CN101255235B - Thermo-sensitive tri-block copolymer having sol-gel conversion characteristic and preparation thereof - Google Patents
Thermo-sensitive tri-block copolymer having sol-gel conversion characteristic and preparation thereof Download PDFInfo
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- CN101255235B CN101255235B CN2008103007577A CN200810300757A CN101255235B CN 101255235 B CN101255235 B CN 101255235B CN 2008103007577 A CN2008103007577 A CN 2008103007577A CN 200810300757 A CN200810300757 A CN 200810300757A CN 101255235 B CN101255235 B CN 101255235B
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Abstract
The present invention relates to medical polymers field, especially a temperature sensitive and biodegradable triblock copolymer with gel-sol transformation characteristics and preparation method thereof and usage. The triblock copolymer is PEG-PCL-PEG copolymer, the aqueous solution thereof performs Sol-Gel phase transformation along with the temperature rise and the phase transformation temperature is 25-35 degree. The PEG-PCL-PEG copolymer has a variety of excellent features to provide a new choice in field which is in need of temperature sensitive material.
Description
Technical field
The present invention relates to pharmaceutical polymeric material field, be specifically related to a kind of temperature sensitively, have sol-gel transition characteristic and biodegradable triblock copolymer and its production and use.
Background technology
In recent years, biodegradable environmental sensitivity hydrogel is because its good sensitivity, biological degradability and biocompatibility have been subjected to the extensive concern of Chinese scholars.The environmental sensitivity hydrogel intelligent aqueous gel capable that is otherwise known as, be meant self can perception external environment (as temperature, pH value, light, electricity, pressure etc.) variation or stimulation, and can produce a family macromolecule hydrogel of corresponding physical structure and chemical property variation.Wherein, the temperature sensitivity physical hydrogel is owing to it receives much concern having broad application prospects aspect the fields such as controlled release drug delivery system, cell embedding and tissue repair.
At present, report in document and the patent along with the temperature biological medical polymer material with sol-gel transition feature that raises comprises: chitosan/Phosphoric acid glycerol esters, poloxamer (Pluronic), polyoxyethylene glycol poly (glycolide-lactide) polyoxyethylene glycol (PEG-PLGA-PEG) triblock copolymer, but at present these materials because self molecular structure former thereby have various defectives.As: poloxamer non-degradable and gel-strength are low; Chitosan/Phosphoric acid glycerol esters hydrogel degradation speed is difficult to control; PEG-PLGA-PEG hydrogel intensity is low and cost an arm and a leg.
Because excellent biological compatibility and environmental change susceptibility, (Pluronic or Poloxamer PEG-PPG-PEG) is widely studied as a kind of controlled drug delivery system poloxamer.But the critical gel strength of poloxamer is higher, gel-strength a little less than, and can not biological degradation, these drawbacks limit the widespread use of poloxamer at biomedical sector.
Application number is to disclose polycaprolactone (PCL) multipolymer that class polyoxyethylene glycol (PEG) block is modified in 03100434.2 the Chinese patent application, wherein specifically disclosing by relative molecular mass is 2000,4000 PCL and relative molecular mass are 2000,4000 PEG synthetic PEG (2000,4000)-PCL (8000,4000)-PEG (2000,4000) amphipathic three block copolymer, relative molecular mass is big, polycaprolactone (PCL) multipolymer that disclosed polyoxyethylene glycol (PEG) block is modified in this invention is mixed with solution with organic solvent, in water, be self-assembled into nanoparticle or micella again, this nanoparticle can degradation in vivo, degraded product is nontoxic, its nanoparticle can disperse to form stable dispersions in water, " being the good auxiliary material of exploitation hydrophobic drug long-acting slow-release preparation ", shortcoming is that this PEG-PCL-PEG multipolymer does not dissolve in water.
Summary of the invention:
First technical problem to be solved by this invention provides a kind of segmented copolymer.This segmented copolymer is the PEG-PCL-PEG triblock copolymer that PCL modifies PEG, and its relative molecular mass is 1000～6000, and wherein the ratio of total relative molecular mass of PCL segmental and the total relative molecular mass of PEG segmental is 1.4～2.6.
Preferably, the ratio of the relative molecular mass of the relative molecular mass of PCL and PEG is preferably 1.75～2.25 in the above-mentioned segmented copolymer.Preferred, the ratio of the relative molecular mass of the relative molecular mass of PCL and PEG is 2 in the above-mentioned segmented copolymer.
Preferably, the relative molecular mass of above-mentioned segmented copolymer is 1500～5000.
Above-mentioned segmented copolymer can be dissolved in the water, and its aqueous solution is along with temperature raises and the transformation mutually of generation Sol phase～Gel phase, and phase transition temperature is at 25 ℃～35 ℃.
Further, above-mentioned segmented copolymer is E
550-C
2000-E
550, E
550-C
2200-E
550, E
750-C
2200E
750, E
750-C
3000-E
750E wherein represents PEG, and C represents PCL, and subscript is represented corresponding each segmental relative molecular mass respectively.
Second technical problem to be solved by this invention provides a kind of method for preparing above-mentioned PEG-PCL-PEG multipolymer.This method comprises the steps:
A, be catalyzer, adopt MPEG to cause the caprolactone ring-opening polymerization, obtain the MPEG-PCL Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock at 130-150 ℃ of reacting by heating 3-12 hour with the stannous octoate;
B, with this multipolymer of step a gained MPEG-PCL Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock with vulcabond do linking agent under vacuum state, continue the reaction 0.5-2 hour, obtain the PEG-PCL-PEG triblock copolymer;
C, step b gained PEG-PCL-PEG triblock copolymer material is cooled to room temperature under nitrogen protection, preserves standby after the purification after the lyophilize at room temperature.
Wherein, vulcabond described in the method for above-mentioned preparation temperature responsive type PEG-PCL-PEG multipolymer is a tolylene diisocyanate, 1, hexamethylene-diisocyanate, ditan-4, at least a in 4 '-vulcabond, the isophorone diisocyanate.
The 3rd technical problem to be solved by this invention provides above-mentioned segmented copolymer in the purposes of medicine in the preparation drug release hierarchy of control, tissue engineering material, degradable water gel.Segmented copolymer of the present invention is particularly suitable for preparing the local fields such as control drug system, temperature sensitivity embolism materials, injectable and degradable tissue engineering bracket material that discharge.
The 4th technical problem to be solved by this invention provides a kind of pharmaceutical composition.This pharmaceutical composition is that above-mentioned segmented copolymer drug loading activeconstituents is prepared from.
Under PEG-PCL-PEG of the present invention (can be expressed as PECE) the segmented copolymer normal condition is solid or thick liquid, and water soluble, its aqueous solution have 25 ℃～35 ℃ critical gelling temp (CGT).That is to say in its aqueous solution, be equal to or greater than when its concentration under the situation of critical gel strength (CGC),, colloidal sol (Sol) transformation mutually of gel (Gel) phase in opposite directions can take place when temperature is elevated to critical gelling temp (CGT) when above.
The gel-strength of the hydrogel of the prepared one-tenth of segmented copolymer of the present invention can be regulated by length and the relative proportion of adjusting PCL and PEG section under the situation that satisfies above-mentioned requirement to critical gelling temp (CGT).Generally speaking, take the conventional measure of this area, can increase its gel-strength, to satisfy application need in fields such as temperature sensitivity embolism materials and tissue engineering bracket materials.
The degradation speed of the hydrogel of the prepared one-tenth of triblock copolymer of the present invention can be under the situation that satisfies above-mentioned requirement to critical gelling temp (CGT), regulate by length and the relative proportion of adjusting PCL and PEG section, to satisfy the needs that degradation speed had the related application field of particular requirement.Generally speaking, take the conventional measure of this area can regulate its degradation speed, thus the slow controlled release requirement of the timing that acquires a certain degree.
The present invention creatively provides the PEG-PCL-PEG with responsive to temperature type segmented copolymer, it has 25 ℃～35 ℃ critical gelling temp (CGT), degradation speed is adjustable, gel-strength is adjustable, good biocompatibility, may preserve with powder type, the preparation gel does not need to use excellent characteristics such as deleterious solvent, and these characteristics have determined thermo-sensitive tri-block polymer of the present invention in the drug release hierarchy of control, field of tissue engineering technology, Application Areass such as degradable water gel and biological medical polymer material have fabulous application prospect, for the field that needs use temperature responsive type multipolymer provides a kind of new selection.The inventive method is easy and simple to handle, and efficiency of pcr product height, purity height, character are controlled, are suitable for large-scale production and application.
Description of drawings:
Fig. 1 is the infrared spectra comparison diagram of diblock PCL-PEG multipolymer (A) and three block PEG-PCL-PEG multipolymers (B).
Fig. 2 is the nuclear-magnetism test collection of illustrative plates of PEG-PCL-PEG multipolymer.
Fig. 3 is E
550-C
2200-E
550Hydrogel is at 30 ℃ (a) and synoptic diagram when 37 ℃ (b).
Fig. 4 is VB
12From VB
12/ PECE (E
550-C
2200-E
550) drug release behavior in the mixture.Wherein: A represents the influence of the concentration of hydrogel to the drug release behavior, its VB
12Content is 0.8 milligram; B represents VB
12Content to the influence of drug release behavior, its gel strength is 30%.
Fig. 5 Honokiol is from Honokiol/PECE (E
550-C
2200-E
550) release behavior in the hydrogel composites, its gel strength is 30%.
Fig. 6 is that BSA is from BSA/PECE (E
550-C
2200-E
550) release behavior in the hydrogel composites.Wherein A represents the influence of BSA initial content to its release behavior, and its gel strength is 30%; B represents the influence of hydrogel concentration to the drug release behavior.Its BSA content is 4 milligrams.
Fig. 7 represents that PEG-PCL-PEG multipolymer (PECE), F127 are injected into the hydrogel of mouse after subcutaneous respectively to be formed and degraded.Wherein: A, B, C, D are respectively that the PECE hydrogel was injected into mouse subcutaneous back 1 day, 3 days, 7 days, 14 days; E, F are respectively that poloxamer F127 had been injected into mouse subcutaneous 2 hours, 4 hours.
Fig. 8 represents the phase transition curve of PECE hydrogel.Wherein A represents the influence of PCL chain segment molecular weight to the phase transition curve, and B represents the influence of hydrogel total molecular weight to the phase transition curve.
Further describe by embodiment below in conjunction with accompanying drawing but do not limit the present invention.
Embodiment:
Main agents and instrument that the embodiment of the invention is used:
Caprolactone (ε-CL, Alfa Aesar company, analytical pure)
Poly glycol monomethyl ether (MPEG, Mn=550,750,1000, Aldrich company, analytical pure)
Stannous octoate (Stannous octoate, Sigma company, analytical pure)
Isophorone diisocyanate (IPDI, Aldrich company, analytical pure)
Varian 400 type nuclear magnetic resonance analyser (U.S. Varian company)
200SXV type Fourier infrared spectrograph (Nicolet company)
Synthetic and the checking of embodiment one PEG-PCL-PEG multipolymer of the present invention
1) PEG-PCL-PEG multipolymer of the present invention is synthetic
The concise and to the point synthetic route of PEG-PCL-PEG multipolymer of the present invention is as follows:
Wherein X, Y are positive integer.
Synthetic route according to following formula; adding a certain amount of poly glycol monomethyl ether (MPEG) and caprolactone in the there-necked flask of agitator is housed (ε-CL); with the stannous octoate is catalyzer; reaction is 6 hours under 130 ℃, the condition of nitrogen protection; be cooled to 80 ℃; adding linking agent isoflurane chalcone diisocyanate (IPDI) continues reaction again and obtains product after 6 hours, is cooled to room temperature and purifies, oven dry.In addition, the vulcabond of Shi Heing also comprises: tolylene diisocyanate, hexamethylene diisocyanate, ditan-4,4 '-vulcabond etc.
According to aforesaid method, synthesized E
550-C
2000-E
550, E
550-C
2200-E
550, E
750-C
2200-E
750, E
750-C
3000-E
750Deng the satisfactory multipolymer of tool (seeing Table 1).
2, the checking of PEG-PCL-PEG multipolymer of the present invention
(1), the characterizing method of PEG-PCL-PEG multipolymer of the present invention
(200SXV Nicolet), adopts the KBr pressed disc method that the synthetic multipolymer is carried out Infrared spectroscopy with Fourier infrared spectrograph (FTIR).
1(Varian 400, Varian) measure, and under 400MHZ, solvent is CDCl with nuclear magnetic resonance analyser for H-NMR
3, be interior mark with tetramethylsilane.
(2), the checking of PEG-PCL-PEG multipolymer of the present invention and sign
In this test, the PEG-PCL-PEG copolymer sheet is shown as E
Y-C
2x-E
Y, wherein 2X and Y represent the molecular weight of PCL and PEG in the multipolymer respectively.Fourier's infrared spectra (see figure 1) and proton nmr spectra (see figure 2) are used for detecting the structure and the molecular weight of multipolymer.The result shows that the PEG-PCL-PEG triblock copolymer successfully synthesizes.
Fig. 1 is to E
750-C
1500Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock and E
750-C
3000-E
750The analysis of the infrared spectra of triblock copolymer relatively.As can be seen from the figure, the characteristic peak of PEG all occurs in two figure, at 1105cm
-1The absorption peak at place is the characteristic peak of C-OC among the PEG.At 1734cm
-1The strong absorption peak at place is the characteristic peak of ester bond in the Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock that obtains after the reaction, and visible Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock successfully synthesizes.In B figure, at 2250-2270cm
-1Absorption peak does not appear in the place, illustrate in the linking agent isoflurane chalcone diisocyanate-the NCO group complete reaction fall.And at 1525cm
-1The absorption peak at place then is the charateristic avsorption band that reacts back generation-NHCO-.So the PEG-PCL-PEG triblock copolymer successfully synthesizes.
Fig. 2's
1In the H-NMR collection of illustrative plates, 3.60 and the spike at 3.38ppm place represented respectively among the MPEG-CH
2CH
2O-and OCH
3The hydrogen atom of group.1.35,1.62,2.30 and the peak at 4.06ppm place then represented respectively among the PCL-(CH
2)
3,-OCCH
2-and-CH
2Hydrogen atom in the OOC-group.4.20 with two more weak peaks, 3.82ppm place have been represented respectively with PCL links to each other PEG in-O-CH
2-CH
2Hydrogen atom on-two methylene radical.0.96 and the peak at 1.11ppm place then represented respectively among the IPDI-CH
3With-CH
2The hydrogen atom of-group.
3, the structure of PEG-PCL-PEG triblock copolymer of the present invention and molecular weight further determines
In order further to determine the structure and the molecular weight of PEG-PCL-PEG triblock copolymer, sample has been carried out the proton nmr spectra detection.The block ratio of the molecular weight of the various PEG-PCL-PEG triblock copolymers of synthetic and PEG and PCL detects to determine according to proton nmr spectra among the embodiment one.Can reach a conclusion according to above-mentioned test-results: it is E that present embodiment has successfully synthesized theoretical value
550-C
2000-E
550, E
550-C
2200-E
550, E
750-C
2200-E
750, E
750-C
3000E
750Deng the PEG-PCL-PEG triblock copolymer.
The sol-gel transition characteristic research of embodiment two PEG-PCL-PEG multipolymers of the present invention
In the present invention, adopt test tube method test gel colloidal sol transition temperature.When system is in the fluxion state, be referred to as dissolved colloidal state (Sol); When system is in not the flow solids state, be referred to as gel state (Gel); When system is in the outstanding turbid state of oyster white, be referred to as outstanding turbid attitude (Sus); When water in the system separates with polymer phase, be referred to as to precipitate attitude (Prep)
1, the preparation of PEG-PCL-PEG aqueous copolymers solution of the present invention
Taking by weighing the PEG-PCL-PEG multipolymer of the different molecular weight of the foregoing description one preparation, is respectively 10%, 15% by weight percentage, 20%, 25%, 30%, 35%, 40% different concns joins full and uniform dissolving in the redistilled water (being distilled water), constant volume 4ml.Under 4 ℃ condition, preserve standby.
2, PEG-PCL-PEG gelling temp response characteristic of the present invention
Fig. 3 is E
550-C
2200-E
550Triblock copolymer solution is view when 30 ℃ and 37 ℃ respectively.Can see that when temperature is lower than in body temperature (30 ℃), the PEG-PCL-PEG aqueous solution shows vitreous state, has flowability; When temperature was 37 ℃, the PEG-PCL-PEG aqueous solution showed the transparent solid attitude, loses flowability.Variation of temperature has caused the sol-gel transition of system.
3, the influence factor of PEG-PCL-PEG triblock copolymer gel colloidal sol transition temperature of the present invention experiment
PEG-PCL-PEG triblock copolymer of the present invention is a kind of amphipathic polymkeric substance, and its aqueous solution shows distinctive sol-gel transition characteristic along with temperature raises.This transformation mainly is subjected to the (see figure 8) that influences of hydrophilic segment and hydrophobic segment ratio and length in the polymer molecular structure, also be subjected to simultaneously the thermal history of hydrogel, volume during test, the influence of the factors such as temperature during the water-soluble formation gel of stored under refrigeration time and multipolymer.
Also investigate the constant rate that keeps hydrophilic segment PEG and hydrophobic segment PCL in the multipolymer simultaneously, increased total molecular weight changes phasor to gel colloidal sol the (see figure 8) that influences.Experimental result shows that the gel colloidal sol of PEG-PCL-PEG triblock copolymer changes the influence that phasor not only is subjected to the hydrophilic hydrophobic segment ratio of intramolecularly, and also part is subjected to the influence of hydrophilic hydrophobic segment length.
Experimental result shows, when test tube method test sol-gel transition, the temperature during the water-soluble formation gel of the volume of gelling system and multipolymer is important parameter, and different parameters can obtain the test result of certain difference.
By above-mentioned experiment as can be known, except the molecular composition of multipolymer, many other factors all have certain influence to the sol-gel transition temperature of copolymer aquagel system of the present invention.By the fine setting to these parameters, the sol-gel transition temperature of hydrogel system can relatively be determined to regulate in the scope at one, and this helps the application of the hydrogel of PEG-PCL-PEG multipolymer of the present invention as the injectable drug Controlled Release System.
The preparation and the release experiment of embodiment three PEG-PCL-PEG multipolymer-medicinal compositions
In the present embodiment, use the multipolymer of the foregoing description preparation to load 3 kinds of medication preparation respectively and become PEG-PCL-PEG multipolymer-medicinal composition, comprise high molecular weight protein medicine (model drug is a bovine serum albumin BSA), (model drug is VB to the small molecules hydrophilic drugs
12), small molecules dewatering medicament (model drug is Honokiol Honokiol).
1, small molecules hydrophilic drugs (vitamins B
12) PEG-PCL-PEG mixture preparation and drug release behavior
At first prepare the PEG-PCL-PEG (E of 200 microlitres
550-C
2200-E
550) the aqueous solution (the PEG-PCL-PEG weight content is 30%wt or 20%wt), in the PEG-PCL-PEG aqueous solution, add 0.8 milligram, 2 milligrams small molecules hydrophilic drugs VB then respectively
12, mix.Then gained solution is joined in 5 milliliters the EP pipe, keep making in 12 hours gel at 37 ℃, then with the phosphate buffer soln PBS (pH=7.4) that adds 2 milliliters in the gained gel, in the airbath shaking table, carry out the drug release experiment, at time T=0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 48h, 72h, 96h, 120h takes a sample respectively when 144h and 168h.Adopt ultraviolet-visible pectrophotometer to measure VB
12Concentration (wavelength is 362nm), thereby study its drug release behavior.
VB
12The accumulative total burst size calculate according to following formula:
Q＝C
nV
t+V
s∑C
n-1
Q wherein is accumulative total burst size, C
nVB during for time t
12Concentration, V
tSolvent volume (V
t=2mL), V
sBe the liquor capacity (V that from supernatant liquor, removes
s=1mL).Detected result is seen Fig. 4.
2, preparation of the PEG-PCL-PEG mixture of small molecules dewatering medicament (Honokiol) and drug release behavior
The compound system that uses Honokiol research small molecules hydrophobic drug and PEG-PCL-PEG multipolymer of the present invention composition is at external release behavior.The preparation method of compound system and test method are the same substantially, and just the mixture drug loading changes into 200 μ l multipolymers and loads 1mg and 2mg Honokiol respectively, detect to change the concentration that detects Honokiol with HPLC system (Waters Alliance 2695) into.Sampling system adds heating constant-temperature equipment and automatic sampler, uses Waters 2996 detector detection signals.Chromatographic column is anti-phase C18 post (4.6 * 150mm-5um, a Sunfire Analysis product), and column temperature remains on 28 ℃, and (60/40, v/v) system's wash-out, flow velocity are 1mL/min to use acetonitrile/water.The typical curve equation is: H=105000*X+4680 (H: peak area; X: the concentration of Honokiol), relation conefficient is 0.999994.Detected result is seen Fig. 5.
3, the preparation of the PEG-PCL-PEG mixture of high molecular weight protein medicine (bovine serum albumin BSA) and drug release behavior
Bovine serum albumin BSA is used for studying albumen that PECE hydrogel of the present invention loads or polypeptide drug at external release behavior as a kind of pattern protein drug.
The preparation process of the test is the same, the BSA total amount that initial medicine loading capacity is respectively 4mg and 10mg. stripping with BCA analysis of protein test kit (PIERCE company USA) is detected. determine the stability of BSA then with SDS-PAGE, the results are shown in Figure 6.
Above-mentioned test-results shows that PEG-PCL-PEG mixture of the present invention can load high molecular weight protein medicine (bovine serum albumin BSA), small molecules hydrophilic drugs (VB respectively
12), small molecules dewatering medicament (Honokiol Honokiol) makes medicinal composition as activeconstituents, and realizes the slow releasing function of long period in phosphate buffer soln PBS (pH=7.4).
Change mutually in the embodiment four drug regimen objects of the present invention, degraded and safety testing
E with embodiment one preparation
550-C
2000-E
550, E
550-C
2200-E
5550, E
750-C
2200-E
5750Or E
750C
3000-E
750Be dissolved in the physiological saline (or glucose injection), be mixed with the certain density aqueous solution being lower than under 20 ℃ the temperature, subcutaneous injection is gone in the mouse body, and after about 30 seconds, at the subcutaneous formation gel piece of mouse, this gel piece disappears after 14 days.Use poloxamer (poloxamer F1F27, U.S. Fluka company product) simultaneously in contrast, be injected into mouse after subcutaneous 4 hours, the gel piece disappearance (see figure 7) that poloxamer F127 forms.
In addition, according to the safety testing requirement of injecting drug use, subcutaneous, thoracic cavity, abdominal injection experiment have been carried out with PEG-PCL-PEG block copolymer hydrogel of the present invention respectively, there is not obvious adverse reaction to occur, the cardiac muscle of test experience group then, liver, spleen, the lung kidney, stomach, tissues such as intestines, comparing with the blank group does not have notable difference, the result shows that test-results of the present invention shows that the security of PEG-PCL-PEG multipolymer is good, meets the medication requirement.
Above-mentioned experimental result shows that PEG-PCL-PEG segmented copolymer of the present invention biology is in vivo degraded at a slow speed, and degraded product is nontoxic, is a kind of good drug release carrier, is the novel vector of medicament slow release preparation and local delivery formulations.
Above-mentioned example shows, PEG-PCL-PEG segmented copolymer of the present invention has 25 ℃～35 ℃ critical gelling temp (CGT), degradation speed is adjustable, gel-strength is adjustable, good biocompatibility, can preserve with form of powder, the preparation gel does not need with outstanding characteristics such as deleterious solvents, and these characteristics have determined thermo-sensitive tri-block polymer of the present invention in the drug release hierarchy of control, field of tissue engineering technology, Application Areass such as degradable water gel and biological medical polymer material have fabulous application prospect, for the field that needs use temperature responsive type multipolymer provides a kind of new selection.
Claims (5)
1. a segmented copolymer is characterized in that: be PEG-PCL-PEG multipolymer E
550-C
2200-E
550, wherein E represents PEG, and C represents PCL, and subscript is represented corresponding segmental relative molecular mass respectively; Described PEG-PCL-PEG segmented copolymer is prepared by following method:
A, be catalyzer, adopt MPEG to cause the caprolactone ring-opening polymerization in 3～12 hours, obtain the MPEG-PCL Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock 130-150 ℃ of reacting by heating with the stannous octoate;
B, the MPEG-PCL Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock that step a is made are made linking agent with isophorone diisocyanate and continue reaction 0.5～2 hour under vacuum states, obtain the PEG-PCL-PEG triblock copolymer;
C, the step b gained PEG-PCL-PEG triblock copolymer back of purifying is cooled to room temperature under nitrogen protection, promptly.
2. a method for preparing the described segmented copolymer of claim 1 is characterized in that comprising the steps:
A, be catalyzer, adopt MPEG to cause the caprolactone ring-opening polymerization in 3～12 hours, obtain the MPEG-PCL Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock 130～150 ℃ of reacting by heating with the stannous octoate;
B, the MPEG-PCL Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock that step a is made are made linking agent with isophorone diisocyanate and continue reaction 0.5～2 hour under vacuum states, obtain the PEG-PCL-PEG triblock copolymer;
C, the step b gained PEG-PCL-PEG triblock copolymer back of purifying is cooled to room temperature under nitrogen protection, promptly.
3. the purposes of the described segmented copolymer of claim 1 in the drug release hierarchy of control, cell embedding material, tissue renovation material, degradable water gel or the tissue engineering material of preparation temperature responsive type.
4. a pharmaceutical composition is prepared from by the described segmented copolymer drug loading of claim 1 activeconstituents.
5. pharmaceutical composition according to claim 4, it is characterized in that this pharmaceutical composition is prepared from by following method: at first prepare the aqueous solution that the PEG-PCL-PEG weight content is 30%wt, drug loading activeconstituents in the PEG-PCL-PEG aqueous solution mixes then.
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| CN102973941A (en) * | 2011-11-11 | 2013-03-20 | 四川大学 | Polymer hydrogel loading chemotherapy drug, and application thereof in preventing tumor recurrence and preventing and treating postoperative abdominal adhesion |
| CN104645425B (en) * | 2015-03-20 | 2017-08-11 | 成都市南丁医用材料有限公司 | Anti- Asherman's syndrom material |
| CN104922740A (en) * | 2015-05-27 | 2015-09-23 | 复旦大学 | Polymer composite material with hemostasis and anti-adhesion properties and preparation method and application thereof |
| CN105153437B (en) * | 2015-08-18 | 2017-11-28 | 九江学院 | A kind of hyperline shape degradable polymer hydrogel and preparation method thereof |
| CN105131302B (en) * | 2015-08-18 | 2018-04-10 | 九江学院 | A kind of degradable polymer hydrogel of time and temperature dual sensitivity and preparation method thereof |
| CN109821067A (en) * | 2019-04-04 | 2019-05-31 | 青岛杰圣博生物科技有限公司 | A kind of polycaprolactone diacrylate/polyethylene glycol hydrogel bracket and its preparation method and application |
| CN113057909B (en) * | 2021-03-10 | 2022-10-18 | 复旦大学 | Intelligent thermotropic hydrogel skin care film and preparation method and application thereof |
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