CN1098882C - Biodegradable high polymer and its preparation method - Google Patents
Biodegradable high polymer and its preparation method Download PDFInfo
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- CN1098882C CN1098882C CN98102212A CN98102212A CN1098882C CN 1098882 C CN1098882 C CN 1098882C CN 98102212 A CN98102212 A CN 98102212A CN 98102212 A CN98102212 A CN 98102212A CN 1098882 C CN1098882 C CN 1098882C
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Abstract
The present invention relates to a polycaprolactone-polylactide-polyether ternary copolymer with biodegradability and a preparation method thereof. The polycaprolactone-polylactide-polyether ternary copolymer is obtained by causing epsilon-caprolactone or derivatives thereof to react with various lactides or mixtures thereof and alkylene oxide polyether at 110 to 170 DEG C under the action of stannous iso-octoate as a catalyst in vacuum (below 13Pa) for 12 to 72 hours. The molecular weight of polyether chain segments can be regulated between 44 and 22000, the polymerization unit ratio of the polycaprolactone and the polylactide to the polyether can be regulated between 95 to 5 and 45 to 55 (mol%), and the polymerization unit ratio of the polycaprolactone to the polylactide can be regulated between 1 to 99 and 99 to 1 (mol%). The ternary copolymer has excellent biodegradability and mechanical property, the rate of biodegradation can be regulated, and the preparation method is simple, so the ternary copolymer is convenient to produce.
Description
The present invention relates to have polycaprolactone-polylactide-polyethers terpolymer of biological degradability and preparation method thereof.
Biodegradable polymer is to be promoted degraded by enzyme or microorganism, thereby molecular weight and molecular weight, loses intensity, so that eventual degradation or be small molecules, monomer, or become the polymer of carbonic acid gas and water.Because after utilizing biodegradable polymer as suture, nail or other medical repair materials, can utilize material degradation in vivo and metabolism voluntarily, final or be excreted, or absorbed by body, after repairing, organ needs trouble that their are taken out again thereby can exempt; Can realize that the long-term control of medicine discharges after as pharmaceutical carrier or constant release or the like with such material, so biodegradable polymer has very important and irreplaceable effect at medical field.Biodegradable polymer has crucial meaning equally for preventing the pollution of the environment, in case their price can access decline, will have immeasurable application prospect on causes such as agricultural, environmental protection.
As biodegradable polymer most important applications performance is to have suitable biodegradation rate.Therefore aliphatic polyester is the good biodegradable polymer of a class because thereby ester bond wherein can hydrolysis cause backbone breaking.Polycaprolactone had both had biological degradability as a kind of aliphatic polyester, had good drug permeability again, thereby was class bio-medical material preferably.Yet because the crystallinity of polycaprolactone is extremely strong, degree of crystallinity is very high, makes structure tightr, so wetting ability is relatively poor, biodegradation rate is very slow.(Chinese invention patent ZL92113100.3) goes up open by polycaprolactone can be reduced the crystallinity of polycaprolactone and the wetting ability of raising multipolymer with the method with polyethers copolymerization of good wetting ability and biocompatibility, reached the purpose of improving polycaprolactone multipolymer biological degradability.In view of polylactide also is a class aliphatic polyester, and has the biodegradability that is better than polycaprolactone, (Macromolecules.1986.19 such as Teyssie, 1828[U.S.]) once reported by the copolymerization of caprolactone with rac-Lactide, can make and both had good drug permeability, have the polycaprolactone-polylactide multipolymer of controllable biodegradable speed again.But this method need be used special catalyzer, the preparation condition harshness, so that the synthesis step of whole multipolymer is longer, the preparation process complexity: and the hydrophilicity of this multipolymer is still relatively poor, degradation speed is wayward.
The present invention has overcome in the prior art needs to adopt special catalyst and preparation method's harshness and hydrophilicity is poor, the uppity shortcoming of degradation speed, and provides a kind of polycaprolactone, polyethers with polylactide terpolymer and preparation method thereof.
The chemical structural formula of Biodegradable polycaprolactone one polylactide one polyethers terpolymer of the present invention is as follows:
In the formula: R=C1～C4
k＝2～10
N=4～440, n is the polyester portion polymerization degree
M=4～440, m is the polyester portion polymerization degree
P=1～500, p is the polymerized unit ratio of aliphatic polyester composition and polyether components in this multipolymer of the polyether moiety polymerization degree, i.e. (m+n): p=95: 5～45: 55 (mol%), the ratio m of two kinds of aliphatic polyester compositions: n=1: 99～99: 1 (mol%).
The preparation method of polycaprolactone one polylactide one polyethers terpolymer of the present invention adopts the method for a direct copolycondensation of step, be about to caprolactone, rac-Lactide and polyethers mixing after, in the presence of catalyzer in the direct copolycondensation of vacuum condition.Polymeric reaction temperature is 110-170 ℃, and the reaction times is 12-72 hour.
The present invention can directly use avirulent commodity stannous iso caprylate to be catalyzer, catalyst levels is 0.001～2% of the reaction mass gross weight that feeds intake, best catalyst levels is 0.005～1.0% of the reaction mass gross weight that feeds intake, and also can use butyl (tetra) titanate to be catalyzer.The biodegradation rate of multipolymer of the present invention can be by the proportioning of regulating polycaprolactone, polyethers and three components of polylactide, kind and the molecular weight of regulating polyethers, the kind of regulating polylactide is (poly--the l-rac-Lactide, poly--the d-rac-Lactide, poly--d, l-rac-Lactide and poly--l-rac-Lactide are with poly--d, the multipolymer of l-rac-Lactide) etc. multiple factor regulate.
First technical characterictic of the present invention is to adopt polyethers and the polylactide polymeric composition comprising body as polycaprolactone, can adopt different polyethers or pfpe molecule amount, adopt different polylactide and ratio thereof, make multipolymer have different crystallinity and wetting ability, to reach the purpose that changes the multipolymer biodegradation rate.
Second technical characterictic of the present invention is to use stronger polyethers of wetting ability and aliphatic polyester copolymerization, improving the wetting ability of multipolymer, thereby reach regulate multipolymer because of ester linkage hydrolyzing causes biodegradable purpose.
The 3rd technical characterictic of the present invention is to use nontoxicity, commercialization and having gone through the chemical stannous iso caprylate that can be used for medical material is a catalyzer, therefore both be beneficial to and carried out scale operation, and also be beneficial to method synthetic multipolymer thus is applied to prepare medical product.In addition, this technology also can use butyl (tetra) titanate etc. as catalyzer.
The 4th technical characterictic of the present invention is to adopt various monomers and direct synthesis of ternary multipolymer of one step of raw material, has that technology is simple, flow process short, inexpensive, the advantage that is beneficial to scale operation.
Polycaprolactone composition among the present invention is poly-ε-methyl caprolactone, poly-ε-alkyl caprolactone, and described alkyl is C
1-C
4Alkyl, any in promptly poly-ε-methyl caprolactone, ε-ethyl caprolactone, poly-ε-propyl group (or sec.-propyl) caprolactone and poly-ε-butyl (or isobutyl-) caprolactone.Any that best is in poly-epsilon-caprolactone and the poly-ε-methyl caprolactone.The polylactide composition is poly--l-rac-Lactide, poly--the d-rac-Lactide, poly--d, the l-rac-Lactide, and poly--l-rac-Lactide is with poly--d, the mixture of l-rac-Lactide.That best is poly--l-rac-Lactide and poly--d, any in the l-rac-Lactide.Polyoxyalkylene constituent can be any in the poly-alkylene oxygen polyethers such as poly-ethylene oxide,1,2-epoxyethane polyethers, poly-Sanya methylene oxygen polyethers, poly-four methylenes support oxygen polyethers.In preferably poly-ethylene oxide,1,2-epoxyethane polyethers and the poly-four methylenes support oxygen polyethers any.
Polycaprolactone-polylactide of the present invention-polyethers terpolymer has excellent biodegradability, excellent drug permeability, biocompatibility and nontoxicity, and reduces the crystallinity of polylactone, has improved the wetting ability and the biodegradation rate of multipolymer.Be a class new bio degraded macromolecular, have wide biomedical applications.The synthetic method of this multipolymer does not need special conversion unit, flow process is short, technology is simple, be convenient to suitability for industrialized production.Because the performance of copolymer products is with its ratio of components, and wherein polyethers kind and molecular weight, and the kind of rac-Lactide and changing, the therefore component and the proportioning thereof that can feed intake by control simply, the effectively performance of regulating copolymerization product easily.
Embodiment 1,
6-caprolactone 8.0 grams; l-rac-Lactide 25.0g, poly-ethylene oxide,1,2-epoxyethane polyethers (molecular weight 6000) 4.0 grams mix the back under inert atmosphere (nitrogen or argon gas) protection; add stannous iso caprylate 0.02 gram, under vacuum condition (being lower than 13Pa), reacted 50 hours then in 120 ℃.The terpolymer intrinsic viscosity [η]=1.50 (dl/g) that obtains, ratio of components (caprolactone units): (lactic acid units): (polyether units)=0.98: 5.07: 1.00 (mol%), its tensile strength of film of being cast by chloroformic solution is 53.3MPa, and extension at break is 650%.
Embodiment 2,
Operation with embodiment 1, the feed ratio that adopts is 6-caprolactone 32.0 grams, l-rac-Lactide 9.8 grams, poly-ethylene oxide,1,2-epoxyethane polyethers is 3.0 grams, the multipolymer ratio of components that obtains is (caprolactone units): (lactic acid units): (polyether units)=3.9: 1.86: 1.00 (mol%), intrinsic viscosity is 1.79dl/g, and the film tensile strength of being cast by chloroformic solution is 32.1MPa, and extension at break is 1304%.
Embodiment 3,
With the operation of embodiment 1, adopt d, l-rac-Lactide and poly-four methylenes support oxygen polyethers, temperature of reaction is 160 ℃, and the reaction times is 24 hours, and the copolymer intrinsic viscosity that obtains is 1.75dl/g,
Embodiment 4,
With the operation of embodiment 1, adopt poly-ethylene oxide,1,2-epoxyethane polyethers 6.0g, l-rac-Lactide 5.8 grams, d, l-rac-Lactide 33.50 grams, 6-caprolactone 31.20 grams are under the 0.075 gram effect of catalyzer stannous iso caprylate, in 12Pa and 150 ℃ of reactions 28 hours.This multipolymer is 40MPa by the tensile strength of film that chloroformic solution becomes, and extension at break is 1079%.
Embodiment 5,
With embodiment 1 method prepared (caprolactone units): (lactic acid units): the polycaprolactone of (poly-ethylene oxide,1,2-epoxyethane ether)=3.90: 1.86: 1.00 (mol%)-poly--l-rac-Lactide-poly-ethylene oxide,1,2-epoxyethane polyethers terpolymer, its [(caprolactone units)+(lactic acid units): (polyether units)=85.2: 14.8 (mol%), wherein (caprolactone units): (rac-Lactide unit)=67.7: 32.3 (mol%).The phosphate buffer solution of pH7.4 and 37 ℃ (under the temperature, no enzyme, the biodegradation rate when pancreatin being arranged and the esterase different condition being arranged is more as shown in Figure 1.Biological degradation is represented by the decline of polymer intrinsic viscosity.
The biodegradability of Fig. 1, polycaprolactone-polylactide-polyethers terpolymer
Copolymerization ratio of components: [caprolactone units]: [lactic acid units]: [ethylene oxide,1,2-epoxyethane unit] (mol%)=
3.90∶1.86∶1.00
Biodegradation condition pH7.4,37 ℃
-△-no enzyme condition :-zero-pancreatin (3mg/10ml);--junket enzyme (3mg/10ml) Embodiment 6,
With the method for embodiment 1 Yu proportioning, the employing butyl titanate is catalyst, the terpolymer intrinsic viscosity that obtains=1.21 (dl/g), ratio of components (caprolactone units): (lactic acid units): (polyether units)=1.25: 2.78=1.00 (mol%)
Claims (9)
1, a kind of biodegradable polymer, it is characterized in that described biodegradable polymer is polycaprolactone one polylactide one a polyethers terpolymer: its chemical structural formula is:
In the formula:
k＝2～10
N=4～440, n is the polyester portion polymerization degree
M=4～440, m is the polyester portion polymerization degree
P=1～500, p is the polyether moiety polymerization degree
And (m+n): p=95: 5～45: 55 (mol%)
m∶n＝1∶99～99∶1(mol％)。
2, a kind of biodegradable polymer according to claim 1 is characterized in that described polycaprolactone is a poly-epsilon-caprolactone.
3, a kind of biodegradable polymer according to claim 1 is characterized in that described polycaprolactone is that poly-ε-alkyl replaces caprolactone, described alkyl be in the alkyl of C1-C4 any.
4, a kind of biodegradable polymer according to claim 1 is characterized in that described polycaprolactone is any in poly-ε-methyl caprolactone and the poly-ε-ethyl caprolactone.
5, a kind of biodegradable polymer according to claim 1 is characterized in that described polyethers is poly-ethylene oxide,1,2-epoxyethane polyethers, poly-Sanya methylene oxygen polyethers, any in the poly-four methylenes support oxygen polyethers.
6, a kind of biodegradable polymer according to claim 1 is characterized in that described polyethers is any in poly-ethylene oxide,1,2-epoxyethane polyethers and the poly-four methylenes support oxygen polyethers.
7, a kind of biodegradable polymer according to claim 1 is characterized in that described polylactide is poly--l-rac-Lactide, and is poly--the d-rac-Lactide, poly--d, and the l-rac-Lactide is poly--d, any in the mixture of l-rac-Lactide and poly--l-rac-Lactide.
8, a kind of biodegradable polymer according to claim 1 is characterized in that described polylactide is poly--l-rac-Lactide and poly--d, any in the l-rac-Lactide.
9, the method for making of a kind of biodegradable polymer according to claim 1, it is characterized in that its two kinds of polyester unit sums and polyethers polymerized unit molar ratio are 95: 5～45: 55, polycaprolactone is 1 with the polymerized unit mol ratio of polylactide: 99-99: 1, use the stannous iso caprylate catalyzer, its consumption is the 0.005-1.0% of the weight that always feeds intake, temperature of reaction is 110-170 ℃, and the reaction times is 12-72 hour.
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| CN98102212A CN1098882C (en) | 1998-06-03 | 1998-06-03 | Biodegradable high polymer and its preparation method |
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| CN98102212A CN1098882C (en) | 1998-06-03 | 1998-06-03 | Biodegradable high polymer and its preparation method |
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| CN1098882C true CN1098882C (en) | 2003-01-15 |
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| CN100457198C (en) * | 2003-06-25 | 2009-02-04 | 朱晓明 | Method for making degradable material of ureter bracket |
| CN101492532B (en) * | 2006-01-27 | 2012-05-16 | 浙江海正生物材料股份有限公司 | Uses of benzoic acid stannous as catalyst |
| CN100518937C (en) * | 2006-01-27 | 2009-07-29 | 浙江海正生物材料股份有限公司 | Use of stannous benzoate as catalyst |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225521A (en) * | 1991-12-31 | 1993-07-06 | E. I. Du Pont De Nemours And Company | Star-shaped hydroxyacid polymers |
| CN1087098A (en) * | 1992-11-19 | 1994-05-25 | 中国科学院化学研究所 | Biodegradable polycaprolactone polyether block polymer and preparation method thereof |
| US5550173A (en) * | 1992-11-06 | 1996-08-27 | Zeneca Limited | Polyester composition |
| EP0781309A1 (en) * | 1994-09-16 | 1997-07-02 | The Procter & Gamble Company | Biodegradable polymeric compositions and products thereof |
| WO1997034953A1 (en) * | 1996-03-19 | 1997-09-25 | The Procter & Gamble Company | Biodegradable polymeric compositions and products thereof |
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- 1998-06-03 CN CN98102212A patent/CN1098882C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225521A (en) * | 1991-12-31 | 1993-07-06 | E. I. Du Pont De Nemours And Company | Star-shaped hydroxyacid polymers |
| US5550173A (en) * | 1992-11-06 | 1996-08-27 | Zeneca Limited | Polyester composition |
| CN1087098A (en) * | 1992-11-19 | 1994-05-25 | 中国科学院化学研究所 | Biodegradable polycaprolactone polyether block polymer and preparation method thereof |
| EP0781309A1 (en) * | 1994-09-16 | 1997-07-02 | The Procter & Gamble Company | Biodegradable polymeric compositions and products thereof |
| WO1997034953A1 (en) * | 1996-03-19 | 1997-09-25 | The Procter & Gamble Company | Biodegradable polymeric compositions and products thereof |
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