CN101831468B - 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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- CN101831468B CN101831468B CN2010101862375A CN201010186237A CN101831468B CN 101831468 B CN101831468 B CN 101831468B CN 2010101862375 A CN2010101862375 A CN 2010101862375A CN 201010186237 A CN201010186237 A CN 201010186237A CN 101831468 B CN101831468 B CN 101831468B
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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 between60 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
Gathering (6-caprolactone) is a kind of hemicrystalline aliphatic polyester, with its good biodegradability, biocompatibility and drug permeability, has obtained extensive studies and application in fields such as biomedicine and medicine sustained release.Gathering (6-caprolactone) present compound method is to adopt the ring-opening polymerization of organo-metallic catalysis 6-caprolactone monomer to obtain; But having limited to synthesize, the harsh reaction conditions and the residual toxicity of heavy metal catalyst gather (6-caprolactone), like the application of biomedical and field of drug delivery at numerous areas.
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 lypase all is used to the ring-opening polymerization of catalysis 6-caprolactone like porcine pancreatic lipase, Pseudomonas fluorescens lypase 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, and package stability is high; Still have advantages of high catalytic activity after reclaim reusing, therefore be applied to enzymatic polymerization research by increasing.
Retrieval through to the prior art document is found; Chinese patent document number CN 1341674A discloses a kind of method that body ring-opening polymerization preparation gathers (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, and technology is more loaded down with trivial details, and the used butyl(tetra)titanate moisture absorption very easily; Preservation condition is harsh, has heavy-metal residual in the reaction system.
Further retrieval is found; Chinese patent document number 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; The catalysis synthetic gathers only 1200～2300g/mol of (6-caprolactone) number-average molecular weight, can't directly precipitate and need to separate through low-temperature centrifugation, and molecular weight is too low can't be widely used in pharmaceutical carrier.
Summary of the invention
The present invention is directed to the above-mentioned deficiency that prior art exists; 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 through catalyst-free prepares biodegradable poly (6-caprolactone).
The present invention realizes through following technical scheme; The present invention is through 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 lypase that is obtained by candida antarctica lipase B (Candida antarcticlipase B); This lypase adopts aspergillus oryzae (Aspergillus oryzae) mikrobe through the gene modification to carry out submerged fermentation and is absorbed on a kind of macroporosity resin and processes; 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, under 60～80 ℃ of temperature, react 2～48h with being full of nitrogen in the capping system.
Described solution polymerization process is meant: 6-caprolactone is mixed the back further add organic solvent with immobilized lipase Novozym 435, and with being full of nitrogen in the capping system, under 60～80 ℃ of temperature, react 2～48h.
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: in reactant, add the methylene dichloride termination reaction; Remove by filter enzyme; The filtrating vacuum concentration is removed organic solvent, and liquid concentrator is poured in sherwood oil or the ethanol of 3～5 times of amounts and precipitated, and filters back collecting precipitation vacuum-drying 48h and is gathered (6-caprolactone).
(6-caprolactone) outward appearance of gathering 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 prepn auxiliary material, medicine equipment material.
The present invention compares with existing compound method of gathering (6-caprolactone), has the following advantages:
1. the present invention uses commercially available immobilized lipase Novozym 435 to be catalyzer, and catalyst filtration can be removed, the immobilized lipase Novozym 435 of recovery, and the repetitive scrubbing final vacuum is dry, and is 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. what the present invention obtained gathers (6-caprolactone) number-average molecular weight 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
Elaborate in the face of embodiments of the invention down, present embodiment provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment being to implement under the prerequisite with technical scheme of the present invention.
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; Filtrating vacuum concentration, liquid concentrator 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 volume ratio of sealing back use syringe adding and 6-caprolactone is 2.0: 1 a toluene; 80 ℃ of following stirring reaction 7h add 10ml methylene dichloride termination reaction, remove by filter enzyme; Filtrating 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 TMS (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 volume ratio of sealing back use syringe adding and 6-caprolactone is 5.0: 1 a toluene; 80 ℃ of following stirring reaction 10h add 20ml methylene dichloride termination reaction, remove by filter enzyme; Filtrating 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 volume ratio of sealing back use syringe adding and 6-caprolactone is 5.0: 1 a dioxane; 80 ℃ of following stirring reaction 48h add 20ml methylene dichloride termination reaction, remove by filter enzyme; Filtrating 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.
Material with above-mentioned compound method obtains can be directly as the auxiliary material of pharmaceutical prepn, and concrete application mode is: adopting the S/O/W solvent evaporation method, is the mould medicine with CH331; With above-mentioned gathering (6-caprolactone) is that base material (number-average molecular weight is 57000) prepares 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 (2)
1. the compound method of a medicinal biodegradable poly 6-caprolactone is characterized in that, adopts mass polymerization reaction or solution polymerization process reaction; Said mass polymerization is that the 5g 6-caprolactone is mixed with 0.05g Novozym 435, puts 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 filtrating vacuum concentration, liquid concentrator is 90.2% through the nuclear magnetic resonance hydrogen spectruming determining monomer conversion; 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 through gel permeation chromatography, and number-average molecular weight is 7000g/mol, and polymolecularity is 1.3;
Said solution polymerization process is that the 5g 6-caprolactone is mixed with 0.5g Novozym 435, puts into the reaction flask of clean dried, with nitrogen ventilation three times; The volume ratio of sealing back use syringe adding and 6-caprolactone is 5.0: 1 a dioxane, and 80 ℃ of following stirring reaction 48h add 20ml methylene dichloride termination reaction; Remove by filter enzyme, the filtrating vacuum concentration, concentrated filtrate is 99.2% through the nuclear magnetic resonance hydrogen spectruming determining monomer conversion; 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 through gel permeation chromatography, and number-average molecular weight is 31000g/mol, and polymolecularity is 1.3.
2. the compound method of medicinal biodegradable poly 6-caprolactone according to claim 1; It is characterized in that; Described immobilized lipase Novozym 435 is a kind of lypase that is obtained by candida antarctica lipase B, and this lypase adopts the aspergillus oryzae mikrobe through the gene modification to carry out submerged fermentation and is absorbed on a kind of macroporosity resin and processes, and wherein the content of candida antarctica lipase B is 10%; Vigor is 10,000PLU/g.
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Non-Patent Citations (3)
| Title |
|---|
| Ajay Kumar and Richard A. Gross.Candida antartica Lipase B Catalyzed Polycaprolactone Synthesis: Effects of Organic Media and Temperature..《Biomacromolecules》.2000,133-138. * |
| Deng et al..Ring-opening bulk polymerization of o-caprolactone and trimethylene carbonate catalyzed by lipase Novozym 435.《International Journal of Biological Macromolecules》.1999,153–159. * |
| Loeker et al..Enzyme-Catalyzed Ring-Opening Polymerization of o-Caprolactone in Supercritical Carbon Dioxide.《Macromolecules》.2004,2450-2453. * |
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