CN101831468A - Synthesis of medicinal biodegradable poly(epsilon-caprolactone) and application method thereof - Google Patents
Synthesis of medicinal biodegradable poly(epsilon-caprolactone) and application method thereof Download PDFInfo
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- CN101831468A CN101831468A CN201010186237A CN201010186237A CN101831468A CN 101831468 A CN101831468 A CN 101831468A CN 201010186237 A CN201010186237 A CN 201010186237A CN 201010186237 A CN201010186237 A CN 201010186237A CN 101831468 A CN101831468 A CN 101831468A
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- caprolactone
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Abstract
The invention relates to synthesis of medicinal biodegradable poly(epsilon-caprolactone) and an application method thereof in the field of high polymer chemistry technique. The medicinal biodegradable poly (epsilon-caprolactone) can be obtained by separating and purifying the reactant after epsilon-caprolactone and immobilized lipase Novozym 435 are mixed and reacted at the temperature of between 60 and 80 DEG C for 2 to 48 hours by using a mass polymerization method or a solution polymerization method in a closed reaction system. Due to the adoption of the immobilized lipase Novozym 435 which serves as a catalyst, the biodegradable poly (epsilon-caprolactone) can be prepared by the method which has the advantages of no catalyst residue and easy control of conditions.
Description
Technical field
What the present invention relates to is a kind of preparation and application method of technical field of polymer chemistry, specifically is the synthetic and application method of a kind of medicinal biodegradable poly (6-caprolactone).
Background technology
Poly-(6-caprolactone) is a kind of hemicrystalline aliphatic polyester, with its good biodegradability, biocompatibility and drug permeability, obtained extensive studies and application in fields such as biomedicine and medicine sustained release.Poly-(6-caprolactone) present synthetic method is to adopt the ring-opening polymerization of organo-metallic catalysis 6-caprolactone monomer to obtain, but the harsh reaction conditions and the residual toxicity of heavy metal catalyst have limited synthetic poly-(6-caprolactone) at numerous areas, as the application of biomedical and field of drug delivery.
Enzymatic polymerization is a kind of novel enzyme catalyzed polymerization means that development in recent years is got up.Compare other catalysis process, enzymatic polymerization has advantages such as reaction conditions gentleness, catalyzer nontoxic residue-free, stereoselectivity.At present, existing multiple free lipase all is used to the ring-opening polymerization of catalysis 6-caprolactone as porcine pancreatic lipase, Pseudomonas fluorescens lipase etc.Compare with these traditional free enzymes, immobilized enzyme has not only kept the catalysis characteristics of free enzyme, and the stability of heat, pH etc. is improved the package stability height, still have advantages of high catalytic activity after reclaiming repeated use, therefore more and more be applied to enzymatic polymerization research.
Find through retrieval the prior art document, Chinese patent literature CN 1341674A discloses a kind of method of body ring-opening polymerization preparation poly-(6-caprolactone) in the presence of initiator butyl (tetra) titanate Ti (OBu) 4, its weak point is that product needs through the multistep separation and purification, technology is more loaded down with trivial details, and used butyl (tetra) titanate is the moisture absorption very easily, the preservation condition harshness has heavy-metal residual in the reaction system.
Further retrieval is found, Chinese patent literature CN105554306C discloses a kind of method of utilizing super thermophilic esterase for catalyst to synthesize (6-caprolactone), what its weak point was to select for use is free enzyme, poly-(6-caprolactone) number-average molecular weight of catalysis synthetic is 1200～2300g/mol only, can't directly precipitate and need and separate, and molecular weight is too low can't be widely used in pharmaceutical carrier through low-temperature centrifugation.
Summary of the invention
The present invention is directed to the prior art above shortcomings, synthetic and the application method of a kind of medicinal biodegradable poly (6-caprolactone) is provided, adopting immobilized lipase Novozym 435 is catalyzer, and, condition manageable method residual by catalyst-free prepares biodegradable poly (6-caprolactone).
The present invention is achieved by the following technical solutions, the present invention is by adopting mass polymerization reaction or solution polymerization process reaction with 6-caprolactone and immobilized lipase Novozym 435 in the capping system, reactant can obtain medicinal biodegradable poly (6-caprolactone) after separation and purification.
Described immobilized lipase Novozym 435 is a kind of lipase that is obtained by candida antarctica lipase B (Candida antarcticlipase B), this lipase adopts aspergillus oryzae (Aspergillus oryzae) microorganism through the gene modification to carry out submerged fermentation and is absorbed on a kind of macroporosity resin and makes, wherein the content of candida antarctica lipase B is 10%, vigor is 10,000PLU/g.
The consumption of described immobilized lipase Novozym 435 and the mass ratio of 6-caprolactone are 1%～20%.
The internal pressure of described capping system is 2～760mm mercury column.
Described mass polymerization is meant: with 6-caprolactone with mix in immobilized lipase Novozym 435 directly places the capping system, and will be full of nitrogen in the capping system, under 60～80 ℃ of temperature, react 2～48h.
Described solution polymerization process is meant: 6-caprolactone is mixed the back further add organic solvent with immobilized lipase Novozym 435, and will be full of nitrogen in the capping system, react 2～48h under 60～80 ℃ of temperature.
Described organic solvent is meant: toluene or dioxane, the volume ratio of this organic solvent and 6-caprolactone are 2.0～5.0: 1.
Described separation and purification is meant: add the methylene dichloride termination reaction in reactant, remove by filter enzyme, the filtrate vacuum concentration is removed organic solvent, and concentrated solution is poured in the sherwood oil of 3～5 times of amounts or the ethanol and precipitated, and filters back collecting precipitation vacuum-drying 48h and is gathered (6-caprolactone).
Poly-(6-caprolactone) outward appearance that method for preparing obtains is white random solid, 59～62 ℃ of fusing points, its number-average molecular weight is 5000～60000g/mol, and polymolecularity 1.1～1.4 can be applied to organizational project substrate material, pharmaceutical preparation auxiliary material, medicine equipment material.
The present invention compares with the synthetic method of existing poly-(6-caprolactone), has the following advantages:
1. the present invention uses commercially available immobilized lipase Novozym 435 to be catalyzer, and catalyzer filters and can remove, the immobilized lipase Novozym 435 of recovery, and repetitive scrubbing final vacuum drying, reusable.Transformation efficiency still can reach 60% after Novozym 435 reused 6 times.
2. technology of the present invention is simple, and the process gentleness is controlled, has improved reaction efficiency greatly, is suitable for amplificationization production.
3. poly-(6-caprolactone) number-average molecular weight of obtaining of the present invention is at 5000～60000g/mol, polymolecularity 1.1～1.4, demand that can the fulfilling medicinal auxiliary material.
Description of drawings
Fig. 1 is embodiment 2 method synthetic products
1H NMR collection of illustrative plates.
Fig. 2 is the IR collection of illustrative plates of embodiment 2 method synthetic products.
Embodiment
Below embodiments of the invention are elaborated, present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
The mass polymerization of 6-caprolactone
The 5g 6-caprolactone is mixed with 0.05g Novozym 435 (is 1% with the mass ratio of 6-caprolactone), put into the reaction flask of clean dried, with nitrogen ventilation three times, be decompressed to the 2mm mercurypressure again, 60 ℃ of following oscillatory reaction 2h add 10ml methylene dichloride termination reaction in reactant, remove by filter enzyme, the filtrate vacuum concentration, concentrated solution through proton nmr spectra (
1H NMR) measuring monomer conversion is 90.2%.Remaining enriched material is poured in 5 times of volume sherwood oils and is precipitated, and filters the back collecting precipitation, vacuum-drying 48h.Product is measured through gel permeation chromatography (GPC), and number-average molecular weight is 7000g/mol, and polymolecularity is 1.3.
The solution polymerization of 6-caprolactone
The 5g 6-caprolactone is mixed with 0.5g Novozym 435 (is 10% with the mass ratio of 6-caprolactone), put into the reaction flask of clean dried, with nitrogen ventilation three times, the back volume ratio with syringe adding and 6-caprolactone of sealing is 2.0: 1 a toluene, 80 ℃ of following stirring reaction 7h add 10ml methylene dichloride termination reaction, remove by filter enzyme, the filtrate vacuum concentration, concentrated filtrate through proton nmr spectra (
1H NMR) measuring monomer conversion is 95.4%.Remaining enriched material is poured in 5 times of volume sherwood oils and is precipitated, and filters the back collecting precipitation, vacuum-drying 48h.Product is measured through gel permeation chromatography (GPC), and number-average molecular weight is 42000g/mol, and polymolecularity is 1.2.
As shown in Figure 1, the 6-caprolactone for preparing for present embodiment
1The HNMR collection of illustrative plates, among the figure: 0ppm is the characteristic peak that interior mark does not have tetramethylsilane (TMS) methyl hydrogen; 7.26ppm locate to be solvent deuterochloroform (CDCl
3) in the characteristic peak of hydrogen in the residual chloroform.1.40ppm locating is the characteristic peak of c place methylene radical hydrogen, the proton peak at 1.66ppm place is the division peak of b and d place methylene radical hydrogen, and the triplet at 2.29ppm place is the characteristic peak of e methylene radical hydrogen, and 4.07ppm place proton peak belongs to a place methylene radical hydrogen.
As shown in Figure 2, the IR collection of illustrative plates of the 6-caprolactone for preparing for present embodiment is among the figure: 3500cm
-1The place has-charateristic avsorption band that the OH stretching vibration causes; 1730cm
-1There is bigger absorption peak at the place, belongs to-stretching vibration of C=O; 1243cm
-1The characteristic peak at place is by ester units-COO-CH
2Middle C-O-C stretching vibration causes; 2930cm
-1The place has-CH
2The charateristic avsorption band of-middle C-H stretching vibration.
The solution polymerization of 6-caprolactone
The 5g 6-caprolactone is mixed with 1g Novozym 435 (is 20% with the mass ratio of 6-caprolactone), put into the reaction flask of clean dried, with nitrogen ventilation three times, the back volume ratio with syringe adding and 6-caprolactone of sealing is 5.0: 1 a toluene, 80 ℃ of following stirring reaction 10h add 20ml methylene dichloride termination reaction, remove by filter enzyme, the filtrate vacuum concentration, concentrated filtrate through proton nmr spectra (
1H NMR) measuring monomer conversion is 98.3%.Remaining enriched material is poured in 5 times of volume ethanol and is precipitated, and filters the back collecting precipitation, vacuum-drying 48h.Product is measured through gel permeation chromatography (GPC), and number-average molecular weight is 57000g/mol, and polymolecularity is 1.4.
The solution polymerization of 6-caprolactone
The 5g 6-caprolactone is mixed with 0.5g Novozym 435 (is 10% with the mass ratio of 6-caprolactone), put into the reaction flask of clean dried, with nitrogen ventilation three times, the back volume ratio with syringe adding and 6-caprolactone of sealing is 5.0: 1 a dioxane, 80 ℃ of following stirring reaction 48h add 20ml methylene dichloride termination reaction, remove by filter enzyme, the filtrate vacuum concentration, concentrated filtrate through proton nmr spectra (
1H NMR) measuring monomer conversion is 99.2%.Remaining enriched material is poured in 5 times of volume ethanol and is precipitated, and filters the back collecting precipitation, vacuum-drying 48h.Product is measured through gel permeation chromatography (GPC), and number-average molecular weight is 31000g/mol, and polymolecularity is 1.3.
The material that obtains with above-mentioned synthetic method can be directly as the auxiliary material of pharmaceutical preparation, concrete application mode is: adopt the S/O/W solvent evaporation method, with CH331 is the mould medicine, with above-mentioned poly-(6-caprolactone) is base material (number-average molecular weight is 57000) preparation microballoon, and medicine/carry than being 1/5 obtains microsphere average grain diameter 94 μ m, the actual medication amount 11.6% of carrying, encapsulation rate 58.2%, release in vitro 12 days, cumulative release reaches 88%.
Claims (10)
1. the synthetic method of a medicinal biodegradable poly (6-caprolactone), it is characterized in that, by 6-caprolactone and immobilized lipase Novozym 435 are adopted mass polymerization reaction or solution polymerization process reaction in the capping system, reactant can obtain medicinal biodegradable poly (6-caprolactone) after separation and purification.
2. the synthetic method of medicinal biodegradable poly according to claim 1 (6-caprolactone), it is characterized in that, described immobilized lipase Novozym 435 is a kind of lipase that is obtained by candida antarctica lipase B (Candida antarctic lipase B), this lipase adopts aspergillus oryzae (Aspergillus oryzae) microorganism through the gene modification to carry out submerged fermentation and is absorbed on a kind of macroporosity resin and makes, wherein the content of candida antarctica lipase B is 10%, vigor is 10,000PLU/g.
3. the synthetic method of medicinal biodegradable poly according to claim 1 and 2 (6-caprolactone) is characterized in that, the consumption of described immobilized lipase Novozym 435 and the mass ratio of 6-caprolactone are 1%～20%.
4. the synthetic method of medicinal biodegradable poly according to claim 1 (6-caprolactone), it is characterized in that, the reaction of described mass polymerization is meant: with 6-caprolactone with mix in immobilized lipase Novozym 435 directly places the capping system, and will be full of nitrogen in the capping system, under 60～80 ℃ of temperature, react 2～48h.
5. the synthetic method of medicinal biodegradable poly according to claim 1 (6-caprolactone), it is characterized in that, described solution polymerization process reaction is meant: 6-caprolactone is mixed the back further add organic solvent with immobilized lipase Novozym 435, and will be full of nitrogen in the capping system, under 60～80 ℃ of temperature, react 2～48h.
6. according to the synthetic method of claim 1 or 4 or 5 described medicinal biodegradable polies (6-caprolactone), it is characterized in that the internal pressure of described capping system is 2～760mm mercury column.
7. according to the synthetic method of claim 4 or 5 described medicinal biodegradable polies (6-caprolactone), it is characterized in that described organic solvent is meant: toluene or dioxane, the volume ratio of this organic solvent and 6-caprolactone are 2.0～5.0: 1.
8. the synthetic method of medicinal biodegradable poly according to claim 1 (6-caprolactone), it is characterized in that, described separation and purification is meant: add the methylene dichloride termination reaction in reactant, remove by filter enzyme, the filtrate vacuum concentration is removed organic solvent, concentrated solution is poured in the sherwood oil of 3～5 times of amounts or the ethanol and is precipitated, and filters back collecting precipitation vacuum-drying 48h and is gathered (6-caprolactone).
9. the medicinal biodegradable poly (6-caprolactone) that the described synthetic method of claim 1 prepares is characterized in that, described poly-(6-caprolactone), and its number-average molecular weight is 5000～60000g/mol, polymolecularity 1.1～1.4
10. the application of the medicinal biodegradable poly (6-caprolactone) for preparing of the described synthetic method of claim 1, it is characterized in that, described medicinal biodegradable poly (6-caprolactone) is used to prepare organizational project substrate material, pharmaceutical preparation auxiliary material or medicine equipment material.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102676603A (en) * | 2012-01-12 | 2012-09-19 | 河南科技大学 | Method for preparing polycaprolactone |
| CN107541530A (en) * | 2017-09-30 | 2018-01-05 | 华东理工大学 | One kind is containing double tellurium biodegradable polymers and preparation method thereof |
-
2010
- 2010-05-28 CN CN2010101862375A patent/CN101831468B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| 《Biomacromolecules》 20001231 Ajay Kumar and Richard A. Gross Candida antartica Lipase B Catalyzed Polycaprolactone Synthesis: Effects of Organic Media and Temperature. 133-138 1-10 , 2 * |
| 《International Journal of Biological Macromolecules》 19991231 Deng et al. Ring-opening bulk polymerization of o-caprolactone and trimethylene carbonate catalyzed by lipase Novozym 435 153-159 1-10 , 2 * |
| 《Macromolecules》 20041231 Loeker et al. Enzyme-Catalyzed Ring-Opening Polymerization of -Caprolactone in Supercritical Carbon Dioxide 2450-2453 9,10 , 2 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102676603A (en) * | 2012-01-12 | 2012-09-19 | 河南科技大学 | Method for preparing polycaprolactone |
| CN102676603B (en) * | 2012-01-12 | 2015-06-17 | 河南科技大学 | Method for preparing polycaprolactone |
| CN107541530A (en) * | 2017-09-30 | 2018-01-05 | 华东理工大学 | One kind is containing double tellurium biodegradable polymers and preparation method thereof |
| CN107541530B (en) * | 2017-09-30 | 2021-05-14 | 华东理工大学 | Double-tellurium-containing biodegradable polymer and preparation method thereof |
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