CN103113495A - Photopolymerizable hyaluronic acid derivative and preparation method thereof - Google Patents
Photopolymerizable hyaluronic acid derivative and preparation method thereof Download PDFInfo
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- CN103113495A CN103113495A CN2013100448403A CN201310044840A CN103113495A CN 103113495 A CN103113495 A CN 103113495A CN 2013100448403 A CN2013100448403 A CN 2013100448403A CN 201310044840 A CN201310044840 A CN 201310044840A CN 103113495 A CN103113495 A CN 103113495A
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Abstract
The invention relates to a preparation method of a photopolymerizable hyaluronic acid derivative and belongs to the field of preparation of natural biopolymers. The preparation method comprises the following steps of: (1) adding hyaluronic acid with the weight average molecular weight being 10,000-2000,000 to an anhydrous solvent and stirring for 24 hours at the temperature of 20-30 DEG C; (2) cooling and stirring for 1-5 hours in an ice-bath at the temperature of -10-0 DEG C; (3) dropwise adding the anhydrous solvent solution containing 30-60wt% of unsaturated acid chloride, wherein the dropwise adding time is 3-5 hours; and the mole number of the dropwise added unsaturated acid chloride is 1-4 times of the mole number of reactive hydrogen of the hyaluronic acid; and (4) reacting for 2-10 hours at the temperature of 20-25 DEG C, and filtering to obtain the photopolymerizable hyaluronic acid derivative. Aiming at the defects of a hyaluronic acid modified method in the prior art that the cost is relatively high, the process is complicated and the residues of a cytotoxicity reagent are serious, the method which is low in cost, simple in process and low in cytotoxicity is provided.
Description
Technical field
The present invention relates to a kind of reactive derivatives of hyaluronic acids preparation method.Belong to the natural biological macromolecule material preparation area.
Background technology
Hyaluronic acid (Hyaluronic acid, HA) is a kind of acid mucopolysaccharide of polyanion that is present in the biological tissue cell epimatrix, be structural unit by β-D-N-acetylglucosamine and β-D-Glucose sulfonic acid, a kind of chain natural polymer that is linked to be with β-Isosorbide-5-Nitrae-glycosidic linkage.It spatially is the screw cylindrical structure of rigidity, and the inboard of post is owing to existing a large amount of hydroxyls to produce strongly hydrophilic.Because hyaluronan molecule can be locked in the water molecules of its combination in its duplex columnar structure, moisture is difficult for running off, and therefore has special water retention.Hyaluronic acid demonstrates multiple important physiological function with its unique molecular structure and physico-chemical property in body, as lubricated joint, regulate the permeability of vessel wall, regulates protein, and Water-Electrolyte diffusion and running promote wound healing etc.There is higher using value due to its highly effective water-keeping and good biocompatibility, biodegradability in hyaluronic acid in field of tissue engineering technology: as tissue engineering bracket, skin wound dressing etc.Hyaluronic acid need to carry out it crosslinked to extend retention time in its application process due to very easily water-soluble and restricted in the bioengineered tissue field usually.Hyaluronic acid adopts chemical crosslink technique crosslinked to it usually, and for example: the crosslinking method by covalent bonding hyaluronan molecule bonding has obtained hyaluronic acid derivatives to United States Patent (USP) 4582865 by divinylsulfone; United States Patent (USP) 4886787 carries out cross-linked-hyaluronic acid by epoxide and has obtained hyaluronic acid derivatives.Yet, having the residual of linking agent what the crosslinked middle linking agent that uses of this class or cross-linking compounds all were difficult to avoid, these linking agents are exclusive usually must cytotoxicity, and restriction hyaluronic acid material is in the application of bioengineering field.
The photopolymerization crosslinking technological is a kind of environmental friendliness, energy-efficient radiation curing technology, and its applied research report at bioengineering field increases year by year.By hyaluronic acid is carried out the derivatives of hyaluronic acids that chemical modification obtains to have the photo-crosslinking activity, become recent studies on direction of cross-linking hyaluronic acid modification and be applied to bioengineering field.Luo Chunhong etc. (polymer material science and engineering, 2011,27(7), 163-166) adopt glycidyl methacrylate to carry out chemical modification to hyaluronic acid, and then be cross-linked into hydrogel under uv-radiation; Zhang Yeli etc. (Beijing University of Chemical Technology's journal (natural science edition), 2011,38,49-53) adopt glyceral methacrylate to hyaluronic acid modified, and crosslinked with gamma-rays, obtained the radiation crosslinking hyaluronic acid derivatives.But because energy of γ ray is higher, easily causes hyaluronic acid backbone fracture degraded, and reduce the hyaluronic acid biological activity.The present invention has the derivatives of hyaluronic acids of photopolymerization activity by the solid-liquid suspension method with acrylate chloride or methacrylic chloride to hyaluronic acid modified acquisition, by the uv photopolymerization cross-linked-hyaluronic acid.
Summary of the invention
The object of the invention is for hyaluronic acid modified method cost in prior art higher, complex process, and the shortcoming that cytotoxic reagent is residual provides a kind of cost low, and technique is simple, the photopolymerization derivatives of hyaluronic acids preparation method that cytotoxicity is little.
The preparation method of a kind of photopolymerization derivatives of hyaluronic acids provided by the present invention comprises the following steps:
(1) hyaluronic acid is joined in anhydrous solvent, stirred 24 hours under 20 ~ 30 ℃;
(2) cooling and stirring 1 ~ 5 hour under the ice bath of-10 ~ 0 ° of C;
(3) drip the anhydrous solvent solution of the unsaturated acyl chlorides of 30～60wt%, time for adding is 3～5 hours, and the unsaturated acyl chlorides mole number of dropping is 1～4 times of reactable hydrogen mole number on hyaluronic acid;
(4) reacted 6 hours under 20 ~ 25 ℃, filter, namely get the photopolymerization derivatives of hyaluronic acids.
Hyaluronic acid weight-average molecular weight in above-mentioned steps (1) is 10,000～2000,000.
Anhydrous solvent in above-mentioned steps (1) and (3) is tetrahydrofuran (THF) or N, N-METHYLFORMAMIDE.
Above-mentioned unsaturated acyl chlorides is acrylate chloride or methacrylic chloride.
The prepared derivatives of hyaluronic acids of the present invention has following general structure:
Wherein x is percentage of grafting, and R is COCH=CH
2Or COC (CH
3)=CH
2
The present invention adopts the solid-liquid suspension method, allows hydroxyl and the reaction of unsaturated acyl chlorides on hyaluronan molecule, and reaction conditions is gentle, and the organic reagent residual volume is few, has prepared good biocompatibility, the natural derivatives of hyaluronic acids of photopolymerization that cytotoxicity is low.Successfully realized the polymerization under ultraviolet lighting of its derivative:
Preparation 20wt% photopolymerization derivatives of hyaluronic acids ethanolic soln adds the 1wt% free radical photo-initiation, at ultraviolet light intensity 30mW/cm
2Condition under irradiation got final product initiated polymerization in 10 minutes.Free radical photo-initiation is 1-[4-(2-hydroxyl hydroxyethyl)-phenyl]-2-hydroxy-2-methyl-1-propane (2959).
Compared with prior art, the invention has the advantages that: the solid-liquid suspension method is easily carried out, the reaction process easy handling; The reaction process controllability is strong, and experimental installation is simple, and product can be realized industrialization; The unsaturated acyl chlorides of experimental raw is widely used in industry, and other organic solvents recoverable after experiment has reduced production cost; Acyl chlorides reacts rear as easy as rolling off a log removing due to its high reaction activity, and after reaction, organic reagent is residual few, hyaluronic acid derivatives cytotoxicity prepared after photopolymerization low (≤1 grade), good biocompatibility.
Description of drawings
Fig. 1 embodiment 1 dynamics data.
Fig. 2 embodiment 2 dynamics datas.
Fig. 3 embodiment 3 dynamics datas.
Fig. 4 embodiment 4 dynamics datas.
Embodiment
With embodiment 1:
(1) be Mw=10 with weight-average molecular weight, 000 hyaluronic acid powder joins in tetrahydrofuran solution, stirs 24 hours under 20 ℃;
(2) cooling and stirring 1 hour under the ice bath of-5 ° of C;
(3) drip the tetrahydrofuran solution of 30wt% acrylate chloride, time for adding is 5 hours, and the acrylate chloride mole number of dropping is 1 times of reactable hydrogen mole number on hyaluronic acid;
(4) reacted 6 hours under 20 ℃, filter, namely get the photopolymerization derivatives of hyaluronic acids.
The photopolymerization derivatives of hyaluronic acids 5g that is synthesized is dissolved in 20 ethanol, adds light trigger 1-[4-(2-hydroxyl hydroxyethyl)-phenyl]-2-hydroxy-2-methyl-1-propane 0.25g, be stirred to solution even.Then, UV-light optical wavelength 320-480nm at room temperature, light intensity 30mW/cm
2Shone 10 minutes, and surveyed its dynamics data as shown in Figure 1 with Nicolet5700FTIR:
Calculating final double bond conversion rate is 90%.
With embodiment 2:
(1) be Mw=2 with weight-average molecular weight, 000,000 hyaluronic acid powder joins in DMF solution, stirs 24 hours under 23 ℃;
(2) cooling and stirring 3 hours under the ice bath of 0 ° of C;
(3) drip the DMF solution of 60wt% methacrylic chloride, time for adding is 5 hours, and the methacrylic chloride mole number of dropping is 4 times of reactable hydrogen mole number on hyaluronic acid;
(4) reacted 8 hours under 23 ℃, filter, namely get the photopolymerization derivatives of hyaluronic acids.
The photopolymerization derivatives of hyaluronic acids 5g that is synthesized is dissolved in 20 ethanol, adds light trigger 1-[4-(2-hydroxyl hydroxyethyl)-phenyl]-2-hydroxy-2-methyl-1-propane 0.25g, be stirred to solution even.Then, UV-light optical wavelength 320-480nm at room temperature, light intensity 30mW/cm
2Shone 10 minutes, and surveyed its dynamics data as shown in Figure 2 with Nicolet5700FTIR:
Calculating final double bond conversion rate is 86%.
With embodiment 3:
(1) be Mw=1 with weight-average molecular weight, 000,000 hyaluronic acid powder joins in DMF solution, stirs 24 hours under 25 ℃;
(2) cooling and stirring 1 hour under the ice bath of-10 ° of C;
(3) drip the N of 50wt% methacrylic chloride, N-METHYLFORMAMIDE solution, time for adding are 4 hours, and the methacrylic chloride mole number of dropping is 3 times of reactable hydrogen mole number on hyaluronic acid;
(4) reacted 10 hours under 25 ℃, filter, namely get the photopolymerization derivatives of hyaluronic acids.
The photopolymerization derivatives of hyaluronic acids 5g that is synthesized is dissolved in 20 ethanol, adds light trigger 1-[4-(2-hydroxyl hydroxyethyl)-phenyl]-2-hydroxy-2-methyl-1-propane 0.25g, be stirred to solution even.Then, UV-light optical wavelength 320-480nm at room temperature, light intensity 30mW/cm
2Shone 15 minutes, and surveyed its dynamics data as shown in Figure 3 with Nicolet5700FTIR:
Calculating final double bond conversion rate is 90%.
With embodiment 4:
(1) be Mw=200 with weight-average molecular weight, 000 hyaluronic acid powder joins in tetrahydrofuran solution, stirs 24 hours under 30 ℃;
(2) cooling and stirring 4 hours under the ice bath of-3 ° of C;
(3) drip the tetrahydrofuran solution of 40wt% acrylate chloride, time for adding is 4 hours, and the acrylate chloride mole number of dropping is 1 times of reactable hydrogen mole number on hyaluronic acid;
(4) reacted 2 hours under 30 ℃, filter, namely get the photopolymerization derivatives of hyaluronic acids.
The photopolymerization derivatives of hyaluronic acids 5g that is synthesized is dissolved in 20 ethanol, adds light trigger 1-[4-(2-hydroxyl hydroxyethyl)-phenyl]-2-hydroxy-2-methyl-1-propane 0.25g, be stirred to solution even.Then, UV-light optical wavelength 320-480nm at room temperature, light intensity 30mW/cm
2Shone 15 minutes, and surveyed its dynamics data as shown in Figure 4 with Nicolet5700FTIR:
Calculating final double bond conversion rate is 89%.
Claims (4)
1. the preparation method of a photo-polymerizable chitosan derivative is characterized in that comprising the following steps:
(1) be that 10,000～2000,000 hyaluronic acid joins in anhydrous solvent with weight-average molecular weight, stirred 24 hours under 20 ~ 30 ℃;
(2) cooling and stirring 1 ~ 5 hour under the ice bath of-10 ~ 0 ° of C;
(3) drip the anhydrous solvent solution of the unsaturated acyl chlorides of 30～60wt%, time for adding is 3～5 hours, and the unsaturated acyl chlorides mole number of dropping is 1～4 times of reactable hydrogen mole number on hyaluronic acid;
(4) reacted under 20 ~ 25 ℃ 2 ~ 10 hours, filter, namely get the photopolymerization derivatives of hyaluronic acids.
2. preparation method according to claim 1, is characterized in that the anhydrous solvent described in step (1) and (3) is tetrahydrofuran (THF) or DMF.
3. preparation method according to claim 1, is characterized in that the unsaturated acyl chlorides described in step (3) is acrylate chloride or methacrylic chloride.
4. preparation method according to claim 1 is characterized in that the photopolymerization derivatives of hyaluronic acids described in step (4) has following general structure:
Wherein x is percentage of grafting, and R is COCH=CH
2Or COC (CH
3)=CH
2
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1144818C (en) * | 1998-11-11 | 2004-04-07 | 阿奎斯蒂奥股份公司 | Cross-linking process for carboxylated polysaccharides |
| CN101133102A (en) * | 2004-12-30 | 2008-02-27 | 诺维信生物聚合物公司 | Hyaluronic acid linked with a polymer of an alpha hydroxy acid |
| CN102391391A (en) * | 2011-12-14 | 2012-03-28 | 常州市晨光树脂有限公司 | Natural high-molecular acrylate and its preparation method |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1144818C (en) * | 1998-11-11 | 2004-04-07 | 阿奎斯蒂奥股份公司 | Cross-linking process for carboxylated polysaccharides |
| CN101133102A (en) * | 2004-12-30 | 2008-02-27 | 诺维信生物聚合物公司 | Hyaluronic acid linked with a polymer of an alpha hydroxy acid |
| CN102391391A (en) * | 2011-12-14 | 2012-03-28 | 常州市晨光树脂有限公司 | Natural high-molecular acrylate and its preparation method |
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Application publication date: 20130522 |