CN103724455A - Hyaluronic acid derivative and preparation method for hyaluronic acid hydrogel - Google Patents
Hyaluronic acid derivative and preparation method for hyaluronic acid hydrogel Download PDFInfo
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Abstract
The invention discloses a hyaluronic acid derivative and a preparation method thereof. The preparation method comprises the following steps: carrying out hybrid reaction on hyaluronic acid/salt and anhydride in an anhydrous solvent, and precipitating, separating and purifying the product, so that the hyaluronic acid derivative with cross-linkable performance is obtained. The preparation method is simple in process, the reaction degree can be controlled through controlling the reaction parameter, and the product obtained through the method is stable in property, and can be kept for a long time; in addition, the obtained hyaluronic acid derivative with the cross-linkable performance can be used for preparing hyaluronic acid hydrogel under a mild condition, has an excellent biocompatibility, and can be applied to the carrier material of a bio-active substance, a tissue engineering scaffold material and a soft tissue filling material.
Description
Technical field
The present invention relates to the preparation method of a kind of derivatives of hyaluronic acids and hydrogel thereof, belong to the preparation field of biomedical material.
Technical background
Hyaluronic acid, due to unique composition and constructional feature, makes it have splendid water retention property, owing to having good biocompatibility, biodegradable concurrently, in field of tissue engineering technology, receives much concern simultaneously, also embodies higher using value simultaneously.In hyaluronic research and application, thereby conventionally all needing that it is carried out to chemical modification realizes in hyaluronan molecule or intermolecular cross-linking, or with other raw material with covalently cross-linked formation matrix material, to obtain, there is more preferably mechanical property, the biomedical material of biological degradability, shaping and the performance such as functional.
In existing report, to the chemical modification method of introducing unsaturated link(age) in hyaluronan molecule, there are two classes: a kind of is in aqueous phase system, under cold condition, to dripping the continuous regulation system pH value of methacrylic acid anhydride solution in hyaluronic acid solution, be weakly alkaline, thus the derivatives of hyaluronic acids of methacrylic acid that obtained grafting; Another kind is in anhydrous solvent, hyaluronic acid is reacted with unsaturated acyl chlorides (acrylate chloride or methacrylic chloride), thereby the derivatives of hyaluronic acids of acrylic or methacrylic acid that obtained grafting, for example: Chinese invention patent, publication number: CN 103113495A.
It is raw material that hyaluronic acid or its salt and unsaturated acid anhydride are take in the present invention, in anhydrous solvent, reacts, and preparation has the derivatives of hyaluronic acids of crosslinkable, overcomes the deficiency of existing method and technology; Can further adopt uv-radiation or peroxide initiator initiated polymerization, prepare single hyaluronic acid gel or form polynary compound water congealing glue material with other materials containing active sulfydryl.Up to the present, there is no relevant documents and materials report.
Summary of the invention
Contriver is by finding to have the following disadvantages in prior art to the comprehensive analysis of prior art:
1. while adopting aqueous phase system reaction, preparation process is loaded down with trivial details, needs constantly to regulate the pH value in reaction solution, easily causes the fluctuation of reaction conditions and affects level of response; Meanwhile, the large and higher derivatives of hyaluronic acids of modification degree for molecular weight, particularly, after preserving after a while, its water-soluble obvious reduction, even can not be water-soluble;
2. adopt in anhydrous solvent, the method that hyaluronic acid reacts with unsaturated acyl chlorides, the reactive behavior of unsaturated acyl chlorides is high, and level of response is wayward; Meanwhile, because reaction product is identical with the product structure of aqueous phase system, equally also there is the shortcoming that is difficult for long-term preservation, water-soluble reduction.
The object of the invention is to for the deficiencies in the prior art, a kind of preparation method who obtains derivatives of hyaluronic acids and the hydrogel thereof of crosslinkable is provided, simple and the level of response of preparation process can realize by controlling reaction parameter, and the product property of acquisition is stable, can preserve for a long time.
The present invention is achieved through the following technical solutions:
A preparation method for derivatives of hyaluronic acids, by hyaluronic acid or its salt and acid anhydrides hybrid reaction in anhydrous solvent, product obtains the derivatives of hyaluronic acids with crosslinkable after precipitation, separation, purifying.
As optional mode, anhydrous solvent described in aforesaid method is at least one in methane amide, DMF, tetrahydrofuran (THF).Hyaluronic acid or its salt being fully dissolved with in this anhydrous solvent is beneficial to the success of modified-reaction and carries out.
As optional mode, the acid anhydrides described in aforesaid method can be a kind of in MALEIC ANHYDRIDE (claiming again maleic anhydride), citraconic anhydride, cis-3-carboxyl glutaconic anhydride (cis-aconitic anhydride), 4-amylene acid anhydride, crotonic anhydride, methacrylic anhydride.Preferentially select ring-type or carboxylic unsaturated acid anhydride, can in hyaluronic acid or its salinity subchain, introduce the unsaturated terminal chain group with carboxyl with ester bond form, not affecting the solvability of derivatives of hyaluronic acids, is one of principal character being different from other derivatives of hyaluronic acids.Particularly, while selecting MALEIC ANHYDRIDE, citraconic anhydride, cis-3-carboxyl glutaconic anhydride, can be with in the following category-A group of ester bond form grafting a kind of; While selecting 4-amylene acid anhydride, crotonic anhydride, methacrylic anhydride, can be with in the following category-B group of ester bond form grafting a kind of.
Category-A:
,
,
,
,
Category-B:
,
,
Wherein, the derivatives of hyaluronic acids to introducing category-A group in hyaluronan molecule and obtaining, not only makes it have crosslinkable, and its water-soluble can be not influenced, even can more be conducive to dissolve.
As optional mode, aforesaid method specifically comprises following process:
1) hyaluronic acid or its salt are joined in anhydrous solvent, be stirred to abundant dissolving;
2) acid anhydrides is dissolved in identical anhydrous solvent, under agitation condition, joins in step 1) gained solution;
3) to step 2) add mole number to account for the catalyzer that can react hydroxyl mole number 0-20% on hyaluronic acid in the reaction solution of gained;
4) at 30-100 ℃, react after 3-30 h, question response liquid cooling is but added drop-wise in the cryoprecipitate agent in stirring afterwards, fully stirs reaction product is separated out;
5) separation;
6) purifying, obtains the derivatives of hyaluronic acids with crosslinkable.
As optional mode, aforesaid method step 1) is carried out at 30-100 ℃, and the concentration of hyaluronic acid or its salt is 1-20mg/ml.
As optional mode, aforesaid method step 2) mole number of acid anhydrides described in be on hyaluronic acid, can react hydroxyl mole number 0.5-50 doubly.The mol ratio of raw material is one of principal element affecting unsaturated terminal chain percentage of grafting on derivatives of hyaluronic acids product molecule.
As optional mode, the catalyzer described in aforesaid method step 3) is a kind of in pyridine, PA, 4-(dimethylamino) pyridine (DMAP).
As optional mode, separating step is specially described in aforesaid method step 5): by the solid-liquid mixed solution high speed centrifugation of gained in step 4), will be deposited in precipitation agent disperse, centrifugal, and repeat this step 2-4 time.Centrifugal by repeatedly disperseing, remove Residual reactants and partial impurities.
As optional mode, described in aforesaid method step 6), purification step is specially: the precipitation of above-mentioned acquisition is fully dissolved in after deionized water, regulator solution pH is to neutral, again this solution is transferred to dialysis band, with the deionized water postlyophilization of fully dialysing, obtain the derivatives of hyaluronic acids with crosslinkable.By dialysis, remove the soluble small molecular impurity in product.
As optional mode, described hyaluronic acid or its salt can be natural hyaluronic acid or its salt extracting in animal tissues, can be also hyaluronic acid or its salt that adopts microbial fermentation technology to produce.Described hyaluronic acid or its salt can be that hyaluronate sodium, potassium hyaluronate, hyaluronic acid ammonium, hyaluronic acid magnesium, Calcium hyaluronate or other have a kind of in the hyaluronic acid inorganic salt of good biocompatibility, the acid of preferably transparent matter or hyaluronate sodium.
As optional mode, described hyaluronic acid or the molecular weight of its salt are at 30 kDa-3 000 kDa, and preferred molecular weight is at 1 000 kDa-2 000 kDa.
As optional mode, described precipitation agent can be a kind of in ethanol, methyl alcohol, Virahol, acetone.
As optional mode, described dialysis time is generally 1-5 d, during every 4-8h change a dialyzate
The present invention also provides a kind of derivatives of hyaluronic acids, and described derivatives of hyaluronic acids adopts aforesaid method to be prepared from.
The present invention also provides a kind of preparation method of hydrogel, the method is that derivatives of hyaluronic acids of the present invention is dissolved in to physiological water medium, through peroxide initiator initiation or when light trigger exists, through uv-radiation, cause self-polymerization reaction or contain the copolyreaction of the material of active mercapto groups with other, obtain the hyaluronic acid gel of single component or contain the polynary composite aquogel of hyaluronic acid of the material covalent cross-linking of active mercapto groups with other.
As optional mode, in the preparation method of above-mentioned hydrogel, the derivatives of hyaluronic acids strength of solution that described derivatives of hyaluronic acids is dissolved in physiological water medium gained is 10-100 mg/mL.
As optional mode, in the preparation method of above-mentioned hydrogel, described physiological water medium can be a kind of in deionized water, physiological saline, phosphate buffered saline (PBS) or other isotonic solution.
As optional mode, in the preparation method of above-mentioned hydrogel, described light trigger can be 2-hydroxyl-4 '-(hydroxy ethoxy)-2-methyl phenyl ketone (I2959), 1-hydroxy-cyclohexyl phenyl-acetone (I184), 2, a kind of in 2-dimethoxy-phenyl methyl phenyl ketone (I651).
As optional mode, in the preparation method of above-mentioned hydrogel, described photoinitiator concentration is 0.08-1.5wt%.
As optional mode, in the preparation method of above-mentioned hydrogel, described uv-radiation is that employing wavelength is 320-480nm, and light intensity is 10-50mW/cm
2ultraviolet radiation 15-900s.
As optional mode, in the preparation method of above-mentioned hydrogel, described peroxide initiator can be a kind of in ammonium persulphate, hydrogen peroxide, Potassium Persulphate, Sodium Persulfate.
As optional mode, in the preparation method of above-mentioned hydrogel, described peroxide initiator concentration is 0.1-2.0wt%.
As optional mode, in the preparation method of above-mentioned hydrogel, the described material containing active mercapto groups be cysteamine or its salt, halfcystine or its ester, dithiothreitol dithio etc. contain active sulfydryl small molecule material at least one or at least one in the natural macromolecular materials such as chondroitin sulfate, dermatan sulfate, chitosan, chitin, heparin, Lalgine or its salt of the above-mentioned small molecule material modification containing active sulfydryl.
As optional mode, in the preparation method of above-mentioned hydrogel, in the polynary composite aquogel of described hyaluronic acid, derivatives of hyaluronic acids and described weight ratio containing active mercapto groups material are 100:1-1:100.
The present invention also provides a kind of hydrogel, and described hydrogel adopts above-mentioned method to be prepared from.Described hydrogel is plastic rapidly under proper condition, be applicable to in-situ injection moulding, and plastic mechanical property is better, has better potential source biomolecule simultaneously concurrently and learns the advantages such as performance.
The present invention also provides the application of a kind of above-mentioned derivatives of hyaluronic acids and hydrogel thereof: use it for the starting raw material of soft tissue filling material or for biologically active substances such as packaging medicine, somatomedin, biological enzymes, as transmitting or the carrier of slowly-releasing or as the timbering material of organizational project, after the various one-tenth somatocyte of embedding, stem cell, can be used for reparation and the reconstruction of tissue.
Disclosed all features in this specification sheets, or the step in disclosed all methods or process, except mutually exclusive feature and/or step, all can combine by any way.
Beneficial effect of the present invention:
1, the derivatives of hyaluronic acids preparation method with crosslinkable of the present invention is simple to operate, and modified-reaction degree is controlled, and the derivatives of hyaluronic acids that adopts optimum condition to prepare has overcome the defect that existing method is prepared like product.It is good water-soluble that the product of preparing by the method can keep for a long time, and stable performance, is easy to long-term preservation.
2, the derivatives of hyaluronic acids with crosslinkable of the present invention can be prepared hyaluronic acid gel under mild conditions, has good biocompatibility, can be used for bioactive substance carrier material, tissue engineering bracket material and soft tissue filling material.
Accompanying drawing explanation
Fig. 1 be in the embodiment of the present invention 1 preparation hyaluronic acid-butene dioic acid ester nucleus magnetic resonance (
1h NMR) collection of illustrative plates;
Fig. 2 is dynamic mechanical analysis (DMA) result of hyaluronic acid-butene dioic acid ester hydrogel of preparation in example 3 of the present invention;
Fig. 3 be the nucleus magnetic resonance that adopts hyaluronic acid-methacrylic ester prepared by traditional aqueous phase system in embodiment 7 (
1h NMR) collection of illustrative plates;
Fig. 4 is the preparation method's of derivatives of hyaluronic acids of the present invention process flow sheet, and in figure, dotted portion is optional step;
specific implementation method:
Preparation technology's flow process of the present invention is (as shown in Figure 4): the dissolving of hyaluronic acid or its salt, the interpolation of acid anhydrides solution and catalyzer, stirring reaction postprecipitation under heating condition, through centrifugal, dissolve, adjust pH fully dialysis after cleaning, lyophilize obtains derivatives of hyaluronic acids.
Wherein, hyaluronic acid or its salt will be dissolved in anhydrous solvent, and add acid anhydrides solution and catalyzer under agitation condition; Under certain temperature condition, react after the regular hour, question response liquid cooling but and be added drop-wise in cryoprecipitate agent it is fully separated out, and repeatedly clean, centrifugal; The precipitation of acquisition is dissolved in to deionized water and regulates pH to neutrality, deionized water is fully dialysed, then lyophilize obtains the derivatives of hyaluronic acids with crosslinkable.
Following classified as several most preferred embodiments of the present invention, it should be understood that these embodiment, only for the object of illustration, never limit the scope of the invention.
embodiment 1
Prepare according to the following steps hyaluronic acid-butene dioic acid ester derivative:
(1) take 0.2 g hyaluronic acid (approximately 0.527 mmol, the molecular weight of its structural unit is 379.32 g/mol, as follows) and join in the anhydrous methane amide of 100 mL, at 50 ℃, be stirred to abundant dissolving;
(2) take 0.517 g maleic anhydride (approximately 5.27 mmol, molecular weight is 98.06 g/mol) and be dissolved in anhydrous methane amide, join above-mentioned (1) solution under agitation condition, the mole number of maleic anhydride is on hyaluronic acid, to react 10 times of hydroxyl mole number;
(3) do not add catalyzer;
(4) at 50 ℃, react 5 h, question response liquid is cooled to after room temperature, is added drop-wise in the cold dehydrated alcohol of 500 mL in stirring, and reaction product is separated out;
(5) by above-mentioned solid-liquid mixed solution high speed centrifugation, will be deposited in dehydrated alcohol disperse, centrifugal, and this step 2-4 time repeatedly;
(6) precipitation of above-mentioned acquisition is fully dissolved in to deionized water, regulator solution pH is to neutral, then this solution is transferred to dialysis band, to the deionized water postlyophilization of fully dialysing, obtains hyaluronic acid-butene dioic acid ester derivative with crosslinkable.
Adopt
1h NMR detects hyaluronic acid-butene dioic acid ester derivative of gained, and result as shown in Figure 1.Contrast unmodified hyaluronic acid nuclear magnetic spectrum and can find that the chemical shift of the unsaturated link(age) both sides hydrogen in butene dioic acid ester is 6.0ppm and 6.7ppm, by the area integral ratio calculation with hyaluronan molecule methyl hydrogen, can show that the percentage of grafting of this hyaluronic acid-butene dioic acid ester derivative is about 27%.
embodiment 2
Prepare according to the following steps hyaluronic acid-4-pentenoate derivative:
(1) take 0.4 g hyaluronic acid (about 1.06mmol) and join in 100 mL anhydrous tetrahydro furans, at 60 ℃, be stirred to abundant dissolving;
(2) take 0.961 g 4-amylene acid anhydride (approximately 5.27 mmol, molecular weight is 182.22g/mol) be dissolved in anhydrous tetrahydro furan, under agitation condition, join above-mentioned (1) solution, the mole number of 4-amylene acid anhydride is on hyaluronic acid, to react 5 times of hydroxyl mole number;
(3) in above-mentioned reaction solution, add 0.1g DMAP catalyzer;
(4) at 60 ℃, react 10 h, question response liquid is cooled to after room temperature, is added drop-wise in the cold anhydrous isopropyl alcohol of 800 mL in stirring, and reaction product is separated out;
(5) by above-mentioned solid-liquid mixed solution high speed centrifugation, will be deposited in anhydrous isopropyl alcohol disperse, centrifugal, and this step 2-4 time repeatedly;
(6) precipitation of above-mentioned acquisition is fully dissolved in to deionized water, regulator solution pH is to neutral, then this solution is transferred to dialysis band, to the deionized water postlyophilization of fully dialysing, obtains hyaluronic acid-4-pentenoate derivative with crosslinkable.
embodiment 3
Hyaluronic acid-butene dioic acid ester hydrogel of preparing according to the following steps single component:
After taking 20 mg lyophilizes, seal hyaluronic acid-butene dioic acid ester derivative of preserving, be dissolved in the aqueous solution that 1.0 mL contain 0.1%2-hydroxyl-4 '-(hydroxy ethoxy)-2-methyl phenyl ketone (I2959) initiator; Get appropriate volume by this solution after particular mold, at wavelength, be that 365nm, light intensity are 30mW/cm
2uv-radiation 120s initiated polymerization, form hyaluronic acid gel.
Adopt single component hyaluronic acid-butene dioic acid ester hydrogel of DMA gained to detect, dynamic force frequency is 1.0Hz and 10Hz, and detected result as shown in Figure 2.As can be seen from the figure, the storage modulus average of this hydrogel is more than 0.2MPa.
embodiment 4
Hyaluronic acid-4-pentenoate hydrogel of preparing according to the following steps single component:
After taking 40 mg lyophilizes, seal hyaluronic acid-4-pentenoate derivative of preserving, be dissolved in 1.0 mL deionized waters; Now join 10% ammonium persulfate solution, get before use 10mL and join above-mentioned derivatives of hyaluronic acids solution, after fully mixing, get that appropriate volume is standing in particular mold treats that polyreaction completes, form hyaluronic acid gel.
Prepare according to the following steps the compound hyaluronic acid-chondroitin sulfate hydrogel of binary:
After taking 20 mg lyophilizes, seal hyaluronic acid-butene dioic acid ester derivative of preserving, be dissolved in the aqueous solution that 1.0 mL contain 0.2% 2-hydroxyl-4 '-(hydroxy ethoxy)-2-methyl phenyl ketone (I2959) initiator; Take 20 mg containing the chondroitin sulfate derivative (as adopted EDC/NHS reaction system, the chondroitin sulfate derivative obtaining after chondroitin sulfate is reacted with Mercaptamine) of active sulfydryl, be dissolved in 1.0mL deionized water; Getting appropriate above-mentioned two kinds of solution and after mixing, will be placed in particular mold by different volumes, is that 365nm, light intensity are 30mW/cm at wavelength
2uv-radiation 60s initiated polymerization, form hyaluronic acid-chondroitin sulfate binary composite aquogel.
embodiment 6solvability contrast experiment
Adopt derivatives of hyaluronic acids preparation method of the present invention to prepare respectively hyaluronic acid-methacrylate derivative (being designated as sample 2) that hyaluronic acid-butene dioic acid ester derivative (being designated as sample 1) that percentage of grafting is 50% left and right and percentage of grafting are 50% left and right, the percentage of grafting that adopts traditional water solution system to prepare is the hyaluronic acid-methacrylate derivative (being designated as sample 3) of 50% left and right, the method that adopts hyaluronic acid to react with unsaturated acyl chlorides is prepared hyaluronic acid-methacrylate derivative that percentage of grafting is 50% left and right (being designated as sample 4), get above-mentioned four kinds of samples and carry out solvability contrast:
Cryodesiccated hyaluronic acid-butene dioic acid ester derivative under agitation condition, the transparent uniform solution of formation 20 mg/ml soluble in water; Long-term preservation does not affect its solvability;
Hyaluronic acid-methacrylate derivative (sample 2-4) that short-term after lyophilize (2-3d) is preserved, under agitation condition, the solid calculating according to 20 mg/ml concentration is difficult to the transparent uniform solution of complete water-soluble formation; Preserve one week or longer time after, its solvability further reduces.Wherein the solvability of sample 2 and shelf time are all slightly better than sample 3 and sample 4.
Higher and the higher derivatives of hyaluronic acids of percentage of grafting for molecular weight, the phenomenon that product water dissolubility prepared by employing traditional method declines is more obvious.
embodiment 7percentage of grafting contrast experiment
The percentage of grafting that adopts method of the present invention to prepare derivatives of hyaluronic acids is affected with several factors of process by following raw material mainly: the water content of anhydrous solvent, acid anhydrides and hyaluronic acid can react molar ratio, temperature of reaction and the reaction times etc. of hydroxyl.Adopt and add siccative or use the method for molecular sieve can obtain dry anhydrous solvent; Hyaluronic acid raw material for different molecular weight, its initial action concentration can be controlled within the scope of 0.2-2 mg/mL, acid anhydrides and hyaluronic mol ratio can be controlled in 1.0-15 doubly, react 4-6h and can obtain the derivatives of hyaluronic acids that percentage of grafting is 5-70% under 40-70 ℃ of condition.
The percentage of grafting that adopts traditional aqueous phase system to prepare derivatives of hyaluronic acids is affected by following factor mainly: in the raw material ratio of reaction, temperature of reaction, reaction times and reaction process, need pH value of regulator solution system always etc.Because acid anhydrides is easy to hydrolysis, more than need to using greatly excessive acid anhydrides raw material while therefore adopting aqueous phase system to react and controlling lower temperature of reaction continuously stirring reaction 12h, need constantly to regulate pH value to promote to react, to carry out between 8-9 simultaneously; This preparation method consumes excess raw material, reaction process is wayward, thereby the percentage of grafting of derivatives of hyaluronic acids is easily fluctuateed.Employing mol ratio is methacrylic anhydride and hyaluronic acid successive reaction 24h in 4 ℃ of aqueous phase systems of 15 times, and the percentage of grafting of the derivatives of hyaluronic acids obtaining in the situation of comparatively ideal control reaction pH is 20% left and right.Employing mol ratio is methacrylic anhydride and hyaluronic acid successive reaction 6h in 4 ℃ of aqueous phase systems of 10 times, and the product of acquisition carries out
1h NMR analyzes, and as shown in Figure 3, its percentage of grafting is about 5.04% to result.
By contrast experiment, find, in the situation that the factors such as the raw material ratio of reaction, temperature of reaction, reaction times are identical, the method for the invention is compared with traditional water method, and percentage of grafting is obviously higher, and reaction is more easily controlled.
In embodiment 1 and embodiment 2, adopt hyaluronate (as hyaluronate sodium, potassium hyaluronate, hyaluronic acid ammonium, hyaluronic acid magnesium, Calcium hyaluronate or other have the hyaluronic acid inorganic salt of good biocompatibility) to replace hyaluronic acid equally successfully to prepare derivatives of hyaluronic acids, adopt commercially available hyaluronic acid or its salt or adopt natural hyaluronic acid or its salt extracting in animal tissues, also or the hyaluronic acid or its salt that adopt microbial fermentation technology to produce all can successfully prepare derivatives of hyaluronic acids of the present invention.Hyaluronic acid or its salt of molecular weight within the scope of 30 kDa-3 000 kDa all can successfully react.
In embodiment 1 and embodiment 2, adopt DMF also successfully to prepare derivatives of hyaluronic acids of the present invention as anhydrous solvent.
In embodiment 1 and embodiment 2, adopt respectively citraconic anhydride, cis-3-carboxyl glutaconic anhydride (cis-aconitic anhydride), 4-amylene acid anhydride, crotonic anhydride as acid anhydrides raw material, successfully prepared corresponding derivatives of hyaluronic acids.Products therefrom passes through
1h NMR analysis confirmation is errorless.
In temperature described in the step (1) of embodiment 2, be 30 ℃ or 100 ℃, gained hyaluronic acid concentration is 1mg/ml or 20mg/ml; The mole number of acid anhydrides is on hyaluronic acid, to react 0.5 or 50 times of hydroxyl mole number in step (2); In step (3), adopt pyridine or PA as catalyzer, catalyzer mole number account on hyaluronic acid, can react hydroxyl mole number ratio 10% or 20%, in step (4) and (5), adopt methyl alcohol or acetone as precipitation agent, in step (4), temperature of reaction is 30 ℃ or 100 ℃, and the reaction times is 3h or 30h; All successfully prepared derivatives of hyaluronic acids of the present invention.
embodiment 9
In embodiment 3 and embodiment 5, adopt various derivatives of hyaluronic acids of the present invention all successfully to prepare hyaluronic acid gel or the polynary composite aquogel of hyaluronic acid of corresponding single component.
The described aqueous solution is changed into physiological saline or phosphate buffered saline (PBS) in embodiment 5; Change described light trigger into 1-hydroxy-cyclohexyl phenyl-acetone (I184) or 2,2-dimethoxy-phenyl methyl phenyl ketone (I651); Making described derivatives of hyaluronic acids strength of solution is 10 mg/mL or 100 mg/mL, and the mass percentage concentration of described light trigger in reaction system is 0.08-1.5wt%; The wavelength adopting during described uv-radiation is 320nm or 480nm, and light intensity is 10 mW/cm
2or 50mW/cm
2uV-light, radiated time is 15 seconds or 900 seconds; Change chondroitin sulfate derivative into cysteamine or its salt, halfcystine or its ester, dithiothreitol dithio or by least one in dermatan sulfate, chitosan, chitin, heparin, Lalgine or its salt of the small molecule material modification containing active sulfydryl, successfully prepare a series of hyaluronic acids with containing the even more polynary composite aquogel of material covalent cross-linking binary, the ternary of active mercapto groups, gained composite aquogel
1h NMR analysis confirmation.
Get a kind of derivatives of hyaluronic acids of preparing in embodiment of the present invention and be dissolved in deionized water, physiological saline, phosphate buffered saline (PBS) or other isotonic solution, be made into 10 mg/mL or 100 mg/mL solution; Add hydrogen peroxide, ammonium persulphate, Potassium Persulphate or Sodium Persulfate as peroxide initiator, making the mass percentage concentration of described peroxide initiator in reaction system is 0.1%-2.0%, after fully mixing, get that appropriate volume is standing in particular mold treats that polyreaction completes, form the hyaluronic acid gel of single component.
In above-mentioned steps, before adding peroxide initiator, add cysteamine or its salt, halfcystine or its ester, dithiothreitol dithio or by least one in the natural macromolecular materials such as chondroitin sulfate, dermatan sulfate, chitosan, chitin, heparin, Lalgine or its salt of the small molecule material modification containing active sulfydryl, successfully prepare a series of hyaluronic acids with containing the even more polynary composite aquogel of material covalent cross-linking binary, the ternary of active mercapto groups, gained composite aquogel
1h NMR analysis confirmation.
The foregoing is only the preferred embodiments of the present invention, is only illustrative for the purpose of the present invention, and nonrestrictive; Those of ordinary skills understand, and in the spirit and scope that limit, can carry out many changes to it in the present invention, revise, and even equivalence change, but all will fall into protection scope of the present invention.
Claims (10)
1. a preparation method for derivatives of hyaluronic acids, is characterized in that, by hyaluronic acid or its salt and acid anhydrides hybrid reaction in anhydrous solvent, product obtains the derivatives of hyaluronic acids with crosslinkable after precipitation, separation, purifying.
2. the preparation method of derivatives of hyaluronic acids according to claim 1, is characterized in that, described anhydrous solvent is at least one in methane amide, DMF, tetrahydrofuran (THF).
3. the preparation method of derivatives of hyaluronic acids according to claim 1, it is characterized in that, described acid anhydrides can be a kind of in MALEIC ANHYDRIDE (claiming again maleic anhydride), citraconic anhydride, cis-3-carboxyl glutaconic anhydride (cis-aconitic anhydride), 4-amylene acid anhydride, crotonic anhydride, methacrylic anhydride.
4. the preparation method of derivatives of hyaluronic acids according to claim 1, is characterized in that, specifically comprises following process:
1) hyaluronic acid or its salt are joined in anhydrous solvent, and be stirred to abundant dissolving at 30-100 ℃;
2) acid anhydrides is dissolved in identical anhydrous solvent, under agitation condition, joins in step 1) gained solution, the mole number of acid anhydrides be on hyaluronic acid, can react hydroxyl mole number 0.5-50 doubly;
3) to step 2) add mole number to account for the catalyzer that can react hydroxyl mole number 0-20% on hyaluronic acid in the reaction solution of gained, described catalyzer is a kind of in pyridine, PA, 4-(dimethylamino) pyridine (DMAP);
4) at 30-100 ℃, react after 3-30 h, question response liquid cooling is but added drop-wise in the cryoprecipitate agent in stirring afterwards, fully stirs reaction product is separated out, and described precipitation agent is a kind of in ethanol, methyl alcohol, Virahol, acetone;
5), by the solid-liquid mixed solution high speed centrifugation of gained in step 4), will be deposited in dispersion, centrifugal in precipitation agent, and repeat this step 2-4 time;
6) precipitation of above-mentioned acquisition is fully dissolved in after deionized water, regulator solution pH is to neutral, then this solution is transferred to dialysis band, with the deionized water postlyophilization of fully dialysing, obtains the derivatives of hyaluronic acids with crosslinkable.
5. a derivatives of hyaluronic acids, is characterized in that, described derivatives of hyaluronic acids adopts in claim 1-4 method described in any one to be prepared from.
6. the preparation method of a hydrogel, it is characterized in that, derivatives of hyaluronic acids claimed in claim 5 is dissolved in to physiological water medium, through peroxide initiator initiation or when light trigger exists, through uv-radiation, cause self-polymerization reaction or contain the copolyreaction of the material of active mercapto groups with other, obtain the hyaluronic acid gel of single component or contain the polynary composite aquogel of hyaluronic acid of the material covalent cross-linking of active mercapto groups with other.
7. the preparation method of hydrogel according to claim 6, is characterized in that, the derivatives of hyaluronic acids strength of solution that described derivatives of hyaluronic acids is dissolved in physiological water medium gained is 10-100 mg/mL.
8. the preparation method of hydrogel according to claim 6, it is characterized in that, the described material containing active mercapto groups be cysteamine or its salt, halfcystine or its ester, dithiothreitol dithio etc. contain active sulfydryl small molecule material at least one or at least one in the natural macromolecular materials such as chondroitin sulfate, dermatan sulfate, chitosan, chitin, heparin, Lalgine or its salt of the above-mentioned small molecule material modification containing active sulfydryl.
9. a hydrogel, is characterized in that, described hydrogel adopts method claimed in claim 6 to be prepared from.
10. the application of a hydrogel according to claim 9, it is characterized in that, use it for the starting raw material of soft tissue filling material or for biologically active substances such as packaging medicine, somatomedin, biological enzymes, as transmitting or the carrier of slowly-releasing or as the timbering material of organizational project, after the various one-tenth somatocyte of embedding, stem cell, can be used for reparation and the reconstruction of tissue.
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