CN101367884A - Cysteamine modified sulfhydryl hyaluronic acid couplet, preparation and application thereof - Google Patents
Cysteamine modified sulfhydryl hyaluronic acid couplet, preparation and application thereof Download PDFInfo
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- CN101367884A CN101367884A CNA2008102004533A CN200810200453A CN101367884A CN 101367884 A CN101367884 A CN 101367884A CN A2008102004533 A CNA2008102004533 A CN A2008102004533A CN 200810200453 A CN200810200453 A CN 200810200453A CN 101367884 A CN101367884 A CN 101367884A
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Abstract
The invention belongs to the technical field of high polymer materials, in particular to a thiolated hyaluronic acid conjugate modified by cysteamine, a preparation method and an application thereof. The method comprises the steps of adding 1-ethyl-3-(3-dimethylamino propyl)-carbodiimide (EDAC) and N-hydroxysuccinimide (NHS) in the hyaluronic acid solution to activate the carboxyl of the hyaluronic acid solution, adding cysteamine hydrochloride to make the amino of cysteamine hydrochloride and the carboxyl of hyaluronic acid to form amido link, regulating the proportions of each material and reaction conditions to obtain the thiolated hyaluronic acid conjugates with different sulfhdryl contents. The invention widens the application range of the thiolated reaction. The adhesive properties of the mucosa and the biocompatibility of the conjugate are good. The invention has strong in-situ gel property and supplies good bio-adhesive materials for non-injected preparations, tissue engineering and the like.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to sulfhydrylation hyaluronic acid couplet of a kind of cysteamine modification and its production and application.
Background technology
Sulfhydrylation polymkeric substance (Thiomer) is the product of the side chain of a class hydrophilic high molecular polymer through sulfhydryl compound modification gained, is a kind of novel mucosa adhesion material.Under the physiological condition its can with mucous membrane rete malpighii glycoprotein in be rich in halfcystine the zone form disulfide linkage, combine closely in mucous membrane with covalent linkage, the prolong drug residence time in vivo, improve the partial concn of medicine, promote drug absorption.In addition, the sulfhydrylation polymkeric substance has situ-gel character, and its intramolecularly can form disulfide linkage, so that rheological property changes.At present, positively charged ion sulfhydrylation polymkeric substance such as chitosan-halfcystine, chitosan-Thiovanic acid, chitosan-sulfo--amidine conjugates etc. have been developed, negatively charged ion sulfhydrylation polymkeric substance such as polyacrylic acid-halfcystine, polyacrylic acid-cysteamine, polyacrylic acid-homocysteine, Xylo-Mucine-halfcystine, sodium alginate-halfcystine conjugates etc.With corresponding unmodified polymer phase ratio, the mucosa adhesion of sulfhydrylation polymkeric substance can increase by 2～140 times.This polymkeric substance can be made into drug administration carriers such as microballoon, nanoparticle, gel, matrix tablet, is used for the non-injection administration of multiple hydrophilic medicament.In addition, the sulfhydrylation polymkeric substance also can be applicable to prepare tissue engineering bracket.
Hyaluronic acid is a kind of macromole acidic mucopolysaccharide, extensively is present in the reticular tissue of organism, has better biocompatibility and biological degradability, can be applicable to organizational project and field of medicaments.By methods such as crosslinked, esterification, grafting hyaluronic acid is carried out chemically modified, can improve its physical strength, slow down it, further enlarge its application prospect at in-house degradation speed.(Int J Pharm such as Krum K., 2007,343:48-58), the L-ethycysteine is bonded on the hyaluronic carboxyl, makes hyaluronic acid-ethycysteine conjugates by 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride/N-hydroxy-succinamide mediation.The free sulfhydryl groups content of every gram polymkeric substance is greater than 200 μ mol/g, disulfide bond content is about 85 μ mol/g, and its mucosa adhesion has improved 6.5 times than the hyaluronic acid of unmodified, and the resistance to enzymolysis ability strengthens, as the wetting ability carrier material of macromolecular medicament, may have slow-releasing and controlled-releasing action preferably.The disulfide bond content of hyaluronic acid-ethycysteine conjugates is lower, and its situ-gel is relatively poor.
Summary of the invention
The purpose of this invention is to provide the sulfhydrylation hyaluronic acid couplet that a kind of cysteamine is modified.
Another object of the present invention provides a kind of preparation method of sulfhydrylation hyaluronic acid couplet of cysteamine modification.
A further object of the invention provides a kind of application of sulfhydrylation hyaluronic acid couplet of cysteamine modification, to overcome the deficiencies in the prior art and defective.
Design of the present invention is as follows:
The present invention is a raw material with biodegradable hyaluronic acid, activate its carboxyl with 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and N-hydroxy-succinamide (NHS), add Mercaptamine, make its amino and hyaluronic carboxyl form amido linkage, make the sulfhydrylation hyaluronic acid couplet.
The process of synthetic sulfhydrylation hyaluronic acid couplet is as follows:
Technical scheme of the present invention is as follows:
The sulfhydrylation hyaluronic acid couplet that cysteamine of the present invention is modified is a skeleton with the hyaluronic acid, and cysteamine is covalently bond to hyaluronic acid.
Described hyaluronic molecular weight is 1.98 * 10
4～1 * 10
6G/mol.
The sulfhydrylation hyaluronic acid couplet that described cysteamine is modified, every relatively gram conjugates, covalently bound free thiohydroxy group are 10～200 μ mol/g, disulfide linkage is 120～500 μ mol/g.
The sulfhydrylation hyaluronic acid couplet that described cysteamine is modified, its aqueous solution ratio of viscosities unmodified hyaluronic acid of 0.5%～3% is high 5～100 times.
The sulfhydrylation hyaluronic acid couplet that cysteamine of the present invention is modified, its preparation method is as follows:
Adding final concentration in the aqueous solution of sodium hyaluronate of (1) 0.4%～1% mass percent is 0.19%～1.9% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.12%～1.2%N-N-Hydroxysuccinimide (NHS), pH5～6 are transferred in the dissolving back, stir 30～120min;
(2) feed intake by hyaluronic acid and Mercaptamine mass ratio 32:1～1:4, conditioned reaction liquid pH 3～5, lucifuge reaction 4～12h, after reaction finishes, dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified.
Described hyaluronic molecular weight is 1.98 * 10
4～1 * 10
6G/mol.
The preferred reaction time is 40～60min in the step (1), and it is incomplete that the time passes short reaction, the overlong time unstable products.
The acid of preferably transparent matter is 8:1～1:2 with the Mercaptamine mass ratio in the step (2), and hyaluronic acid and Mercaptamine mass ratio are too high, and then the substitution value of carboxyl is low excessively; Hyaluronic acid and Mercaptamine mass ratio are low excessively, the more difficult Ex-all in subsequent purification is handled of then excessive Mercaptamine.
The preferred reaction times is 5～8h in the step (2), and it is incomplete that the time passes short reaction, and overlong time then product is easily oxidized.
The sulfhydrylation hyaluronic acid couplet that cysteamine of the present invention is modified can be applicable to drug delivery system, cell cultures and organizational project.
The invention has the advantages that:
(1) aqueous solution of conjugates of the present invention makes solution viscosity increase owing to disulfide linkage is more, is gel under the physiological condition, can be developed into in-situ gel preparation;
(2) material of forming conjugates is natural Biodegradable material, has nontoxicity, non-immunogenicity and antigenicity, characteristics that biocompatibility is good;
(3) conjugates of the present invention has wetting ability preferably, can be used as the carrier of hydrophilic medicament, in conjunction with in the mucous membrane rete malpighii, improves the interior residence time of body of medicine with chemical bond, increases the partial concn of medicine, improves bioavailability of medicament;
(4) conjugates of the present invention improves with respect to the hyaluronic acid mechanical property, and the resistance to enzymolysis ability strengthens, and as tissue engineering material, can slow down its vivo degradation speed.
Embodiment
Can further understand the present invention by the following specific embodiments.But they are not limitation of the invention.
Embodiment 1
With the 200mg molecular weight is 5 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.4% hyaluronic acid solution, add final concentration respectively and be 0.96% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.58% N-hydroxy-succinamide (NHS), pH 5.5 is transferred in the dissolving back, stirs 45min; Add 400mg half light amine hydrochlorate, conditioned reaction liquid pH 4.75, lucifuge reaction 5h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 2
With the 300mg molecular weight is 1.98 * 10
4The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.6% hyaluronic acid solution, add final concentration respectively and be 0.19% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.12% N-hydroxy-succinamide (NHS), pH5 is transferred in the dissolving back, stirs 30min; Add 300mg half light amine hydrochlorate, conditioned reaction liquid pH3, lucifuge reaction 4h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 3
With the 400mg molecular weight is 1 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.8% hyaluronic acid solution, add final concentration respectively and be 0.48% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.29% N-hydroxy-succinamide (NHS), pH 5.5 is transferred in the dissolving back, stirs 40min; Add 200mg half light amine hydrochlorate, conditioned reaction liquid pH 4, lucifuge reaction 5h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 4
With the 200mg molecular weight is 1 * 10
6The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.4% hyaluronic acid solution, add final concentration respectively and be 1.4% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.86% N-hydroxy-succinamide (NHS), pH 6 is transferred in the dissolving back, stirs 60min; Add 800mg half light amine hydrochlorate, conditioned reaction liquid pH 5, lucifuge reaction 6h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 5
With the 500mg molecular weight is 1.98 * 10
4The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 1% hyaluronic acid solution, add final concentration respectively and be 1.9% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 1.2% N-hydroxy-succinamide (NHS), pH 5 is transferred in the dissolving back, stirs 90min; Add 15.6mg half light amine hydrochlorate, conditioned reaction liquid pH 3, lucifuge reaction 8h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 6
With the 300mg molecular weight is 1 * 10
6The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.6% hyaluronic acid solution, add final concentration respectively and be 0.19% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.12% N-hydroxy-succinamide (NHS), pH 5.5 is transferred in the dissolving back, stirs 120min; Add 18.8mg half light amine hydrochlorate, conditioned reaction liquid pH 4, lucifuge reaction 10h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 7
With the 400mg molecular weight is 5 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.8% hyaluronic acid solution, add final concentration respectively and be 0.48% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.29% N-hydroxy-succinamide (NHS), pH 6 is transferred in the dissolving back, stirs 30min; Add 50mg half light amine hydrochlorate, conditioned reaction liquid pH 4.75, lucifuge reaction 12h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 8
With the 500mg molecular weight is 1 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 1% hyaluronic acid solution, add final concentration respectively and be 0.96% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.58% N-hydroxy-succinamide (NHS), pH 5 is transferred in the dissolving back, stirs 40min; Add 125mg half light amine hydrochlorate, conditioned reaction liquid pH 5, lucifuge reaction 4h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 9
With the 400mg molecular weight is 1 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.8% hyaluronic acid solution, add final concentration respectively and be 1.4% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.86% N-hydroxy-succinamide (NHS), pH 5.5 is transferred in the dissolving back, stirs 45min; Add 12.5mg half light amine hydrochlorate, conditioned reaction liquid pH 4, lucifuge reaction 6h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 10
With the 500mg molecular weight is 5 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 1% hyaluronic acid solution, add final concentration respectively and be 1.9% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 1.2% N-hydroxy-succinamide (NHS), pH 6 is transferred in the dissolving back, stirs 60min; Add 31.2mg half light amine hydrochlorate, conditioned reaction liquid pH 4.75, lucifuge reaction 8h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 11
With the 200mg molecular weight is 1 * 10
6The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.4% hyaluronic acid solution, add final concentration respectively and be 0.19% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.12% N-hydroxy-succinamide (NHS), pH 5 is transferred in the dissolving back, stirs 90min; Add 25mg half light amine hydrochlorate, conditioned reaction liquid pH 5, lucifuge reaction 10h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 12
With the 300mg molecular weight is 1.98 * 10
4The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.6% hyaluronic acid solution, add final concentration respectively and be 0.48% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.29% N-hydroxy-succinamide (NHS), pH 5.5 is transferred in the dissolving back, stirs 120min; Add 75mg half light amine hydrochlorate, conditioned reaction liquid pH 3, lucifuge reaction 12h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 13
With the 500mg molecular weight is 5 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 1% hyaluronic acid solution, add final concentration respectively and be 0.96% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.58% N-hydroxy-succinamide (NHS), pH 6 is transferred in the dissolving back, stirs 30min; Add 250mg half light amine hydrochlorate, conditioned reaction liquid pH 3, lucifuge reaction 5h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 14
With the 200mg molecular weight is 1 * 10
6The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.4% hyaluronic acid solution, add final concentration respectively and be 1.4% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.86% N-hydroxy-succinamide (NHS), pH 5 is transferred in the dissolving back, stirs 40min; Add 200mg half light amine hydrochlorate, conditioned reaction liquid pH 4, lucifuge reaction 6h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 15
With the 300mg molecular weight is 1.98 * 10
4The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.6% hyaluronic acid solution, add final concentration respectively and be 1.9% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 1.2% N-hydroxy-succinamide (NHS), pH 5.5 is transferred in the dissolving back, stirs 45min; Add 600mg half light amine hydrochlorate, conditioned reaction liquid pH 4.75, lucifuge reaction 8h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 16
With the 400mg molecular weight is 1 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.8% hyaluronic acid solution, add final concentration respectively and be 0.19% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.12% N-hydroxy-succinamide (NHS), pH 6 is transferred in the dissolving back, stirs 60min; Add 1600mg half light amine hydrochlorate, conditioned reaction liquid pH 5, lucifuge reaction 10h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 17
With the 200mg molecular weight is 1 * 10
6The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.4% hyaluronic acid solution, add final concentration respectively and be 0.48% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.29% N-hydroxy-succinamide (NHS), pH 5 is transferred in the dissolving back, stirs 90min; Add 6.2mg half light amine hydrochlorate, conditioned reaction liquid pH 4, lucifuge reaction 12h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 18
With the 300mg molecular weight is 1.98 * 10
4The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.6% hyaluronic acid solution, add final concentration respectively and be 0.96% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.58% N-hydroxy-succinamide (NHS), pH 5.5 is transferred in the dissolving back, stirs 120min; Add 18.8mg half light amine hydrochlorate, conditioned reaction liquid pH 4.75, lucifuge reaction 4h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 19
With the 400mg molecular weight is 1 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.8% hyaluronic acid solution, add final concentration respectively and be 1.4% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.86% N-hydroxy-succinamide (NHS), pH 6 is transferred in the dissolving back, stirs 30min; Add 50mg half light amine hydrochlorate, conditioned reaction liquid pH 5, lucifuge reaction 4h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCI, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 20
With the 500mg molecular weight is 5 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 1% hyaluronic acid solution, add final concentration respectively and be 1.9% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 1.2% N-hydroxy-succinamide (NHS), pH 5 is transferred in the dissolving back, stirs 40min; Add 125mg half light amine hydrochlorate, conditioned reaction liquid pH 3, lucifuge reaction 5h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 21
With the 300mg molecular weight is 1.98 * 10
4The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.6% hyaluronic acid solution, add final concentration respectively and be 0.19% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.12% N-hydroxy-succinamide (NHS), pH 5.5 is transferred in the dissolving back, stirs 60min; Add 150mg half light amine hydrochlorate, conditioned reaction liquid pH 4.75, lucifuge reaction 6h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCI solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 22
With the 400mg molecular weight is 1 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.8% hyaluronic acid solution, add final concentration respectively and be 0.48% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.29% N-hydroxy-succinamide (NHS), pH6 is transferred in the dissolving back, stirs 90min; Add 400mg half light amine hydrochlorate, conditioned reaction liquid pH 5, lucifuge reaction 8h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 23
With the 500mg molecular weight is 5 * 10
5The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 1% hyaluronic acid solution, add final concentration respectively and be 0.96% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.58% N-hydroxy-succinamide (NHS), pH 5 is transferred in the dissolving back, stirs 120min; Add 1000mg half light amine hydrochlorate, conditioned reaction liquid pH 3, lucifuge reaction 10h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 24
With the 200mg molecular weight is 1 * 10
6The hyaluronate sodium of Da is dissolved in the 50ml deionized water, get 0.4% hyaluronic acid solution, add final concentration respectively and be 1.4% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDAC) and 0.86% N-hydroxy-succinamide (NHS), pH 5.5 is transferred in the dissolving back, stirs 45min; Add 800mg half light amine hydrochlorate, conditioned reaction liquid pH 4, lucifuge reaction 12h.After reaction finishes, reaction mixture is put the dialysis tubing of the molecular weight 3500Da that dams, with HCl solution (pH 4), the HCl solution (pH 4) that contains 1%NaCl, HCl solution (pH 4) dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified successively.
Embodiment 25
The sulfhydrylation hyaluronic acid couplet that the cysteamine of embodiment 1 gained is modified is dissolved in respectively in the 0.2M phosphate buffered saline buffer (pH5.8,6.8,7.4), final concentration is 0.5%, measure the viscosity of solution under 37 ℃ in 0～6h respectively with Rotary Viscosimeter, the result is as shown in table 1.The result shows that pH value of solution is higher than at 6 o'clock, and the ratio of viscosities start time point viscosity of 6h interpolymer solution improves more than 100 times.
Table 1 polymer solution concentration (final concentration is 0.5%)
Claims (13)
1. the sulfhydrylation hyaluronic acid couplet that cysteamine is modified is characterized in that with the hyaluronic acid being skeleton, and the amino of cysteamine becomes amido linkage with hyaluronic carboxyl covalent attachment.
2. conjugates according to claim 1 is characterized in that every relatively gram polymkeric substance conjugates, and covalently bound free thiohydroxy group is 10～200 μ mol/g, and disulfide linkage is 120～500 μ mol/g.
3. conjugates according to claim 1 is characterized in that described hyaluronic molecular weight is 1.98 * 10
4～1 * 10
6G/mol.
4. conjugates according to claim 1 is characterized in that its aqueous solution ratio of viscosities unmodified hyaluronic acid of 0.5%～3% is high 5～100 times.
5. the preparation method of the sulfhydrylation hyaluronic acid couplet that cysteamine as claimed in claim 1 is modified is characterized in that preparing as follows:
Adding final concentration in (1) 0.4%～1% aqueous solution of sodium hyaluronate is 0.19%～1.9% 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride and 0.12%～1.2% N-hydroxy-succinamide, pH to 5～6 are transferred in the dissolving back, stir 30～120min; Wherein hyaluronic molecular weight is 1.98 * 10 in the hyaluronate sodium
4～1 * 10
6G/mol;
(2) feed intake by hyaluronic acid and Mercaptamine mass ratio 32:1～1:4, conditioned reaction liquid pH 3～5, lucifuge reaction 4～12h, after reaction finishes, dialysis, lyophilize gets the sulfhydrylation hyaluronic acid couplet that cysteamine is modified.
6. the preparation method of sulfhydrylation hyaluronic acid couplet according to claim 5 is characterized in that the reaction times is 40～60min in the step (1).
7. the preparation method of sulfhydrylation hyaluronic acid couplet according to claim 5 is characterized in that middle hyaluronic acid of step (2) and Mercaptamine mass ratio are 8:1～1:2.
8. the preparation method of sulfhydrylation hyaluronic acid couplet according to claim 5 is characterized in that the reaction times is 5～8h in the step (2).
9. the application of sulfhydrylation hyaluronic acid couplet in drug delivery system of modifying as each cysteamine in the claim 1～4.
10. the application of sulfhydrylation hyaluronic acid couplet in cell cultures of modifying as each cysteamine in the claim 1～4.
11. the application of sulfhydrylation hyaluronic acid couplet in organizational project as each cysteamine modification in the claim 1～4.
12. comprise the support of the sulfhydrylation hyaluronic acid couplet of each cysteamine modification in the claim 1～4 as biomass cells or tissue.
13. the sulfhydrylation hyaluronic acid couplet that each cysteamine is modified in the claim 1～4 or the support of claim 12 are in the application of preparation implant.
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