CN101717496B - Copolymer of fibroin and poly L-lactic acid, preparation method thereof through ring-opening polymerization and application thereof - Google Patents
Copolymer of fibroin and poly L-lactic acid, preparation method thereof through ring-opening polymerization and application thereof Download PDFInfo
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Abstract
The invention discloses a copolymer of fibroin and poly L-lactic acid, which comprises the following structure. The invention also discloses a preparation method for the copolymer through ring-opening polymerization and application of the copolymer in biomedical materials. The preparation method comprises the following steps of: preparing the copolymer of the fibroin and the poly L-lactic acid by performing the ring-opening polymerization on L-lactide in a molten state and performing copolymerization with the fibroin; and adopting solid phase polymerization to perform post condensation polymerization so as to further improve the molecular weight of the copolymer, reduce the contents of a monomer and a low molecular weight polymer in the system, and prepare a copolymer with narrow molecular weight distribution. A solvent is not used in the polymerization process, so the process is simple and the product cost is low. The preparation method can prepare the copolymers of the fibroin and poly the L-lactic acid with different number-average molecular weights. The copolymer of the fibroin and poly the L-lactic acid prepared by the method can improve the hydrophilic property, the biocompatibility and the cellular affinity of a polylactic acid material, and control the degrading speed of the material.
Description
Technical field:
The invention belongs to technical field of polymer materials, be specifically related to the multipolymer of a kind of fibroin and poly (l-lactic acid).
Background technology:
POLYACTIC ACID (PLA) is the good biodegradable absorption macromolecular material of a kind of biocompatibility, has excellent mechanical property, and its raw material can be realized the regeneration of resource through the amylofermentation preparation.PLA has been widely used in organizational project and other biological field of medicaments, and metabolism, toxicity that its degraded product can be participated in human body are low.PLA is hydrophobic polymer, and the adhesivity of pair cell is relatively poor.Pure POLYACTIC ACID can cause the inflammatory reaction that some are gentle after as tissue engineering material implantable bioartificial body.The fragility of POLYACTIC ACID is bigger, and mechanical strength is on the low side, and degradation cycle is restive.Therefore, in order to improve poly-lactic acid material mechanical property, biodegradability and biocompatibility, often adopt modification by copolymerization method, plasma surface treatment, finishing method etc. that poly-lactic acid material is carried out modification.Wherein, Modification by copolymerization is the important molecular engineering mode of POLYACTIC ACID; Wetting ability, crystallinity through can changing material with the copolymerization of other monomers or oligopolymer etc.; The degradation speed of polymkeric substance can be controlled according to the molecular weight of multipolymer and comonomer or oligopolymer kind and proportioning etc., thereby realizes the widespread use of poly-lactic acid material aspect organizational project.
The modification by copolymerization operational path of POLYACTIC ACID comprises two kinds of the copolycondensations of ring-opening polymerization and the lactic acid/comonomer of rac-Lactide/comonomer.Rac-Lactide or lactic acid and hydrophilic monomer or polymkeric substance such as polyoxyethylene glycol, amino acid, gather copolymerization such as peptide and polyose, in hydrophobic polylactic acid chain segment, introduce hydrophilic polymer segment, can improve the biocompatibility of material, regulate its degradation rate.
Polyamino acid has a plurality of active function groups, can the immobilizing biologically active molecule, and like protein, carbohydrate, polypeptide etc., its side chain can be connected with little peptide, medicine or linking agent etc., promotes the adhesion and the growth of cell.Polyamino acid itself also has excellent biological compatibility and biodegradable, and its degraded product amino acid is to the effect of human non-toxic evil.The polyamino acid segment is introduced POLYACTIC ACID, can reduce percent crystallinity, adjusting degradation property, the raising wetting ability of POLYACTIC ACID.The reactive functional of multipolymer side chain can adsorbed proteins, carbohydrate, polypeptide etc., makes whole multipolymer macromolecular chain obtain specific amino-acid sequence so that cell recognition, thereby the effective immobilizing biologically active factor improves the affinity of POLYACTIC ACID and cell.
Lactic acid-amino acid copolymer generally prepares through the ring opening copolymer of rac-Lactide and amino acid cyclic derivatives, and wherein the copolymerization of lactic acid/Methionin system research at most.Barrera etc. then synthesize earlier and contain lactic acid structural unit and the unitary cyclic dimer of amino protected Methionin, obtain containing the lactic acid-Methionin multipolymer of Methionin unit 2.6% again with rac-Lactide positively charged ion ring-opening copolymerization.But the amino coupling small peptide of this multipolymer is given its better biological activity, can effectively improve bonding strength (J.Am.Chem.Soc., 2004,115 (23): 11010-11011) of its pair cell.Jin etc. have synthesized the unitary cyclic dimer of amino protected Serine earlier, then with rac-Lactide reaction, have synthesized the lactic acid that contains Serine 2% and multipolymer (Polymer, 1998,39 (21): 5155-5162) of Serine.Elisseeff and Kimura etc. prepare the alternating copolymer of lactic acid and glycocoll, Methionin through designing new ring, and these materials are good carriers of cell cultures and organizational project.Aminoacids content has remarkably influenced to its performance in the multipolymer, and its second-order transition temperature, fusing point, percent crystallinity all are lower than poly (l-lactic acid) (PLLA), and its degradation speed is slightly faster than PLLA.Aminoacids content is high more in the multipolymer, and degradation speed is fast more.Through changing Modulatory character (Elisseeff, Macromolecules, 1997,30 (7): 2182～2184 that aminoacids content can be realized the degradation speed of polylactic acid-based material in the multipolymer.Kimura，Macromolecules，2006，21(11)：3338～3340)。Chinese patent ZL03135454.8 discloses a kind of POLYACTIC ACID-amino acid ester blend and preparation method thereof; Adopt the solution blended process polydactyl acid; Obtain the blend of POLYACTIC ACID/amino acid ester; This blend material has good biocompatibility and interface compatibility, can be used as tissue stent material.But amino acid whose preparation and polymerization cost are high, complex process, and the content of amino acid segment is lower in the multipolymer, has influenced the improvement of material property.
Fibroin (SF) is a kind of natural amino acid multipolymer, has good mechanical property and biocompatibility.Contain 18 seed amino acids in the fibroin protein, wherein glycocoll (36%), L-Ala (28%), Serine (14%) and tyrosine (10%) content are more.Some amino acid of fibroin extensively are present in people and the vertebrate tissue, and human body cell is had affinity.Fibroin can be made as various ways such as fiber, powder, gel, silk peptide powder and fibroin membrane according to different research purposes and preparation condition, can be used as makeup base material, foodstuff additive and medical material etc.In recent years; The gel of fibroin and porous material are developed as drug release carrier, three-dimensional cell substratum, artificial skin, anticoagulant material and dialysis membrane etc., but the regenerated silk protein material remains in mechanical property and the unmanageable problem of degradation speed.And pure fibroin membrane dissolve-loss ratio is very high, can not directly use, and after the insoluble processing, intensity is bigger, but elongation is very little, and Tg surpasses 200 ℃, and film is not only hard but also crisp, is difficult to use in vivo, uses so must just can be used as medical material later on through modification.Domestic having mixed fibroin and POLYACTIC ACID, the research report of the preparation bio-medical material that cell adhesion property is good, degradation property is good.Chen Jianyong, Zhang Jiazhong etc. carry out modification with poly (l-lactic acid) to fibroin membrane, and the mechanical property of co-blended film obviously improves, and vapour permeability also increases, (chemical industry journal, 2008,3 (59): 773～777 but water vapour permeability slightly descends; Functional materials, 2007,12 (38): 2048～2051).Zhou Yan, Liu Yang etc. utilize fibroin protein solution and POLYACTIC ACID solution thorough mixing to make blend film.Change the structure properties effect of fibroin, preparation Biodegradable films (silk monthly magazine, 2007,4:16～18).
POLYACTIC ACID has good performance as biodegradable material.Fibroin can carry out acid or alkali catalyzed hydrolysis, generates the fibroin than small molecular weight.Can obtain the water miscible fibroin (SF) of desired molecule amount through the concentration, hydrolysis time, temperature etc. of control silk fibroin solution.Therefore, on the basis of taking all factors into consideration these two kinds of material properties of fibroin and POLYACTIC ACID, utilize fibroin as hydrophilic radical, modified polylactic acid material.
The inventor has adopted fibroin and D, and L-rac-Lactide ring opening copolymer has prepared fibroin/D, L-lactide copolymer (number of patent application: 200810242818.9).D contains two kinds of optical isomers of D-type and L-type in the L-rac-Lactide segment, the copolymer p SDLLA that therefore obtains does not have optical activity basically.Only contain the enzyme that can decompose the L-type in the human body, the D-type lactic acid that produces during the PSDLLA degraded is difficult to decompose, and possibly form harm to human body.Therefore, need the optically active fibroin of development L-type/poly (l-lactic acid) copolymer material.
The inventor has adopted L-lactic acid and fibroin direct melting copolymerization and fusion/solid state polymerization to prepare the optically active multipolymer of L-type (number of patent application: 200810242817.4 and 200810242819.3).But L-lactic acid is easy to generate the racemization phenomenon when high temperature polymerization, has reduced the optical activity of product, and therefore, the method for above-mentioned employing L-lactic acid can only prepare the active copolymer material of L-type low optical.Have D-type structural unit in the multipolymer, and D-type structure distribution is inhomogeneous, causes performance of copolymer to descend.In the melt polymerization and fusion/solid-phase polymerization of L-lactic acid and silk fibroin; Exist more transesterification reaction; Cause the block structure of PLA and SF of sample and the sample of ring-opening polymerization of sample, fusion/solid state polymerization of melt polymerization different; Its form difference is bigger, and performance also has notable difference.Melt polymerization forms multi-block polymer easily, and ring-opening polymerization forms two block polymers more easily, and fusion/solid state polymerization then possibly either way exist.
Fibroin and L-rac-Lactide carry out ring opening copolymer, and reaction is carried out more easily, can obtain long L-segment ground segmented copolymer, improve the optical activity of multipolymer, the synthetic optically active copolymer material of high L-type.But when L-rac-Lactide and silk fibroin fusion copolymerization, the copolymerization system of gained possibly contain more monomer and low-molecular weight polymer, the MWD broad.Therefore; Take solid state polymerization to carry out the aftercondensated reaction; Polymerization can keep the high optical activity of multipolymer at low temperatures, also can further improve the molecular weight of multipolymer simultaneously, the content of monomer and low-molecular weight polymer in the minimizing system; The multipolymer of preparation narrow molecular weight distributions, but this respect does not still have the research report at present both at home and abroad.
The serious lack of China's oil resource has restricted expanding economy, and China has the Biological resources of abundant lactic acid class, can substitute petroleum chemicals.Simultaneously, China is silk big country in the world, and waste silk in the production and waste cocoon can prepare the fibroin peptide chain.Fibroin/polylactic acid modified material all is with a wide range of applications in fields such as bio-medical material, textile materials, plastics and coating.
Summary of the invention:
Technical problem to be solved by this invention provides the multipolymer of a kind of fibroin and poly (l-lactic acid), with wetting ability, biocompatibility, the cellular affinity that improves poly-lactic acid material, the degradation speed of control material.
The technical problem that the present invention also will solve provides the ring-opening polymerization preparation method of above-mentioned multipolymer.
Another technical problem that the present invention also will solve provides the application of above-mentioned multipolymer.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is following:
The multipolymer of a kind of fibroin and poly (l-lactic acid), this multipolymer has following structure:
Wherein, X is 1～3000 a integer, and Y is 1～3200 a integer, and R is: H ,-CH
3,-CH
2OH ,-CH
2SH ,-CH (HO) CH
3,-CH (CH
3)
2,-CH
2CH (CH
3)
2,-CH (CH
3) CH
2CH
3,-CH
2CH
2SCH
3,-CH
2COOH ,-CH
2CH
2CONH
2,-CH
2CH
2CH
2CH
2NH
2,-CH
2CH
2CH
2CH
2NH
2,
In any one or multiple;
This molecular weight of copolymer is 5000～250000, and fibroin segment and poly (l-lactic acid) segmental mass ratio are 0.5/99.5～99.5/0.5.
The ring-opening polymerization preparation method of the multipolymer of above-mentioned fibroin and poly (l-lactic acid) comprises the steps:
(1) the fusion ring-opening polymerization prepares the multipolymer (PLLASF) of fibroin and L-rac-Lactide:
Silk fibroin powder after catalyzer, L-rac-Lactide and the dehydration is added in the polymeric kettle, under 0～30 mmhg pressure, under 140～200 ℃, reacted 2～40 hours; Described catalyzer is the compound system of metallic compound or metallic compound and protonic acid or the compound system of metallic compound and alkylating reagent; In the catalyst composite system, the molar content of metallic compound accounts for 1～99% of whole catalyst composite system; The quality of metallic compound is 0.01～6.0% of a L-rac-Lactide quality in the catalyzer, and the mass ratio of fibroin and L-rac-Lactide is 1/99～99/1;
(2) solid state polymerization prepares the multipolymer of high-molecular weight fibroin and poly (l-lactic acid):
The fibroin that (1) is obtained and the multipolymer melt of poly (l-lactic acid) are kept pressure 0～30 mmhg, and temperature of reaction is reduced to 100～160 ℃, makes system become solid phase, keeps this temperature of reaction and carries out solid state polymerization, and the reaction times is 2～40 hours;
(3) purifying of the multipolymer of fibroin peptide chain and poly (l-lactic acid) (PLLASF):
The multipolymer that step (2) is obtained is dissolved in ETHYLE ACETATE, and filtration is also used ether sedimentation, and the throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 10～16 hours.The structure of PLLASF can be confirmed (seeing Fig. 1, Fig. 2) by nuclear magnetic resonance spectrum.Have poly (l-lactic acid) segmental absorption peak among Fig. 1 at 1.6ppm, 5.2ppm place, and the absorption peak of fibroin is at 3.75ppm, 7.07ppm and 7.48ppm place.At PLLASF multipolymer shown in Figure 2
13On the C-NMR nuclear magnetic resonance spectrum; Fibroin segmental charateristic avsorption band is 44.8ppm, 50.6ppm, 166.6ppm and 169.6ppm; Poly (l-lactic acid) segmental charateristic avsorption band is positioned at 69.2ppm, 169.48ppm; And the poly (l-lactic acid) segment absorption peak 66-72ppm place that copolymerization is connected with fibroin, promptly this multipolymer is made up of polylactic acid chain segment and fibroin peptide segment.
The relative molecular mass of the described fibroin of step (1) is 1000～100000.The molecular weight of fibroin has tangible influence equally to the structure and the performance of multipolymer, can obtain the silk peptide segment of different chain lengths through the hydrolysising condition of fibroin, and the molecular weight of the used fibroin of the present invention is 1000～100000.
The described catalyzer of step (1) is the compound system of metallic compound or metallic compound and protonic acid or the compound system of metallic compound and alkylating reagent, and so-called compound system is about to the system that above-mentioned two kinds of materials mix formation.Metallic compound is the mixture of any one or two or more arbitrary proportions in the hydrate of oxide compound, halogenide, oxyhydroxide, organometallics, carboxylate salt and these metallic compounds of metal and transition metal of I, II, III, IV, V family, preferred SnCl
2, SnCl
22H
2O, SnCl
4, SnCl
42H
2O, ZnCl
2H
2O, SbF
3, TiCl
4, MgCl
2, Sb
2O
3, any one or two or more arbitrary proportions in MgO, PbO, diethoxy aluminium, aluminium isopropoxide, stannous octoate, stannous iso caprylate and the tributyl methoxyl group tin mixture; Protonic acid is the mixture of any one or two or more arbitrary proportions in hydrochloric acid, phosphoric acid, phosphorous acid, acetate, the sad and halogenated carboxylic acid; Alkylating reagent is the mixture of any one or two or more arbitrary proportions in fluosulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid, naphthalene disulfonic acid and Phenylsulfonic acid, naphthene sulfonic acid and the naphthalene disulfonic acid that contains methyl, dimethyl-, trimethylammonium, methylol, ethyl, diethylammonium, propyl group or sec.-propyl.
Described catalyzer is for the preferred SnCl of the compound system of metallic compound and protonic acid
2/ acetate, SnCl
22H
2Sad, the MgCl of O/
2The mixture of any one in/Mono Chloro Acetic Acid, stannous iso caprylate/sad and the stannous octoate/sad or two or more arbitrary proportions; The preferred SnCl of the compound system of metallic compound and alkylating reagent
2/ Phenylsulfonic acid, SnCl
4/ Phenylsulfonic acid, SnCl
2/ p-methyl benzenesulfonic acid, SnCl
2/ naphthene sulfonic acid, SnCl
2The mixture of any one in/naphthalene disulfonic acid, stannous iso caprylate/naphthene sulfonic acid and the stannous octoate/naphthalene disulfonic acid or two or more arbitrary proportions.
When fusion/solid phase ring-opening polymerization, factors such as catalyst type, catalyst levels, catalyst proportion, raw material monomer proportioning, temperature of reaction, reaction times, reaction pressure have remarkable influence to microstructure, molecular weight, MWD and the optical activity of copolymer p LLASF.Table 1 and table 2 are intrinsic viscosity and optical activities of PLLASF under the different catalysts proportioning.Data by in the table can find out that the proportioning of catalyzer has remarkable influence to molecular weight (representing with intrinsic viscosity) and the optical activity of PLLASF.Work as SnCl
2The mol ratio of/naphthalene disulfonic acid is 1: 1 o'clock, can obtain the optically active fibroin/copolymer of poly lactic acid of high L-, and along with the increase of L-rac-Lactide consumption, the optical activity of PLLASF also increases.But D, the multipolymer of L-rac-Lactide and silk fibroin copolymerization gained, its optical activity is zero basically.
The intrinsic viscosity of PLLASF under the table 1 different catalysts proportioning
Reaction conditions: L-rac-Lactide: fibroin=10: 1 (mass ratio), reaction times 6h, 170 ℃ of temperature of reaction, SnCl
2Consumption 0.5wt%.Solid state polymerization time 10h.
Catalyst proportion: A: SnCl
2/ naphthalene disulfonic acid=2: 1 (mol ratio); B: SnCl
2/ naphthalene disulfonic acid=1: 1 (mol ratio); C: SnCl
2/ naphthalene disulfonic acid=1: 2 (mol ratio).
The intrinsic viscosity of PLLASF under the table 2 different catalysts proportioning
Reaction conditions: rac-Lactide: fibroin=6: 1 (mass ratio), reaction times 6h, 170 ℃ of temperature of reaction, SnCl
2Consumption 0.5wt%.Solid state polymerization time 15h.
Catalyst proportion: A: SnCl
2/ naphthalene disulfonic acid=2: 1 (mol ratio); B: SnCl
2/ naphthalene disulfonic acid=1: 1 (mol ratio); C: SnCl
2/ naphthalene disulfonic acid=1: 2 (mol ratio).
The L-rac-Lactide is formed by L-lactic acid cyclisation dimerization; Major impurity is residual lactic acid, water, and oligopolymer, and their contained-OH are very big to the ring-opening polymerization influence of L-rac-Lactide, can make catalyzer lose catalytic activity; In addition-OH can participate in chain initiation, shift, stop; Therefore be difficult to obtain high molecular weight polylactic acid,, just can be used for the preparation of homopolymer and multipolymer so that rough L-rac-Lactide must pass through is refining.Fibroin protein absorbs water easily, and minor amount of water possibly cause the hydrolysis of L-rac-Lactide, thereby influences the smooth implementation of ring-opening polymerization.Therefore the used fibroin protein of the present invention need pass through ability use in 40-70 ℃ of vacuum hydro-extraction 8-10 hour, and the main purpose of dehydration is the moisture of removing in the raw material, suppresses the hydrolysis reaction of L-rac-Lactide.
The L-rac-Lactide can carry out ring-opening polymerization with a spot of reactive group under the condition that catalyzer exists.The carboxyl end groups of fibroin and amino end group all have higher activity, under the effect of catalyzer, can with the ring-opening polymerization of L-rac-Lactide, reactional equation is shown in the following figure:
Wherein, X is 1～3000 a integer, and Y is 1～3200 a integer, and side group R is: H ,-CH
3,-CH
2OH ,-CH
2SH ,-CH (HO) CH
3,-CH (CH
3)
2,-CH
2CH (CH
3)
2,-CH (CH
3) CH
2CH
3,-CH
2CH
2SCH
3,-CH
2COOH ,-CH
2CH
2CONH
2,-CH
2CH
2CH
2CH
2NH
2,-CH
2CH
2CH
2CH
2NH
2,
In any one or multiple;
The multipolymer of above-mentioned fibroin and poly (l-lactic acid) can be in the widespread use of biomedical materials field such as suture, medicine sustained release, artificial organ and tissue engineering material; Also can be in suture, medicine sustained release, artificial organ and tissue engineering material extensive applications, and develop it and using in fields such as textile materials, plastics and coating.
The present invention is through changing the proportioning of L-rac-Lactide and fibroin, and poly (l-lactic acid)-fibroin multipolymer that preparation has different degradation rates and mechanical property satisfies different purposes.The molecular weight of multipolymer, fusing point, second-order transition temperature, percent crystallinity and degradation rate all change and change along with monomeric ratio.The result of X-ray diffraction shows, with SnCl
2/ naphthalene disulfonic acid (two component mol ratios are 1: 1) when the catalyzer, when the mass ratio of L-rac-Lactide/fibroin more than or equal to 6/1 the time, the PLLASF sample has the crystal form structure.And the mass ratio of L-rac-Lactide/fibroin is smaller or equal to 4/1 o'clock, and the PLLASF sample has amorphous state structure (see figure 3).Low-molecular-weight PLLASF can be used for pharmaceutical auxiliary agent, pharmaceutical carrier, protein release vehicle and vaccine adjuvant etc., and high-molecular weight PLLASF then can be used to prepare film, wet-spinning and tissue engineering material.
Beneficial effect: the present invention adopts the ring-opening polymerization under molten state of L-rac-Lactide; Multipolymer with fibroin copolymerization fibroin and poly (l-lactic acid); And take solid state polymerization to carry out the aftercondensated reaction; Further improve the molecular weight of multipolymer, the content of monomer and low-molecular weight polymer in the minimizing system, the multipolymer of preparation narrow molecular weight distributions.In synthesis technique, do not use solvent, thereby technology is simple, product cost is low.The present invention can prepare the fibroin of different number-average molecular weights and the multipolymer of poly (l-lactic acid), and molecular weight is 5000～250000.The fibroin of the present invention preparation and the multipolymer of poly (l-lactic acid) can improve wetting ability, biocompatibility, the cellular affinity of poly-lactic acid material, the degradation speed of control material.
Description of drawings
Fig. 1 is the multipolymer of fibroin and poly (l-lactic acid)
1The H-NMR spectrogram.
Fig. 2 is the multipolymer of fibroin and poly (l-lactic acid)
13The C-NMR spectrogram.
Fig. 3 is the X-diffraction spectrogram of the PLLASF of different poly (l-lactic acid)s and fibroin proportioning.Polymeric reaction condition: monomeric mass ratio is a rac-Lactide: fibroin=8: 1, reaction times 6h, 170 ℃ of temperature of reaction, solid state polymerization time 8h.SnCl
2Consumption 0.5wt%; The mole proportioning of catalyst system is 1: 1.A: L-rac-Lactide and silk-protein proportioning are 2: 1; B: L-rac-Lactide and silk-protein proportioning are 4: 1; C: L-rac-Lactide and silk-protein proportioning are 6: 1.
Embodiment:
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand that the described concrete material proportion of embodiment, processing condition and result thereof only are used to explain the present invention, and the present invention that should also can not limit in claims to be described in detail.
Embodiment 1:
With silk fibroin powder (number average relative molecular mass 3000), the SnCl after L-rac-Lactide, the dehydration
2/ Catalyzed by p-Toluenesulfonic Acid agent system (SnCl
2Molar content account for whole catalyst system 50%) add in the polymeric kettle.SnCl
2Consumption be the 0.5wt% of L-rac-Lactide, the L-rac-Lactide is 4: 1 with fibroin quality ratio.The pressure of system progressively is reduced to the sealing of 0 mmhg (pressure warning unit reading) back, and temperature of reaction is 170 ℃, and the reaction times is 10 hours.Be cooled to 130 ℃ then, solid state reaction 10 hours.After the finishing polymerization, the multipolymer that obtains is dissolved in ETHYLE ACETATE, filtration is also used ether sedimentation, and the throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 16 hours.Be yellow powder behind this multipolymer purifying, molecular weight 1.80 ten thousand, yield are 73%, no fusing point, and specific rotatory power is 93 °.
Embodiment 2:
With silk fibroin powder (the number average relative molecular mass is 3000), the SnCl after L-rac-Lactide, the dehydration
2/ naphthene sulfonic acid catalyst system (SnCl
2Molar content account for whole catalyst system 50%) add in the polymeric kettle.SnCl
2Consumption be the 0.5wt% of L-rac-Lactide, the mass ratio of L-rac-Lactide and fibroin is 6: 1.Seal after the pressure of system progressively is reduced to 10 mmhg, temperature of reaction is 170 ℃, and the reaction times is 10 hours.Be cooled to 130 ℃ then, solid state reaction 10 hours.After the finishing polymerization, the multipolymer that obtains is dissolved in ETHYLE ACETATE, filters and use ether sedimentation.The throw out that leaches obtains the POLYACTIC ACID and the fibroin protein peptide chain multipolymer of purifying 65 ℃ of following vacuum-dryings 16 hours.Be yellow powder behind this multipolymer purifying, molecular weight 2.4 ten thousand, yield are 73%, 126 ℃ of fusing points, and specific rotatory power is 108 °.
Embodiment 3:
Silk fibroin powder (the number average relative molecular mass is 1000), stannous iso caprylate/naphthene sulfonic acid catalyst system after L-rac-Lactide, the dehydration (molar content of stannous iso caprylate account for whole catalyst system 50%) are added in the polymeric kettle.The amount of stannous iso caprylate is the 0.5wt% of L-rac-Lactide, and the mass ratio of L-rac-Lactide and fibroin is 10: 1.Seal after the pressure of system progressively is reduced to 2 mmhg, temperature of reaction is 170 ℃, and the reaction times is 15 hours.Be cooled to 140 ℃ then, solid state reaction 15 hours.After the finishing polymerization, multipolymer is dissolved in ETHYLE ACETATE, filters and use ether sedimentation.The throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 10 hours.Be yellow powder behind this multipolymer purifying, molecular weight 3.0 ten thousand, yield are 75%, 130 ℃ of fusing points, 112 ° of specific rotatory powers.
Embodiment 4:
With silk fibroin powder (the number average relative molecular mass is 1000), the SnCl after L-rac-Lactide, the dehydration
4/ Phenylsulfonic acid catalyst system (SnCl
4Molar content account for whole catalyst system 50%) add in the polymeric kettle.SnCl
4Consumption be the 0.5wt% of L-rac-Lactide, the mass ratio of L-rac-Lactide and fibroin is 2: 1.The pressure of system progressively is reduced to the sealing of back below 1 mmhg, and temperature of reaction is 170 ℃, and the reaction times is 12 hours.Be cooled to 100 ℃ then, solid state reaction 15 hours.After the finishing polymerization, the multipolymer that obtains is dissolved in ETHYLE ACETATE, filters and use ether sedimentation.The throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 16 hours.Be yellow powder behind this multipolymer purifying, molecular weight 2.0 ten thousand, no fusing point, yield are 65%, specific rotatory power is 63 °.
Embodiment 5:
With the silk fibroin powder (the number average relative molecular mass is 1000) after L-rac-Lactide, the dehydration, SnCl
2/ tosic acid/naphthalene disulfonic acid catalyst system (SnCl
2Molar content account for 50% of whole catalyst system, the mol ratio 1/1 of tosic acid and naphthalene disulfonic acid) add in the polymeric kettle.SnCl
2Consumption be the 0.5wt% of L-rac-Lactide, the mass ratio of L-rac-Lactide and fibroin is 99: 1.The pressure of system progressively is reduced to the sealing of back below 1 mmhg, and temperature of reaction is 200 ℃, and the reaction times is 8 hours.Be cooled to 160 ℃ then, solid state reaction 9 hours.After the finishing polymerization, the multipolymer that obtains is dissolved in ETHYLE ACETATE, filters and use ether sedimentation.The throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 16 hours.Be yellow powder behind this multipolymer purifying, molecular weight 2.2 ten thousand, 130 ℃ of fusing points, yield are 69%, specific rotatory power is 111 °.
Embodiment 6:
With silk fibroin powder (the number average relative molecular mass is 1000000), the SnCl after L-rac-Lactide, the dehydration
2/ acetic acid catalyst system (SnCl
2Molar content account for whole catalyst system 99%) add in the polymeric kettle.SnCl
2Consumption be the 6.0wt% of L-rac-Lactide, the mass ratio of L-rac-Lactide and fibroin is 1: 99.The pressure of system progressively is reduced to the sealing of back below 1 mmhg, and temperature of reaction is 140 ℃, and the reaction times is 40 hours.Be cooled to 100 ℃ then, solid state reaction 2 hours.After the finishing polymerization, the multipolymer that obtains is dissolved in ETHYLE ACETATE, filters and use ether sedimentation.The throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 16 hours.Be yellow powder behind this multipolymer purifying, molecular weight 11.5 ten thousand, no fusing point, yield are 65%, specific rotatory power is 20 °.
Embodiment 7:
With silk fibroin powder (number average relative molecular mass 3000), the SnCl after L-rac-Lactide, the dehydration
2/ Catalyzed by p-Toluenesulfonic Acid agent system (SnCl
2Molar content account for whole catalyst system 50%) add in the polymeric kettle.SnCl
2Consumption be the 0.5wt% of L-rac-Lactide, the L-rac-Lactide is 4: 1 with fibroin quality ratio.The pressure of system progressively is reduced to the sealing of 0 mmhg (pressure warning unit reading) back, and temperature of reaction is 170 ℃, and the reaction times is 2 hours.Be cooled to 100 ℃ then, solid state reaction 2 hours.After the finishing polymerization, the multipolymer that obtains is dissolved in ETHYLE ACETATE, filtration is also used ether sedimentation, and the throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 16 hours.Be yellow powder behind this multipolymer purifying, molecular weight 7000, yield are 45%, no fusing point, and specific rotatory power is 55 °.
Embodiment 8:
With silk fibroin powder (number average relative molecular mass 3000), the SnCl after L-rac-Lactide, the dehydration
2/ naphthalene disulfonic acid catalyst system (SnCl
2Molar content account for whole catalyst system 1%) add in the polymeric kettle.SnCl
2Consumption be the 0.05wt% of L-rac-Lactide, the mass ratio of L-rac-Lactide and fibroin is 2: 1.The pressure of system progressively is reduced to the sealing of back below 2 mmhg, and temperature of reaction is 170 ℃, and the reaction times is 6 hours.Be cooled to 110 ℃ then, solid state reaction 40 hours.After the finishing polymerization, the multipolymer that obtains is dissolved in ETHYLE ACETATE, filters and use ether sedimentation.The throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 16 hours.This molecular weight of copolymer 2.0 ten thousand, yield are 76%, no fusing point, 70 ° of specific rotatory powers.
Embodiment 9:
With silk fibroin powder (number average relative molecular mass 3000), the SnCl after L-rac-Lactide, the dehydration
2/ naphthalene disulfonic acid catalyst system (SnCl
2Molar content account for whole catalyst system 60%) add in the polymeric kettle.SnCl
2Consumption be the 0.5wt% of L-rac-Lactide, the mass ratio of L-rac-Lactide and fibroin is 20: 1.Seal after the pressure of system progressively is reduced to 30 mmhg, temperature of reaction is 170 ℃, and the reaction times is 10 hours.Be cooled to 150 ℃ then, solid state reaction 15 hours.After the finishing polymerization, the multipolymer that obtains is dissolved in ETHYLE ACETATE, filters and use ether sedimentation.The throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 16 hours.This molecular weight of copolymer 25.0 ten thousand, yield is 73%, 154 ℃ of fusing points, 118 ° of specific rotatory powers.
Embodiment 10:
With silk fibroin powder (number average relative molecular mass 3000), the catalyst S nCl after L-rac-Lactide, the dehydration
2Add in the polymeric kettle.SnCl
2Consumption be the 0.5wt% of L-rac-Lactide, the L-rac-Lactide is 4: 1 with fibroin quality ratio.The pressure of system progressively is reduced to the sealing of 0 mmhg (pressure warning unit reading) back, and temperature of reaction is 170 ℃, and the reaction times is 2 hours.Be cooled to 100 ℃ then, solid state reaction 2 hours.After the finishing polymerization, the multipolymer that obtains is dissolved in ETHYLE ACETATE, filtration is also used ether sedimentation, and the throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 16 hours.Be yellow powder behind this multipolymer purifying, molecular weight 5000, yield are 45%, no fusing point, and specific rotatory power is 45 °
Claims (5)
1. the ring-opening polymerization preparation method of the multipolymer of fibroin and poly (l-lactic acid) is characterized in that this method comprises the steps:
(1) the fusion ring-opening polymerization prepares the multipolymer of fibroin and poly (l-lactic acid):
Silk fibroin powder after catalyzer, L-rac-Lactide and the dehydration is added in the polymeric kettle, under 0～30 mmhg pressure, under 140～200 ℃, reacted 2～40 hours; Described catalyzer is the compound system of metallic compound or metallic compound and protonic acid or the compound system of metallic compound and alkylating reagent; In the catalyst composite system, the molar content of metallic compound accounts for 1～99% of whole catalyst composite system; The quality of metallic compound is 0.01～6.0% of a L-rac-Lactide quality in the catalyzer, and the mass ratio of fibroin and L-rac-Lactide is 1/99～99/1;
(2) solid state polymerization prepares the multipolymer of high-molecular weight fibroin and poly (l-lactic acid):
The fibroin that (1) is obtained and the multipolymer melt of poly (l-lactic acid) are kept pressure 0～30 mmhg, and temperature of reaction is reduced to 100～160 ℃, makes system become solid phase, keeps this temperature of reaction and carries out solid state polymerization, and the reaction times is 2～40 hours;
(3) purifying of the multipolymer of fibroin and poly (l-lactic acid):
The multipolymer that step (2) is obtained is dissolved in ETHYLE ACETATE, and filtration is also used ether sedimentation, and the throw out that leaches obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid) 65 ℃ of following vacuum-dryings 10～16 hours;
The multipolymer of described fibroin and poly (l-lactic acid) has following structure:
Wherein, X is 1～3000 a integer, and Y is 1～3200 a integer, and side group R is: H ,-CH
3,-CH
2OH ,-CH
2SH ,-CH (HO) CH
3,-CH (CH
3)
2,-CH
2CH (CH
3)
2,-CH (CH
3) CH
2CH
3,-CH
2CH
2SCH
3,-CH
2COOH ,-CH
2CH
2CONH
2,-CH
2CH
2CH
2CH
2NH
2,
In any one or multiple;
This multipolymer number-average molecular weight is 5000～250000, and fibroin segment and poly (l-lactic acid) segmental mass ratio are 0.5/99.5～99.5/0.5.
2. the ring-opening polymerization preparation method of the multipolymer of fibroin according to claim 1 and poly (l-lactic acid) is characterized in that the equal molecular mass of relative number of the described fibroin of step (1) is 1000～100000.
3. the ring-opening polymerization preparation method of the multipolymer of fibroin according to claim 1 and poly (l-lactic acid); It is characterized in that in the described catalyzer of step (1) that metallic compound is the mixture of any one or two or more arbitrary proportions in the hydrate of oxide compound, halogenide, oxyhydroxide, organometallics, carboxylate salt and these metallic compounds of metal and transition metal of I, II, III, IV, V family; Protonic acid is the mixture of any one or two or more arbitrary proportions in hydrochloric acid, phosphoric acid, phosphorous acid, acetate, the sad and halogenated carboxylic acid; Alkylating reagent is the mixture of any one or two or more arbitrary proportions in fluosulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid, naphthalene disulfonic acid and Phenylsulfonic acid, naphthene sulfonic acid and the naphthalene disulfonic acid that contains methyl, dimethyl-, trimethylammonium, methylol, ethyl, diethylammonium, propyl group or sec.-propyl.
4. the ring-opening polymerization preparation method of the multipolymer of fibroin according to claim 3 and poly (l-lactic acid) is characterized in that metallic compound is SnCl in the described catalyzer of step (1)
2, SnCl
22H
2O, SnCl
4, SnCl
42H
2O, ZnCl
2H
2O, SbF
3, TiCl
4, MgCl
2, Sb
2O
3, any one or two or more arbitrary proportions in MgO, PbO, diethoxy aluminium, aluminium isopropoxide, stannous octoate, stannous iso caprylate and the tributyl methoxyl group tin mixture.
5. the ring-opening polymerization preparation method of the multipolymer of fibroin according to claim 4 and poly (l-lactic acid), the compound system that it is characterized in that described metallic compound of step (1) and protonic acid is SnCl
2/ acetate, SnCl
22H
2Sad, the MgCl of O/
2In/Mono Chloro Acetic Acid and the stannous iso caprylate/sad any one; The compound system of metallic compound and alkylating reagent is SnCl
2/ Phenylsulfonic acid, SnCl
4/ Phenylsulfonic acid, SnCl
2/ p-methyl benzenesulfonic acid, SnCl
2/ naphthene sulfonic acid, SnCl
2The mixture of any one in/naphthalene disulfonic acid, stannous iso caprylate/naphthene sulfonic acid and the stannous octoate/naphthalene disulfonic acid or two or more arbitrary proportions.
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|---|---|---|---|
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