and 48h cumulative release amount is near 62%.
Embodiment 24:
The chitosan particle that is loaded with the 5%5-Fluracil is distributed to 25% (ABA) of embodiment 16 methods preparation
nIn the liquid gel system of-S α 3, through about temperature regulation to 37 ℃, form the gel that is loaded with particulate again, be used for the sustained release of 5 FU 5 fluorouracil.
Embodiment 25:
Trypsinase is dissolved into 25% (ABA) of embodiment 10 methods preparation
nThe sodium chloride injection aquogel system of-S α 3 is processed the 20% tryptic aqueous solution, adjusts the temperature to 37 ℃, or is expelled in the human or animal body, forms tryptic gel, controls tryptic release.
According to the method for embodiment 17～25 also can other protein of load, water-soluble, hydrophobic drug such as polypeptide, DNA, enzyme, polysaccharide, Zorubicin, cis-platinum, Docetaxel; Or load medicine carrying micro mist, particulate are processed the medicine sustained and controlled release preparation; Be expelled to internal in-situ and form gel; The slow controlled release drug administration that is used for medicine also can mix cell, nutritive ingredient etc. with temperature-sensitive hydrogel under the above-mentioned liquid state, mixed system forms gel through temperature variation.
Claims (8)
1. a thermo-sensitive biodegradable gathers (polyether ester diacid) anhydride copolymer; It is characterized in that: described gathering (polyether ester diacid) acid anhydride be that the polyether ester diacid obtains (ABA) n type amphipathic multi-block multipolymer through acid anhydridesization and polymerization; Wherein A is a hydrophobic section, and B is the polyoxyethylene glycol block, and n is between 1～60; The mass content of polyoxyethylene glycol block is 27% to 73%, and the number average relative molecular mass of polyoxyethylene glycol block is 200 to 800.
2. gather (polyether ester diacid) anhydride copolymer according to the described thermo-sensitive biodegradable of claim 1; It is characterized in that: described polyether ester diacid is that wherein aliphatic dibasic acid is fumaric acid, pentanedioic acid, hexanodioic acid, pimelic acid, suberic acid, nonane diacid, sebacic acid, SL-AH, tridecanyldicarboxylic acid, ten four-carbon dicarboxylic acids, 15 carbon dicarboxylic acids, 16-dicarboxylic acid, 18 carbon dicarboxylic acids by a kind of diprotic acid of polyoxyethylene glycol and aliphatic dibasic acid or the generation of aromatic dicarboxylic acid-respons; Aromatic acid is two (to the carboxyl phenoxy) methane, 1, two (to the carboxyl phenoxy) propane, 1 of 3-, two (to the carboxyl phenoxy) hexanes of 3-, to the carboxyl phenylium, to the positive valeric acid of carboxyl phenoxy or to carboxyl phenoxy pelargonic acid.
3. gather (polyether ester diacid) anhydride copolymer according to the described thermo-sensitive biodegradable of claim 1, it is characterized in that: described polyether ester diacid is a kind of diprotic acid that polyether ester divalent alcohol and maleic anhydride, succinyl oxide, Tetra hydro Phthalic anhydride or Pyroglutaric acid reaction generate.
4. gather (polyether ester diacid) anhydride copolymer according to the described thermo-sensitive biodegradable of claim 3; It is characterized in that: described polyether ester divalent alcohol is polyoxyethylene glycol and D-lactic acid, L-lactic acid, D, the polyether ester divalent alcohol that L-lactic acid, oxyacetic acid, 3-hydroxybutyric acid, hydroxypentanoic acid or hydroxycaproic acid reaction generate; Or by polyoxyethylene glycol initiation D-rac-Lactide, L-rac-Lactide, D, the polyether ester divalent alcohol that L-rac-Lactide, NSC 403079, GBL, valerolactone or 6-caprolactone ring-opening polymerization generate.
5. gather (polyether ester diacid) anhydride copolymer according to the described thermo-sensitive biodegradable of claim 1, it is characterized in that described polyoxyethylene glycol block comes from polyoxyethylene glycol or T 46155 and polyoxypropylene block copolymers.
6. thermo-sensitive biodegradable as claimed in claim 1 gathers the aquogel system of (polyether ester diacid) anhydride copolymer; It is characterized in that to gather (polyether ester diacid) anhydride copolymer homodisperse or be dissolved in the water medium; Formation gathers the water solution system of the flow state of (polyether ester diacid) anhydride copolymer, forms immobilising gel state through temperature variation again; Described water medium is aqueous liquid system: pure water, the aqueous solution of organic or inorganic thing, water miscible liquid or aqueous dispersions, the body fluid of various damping fluids, animal or human's body.
7. thermo-sensitive biodegradable as claimed in claim 1 gathers the aquogel system of (polyether ester diacid) anhydride copolymer, it is characterized in that this water gel ties up between 0～80 ℃ the character that has solution-gel phase co-conversion with temperature variation; Gathering (polyether ester diacid) anhydride copolymer content in the aquogel system is 10%～50%, and the content of water is no less than 30%.
8. thermo-sensitive biodegradable as claimed in claim 1 gathers the application of the aquogel system of (polyether ester diacid) anhydride copolymer; It is characterized in that said aquogel system and medicine, protein, polypeptide, polysaccharide, enzyme, cell are combined to form the liquid state compsn; Form gel through temperature variation; Be used to control the release of medicine, enzyme and contained material, or cell, enzyme fixing, cultivate.
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| CN104629026A (en) * | 2015-02-15 | 2015-05-20 | 东华大学 | Biomedical polybasic copolymerized crosslinked polyester elastomer material and preparation method thereof |
| CN105683247A (en) * | 2013-10-31 | 2016-06-15 | 日油株式会社 | Method for producing medical polyoxypropylene polymer, and method for producing medical polyoxypropylene/polyoxyethylene block copolymer |
| CN108276564A (en) * | 2018-01-17 | 2018-07-13 | 江苏工程职业技术学院 | A kind of preparation method of more block novel temperature-sensitive materials containing maleic anhydride |
| CN109999218A (en) * | 2019-05-08 | 2019-07-12 | 西南交通大学 | A kind of temperature sensitive type high intensity tissue adhesive |
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| CN101265312A (en) * | 2008-05-07 | 2008-09-17 | 天津大学 | Amphipathic three block copolymer and its preparation method and application |
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| CN101265312A (en) * | 2008-05-07 | 2008-09-17 | 天津大学 | Amphipathic three block copolymer and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105683247A (en) * | 2013-10-31 | 2016-06-15 | 日油株式会社 | Method for producing medical polyoxypropylene polymer, and method for producing medical polyoxypropylene/polyoxyethylene block copolymer |
| US9777113B2 (en) | 2013-10-31 | 2017-10-03 | Nof Corporation | Production method of medical polyoxypropylene polymer and production method of medical polyoxypropylene/polyoxyethylene block copolymer |
| CN105683247B (en) * | 2013-10-31 | 2018-05-04 | 日油株式会社 | The manufacture method of the manufacture method of medical polyoxypropylene polymer and medical polyoxypropylene/polyoxyethylene block copolymer |
| CN104629026A (en) * | 2015-02-15 | 2015-05-20 | 东华大学 | Biomedical polybasic copolymerized crosslinked polyester elastomer material and preparation method thereof |
| CN108276564A (en) * | 2018-01-17 | 2018-07-13 | 江苏工程职业技术学院 | A kind of preparation method of more block novel temperature-sensitive materials containing maleic anhydride |
| CN109999218A (en) * | 2019-05-08 | 2019-07-12 | 西南交通大学 | A kind of temperature sensitive type high intensity tissue adhesive |
| CN109999218B (en) * | 2019-05-08 | 2020-06-02 | 西南交通大学 | Temperature-sensitive high-strength tissue adhesive |
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