CN101445608B - Copolymer of fibroin and poly L-lactic acid, solid phase polymerization preparation method and application thereof - Google Patents
Copolymer of fibroin and poly L-lactic acid, solid phase polymerization preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a copolymer of fibroin and a poly L-lactic acid. The molecular weight of the copolymer having the structure is 5,000-200,000, and the mass ratio of the fibroin chain segment and the poly L-lactic acid chain segment is 1/99-99/1. The invention also discloses a solid phase polymerization preparation method thereof and the application thereof in biomedical materials. The invention adopts the method of direct polymerization, the copolymer of fibroin and the poly L-lactic acid is prepared through main body melt/solid phase polymerization, and solvent is not used in the synthesis technique; therefore, the invention has the advantages that the process is simple, the product cost is low, the production cycle is short, and no pollution is generated. Through the invention, copolymer of fibroin and poly L-lactic acid with different number average molecular weight can be prepared, with the molecular weight of 5,000-200,000. Copolymer of fibroin and poly L-lactic acid prepared through the invention can improve the hydrophilicity, the biocompatibility and the cellualar affinity of lactic acid material and control the degradation speed of the material.
Description
Technical field:
The invention belongs to technical field of polymer materials, be specifically related to multipolymer of a kind of fibroin and poly (l-lactic acid) and its production and application.
Background technology:
Poly(lactic acid) (PLA) is the good biodegradable absorption macromolecular material of a kind of biocompatibility, product with good biocompatibility, degraded can participate in metabolism, the low toxin of human body, has been widely used in organizational project and other biological field of medicaments.But also there is performance deficiency in poly(lactic acid), as fragility is big, mechanical strength is lower and degradation cycle is restive etc.In addition, PLA is hydrophobic polymer, and the adhesivity of pair cell is relatively poor.Pure poly(lactic acid) can cause the inflammatory reaction that some are gentle after as tissue engineering material implantable bioartificial body, therefore must carry out modification to poly-lactic acid material.Therefore, in order to improve poly-lactic acid material consistency and cellular affinity in vivo, the normal method of modifying that adopts comprises modification by copolymerization method, plasma surface treatment, finishing method etc.Copolymerization is the important molecular engineering mode of poly(lactic acid), wetting ability, crystallinity by 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 poly(lactic acid) comprises two kinds of the copolycondensations of the ring-opening polymerization of rac-Lactide/comonomer and lactic acid/comonomer.Hydrophilic polymer segment is introduced in copolymerization such as rac-Lactide or lactic acid and hydrophilic monomer or polymkeric substance such as polyoxyethylene glycol, amino acid, poly-peptide and polyose in hydrophobic polylactic acid chain segment, can improve the biocompatibility of material, regulates its degradation rate.
Polyamino acid has a plurality of active function groups, can the immobilizing biologically active molecule, and as 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 human body toxicological harmless effect.The polyamino acid segment is introduced poly(lactic acid), and premium properties that can comprehensive two base polymers reaches the purpose of modified polylactic acid material.Lactic acid-amino acid copolymer has broad varietys such as random copolymers, alternating copolymer, segmented copolymer, graft copolymer.The introducing of amino acid segment can reduce degree of crystallinity, adjusting degradation property, the raising wetting ability of poly(lactic 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 poly(lactic acid) and cell.
Lactic acid and amino acid copolymer generally prepare by 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 glycine, Methionin by 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, degree of 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.By 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 poly(lactic acid)-amino acid ester blend and preparation method thereof, adopt the solution blended process polydactyl acid, obtain the blend of poly(lactic 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 height, complex process, and the content of amino acid segment is lower in the multipolymer, has influenced the improvement of material property.
Fibroin protein (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 glycine (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 protein and porous material have been 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.Improving the aspect of performance that improves fibroin membrane, the method that mainly is employing and other polymer blendings realizes, as adopting polymer blending modification fibroin proteins such as polymeric amide, polyoxyethylene glycol, poly-L-L-Ala, polyacrylic acid, sodium alginate, cellulose blending film, chitosan.
Domestic having mixed fibroin and poly(lactic acid), the research report of the preparation bio-medical material that cell adhesion 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 solution and poly(lactic acid) solution thorough mixing to make blend film.Change the structure properties effect of fibroin protein, preparation Biodegradable films (silk monthly magazine, 2007,4:16～18).
Poly(lactic 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 protein (SF) of desired molecule amount by the concentration, hydrolysis time, temperature etc. of control silk fibroin solution.The contained amino acid whose NH of silk peptide
2Can carry out copolycondensation with the OH and the COOH end group of poly(lactic acid) with the COOH end group.Therefore, on the basis of taking all factors into consideration these two kinds of material properties of fibroin and poly(lactic acid), carry out Bionic Design, fibroin can be used as hydrophilic radical, carries out the copolymerization synthetic segmented copolymer with poly(lactic acid).This multipolymer has amphipathic, can be used as the poly(lactic acid) self-assembled material, improves the cell compatibility of PLA material.But this respect does not still have the research report at present both at home and abroad.
At present, by the set out direct polycondensation method of synthesizing polylactic acid class Biodegradable material of lactic acid and other small molecule monomers (as oxyacetic acid) marked improvement has been arranged, reaching that molecular weight is high is hundreds thousand of, and synthesis technique is simple, and the material that obtains has practical value.
The serious scarcity 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 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 solution used in the present invention is as follows:
The multipolymer of a kind of fibroin and poly (l-lactic acid), this multipolymer has following structure:
Wherein, poly (l-lactic acid) segmental polymerization degree X is 1～2000 a integer,
Fibroin segmental polymerization degree Y is 1～2000 a integer,
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;
This molecular weight of copolymer is 5000～200000, and fibroin segment and poly (l-lactic acid) segmental mass ratio are 1/99～99/1.
The preparation method of the multipolymer of above-mentioned fibroin and poly (l-lactic acid) comprises the steps:
(1) L-lactic acid aqueous solution dehydration prepolymerization prepares the L-lactic acid oligomer:
Under 140～180 ℃ (steady temperature), with mass concentration is first the dehydration under normal pressure 1～4 hour of the L-lactic acid monomer aqueous solution of 70～99% (g/g), and then be depressurized to 100～200 mmhg and continue dehydration 1～4 hour, continue dehydration 1～6 hour at 10～50 mmhg at last, obtain the L-lactic acid oligomer;
(2) melt polymerization process poly (l-lactic acid):
Catalyst system is added in the L-lactic acid oligomer that step (1) obtains, under 0～30 mmhg pressure, under 160～200 ℃, reacted 0～20 hour; The by product rac-Lactide that produces in the polymerization process turns back to reactor by the condensation reflux unit that molecular sieve and water trap are housed, and the temperature of condensation reflux unit is controlled at 20～90 ℃; Described catalyst body is the compound system of metallic compound and protonic acid, or the compound system of metallic compound and alkylating reagent, and wherein the molar content of metallic compound accounts for 1～99% of whole catalyst system; The consumption of the metallic compound in the catalyst system is 0.01～6wt% of L-lactic acid oligomer quality;
(3) solid state polymerization prepares the multipolymer (PLLASF) of fibroin and poly (l-lactic acid):
Fibroin is added in the poly (l-lactic acid) melt that step (2) obtains, and the mass ratio of fibroin and poly (l-lactic acid) is 5/95～95/5, is stirred to evenly; Keep pressure 0～30 mmhg, the temperature of reaction progressively system of being reduced to becomes solid phase; Keep temperature of reaction and be 100～160 ℃ and carry out solid state polymerization, the reaction times is 2～40 hours;
(4) purifying of the multipolymer of fibroin and poly (l-lactic acid) (PLLASF):
The fibroin that step (3) is obtained and the multipolymer of L-poly(lactic acid) are dissolved in ethyl acetate, filter and use ether sedimentation, the throw out that leaches, 65 ℃ of following vacuum-dryings 10～16 hours, obtain the fibroin of purifying and the multipolymer of L-poly(lactic acid), by the nuclear magnetic resonance spectrum of PLLASF multipolymer as can be known, this multipolymer is formed (as depicted in figs. 1 and 2) by polylactic acid chain segment and fibroin peptide chain.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.Among Fig. 2, the charateristic avsorption band of fibroin is 44.8ppm, 50.6ppm, 166.6ppm, 169.6ppm, and poly (l-lactic acid) segment absorption peak is at 69.2ppm, 169.48ppm, the poly (l-lactic acid) segment absorption peak 66-72ppm place that copolymerization is connected with fibroin.Have poly (l-lactic acid) segmental methyl absorption peak (1.6ppm place), methyne absorption peak (5.2ppm place) among Fig. 1, the Ala absorption peak in the fibroin is the absorption peak of phenyl ring proton in the substituting group p-methyl phenol of Try at the absorption peak at 3.75ppm, 7.07ppm and 7.48ppm place.
The L-lactic acid oligomer molecular weight that step (1) obtains is 500～2000.
Step (1) the prepolymerized main purpose of dewatering is the moisture of removing in the lactic acid, forms lactic acid oligomer.The molecular weight control of oligopolymer can be selected relatively mild dehydration temperaturre and short dewatering time like this 500～2000.
The poly (l-lactic acid) molecular weight that step (2) obtains is 500～100000.
The molecular weight of the described fibroin of step (3) 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 by the hydrolysising condition of fibroin, and the molecular weight of the used fibroin of the present invention is 1000～100000.
The described catalyst body of step (2) is the compound system of 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 the metal of I, II, III, IV, V family and transition metal, 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 PbO, stannous octoate 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, diethyl, propyl group or sec.-propyl.
In the above-mentioned catalyst system, the preferred SnCl of the compound system of metallic compound and protonic acid
2/ acetate, SnCl
22H
2The mixture of any one in the sad and stannous octoate of O//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 octoate/naphthene sulfonic acid, the stannous octoate/naphthalene disulfonic acid or two or more arbitrary proportions.
The functional group of L-lactic acid is carboxyl and hydroxyl, and the end group of silk peptide is carboxyl and amino.The two reaction is exactly in fact the reaction between the polyfunctional group, has esterification and amidation, and reactional equation is as follows:
The present invention is by changing the proportioning of poly(lactic acid) and fibroin, and 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, degree of crystallinity and degradation rate are all along with two kinds of monomeric ratios change and change.When the mass ratio of the poly(lactic acid)/fibroin of raw material more than or equal to 6/1 the time, PLLASF is the crystal form polymkeric substance, and crystallization forms by polylactic acid chain segment, the melting peak temperature of its DSC collection of illustrative plates is 130 ℃ (as shown in Figure 4).When the mass ratio of poly(lactic acid)/fibroin was lower than 6/1, PLLASF was the polymkeric substance of unformed shape.
The multipolymer of above-mentioned fibroin and poly (l-lactic acid) is in the widespread use of biomedical materials field such as suture, medicine sustained release, artificial organ and tissue engineering material, also can be in the widespread use in suture, medicine sustained release, artificial organ and tissue engineering material field, and develop it and using in fields such as textile materials, plastics and coating.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 multipolymer then can be used to prepare film, wet-spinning and tissue engineering material.
Beneficial effect: the present invention adopts the direct polymerization method, and body fusion/solid state polymerization prepares the multipolymer of fibroin and poly (l-lactic acid), does not use solvent in synthesis technique, thereby technology is simple, and product cost is low, and with short production cycle, pollution-free.The present invention can prepare the fibroin and the L-copolymer of poly lactic acid of different number-average molecular weights, and molecular weight is 5000～200000.By the fibroin of the present invention's 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 intrinsic viscosity (molecular weight) of multipolymer and the relation of melt polymerization temperature, and as seen from the figure, the intrinsic viscosity of multipolymer is big more, and its molecular weight is also big more.
Fig. 4 is the DSC spectrogram (poly(lactic acid)/fibroin quality ratio is, 130 ℃ of fusing points) of the multipolymer of fibroin and poly (l-lactic acid) at 6/1 o'clock.
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 illustrate the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1:
90% aqueous solution of L-lactic acid is added reactor, dewater under 180 ℃ of temperature, at first the normal pressure dehydration is 4 hours, is depressurized to 100 mmhg dehydration 4 hours then, at last 10 mmhg dehydration 6 hours, obtains molecular weight and be 2000 L-lactic acid oligomer.
After dehydration finishes, with SnCl
22H
2O/ Catalyzed by p-Toluenesulfonic Acid agent system (SnCl
22H
2The molar content of O account for whole catalyst system 50%) add in the prepolymer SnCl
22H
2The consumption of O is the 0.4wt% of L-lactic acid oligomer.The pressure of system progressively is reduced to 0 mmhg (pressure warning unit reading), and temperature of reaction rises to 200 ℃, carries out polyreaction.Along with the carrying out of reaction, begin to occur lactide monomer and reflux, the temperature of condensation reflux unit is controlled at 90 ℃, the reactant thickness that becomes gradually.Polyreaction stopped after 4 hours, obtained poly (l-lactic acid), and molecular weight is 12000.
Silk fibroin powder (the number average relative molecular mass is 3000) is added in the poly (l-lactic acid) melt, silk fibroin powder and poly (l-lactic acid) mass ratio are 1/8 again, stop after stirring stirring.Maintenance system pressure 0 mmhg, the temperature of reaction progressively system of being reduced to becomes solid phase.Keep temperature of reaction and be 100 ℃ and carry out solid state polymerization.Solid state reaction finished after 10 hours, obtained the multipolymer of fibroin and poly (l-lactic acid).
This multipolymer is dissolved in ethyl acetate, and filtration is also used ether sedimentation, and the throw out that leaches 65 ℃ of following vacuum-dryings 12 hours, is buff powder behind the purifying, and molecular weight 1.4 ten thousand, yield are 53%, and fusing point is 125 ℃.
Embodiment 2:
85% aqueous solution of L-lactic acid is added reactor, under 140 ℃ of temperature, dewater.At first mix monomer was dewatered 1 hour under normal pressure, and then be depressurized to 100 mmhg and continue dehydration 4 hours, continue dehydration 1 hour at 50 mmhg at last, obtain molecular weight and be 500 L-lactic acid oligomer.
After dehydration finishes, with SnCl
2/ p-methyl benzenesulfonic acid catalyst system (SnCl
2Molar content account for whole catalyst system 1%) add in the prepolymer SnCl
2Consumption be the 0.01wt% of L-lactic acid oligomer.The pressure of system progressively is reduced to 1 mmhg, and temperature of reaction rises to 180 ℃, and the condensing reflux temperature is 50 ℃, carries out polyreaction.Along with the carrying out of reaction, lactide monomer produces and also to begin to reflux, the reactant thickness that becomes gradually, and the reaction times is 20 hours, obtains poly (l-lactic acid), molecular weight is 1.3 ten thousand.
Silk fibroin powder (the number average relative molecular mass is 3000) is added in the poly-L-acid melt, the mass ratio of silk fibroin powder and poly (l-lactic acid) is 5/95, stops after stirring stirring again.Maintenance system pressure 1 mmhg, the temperature of reaction progressively system of being reduced to becomes solid phase.Keep temperature of reaction and be 160 ℃ and carry out solid state polymerization.Solid state reaction finished after 10 hours, the multipolymer of fibroin and poly (l-lactic acid).
This multipolymer is dissolved in ethyl acetate, and filtration is also used ether sedimentation, and the throw out that leaches 65 ℃ of following vacuum-dryings 16 hours, is faint yellow fibrous polymer behind the purifying, yield 70%, molecular weight 70,000,126 ℃ of fusing points.
Embodiment 3:
90% aqueous solution of L-lactic acid is added reactor, under 150 ℃ of temperature, dewater.At first monomer was dewatered 2 hours under normal pressure, and then be depressurized to 150 mmhg and continue dehydration 2 hours, continue dehydration 6 hours at 10 mmhg at last, obtain molecular weight and be 1500 L-lactic acid oligomer.
After dehydration finishes, with SnCl
22H
2O/ stannous octoate catalyst system (SnCl
22H
2The molar content of O account for whole catalyst system 60%) add in the prepolymer.SnCl
22H
2The consumption of O is the 0.80wt% of L-lactic acid oligomer.The pressure of system progressively is reduced to 10 mmhg, and temperature of reaction is 180 ℃, and the condensing reflux temperature is 20 ℃.Along with the carrying out of reaction, begin to occur lactide monomer and reflux, the reactant thickness that becomes gradually.React and stop after 25 hours, obtain poly (l-lactic acid), molecular weight is 1.8 ten thousand.
Silk fibroin powder (the number average relative molecular mass is 30000) is added in the poly (l-lactic acid) melt, the mass ratio of silk fibroin powder and poly (l-lactic acid) is 1/1 again, stops after stirring stirring.Maintenance system pressure 0 mmhg, the temperature of reaction progressively system of being reduced to becomes solid phase.Keep temperature of reaction and be 150 ℃ and carry out solid state polymerization.Solid state reaction finished after 15 hours, obtained the multipolymer of fibroin and poly (l-lactic acid).
This multipolymer is dissolved in ethyl acetate, and filtration is also used ether sedimentation, the throw out that leaches, and 65 ℃ of following vacuum-dryings 12 hours, yield was 60% behind this multipolymer purifying, molecular weight 12.0 ten thousand, this multipolymer amorphous polymer.
Embodiment 4:
The aqueous solution of L-lactic acid 95% is added reactor, under 150 ℃ of temperature, dewater.At first dehydration 4 hours under normal pressure was depressurized to 200 mmhg dehydrations 4 hours then, at last 10 mmhg dehydration 6 hours, obtained molecular weight and be 2000 L-lactic acid oligomer.
After dehydration finishes, with SnCl
22H
2O/ naphthalene disulfonic acid/naphthene sulfonic acid catalyst system (SnCl
22H
2The molar content of O accounts for 50% of whole catalyst system, and naphthalene disulfonic acid/naphthene sulfonic acid mol ratio is 1/1) add in the prepolymer.SnCl
22H
2The consumption of O is the 0.5wt% of L-lactic acid oligomer.The pressure of system progressively is reduced to 10 mmhg, and temperature of reaction is 180 ℃, and the condensing reflux temperature is controlled at 50 ℃.The rac-Lactide condensing reflux that produces in the polymerization process is to reactor.Along with the carrying out of reaction, the reactant thickness that becomes gradually react end after 5 hours, obtains poly (l-lactic acid), and molecular weight is 1.6 ten thousand.
Silk fibroin powder (the number average relative molecular mass is 3000) is added in the poly (l-lactic acid) melt, and the mass ratio of silk fibroin powder and poly (l-lactic acid) is 3/1, stops after stirring stirring.Maintenance system pressure 2 mmhg, the temperature of reaction progressively system of being reduced to becomes solid phase.Keep temperature of reaction and be 140 ℃ and carry out solid state polymerization.Solid state reaction finished after 15 hours, obtained the multipolymer of fibroin and poly (l-lactic acid).
This multipolymer is dissolved in ethyl acetate, and filtration is also used ether sedimentation, the throw out that leaches, and 65 ℃ of following vacuum-dryings 16 hours, the purified back of this multipolymer yield was 60%, molecular weight is 26000, belongs to amorphous polymer.
Embodiment 5:
The aqueous solution of L-lactic acid 80% is added reactor, under 150 ℃ of temperature, dewater.At first dehydration 4 hours under normal pressure was depressurized to 200 mmhg dehydrations 4 hours then, at last 10 mmhg dehydration 4 hours, obtained molecular weight and be 1400 L-lactic acid oligomer.
After dehydration finishes, stannous octoate/naphthene sulfonic acid catalyst system (molar content of stannous octoate account for whole catalyst system 99%) is added in the prepolymer.The consumption of stannous octoate is the 6.0wt% of L-lactic acid oligomer.The pressure of system progressively is reduced to 10 mmhg, and temperature of reaction is 180 ℃, and the condensing reflux temperature is 20 ℃.Along with the carrying out of reaction, begin to occur lactide monomer and reflux, the reactant thickness that becomes gradually.React and stop after 12 hours, obtain poly (l-lactic acid), molecular weight is 1.1 ten thousand.
Silk fibroin powder (the number average relative molecular mass is 3000) is added in the poly (l-lactic acid) melt, the mass ratio of silk fibroin powder and poly (l-lactic acid) is 95/5 again, stops after stirring stirring.Maintenance system pressure 0 mmhg, the temperature of reaction progressively system of being reduced to becomes solid phase.Keep temperature of reaction and be 150 ℃ and carry out solid state polymerization.Solid state reaction finished after 15 hours, obtained the multipolymer of fibroin and poly (l-lactic acid).
This multipolymer is dissolved in ethyl acetate, and filtration is also used ether sedimentation, the throw out that leaches, and 65 ℃ of following vacuum-dryings 16 hours, the purified back of this multipolymer yield was 60%, molecular weight is 15000, belongs to amorphous polymer.Embodiment 6:
The aqueous solution of L-lactic acid 80% is added reactor, under 150 ℃ of temperature, dewater.At first dehydration 4 hours under normal pressure was depressurized to 200 mmhg dehydrations 4 hours then, at last 10 mmhg dehydration 4 hours, obtained molecular weight and be 1400 L-lactic acid oligomer.
After dehydration finishes, stannous octoate/naphthalene disulfonic acid catalyst system and silk fibroin powder (the number average relative molecular mass is 3000) are added in the L-lactic acid prepolymer melt.The mass ratio of silk fibroin powder and lactic acid oligomer is 2/1.The consumption of stannous octoate is the 0.5wt% of L-lactic acid oligomer, and the molar content of stannous octoate accounts for 50% of whole catalyst system.Stop after stirring stirring, reduction system pressure to 0 mmhg is also kept, and the temperature of reaction progressively system of being reduced to becomes solid phase.Keep temperature of reaction and be 120 ℃ and carry out solid state polymerization.Solid state reaction finished after 15 hours, obtained the multipolymer of fibroin and poly (l-lactic acid).
This multipolymer is dissolved in ethyl acetate, and filtration is also used ether sedimentation, the throw out that leaches, and 65 ℃ of following vacuum-dryings 16 hours, the purified back of this multipolymer yield was 60%, molecular weight is 10000, belongs to amorphous polymer.
Claims (7)
1. the solid phase polymerization preparation method of fibroin and poly (l-lactic acid) is characterized in that this method comprises the steps:
(1) L-lactic acid aqueous solution dehydration prepolymerization prepares the L-lactic acid oligomer:
Under 140～180 ℃, with mass concentration is that 70～99% the L-lactic acid monomer aqueous solution dewatered under normal pressure 1～4 hour earlier, and then be depressurized to 100～200 mmhg continuation dehydration 1～4 hour, and continue dehydration 1～6 hour at 10～50 mmhg at last, obtain the L-lactic acid oligomer;
(2) melt polymerization process poly (l-lactic acid):
Catalyst system is added in the L-lactic acid oligomer that step (1) obtains, under 0～30 mmhg pressure, under 160～200 ℃, reacted 0～20 hour; The by product rac-Lactide that produces in the polymerization process turns back to reactor by the condensation reflux unit that molecular sieve and water trap are housed, and the temperature of condensation reflux unit is controlled at 20～90 ℃; Described catalyst body is the compound system of metallic compound and protonic acid, or the compound system of metallic compound and alkylating reagent, and wherein the molar content of metallic compound accounts for 1～99% of whole catalyst system; The consumption of the metallic compound in the catalyst system is 0.01～6wt% of L-lactic acid oligomer quality;
(3) solid state polymerization prepares the multipolymer of fibroin and poly (l-lactic acid):
Fibroin is added in the poly (l-lactic acid) melt that step (2) obtains, and the mass ratio of fibroin and poly (l-lactic acid) is 5/95～95/5, is stirred to evenly; Keep pressure 0～30 mmhg, the temperature of reaction progressively system of being reduced to becomes solid phase; Keep temperature of reaction and be 100～160 ℃ and carry out solid state polymerization, the reaction times is 2～40 hours;
(4) purifying of the multipolymer of fibroin and poly (l-lactic acid):
The fibroin that step (3) is obtained and the multipolymer of poly (l-lactic acid) are dissolved in ethyl acetate, filter also and use ether sedimentation, and the throw out that leaches 65 ℃ of following vacuum-dryings 10～16 hours, obtains the fibroin of purifying and the multipolymer of poly (l-lactic acid);
Wherein, the multipolymer of described fibroin and poly (l-lactic acid) has following structure:
Wherein, X is 1～2000 a integer, and Y is 1～2000 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;
This molecular weight of copolymer is 5000～200000, and fibroin segment and poly (l-lactic acid) segmental mass ratio are 1/99～99/1.
2. the solid phase polymerization preparation method of fibroin according to claim 1 and poly (l-lactic acid) is characterized in that the L-lactic acid oligomer molecular weight that step (1) obtains is 500～2000.
3. the solid phase polymerization preparation method of fibroin according to claim 1 and poly (l-lactic acid) is characterized in that the poly (l-lactic acid) molecular weight that step (2) obtains is 500～100000.
4. the solid phase polymerization preparation method of fibroin according to claim 1 and poly (l-lactic acid) is characterized in that the molecular weight of the described fibroin of step (3) is 1000～100000.
5. the solid phase polymerization preparation method of fibroin according to claim 1 and poly (l-lactic acid), it is characterized in that in the described catalyst system of step (2) 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 the metal of I, II, III, IV, V family and transition metal; 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, diethyl, propyl group or sec.-propyl.
6. the solid phase polymerization preparation method of fibroin according to claim 5 and poly (l-lactic acid) is characterized in that metallic compound is SnCl in the described catalyst system of step (2)
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 PbO, stannous octoate and the tributyl methoxyl group tin mixture.
7. the solid phase polymerization preparation method of fibroin according to claim 6 and poly (l-lactic acid), the compound system that it is characterized in that described metallic compound of step (2) and protonic acid is SnCl
2/ acetate, SnCl
22H
2The mixture of any one in the sad and stannous octoate of O//sad or two or more arbitrary proportions; 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 octoate/naphthene sulfonic acid, the stannous octoate/naphthalene disulfonic acid or two or more arbitrary proportions.
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| 寇琴.丝蛋白肽链/聚乳酸共聚改性的研究.中国优秀硕士学位论文全文数据库医药卫生科技辑.2008,正文第9至13页. * |
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