CN101475677A - Multi-block biodegradable shape memory polymeric compound with regular structure and preparation thereof - Google Patents

Multi-block biodegradable shape memory polymeric compound with regular structure and preparation thereof Download PDF

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CN101475677A
CN101475677A CNA2008101631759A CN200810163175A CN101475677A CN 101475677 A CN101475677 A CN 101475677A CN A2008101631759 A CNA2008101631759 A CN A2008101631759A CN 200810163175 A CN200810163175 A CN 200810163175A CN 101475677 A CN101475677 A CN 101475677A
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diol
alcohol
pcg
glycollide
pllg
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吴林波
姬斌
袁征
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Zhejiang University ZJU
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Zhejiang University ZJU
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Abstract

The invention discloses a regular structure multi-block biodegradable thermic shape memory polymer and a preparation method thereof. The shape memory polymer consists of a plurality of soft blocks and hard blocks which are alternately arranged. The soft blocks and the hard blocks are both copolymers and both have even chain length; the content of the hard blocks is between 50 and 90 weight percent; and the content of the soft blocks is between 10 and 50 weight percent. Each soft block is a crystalline poly(epsilon-caprolactone-glycolide)chain segment which has the fusion point 3 DEG C above a body temperature; and each hard block is a crystalline poly(L-lactide-glycolide)chain segment which has the fusion point 50 DEG C above the body temperature and a controllable deformation recovery rate. The shape memory polymer can relatively independently control the mechanical properties and the degradation rate, thereby having the mechanical properties and the controllable degradation rate matched with the implanted tissue in vivo. With good forming machining performance and excellent biocompatibility, the shape memory polymer can be used as a new functional biological medical material. The preparation method is characterized by simplicity, short reaction time, no residual harmful reagent content, and the like, thereby facilitating the commercialization.

Description

Multi-block biodegradable shape memory polymeric of compound with regular structure and preparation method thereof
Technical field
The present invention relates to biodegradable polymer and preparation method thereof, relate in particular to multi-block biodegradable shape memory polymeric of a kind of compound with regular structure and preparation method thereof.
Background technology
Shape-memory material is the intelligent material of a quasi-representative, comprises shape memory alloy (SMA), shape memory ceramics (SMC) and shape-memory polymer (SMP).After its original-shape that is obtained by once shaped is become interim shape by secondary processing, its energy " memory " original-shape, and under extraneous hormesis, recover original-shape.Its shape restore funcitons can be triggered by stimulations such as the heat that adds, light, electricity, magnetic.From the material application point of view, it is the most direct, efficient manner that heat triggers, thereby the thermal shape memory polymkeric substance has practical value most, also is the emphasis of research and development at present.2002, the Lendlein of Massachusetts Institute Technology (MIT) and Langer professor deliver report (the Science 296:1673-6 about biodegradable thermal shape memory polymkeric substance (thermic BSMP) on the Science magazine, 2002), from then on thermic BSMP is subjected to paying close attention to widely as biomaterial.
Thermic BSMP integrates biocompatibility, biological degradation absorptivity and shape memory function, is the ideal medical embedded material.Owing to can make undersized interim shape, be particularly suitable for Minimally Invasive Surgery, implant the back redeformation and return to original shape and size, can be widely used in suture, prevent occasions such as pipeline restenosis implant frame, blood vessel joint/colligation, tendon are fixed, bone is fixed, and can be simultaneously as the carrier of medicine sustained release, this uses as treat the pipeline restenosis to some particularly useful.
As biomaterial, thermic BSMP compares with SMA has following superiority: (1) dependent variable is big, can reach 100-400%, even higher, and SMA only 8%; (2) biodegradable, postoperative need not take out, and the patient can exempt the misery of second operation; (3) can accept nuclear magnetic resonance check, and SMA is not all right; (4) lighter to the compressing damage of adjoining tissue; (5) easy to process, cost is low, and price is relatively cheap.
For thermic BSMP material with practical value and device, except biocompatibility and degradable absorptivity, also must meet the following conditions:
(1) under body temperature, do not take place or shape memory effect does not significantly take place, but under the temperature of a little higher than body temperature, shape memory effect takes place, and the deformation recovery rate is controlled, helps the carrying out of implant surgery like this;
(2) high deformation fixed rate and recovery rate;
(3) degradation rate is controlled;
(4) has the mechanical property that is complementary with implanting tissue in the environment in vivo.
(5) mechanical property and degradation rate can be regulated and control independently, i.e. the change of degradation rate does not influence or not remarkably influenced mechanical property.
(6) has good forming process.
On material structure, thermic BSMP mainly comprises the segmented copolymer of physical crosslinking and the polymer network two big class (Angew.Chem.Int.Ed. of chemically crosslinked, 41:2034-57,2002), also there are simple homopolymer, multipolymer, blend to have the report (US6281262) of shape memory function.
In patent US6160084, WO9942147, Lendlein etc. disclose the thermic BSMP of two kinds of structures, i.e. physical crosslinking/thermoplastic segmented copolymer and chemically crosslinked/heat cured polymer network.In segmented copolymer, the section employing gathers the dioxy pimelinketone firmly, and soft section is polycaprolactone, and hard section and soft section is randomly coupled together by ammonia ester bond, and promptly hard section and soft section is random arrangement; And the transition temperature of hard section and soft section is all on the low side, only 77-85 ℃ of hard section, soft section only 33.5-37 ℃, plastification owing to water when using in vivo also can further reduce, mechanical property is not high when therefore using in vivo, and under the temperature that is lower than body temperature (37 ℃) the shape restitution takes place promptly, in fact be not suitable for using in vivo.In the chemically crosslinked network, soft section is lower molecular weight polycaprolactone segment, and its transition temperature in fact also is difficult to use in vivo below body temperature; And the preparation time of these materials is long especially, more than 10 days, is unfavorable for commercialization; Adopt the chemically crosslinked network also to be not easy to the processing of material, and have more non-degradable segment.In addition, Lendlein etc. has also applied for the crosslinked thermic BSMP of star (CN200480025126.9), thermic BSMP suture line (US20040015187), has had the thermic BSMP patents such as (US20060140999) of drug release function.
Calendar year 2001, Japanese Takiron company has applied for poly(lactic acid) and multipolymer, blend and weighting material being the patent (US6281262) 9 of thermic BSMP, but has the deformation recovery temperature too high (65-85 ℃) and the deficiency of easy-regulating not, is inconvenient to use.
At home, west Beijing Polytechnical University, northization institute of the Chinese Academy of Sciences, institute should be changed in Changchun, units such as Harbin Institute of Technology have also carried out the research of biodegradable shape memory polymeric, SEPARATE APPLICATION radiation crosslinking polycaprolactone (CN03114594.9), segmented copolymer (CN200410043386.0), urethane (200410010734.4), the patent of pure poly(lactic acid) thermic BSMP materials such as (ZL200410013749.6), and use it for external immobilization material (CN200310115834.925, CN200610017025.826), snap close (CN200610023175.x27), endoluminal stent (200610030159.328) etc.
Chinese patent 200410010734.4 disclosed urethane adopt the prepolymer method preparation, structure and conventional urethane are similar, also belong to many block structures, the soft or hard section alternately, but, although its soft section degradable can not be degraded and account for hard section of very big proportion in composition, therefore, in human body, use and in fact have difficulties.
Soft, hard section equal degradable of the disclosed segmented copolymer of Chinese patent CN200410043386.0, but hard section and soft section all is random arrangement; And hard section adopts the polylactide homopolymer, and mechanical property and degradation rate inconvenience are regulated.In addition, in patent CN200410043386.0 and relevant document (Polymers forAdvanced Technologies, 16:608-615,2005), soft section composition is all near 2: 1 (caprolactones: glycollide).Under such composition, soft section macromolecule dihydric alcohol fusing point very low (31-39 ℃) is difficult to reach that material under body temperature shape memory effect does not take place and the purpose of shape memory effect only takes place under the temperature at a little higher than body temperature.
Generally speaking, compare with chemically crosslinked, heat cured polymer network, physical crosslinking, thermoplastic segmented copolymer have many, the advantages such as modification scope big, easy-formation processing of structure/performance regulation and control factor, and can accomplish high-fall separating, and are the better selections of thermic BSMP.But, sum up existing disclosed many blocks thermic BSMP material, structurally still exist hard section and soft section random arrangement, hard section or defectives such as soft segment structure is single, non-degradable segment content height, cause performance non-adjustable or regulation range is narrow, transition temperature is higher or on the low side, biological degradability variation, mechanical property and degradation property such as can not independently regulate and control at defective and deficiency, thereby still can not or can not reach above-mentioned requirements fully.Therefore, thus the design, the preparation have the thermic BSMP material that perfect structure has above-mentioned premium properties, be that technical problem to be solved is arranged.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, biodegradable shape memory polymeric of a kind of compound with regular structure and preparation method thereof is provided.
The multi-block biodegradable thermal shape memory polymkeric substance of compound with regular structure is by a plurality of soft section and the hard section multi-block polymers of forming, it is characterized in that, soft section and the alternately arrangement of hard section, soft section and hard section is multipolymer, all has uniform chain length, the content of hard section is 50wt%~90wt%, and soft section content is 10wt%~50wt%, and its structural formula is:
Figure A200810163175D00071
Or
Figure A200810163175D00072
Or
Figure A200810163175D00073
Wherein,
Figure A200810163175D00074
The hard section of expression, hard section is crystalline L-poly (lactide-co-glycolide), and its number-average molecular weight is 2000~20000, and polydispersity index is 1.05~1.5, the mol ratio of L-rac-Lactide structural unit and glycollide structural unit is 99:1~75:25, and fusing point surpasses body temperature more than 50 ℃;
Figure A200810163175D00075
Represent soft section, soft section is crystalline 6-caprolactone/glycolide copolymer multipolymer, and its molecular weight is 2000~20000, and polydispersity index is 1.05~1.5, the mol ratio of 6-caprolactone structural unit and glycollide structural unit is 99:1~75:25, and fusing point surpasses body temperature more than 3 ℃;
Figure A200810163175D00076
Be linking group, its structure is OCONH-R-NHCOO or OCO-R-COO, and R is selected from: (CH 2) 2, (CH 2) 4, (CH 2) 6, (CH 2) 8, CH 2C (CH 3) 2CH 2CH (CH 3) CH 2CH 2, CH 2CH (CH 3) CH 2C (CH 3) 2CH 2CH 2,
Figure A200810163175D00081
Or
Figure A200810163175D00082
G is an end of the chain functional group, be selected from hydroxyl ,-OCONH-R-NHCOOR ' or-OCO-R-COOR ', R ' is methyl, ethyl, propyl group, sec.-propyl or butyl;
N is 1~30 a integer.
A kind of preparation method of multi-block biodegradable thermal shape memory polymkeric substance of compound with regular structure comprises the steps:
(1) with the dibasic alcohol is initiator, with the stannous octoate is catalyzer, add 6-caprolactone and glycollide, reacted 4~16 hours down at 100 ℃~150 ℃, obtain 6-caprolactone/glycolide copolymer macromolecule dihydric alcohol (PCG-diol), the mol ratio of 6-caprolactone and glycollide is 99:1~75:25, and the total amount of 6-caprolactone and glycollide and the mol ratio of initiator are 17~200; With the dibasic alcohol is initiator, with the stannous octoate is catalyzer, add L-rac-Lactide and glycollide, reacted 4~16 hours down at 120 ℃~165 ℃, obtain L-poly (lactide-co-glycolide) macromolecule dihydric alcohol (PLLG-diol), the mol ratio of L-rac-Lactide and glycollide is 99:1~75:25, and the total amount of L-rac-Lactide and glycollide and the mol ratio of initiator are 14~200;
(2) PCG-diol that step (1) is obtained or PLLG-diol and vulcabond in molar ratio 1:2~1:2.1 under 80 ℃~170 ℃, carry out prepolymerization reaction, reacted 4~8 hours, obtain isocyanate-terminated PCG prepolymer or PLLG prepolymer;
(3) PCG prepolymer or the PLLG prepolymer at step (2) gained adds PLLG-diol or PCG-diol, carries out chain extending reaction under 80 ℃~170 ℃, reacts 4~8 hours; PCG-diol in the mole number of PLLG-diol or PCG-diol and the step (2) or the mole number of PLLG-diol equate;
(4) add the small molecules monohydroxy-alcohol and carry out the end-blocking aftertreatment, remove excessive monohydroxy-alcohol then, obtain the multi-block biodegradable shape memory polymeric of compound with regular structure.
Described glycol initiators is selected from ethylene glycol, 1, ammediol or 1,4-butyleneglycol; Vulcabond is selected from hexamethylene diisocyanate, 2,2,4-trimethyl cyclohexane vulcabond, 2,4,4-trimethyl cyclohexane vulcabond, tolylene diisocyanate or diphenylmethanediisocyanate; The small molecules monohydroxy-alcohol is selected from propyl carbinol, Pentyl alcohol or n-hexyl alcohol.
The preparation method of the multi-block biodegradable thermal shape memory polymkeric substance of another kind of compound with regular structure comprises the steps:
(1) with the dibasic alcohol is initiator, with the stannous octoate is catalyzer, add 6-caprolactone and glycollide, reacted 4~16 hours down at 100 ℃~150 ℃, obtain 6-caprolactone/glycolide copolymer macromolecule dihydric alcohol (PCG-diol), the mol ratio of 6-caprolactone and glycollide is 99:1~75:25, and the total amount of 6-caprolactone and glycollide and the mol ratio of initiator are 17~200; With the dibasic alcohol is initiator, with the stannous octoate is catalyzer, add L-rac-Lactide and glycollide, reacted 4~16 hours down at 120 ℃~165 ℃, obtain L-poly (lactide-co-glycolide) macromolecule dihydric alcohol (PLLG-diol), the mol ratio of L-rac-Lactide and glycollide is 99:1~75:25, and the total amount of L-rac-Lactide and glycollide and the mol ratio of initiator are 14~200;
(2) PCG-diol that step (1) is obtained or PLLA-diol and diacid chloride in molar ratio 1:2~1:2.1 in containing the organic solvent of acid-acceptor, under 0 ℃~80 ℃, carry out prepolymerization reaction, reacted 4~8 hours, and obtained end capped PCG of acid chloride group or PLLG prepolymer;
(3) in the PCG of step (2) gained or PLLG prepolymer, add PLLG-diol or PCG-diol, under 0 ℃~80 ℃, carry out chain extending reaction, reacted 4~8 hours; PCG-diol in the mole number of PLLG-diol or PCG-diol and the step (2) or the mole number of PLLG-diol equate;
(4) add the small molecules monohydroxy-alcohol and carry out the end-blocking aftertreatment, remove by product, solvent and excessive monohydroxy-alcohol then, obtain the multi-block biodegradable shape memory polymeric of compound with regular structure.
Described initiator is selected from ethylene glycol, 1, ammediol or 1,4-butyleneglycol; Diacid chloride is selected from succinic chloride, hexanedioyl chlorine or sebacoyl chloride; The small molecules monohydroxy-alcohol is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol; Acid-acceptor is selected from triethylamine, pyridine; Organic solvent is selected from methylene dichloride, ethylene dichloride, chloroform, tetrahydrofuran (THF), acetone or toluene.
The thermic BSMP material that the present invention proposes is the multi-block polymer of physical crosslinking, structurally have soft section and the hard section characteristics that are multipolymer, chain length homogeneous, replace arrangement, soft section fusing point surpasses body temperature more than 3 ℃, the fusing point of hard section surpasses body temperature more than 50 ℃, therefore, have following characteristics on the performance: shape memory effect does not take place under body temperature, but under the temperature of a little higher than body temperature shape memory effect takes place, deformation fixed rate and recovery rate height, and the deformation recovery rate is controlled; Can regulate and control mechanical property and degradation rate as required relatively independently, make it have the mechanical property that is complementary with implanting tissue and controlled degradation rate in vivo in environment; Forming process is good; The biocompatibility excellence.
The method of the multi-block biodegradable shape memory polymeric of the preparation compound with regular structure that the present invention proposes have efficient height, reaction times short, do not contain characteristics such as residual harmful reagent, help realizing commercialization.
Embodiment
The present invention is directed on the existing multi-block biodegradable shape memory polymeric structure and exist hard section and soft section random arrangement, hard section or soft segment structure are single, defectives such as non-degradable segment content height, cause performance non-adjustable or regulation range is narrow, transition temperature is higher or on the low side, the biological degradability variation, mechanical property and degradation property such as can not independently regulate and control at defective and deficiency, design, the multi-block biodegradable shape memory polymeric that synthesizes a kind of compound with regular structure, its soft section and hard section is multipolymer, chain length homogeneous and alternately arrangement, soft section fusing point surpasses body temperature more than 3 ℃, the fusing point of hard section surpasses body temperature more than 50 ℃, therefore, this polymkeric substance fully biodegradable; Can regulate and control mechanical property and degradation rate as required relatively independently, make it have the mechanical property that is complementary with implanting tissue and controlled degradation rate in vivo in environment; Shape memory effect does not take place under body temperature, but under the temperature of a little higher than body temperature shape memory effect takes place, deformation fixed rate and recovery rate height, and the deformation recovery rate is controlled; Forming process is good, the biocompatibility excellence.
The principle that physical crosslinking/thermoplastic segmented copolymer has shape memory function is, soft section and hard section generation micron-scale phase separation, and hard section constitutes stationary phase, but soft section constitutes anti-phase.Therefore, the be separated size of degree all has very big influence to the recovery fixing and original-shape of mechanical property, post forming, interim shape.If be separated fully, then segmented copolymer shows the transition temperature of soft section and hard section significantly, also helps improving mechanical property, deformation fixed rate and deformation-recovery rate; Insufficient if be separated, then corresponding degradation.
The degree of being separated of segmented copolymer is subjected to the influence of segmental molecular weight and molecular weight distribution.Molecular weight is big more, molecular weight distribution is narrow more, helps phase-splitting more.For as for the biodegradable segmented copolymer of shape-memory material, generally be that the ring-opening polymerization by lactone or lactide monomers prepares soft section and hard section respectively, make segmented copolymer by chain extending reaction again.Because this ring-opening polymerization often has the living polymerization feature, therefore be easy to obtain the soft section macromolecule dihydric alcohol and the hard section macromolecule dihydric alcohol of certain molecular weight, narrow molecular weight distribution.But, further synthesizing in the process of segmented copolymer with di-isocyanate reaction, because vulcabond and soft section reaction that reaches hard section do not have selectivity, if with soft section macromolecule dihydric alcohol, hard section macromolecule dihydric alcohol and vulcabond feed intake together and react (being one kettle way), reaction is randomly carried out, cause soft section and randomly arrangement rather than the alternately arrangement of hard section, the molecular weight distribution that is equivalent in the gained segmented copolymer soft section and hard section has broadened (as follows) greatly, thereby has influence on the degree of being separated and final mechanical property and shape-memory properties.
Figure A200810163175D00101
For addressing the above problem, the present invention at first utilizes the ring opening copolymer of lactone or lactide monomers to prepare soft section and hard section multipolymer macromolecule dihydric alcohol of narrow distribution, again soft section or hard section multipolymer macromolecule dihydric alcohol are carried out prepolymerization reaction with vulcabond by the mol ratio of 1:2~1:2.1, obtain isocyanate-terminated soft section or hard section prepolymer; In the gained prepolymer, add hard section or soft section multipolymer macromolecule dihydric alcohol again, carry out chain extending reaction; Add the small molecules monohydroxy-alcohol at last and carry out the end-blocking aftertreatment, obtain the multi-block biodegradable shape memory polymeric of compound with regular structure.In the segmented copolymer that makes like this, hard section and soft section alternately arrangement and chain length all keep homogeneous, compound with regular structure, as follows, help taking place micron-scale phase separation, thereby help improving mechanical property and shape-memory properties, deformation fixed rate and deformation-recovery rate are all very high, and this is one of characteristic of the present invention.The mol ratio of monomer and initiator during by the adjusting ring opening copolymer can be regulated soft section, hard section molecular weight or chain length, thereby regulates soft section, hard section relative content.
Figure A200810163175D00111
Have no need for reticence, urethane comprises biodegradable polyurethane pre-polymerization method preparation commonly used, but existing biodegradable polyurethane segmented copolymer generally adopts macromolecule dihydric alcohol, small molecules dibasic alcohol and vulcabond three component reaction to make, though the soft or hard section also is alternately to arrange, and can not degrade for account for very big proportion in composition hard section.The employing one kettle way is also arranged, the report that promptly hard section macromolecule dihydric alcohol, soft section macromolecule dihydric alcohol and vulcabond three components one react, soft section and the equal degradable (having a small amount of nondegradable ammonia ester bond between the segment) of hard section of the biodegradable segmented copolymer of gained, but soft section, hard section random arrangement, the structure irregularity.The present invention is a raw material with biodegradable soft section multipolymer macromolecule dihydric alcohol, biodegradable hard section multipolymer macromolecule dihydric alcohol, vulcabond, adopt pre-polymerization-chain extension legal system to be equipped with segmented copolymer, compound with regular structure not only, and soft section and the equal degradable of hard section, only there is a small amount of nondegradable ammonia ester bond key between the segment, (these a spot of nondegradable ammonia ester bonds do not influence the degraded and the absorption of segmented copolymer substantially).For obtaining the segmented copolymer of degraded fully, the present invention proposes the method for the multi-block biodegradable shape memory polymeric of another kind of preparation compound with regular structure, promptly replace vulcabond with diacid chloride, make by pre-polymerization-chain extension method equally.This reaction design can make the segmented copolymer of compound with regular structure equally, and all connects with degradable ester bond between all segments, and the gained segmented copolymer can degrade and absorb fully.This totally biodegradable is two of a characteristic of the present invention.
Soft section and hard section of the multi-block biodegradable shape memory polymeric of the compound with regular structure that the present invention proposes is copolymer structure, therefore, the performance of soft section and hard section comprises that degradation rate, mechanical property, transition temperature all can regulate by soft, hard section molecular weight and composition as required, and can regulate relatively independently.This is three of a characteristic of the present invention.
The multi-block biodegradable shape memory polymeric of the compound with regular structure that the present invention proposes, soft section fusing point surpass body temperature more than 3 ℃.Therefore, be implanted into when operation carrying out body, the shape recovery can not take place under body temperature, help the carrying out of performing the operation; After operation is finished, by the mode of outer heating, shape is recovered, and the length of shape time of recovery can be regulated as required by the temperature or the biological speed of outer heating.This is four of a characteristic of the present invention.
Existing biodegradable segmented copolymer generally adopts dibasic alcohol (comprising macromolecule dihydric alcohol and small molecules dibasic alcohol) and di-isocyanate reaction directly to make, the end group of product both may be a hydroxyl, may be isocyanate group also, also may have unreacted vulcabond completely in the product.This processing to product, packing and biocompatibility are obviously unfavorable.Also there is similar problem in reaction to dibasic alcohol and diacid chloride, and promptly the end group of product both may be a hydroxyl, may be acid chloride group also, also may have a small amount of unreacted diacid chloride completely in the product.For overcoming this point, the present invention is after chain extending reaction, add the small molecules monohydroxy-alcohol again and carry out the end-blocking aftertreatment, convert terminated isocyanate group or acid chloride group to ammonia ester bond or ester bond, the vulcabond of complete reaction or diacid chloride are not eliminated simultaneously, thereby improve the biocompatibility of product greatly.This is five of a characteristic of the present invention.
Among the present invention, the soft section transition temperature with hard section macromolecule dihydric alcohol and segmented copolymer measured 10 ℃/min of temperature rise rate by dsc (PE DSC7).Molecular weight is measured by gel permeation chromatography (GPC, Waters 150C), and tetrahydrofuran (THF) is a moving phase, and flow rate is 1.0ml/min, and narrow distribution polystyrene is done correction.Soft section and a hard section macromolecule dihydric alcohol molecular weight adopt pervasive correction, K PS=1.258 * 10 -2, α PS=0.717, K Hard section=5.4 * 10 -2, α Hard section=0.639, K Soft section=1.09 * 10 -3, α Soft section=0.6.Among the present invention, shape memory effect adopts German Zwick/Roell Z202 type universal testing machine by hot mechanical cycles measuring.
The embodiment that the invention is further illustrated by the following examples, but scope of the present invention is not limited to these embodiment.
Synthesizing of embodiment 1 6-caprolactone/glycolide copolymer macromolecule dihydric alcohol (PCG-diol)
In fully taking out/bake the reaction flask of handling, adding 6-caprolactone (CL, 51.3g, 0.45mol), glycollide (5.8g, 0.05mol), 1,4-butyleneglycol (0.52g, 5.8mmol), stir, add again the inferior tin of octoate catalyst (28.6mg, 0.05wt%), mixing, vacuumize the back tube sealing, at 120 ℃ of following reaction 8h; Product is dissolved in the chloroform, with excessive methanol extraction, throw out through repeatedly the washing after under 50 ℃ of vacuum dry 48h, the gained sample is designated as PCG-diol (90/10,10000), the mol ratio of 90/10 expression 6-caprolactone and glycollide wherein, the number-average molecular weight that 10000 expressions design.The number-average molecular weight of PCG-diol (90/10,10000) is 10000, and polydispersity index is for being 1.49, and fusing point is 49.5 ℃.
Change proportioning or the monomer (6-caprolactone and glycollide sum of the two) and initiator 1 of 6-caprolactone and glycollide, the proportioning of 4-butyleneglycol makes the adjustable PCG-diol macromolecule dihydric alcohol of a series of compositions, molecular weight and fusing point, specifically sees Table 1.
The synthesis condition and the result of table 1 PCG-diol macromolecule dihydric alcohol
Figure A200810163175D00131
Synthesizing of embodiment 2 L-poly (lactide-co-glycolide) macromolecule dihydric alcohols (PLLG-diol)
In fully taking out/bake the reaction flask of handling, add LLA (64.8g, 0.45mol), GA (5.8g, 0.05mol), BDO (0.52g, 5.8mmol), stir, add the inferior tin (35.3mg of octoate catalyst again, 0.05wt%), mixing, vacuumize the back tube sealing, at 160 ℃ of following reaction 8h; Product is dissolved in the chloroform, with excessive methanol extraction, throw out through repeatedly the washing after under 75 ℃ of vacuum dry 48h, the gained sample is designated as PLLG-diol (90/10,10000), and its number-average molecular weight is 10500, polydispersity index is 1.10, and second-order transition temperature is 44.3, and fusing point is 136 ℃.
The synthesis condition and the result of table 2 PLLG-diol macromolecule dihydric alcohol
Figure A200810163175D00141
Embodiment 3
In the there-necked flask that constant pressure funnel, thermometer and nitrogen tube are housed, add PCG-diol (90/10,6000,5.1 gram, 0.81mmol), under nitrogen protection, be warming up to 80 ℃, drip TDI (1.7mmol while stirring, with the mol ratio of PCG-diol be 2.1:1), dropwise the back 80 ℃ of following pre-polymerizations 4 hours; Then, (90/10,6000,5 grams 0.81mmol), carry out chain extending reaction under 110 ℃, reacted 8 hours to add PLLG-diol; Be cooled to 110 ℃, add propyl carbinol 1 gram again, carry out aftertreatment, reacted 1 hour; Vacuumize, remove excessive propyl carbinol, obtain P (LLG-mb-CG) segmented copolymer, its molecular weight is 53000, and soft section/hard section mol ratio is 50/50.
Reaction adds polymer melt in the mould after finishing while hot, obtains laminar sample after the cooling.Suppress the dumbbell shape sample with the dumbbell shape mould, its effective dimensions is 20 * 4 * 0.2~0.3 (mm).On universal testing machine, sample is heated to 49 ℃, constant temperature 5min, the speed with 10mm/min is stretched to strain stress then mBe 100%; Keeping under the constant situation of strain sample being cooled to 30 ℃; Behind the insulation 5min sample is taken out, with the strain stress under the vernier caliper measurement stress-free conditions u, press R fu/ ε mCalculating the strain fixed rate, is 98.5%; Then, in the middle of two sheet glass, an end is fixed with this sample holder, keeps a little space between the sheet glass, puts into the baking oven that temperature is redefined for 49 ℃, keeps 5min, measures residual strain ε p, press R r=(ε mp)/ε mCalculate strain recovery rate R r, be 97.3%.
Embodiment 4
With embodiment 3, but macromolecule dihydric alcohol adopts PCG-diol (99/1,2000) and PLLG-diol (80/20,18000), the prepolymerization reaction condition is 100 ℃/4 hours, and the chain extending reaction condition is 150 ℃/8 hours, and n-hexyl alcohol is adopted in aftertreatment, the molecular weight of the P that obtains (LLG-mb-CG) segmented copolymer is 67000, and soft section/hard section mol ratio is 10/90.Distortion and shape are recovered to carry out under 42 ℃, and the strain fixed rate is 98.8%, and the strain recovery rate is 95.9%.
Embodiment 5
With embodiment 3, but macromolecule dihydric alcohol adopts PCG-diol (90/10,4000) and PLLG-diol (75/25,20000), and by PLLG-diol (75/25,20000) with hexamethylene diisocyanate (HDI, PLLG-diol:HDI=1:2) carry out prepolymerization reaction earlier, condition is 135 ℃/8 hours, adds PCG-diol (90/10,4000) again and carries out chain extending reaction, condition is 135 ℃/4 hours, Pentyl alcohol is adopted in aftertreatment, and the molecular weight of the P that obtains (LLG-mb-CG) segmented copolymer is 77000, and soft section/hard section mol ratio is 16.7/83.3.Distortion and shape are recovered to carry out under 43 ℃, and the strain fixed rate is 99.1%, and the strain recovery rate is 96.3%.
Embodiment 6
With embodiment 3, but macromolecule dihydric alcohol adopts PCG-diol (90/10,2000) and PLLG-diol (90/10,8000), the prepolymerization reaction condition is 120 ℃/4 hours, and the chain extending reaction condition is 145 ℃/8 hours, and n-hexyl alcohol is adopted in aftertreatment, the molecular weight of the P that obtains (LLG-mb-CG) segmented copolymer is 83000, and soft section/hard section mol ratio is 20/80.Distortion is carried out under 40 ℃, and the strain fixed rate is 98.8%; Shape does not take place and recovers in the sample after the distortion under 37 ℃, recovering shape under 40 ℃ in 1.5 minutes, and the strain recovery rate is 97.3%; Recover shape at 45 ℃ after following 30 seconds, in 15 seconds, recovering shape under 50 ℃.
Embodiment 7
In the there-necked flask that constant pressure funnel, thermometer and nitrogen tube are housed, add PCG-diol (90/10,6000,5.1 gram, 0.81mmol) and ethylene dichloride 40mL, under nitrogen protection, at room temperature drip succinic chloride (1.7mmol, with the mol ratio of PCG-diol be 2.1:1) while stirring, pre-polymerization at room temperature is 4 hours after dropwising; Then, (90/10,10000,8.5 restrain, and 0.81mmol), at room temperature chain extension is 8 hours to add PLLG-diol; Add n-hexyl alcohol 1 gram again, aftertreatment 1 hour; Vacuumize, remove excessive n-hexyl alcohol, the molecular weight that obtains P (LLG-mb-CG) segmented copolymer is 67000, and soft section/hard section mol ratio is 37.5/62.5.Distortion and shape are recovered to carry out under 49 ℃, and the strain fixed rate is 99.3%, and the strain recovery rate is 96.9%.

Claims (5)

1, a kind of multi-block biodegradable thermal shape memory polymkeric substance of compound with regular structure, it is characterized in that, it is by a plurality of soft section and the hard section multi-block polymers of forming, soft section and the alternately arrangement of hard section, soft section and hard section is multipolymer, all has uniform chain length, and the content of hard section is 50wt%~90wt%, soft section content is 10wt%~50wt%, and its structural formula is:
Or
Figure A200810163175C00022
Or
Figure A200810163175C00023
Wherein,
Figure A200810163175C00024
The hard section of expression, be crystalline L-poly (lactide-co-glycolide), its number-average molecular weight is 2000~20000, and polydispersity index is 1.05~1.5, the mol ratio of L-rac-Lactide structural unit and glycollide structural unit is 99:1~75:25, and fusing point surpasses body temperature more than 50 ℃;
Figure A200810163175C00025
Represent soft section, be crystalline 6-caprolactone/glycolide copolymer multipolymer, its molecular weight is 2000~20000, and polydispersity index is 1.05~1.5, the mol ratio of 6-caprolactone structural unit and glycollide structural unit is 99:1~75:25, and fusing point surpasses body temperature more than 3 ℃;
Figure A200810163175C00026
Linking group, its structure is OCONH-R-NHCOO or OCO-R-COO, R is selected from: (CH 2) 2, (CH 2) 4, (CH 2) 6, (CH 2) 8, CH 2C (CH 3) 2CH 2CH (CH 3) CH 2CH 2, CH 2CH (CH 3) CH 2C (CH 3) 2CH 2CH 2,
Figure A200810163175C00027
Or
Figure A200810163175C00028
G is an end of the chain functional group, be selected from hydroxyl ,-OCONH-R-NHCOOR ' or-OCO-R-COOR ', R ' is methyl, ethyl, propyl group, sec.-propyl or butyl;
N is 1~30 a integer.
2, the preparation method of the multi-block biodegradable thermal shape memory polymkeric substance of the described compound with regular structure of a kind of claim 1 is characterized in that comprising the steps:
(1) with the dibasic alcohol is initiator, with the stannous octoate is catalyzer, add 6-caprolactone and glycollide, reacted 4~16 hours down at 100 ℃~150 ℃, obtain 6-caprolactone/glycolide copolymer macromolecule dihydric alcohol (PCG-diol), the mol ratio of 6-caprolactone and glycollide is 99:1~75:25, and the total amount of 6-caprolactone and glycollide and the mol ratio of initiator are 17~200; With the dibasic alcohol is initiator, with the stannous octoate is catalyzer, add L-rac-Lactide and glycollide, reacted 4~16 hours down at 120 ℃~165 ℃, obtain L-poly (lactide-co-glycolide) macromolecule dihydric alcohol (PLLG-diol), the mol ratio of L-rac-Lactide and glycollide is 99: 1~75: 25, and the total amount of L-rac-Lactide and glycollide and the mol ratio of initiator are 14~200;
(2) PCG-diol that step (1) is obtained or PLLG-diol and vulcabond in molar ratio 1:2~1:2.1 under 80 ℃~170 ℃, carry out prepolymerization reaction, reacted 4~8 hours, obtain isocyanate-terminated PCG prepolymer or PLLG prepolymer;
(3) PCG prepolymer or the PLLG prepolymer at step (2) gained adds PLLG-diol or PCG-diol, carries out chain extending reaction under 80 ℃~170 ℃, reacts 4~8 hours; PCG-diol in the mole number of PLLG-diol or PCG-diol and the step (2) or the mole number of PLLG-diol equate;
(4) add the small molecules monohydroxy-alcohol and carry out the end-blocking aftertreatment, remove excessive monohydroxy-alcohol then, obtain the multi-block biodegradable shape memory polymeric of compound with regular structure.
3, the preparation method of the multi-block biodegradable thermal shape memory polymkeric substance of a kind of compound with regular structure as claimed in claim 2 is characterized in that described glycol initiators is selected from ethylene glycol, 1, ammediol or 1,4-butyleneglycol; Vulcabond is selected from hexamethylene diisocyanate, 2,2,4-trimethyl cyclohexane vulcabond, 2,4,4-trimethyl cyclohexane vulcabond, tolylene diisocyanate or diphenylmethanediisocyanate; The small molecules monohydroxy-alcohol is selected from propyl carbinol, Pentyl alcohol or n-hexyl alcohol.
4, the preparation method of the multi-block biodegradable thermal shape memory polymkeric substance of the described compound with regular structure of a kind of claim 1 is characterized in that comprising the steps:
(1) with the dibasic alcohol is initiator, with the stannous octoate is catalyzer, add 6-caprolactone and glycollide, reacted 4~16 hours down at 100 ℃~150 ℃, obtain 6-caprolactone/glycolide copolymer macromolecule dihydric alcohol (PCG-diol), the mol ratio of 6-caprolactone and glycollide is 99:1~75:25, and the total amount of 6-caprolactone and glycollide and the mol ratio of initiator are 17~200; With the dibasic alcohol is initiator, with the stannous octoate is catalyzer, add L-rac-Lactide and glycollide, reacted 4~16 hours down at 120 ℃~165 ℃, obtain L-poly (lactide-co-glycolide) macromolecule dihydric alcohol (PLLG-diol), the mol ratio of L-rac-Lactide and glycollide is 99:1~75:25, and the total amount of L-rac-Lactide and glycollide and the mol ratio of initiator are 14~200;
(2) PCG-diol that step (1) is obtained or PLLA-diol and diacid chloride in molar ratio 1:2~1:2.1 in containing the organic solvent of acid-acceptor, under 0 ℃~80 ℃, carry out prepolymerization reaction, reacted 4~8 hours, and obtained end capped PCG of acid chloride group or PLLG prepolymer;
(3) in the PCG of step (2) gained or PLLG prepolymer, add PLLG-diol or PCG-diol, under 0 ℃~80 ℃, carry out chain extending reaction, reacted 4~8 hours; PCG-diol in the mole number of PLLG-diol or PCG-diol and the step (2) or the mole number of PLLG-diol equate;
(4) add the small molecules monohydroxy-alcohol and carry out the end-blocking aftertreatment, remove by product, solvent and excessive monohydroxy-alcohol then, obtain the multi-block biodegradable shape memory polymeric of compound with regular structure.
5, the preparation method of the multi-block biodegradable thermal shape memory polymkeric substance of a kind of compound with regular structure as claimed in claim 4 is characterized in that described initiator is selected from ethylene glycol, 1, ammediol or 1,4-butyleneglycol; Diacid chloride is selected from succinic chloride, hexanedioyl chlorine or sebacoyl chloride; The small molecules monohydroxy-alcohol is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol; Acid-acceptor is selected from triethylamine, pyridine; Organic solvent is selected from methylene dichloride, ethylene dichloride, chloroform, tetrahydrofuran (THF), acetone or toluene.
CNA2008101631759A 2008-12-18 2008-12-18 Multi-block biodegradable shape memory polymeric compound with regular structure and preparation thereof Pending CN101475677A (en)

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