CN103333349A - Hyaluronic acid-collagen composite hydrogel for injection and preparation method thereof - Google Patents
Hyaluronic acid-collagen composite hydrogel for injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to hyaluronic acid-collagen composite hydrogel for injection and a preparation method thereof. Current hyaluronic acid cross-linked hydrogel cannot remove toxicity residue through cleaning in a preparation process, thus having a potential safety hazard. The preparation method comprises the steps of mixing and dissolving sodium hyaluronate and collagen in an alkaline solution, uniformly stirring and adding a cross-linking agent to a reaction system, uniformly mixing and reacting to obtain gel in a block form, processing the gel to remove residual cross-linking agent, and grinding to obtain granular hydrogel. Due to introduction of the collagen, the prepared hydrogel is more ideal, and low in residue of the cross-linking agent and relatively low in damage to a living organism; the collagen can improve the mechanical strength of the hydrogel, and bring about positive influence to cell adhesion and cell growth promotion property of the product, so that the hydrogel, as a soft tissue filling material, shows a greater advantage.
Description
Technical field
The present invention relates to a kind of hydrogel, be specifically related to a kind of injection hyaluronic acid-collagen protein composite aquogel and preparation method thereof.
Background technology
Hyaluronic acid is a kind of acidic mucopolysaccharide, claims uronic acid, Hyaluronic Acid again, the natural polymers of being made up of two D-of disaccharide unit glucuronic acids and N-acetyl-glucosamine.Its moisture of molecule portability more than 500 times is the good composition of preserving moisture of a kind of effect, is called as desirable natural moisturizing factor.Hyaluronic acid, its esters and derivative have good Bioabsorbable, biocompatibility, visco-elasticity and water-retentivity, therefore are widely used in beauty treatment, medicine and other fields.Clinically, hyaluronic acid can be used for ophthalmologic operation, prevention of postoperative adhesion in the surgical operation, aspects such as the healing of promotion wound and beauty and shaping, some medicines are attached to the effect that the compound that forms on the hyaluronic acid can also be brought into play medicine control slowly-releasing, thereby reach the purpose that medicine timing and fixed point discharge, but because hyaluronic acid exists degradation speed fast, defectives such as physical strength is lower, and limited its range of application, therefore in actual applications, often make in the hyaluronan molecule by method such as cross-linking modified or the crosslinked preparation of intermolecular generation becomes hyaluronic acid gel, thereby prolong its action time in vivo.
About the existing patent report of the preparation of cross-linking hyaluronic acid hydrogel.Patent CN 101538377 A disclose a kind of preparation method of cross-linked hyaluronic acid gel.In this invention, adopt 1,4-butanediol diglycidyl ether as linking agent under alkaline condition with hyaluronic acid in hydroxyl react, remove unreacted linking agent and prepare product thereby clean with physiological balance liquid again.But in reaction process, the butanediol diglycidyl ether that has has only an epoxide group to participate in reaction, and these linking agents can't be removed by cleaning, therefore also can have the problem of residual toxicity.
Patent CN 101724164 B disclose a kind of method of making cross-linked-hyaluronic acid.In this method, make hyaluronic acid solution under 10-30 ℃, carry out crosslinking reaction and surpass 48h.The crosslinking reaction of carrying out under this low reaction temperatures, formed cross-linked-hyaluronic acid can be not termination reaction after making linking agent be consumed to rational content because of the quick deterioration of the hydrolytic action of alkali.Do not remove residual BDDE in the method, can have potential safety hazard.
Collagen protein is a kind of macromolecule protein, generally is white in color, opaque fibrous.It is one of main component of human body composition structure, also is the necessary material of delaying human body caducity, is distributed in widely in skin, bone, cartilage, muscle, joint and the hair tissue of human body, can play the function that supports organ, protection human body and reparation.Human-like Collagen is that the mRNA reverse transcription with human collagen albumen becomes cDNA, and the fragment gene after enzyme is cut is reconstituted in the E.coli(intestinal bacteria) in, a kind of high-molecular biologic albumen of producing through high density fermentation, separation, renaturation, purifying process.It has good bioresorbable, cell adhesion and biocompatibility, and can obviously promote the cell growth, therefore is fit to very much be applied to aspects such as medical science, shaping.
The epoxy compounds class is widely used in the preparation of hyaluronic acid derivatives as linking agent.It can with hyaluronan molecule in hydroxyl and carboxyl react and form ehter bond and ester bond, the present invention is mixed into collagen protein in reaction system after, epoxy compounds also can with collagen protein in hydroxyl and carboxyl reaction, and also can form the parahelium group with amino reaction wherein, therefore, make that the epoxy compounds reaction is more thorough, formed three-dimensional structure is finer and close, can effectively promote the mechanical property of product water gel.
Summary of the invention
The purpose of this invention is to provide that a kind of use is safer, the better injection hyaluronic acid of slow releasing function-collagen protein composite aquogel and preparation method thereof.
The technical solution adopted in the present invention is:
The preparation method of a kind of injection hyaluronic acid-collagen protein composite aquogel is characterized in that:
Realized by following steps:
Step 1: hyaluronate sodium is dissolved in the basic solution, stirs it is dissolved fully, make that hyaluronic mass concentration is 6%-20% in the mixing solutions;
Step 2: add collagen protein, making the mass concentration of collagen protein in the mixing solutions is 1-6%, stirs;
Step 3: add linking agent, the mass concentration that makes linking agent in the mixing solutions is 1-10%, temperature of reaction 30-60 ℃, and reaction times 1-14 hour;
Step 4: remove residual cross-linker;
Step 5: the product that obtains in physiological saline balance 3-6 hour;
Step 6: the centrifugal physiological saline of removing, products therefrom is pulverized the formation particle.
In the step 1, the molecular weight of hyaluronate sodium is 50-300 ten thousand.
In the step 1, basic solution is selected from sodium hydroxide, potassium hydroxide, sodium carbonate solution, and the molecular volume mark is 0.02-2 mol/L.
In the step 2, collagen protein is selected from total length collagen protein, collagen polypeptide, the gelatin that extracts from animal tissues; Or the recombined collagen, the Human-like Collagen that adopt gene engineering method to produce.
In the step 3, linking agent is selected from ethylene glycol diglycidylether, 1,4-butanediol diglycidyl ether, glycol ether diglycidylether, polyethyleneglycol diglycidylether, polypropylene glycol diglycidyl ether, 1,6-hexanediol diglycidyl ether, 1,2,7,8-diepoxy octane, divinylsulfone.
In the step 4, the method for removing residual cross-linker is selected from washing, organic solvent cleaning, High Temperature High Pressure distillation.
In the step 6, pulverization process is selected from extruding, grinding, cutting mode.
Injection hyaluronic acid-collagen protein composite aquogel that a kind of preparation method as described makes.
The present invention has the following advantages:
It is raw material that the present invention adopts hyaluronate sodium and collagen protein, and the Racemic glycidol ethers is that linking agent prepares hydrogel.There is the problem that degradation speed is too fast, physical strength is low in simple use hyaluronate sodium when preparing hydrogel, can not satisfy clinical application fully.Therefore we introduce collagen protein and prepare more desirable hydrogel.The linking agent residual quantity is low in the product that obtains, less to the organism infringement, and collagen protein can improve the physical strength of hydrogel, and to cell adhesion and the promoting growth of cell generation active influence of product, thereby make this hydrogel show bigger advantage as soft tissue filling material.
Description of drawings
Fig. 1 is that hydrogel is respectively at vitro culture 1, relative cell survival rate after 3,5 days.
Fig. 2 is the compression displacement of hydrogel and the relation curve between the compressive load.
Embodiment
The present invention will be described in detail below in conjunction with embodiment.
The purpose of this invention is to provide a kind of injection hyaluronic acid-collagen protein composite aquogel and preparation method, hyaluronate sodium mixed with certain proportion with collagen protein be dissolved in the basic solution, in reaction system, add glycidyl ether after stirring, mix under certain temperature and react, obtain block gel, through cleaning or distilling and remove residual cross-linker, homogenizing makes it become the particulate state hydrogel.
The preparation method of a kind of injection hyaluronic acid-collagen protein composite aquogel involved in the present invention is characterized in that:
Realized by following steps:
Step 1: hyaluronate sodium is dissolved in the basic solution, stirs it is dissolved fully, make that hyaluronic mass concentration is 6%-20% in the mixing solutions.
The molecular weight of hyaluronate sodium is 50-300 ten thousand; Basic solution is selected from sodium hydroxide, potassium hydroxide, sodium carbonate solution, and the molecular volume mark is 0.02-2 mol/L.
Step 2: add collagen protein, making the mass concentration of collagen protein in the mixing solutions is 1-6%, stirs.
Collagen protein is selected from total length collagen protein, collagen polypeptide, the gelatin that extracts from animal tissues; Or the recombined collagen, the Human-like Collagen that adopt gene engineering method to produce.
Step 3: add linking agent, the mass concentration that makes linking agent in the mixing solutions is 1-10%, temperature of reaction 30-60 ℃, and reaction times 1-14 hour.
Linking agent is selected from ethylene glycol diglycidylether, 1,4-butanediol diglycidyl ether, glycol ether diglycidylether, polyethyleneglycol diglycidylether, polypropylene glycol diglycidyl ether, 1,6-hexanediol diglycidyl ether, 1,2,7,8-diepoxy octane, divinylsulfone.
Step 4: remove residual cross-linker.
The method of removing residual cross-linker is selected from washing, organic solvent cleans (ethanol, acetone etc.), High Temperature High Pressure distillation, but also several different methods is used.
Step 5: the product that obtains in physiological saline balance 3-6 hour.
Step 6: the centrifugal physiological saline of removing, products therefrom is pulverized the formation particle.
Pulverization process is selected from extruding, grinding, cutting mode.
Embodiment 1:
Step 1: hyaluronate sodium is dissolved in the basic solution, stirs it is dissolved fully, make that hyaluronic mass concentration is 6% in the mixing solutions.
The molecular weight of hyaluronate sodium is 50-300 ten thousand; Basic solution is chosen sodium hydroxide solution, and the molecular volume mark is 0.02mol/L.
Step 2: add collagen protein, making the mass concentration of collagen protein in the mixing solutions is 1%, stirs.
Collagen protein is chosen the total length collagen protein that extracts from animal tissues.
Step 3: add linking agent, the mass concentration that makes linking agent in the mixing solutions is 1%, 30 ℃ of temperature of reaction, 1 hour reaction times.
Linking agent is selected from ethylene glycol diglycidylether, 1, the 4-butanediol diglycidyl ether.
Step 4: remove residual cross-linker.
Remove the method for residual cross-linker and choose washing.
Step 5: the product that obtains balance 3 hours in physiological saline.
Step 6: the centrifugal physiological saline of removing, products therefrom is pulverized the formation particle.
Pulverization process is chosen fashion of extrusion.
Embodiment 2:
Step 1: hyaluronate sodium is dissolved in the basic solution, stirs it is dissolved fully, make that hyaluronic mass concentration is 10% in the mixing solutions.
The molecular weight of hyaluronate sodium is 50-300 ten thousand; Basic solution is chosen potassium hydroxide solution, and the molecular volume mark is 0.5 mol/L.
Step 2: add collagen protein, making the mass concentration of collagen protein in the mixing solutions is 2%, stirs.
Collagen protein is chosen the collagen polypeptide that extracts from animal tissues.
Step 3: add linking agent, the mass concentration that makes linking agent in the mixing solutions is 4%, 40 ℃ of temperature of reaction, 5 hours reaction times.
Linking agent is selected from glycol ether diglycidylether, polyethyleneglycol diglycidylether.
Step 4: remove residual cross-linker.
Remove the method for residual cross-linker and choose organic solvent cleaning (ethanol, acetone etc.).
Step 5: the product that obtains balance 4 hours in physiological saline.
Step 6: the centrifugal physiological saline of removing, products therefrom is pulverized the formation particle.
Pulverization process is chosen grinding.
Embodiment 3:
Step 1: hyaluronate sodium is dissolved in the basic solution, stirs it is dissolved fully, make that hyaluronic mass concentration is 15% in the mixing solutions.
The molecular weight of hyaluronate sodium is 50-300 ten thousand; Basic solution is chosen sodium carbonate solution, and the molecular volume mark is 1 mol/L.
Step 2: add collagen protein, making the mass concentration of collagen protein in the mixing solutions is 4%, stirs.
Collagen protein is chosen the gelatin that extracts from animal tissues.
Step 3: add linking agent, the mass concentration that makes linking agent in the mixing solutions is 7%, 50 ℃ of temperature of reaction, 10 hours reaction times.
Linking agent is selected from polypropylene glycol diglycidyl ether, 1, the 6-hexanediol diglycidyl ether.
Step 4: remove residual cross-linker.
Remove the method for residual cross-linker and choose the High Temperature High Pressure distillation.
Step 5: the product that obtains balance 5 hours in physiological saline.
Step 6: the centrifugal physiological saline of removing, products therefrom is pulverized the formation particle.
Pulverization process is chosen cutting mode.
Embodiment 4:
Step 1: hyaluronate sodium is dissolved in the basic solution, stirs it is dissolved fully, make that hyaluronic mass concentration is 20% in the mixing solutions.
The molecular weight of hyaluronate sodium is 50-300 ten thousand; Basic solution is chosen sodium carbonate solution, and the molecular volume mark is 2 mol/L.
Step 2: add collagen protein, making the mass concentration of collagen protein in the mixing solutions is 6%, stirs.
Collagen protein is chosen recombined collagen, the Human-like Collagen that adopts gene engineering method to produce.
Step 3: add linking agent, the mass concentration that makes linking agent in the mixing solutions is 10%, 60 ℃ of temperature of reaction, 14 hours reaction times.
Linking agent is selected from 1,2,7,8-diepoxy octane, divinylsulfone.
Step 4: remove residual cross-linker.
The method of removing residual cross-linker adopts washing, organic solvent to clean the cooperation of several different methods in (ethanol, acetone etc.), the High Temperature High Pressure distillation.
Step 5: the product that obtains balance 6 hours in physiological saline.
Step 6: the centrifugal physiological saline of removing, products therefrom is pulverized the formation particle.
Pulverization process adopts the cooperation of several different methods in extruding, grinding, the cutting mode.
Below be the correlated performance test of injection water gel involved in the present invention:
1, the cytotoxicity of material detects
Bhk cell is the hamster nephrocyte, and material is analyzed by novel cell propagation and cytotoxicity detection kit (cck-8) the growth of this cell and the influence of propagation.Its ultimate principle is that the succinodehydrogenase in the viable cell plastosome can be with 2-(2-methoxyl group-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid benzene)-2H-tetrazolium list sodium salt (WST-8) is reduced to water miscible yellow De Jia Za product, cell proliferation is more fast more many, color is more dark, cytotoxicity is more big, color is more shallow, and the depth of color is directly proportional with the quantity of viable cell, thereby can obtain the propagation situation of cell.
With attached cell with tryptic digestion after, make cell suspending liquid with nutrient solution, according to every hole 10
3-10
4Individual cell inoculation is in 96 orifice plates, and every hole 100 μ L, and orifice plate placed cell culture incubator cultivate 1d and make cell attachment.
Material is immersed in the nutrient solution behind 37 ℃ of following lixiviate 72h, cultivates attached cell with vat liquor, with the hole that adds normal nutrient solution in contrast.Behind 1,3,5d, every hole adds 10 μ L cck-8, continues to cultivate after 4 hours, uses microplate reader to measure absorbancy at the 450nm place.
After each was organized the OD value and gets average, it was as follows to calculate the cell relative survival rate:
According to ISO10993-1.1997 and standard GB/T16886.5-2003, the cytotoxicity grade of hyaluronic acid derivatives and hyaluronic acid-collagen protein plural gel is 0 grade, and after cultivating 5 days, the promoting growth of cell effect of composite aquogel is obviously good than hyaluronic acid derivatives.By contrast and experiment, we can draw: compound after the collagen protein on the hyaluronic acid derivatives basis, and the growth of cell be can effectively promote, thereby the cell growth of this material and the promoter action of propagation proved.Therefore, the vat liquor that experimental results show that two kinds of hydrogels has promoter action to the growth of cell, makes the relative survival rate of cell increase with incubation time, illustrates that this hydrogel does not have significant cytotoxicity, and have excellent biological compatibility, meet the requirement that biomaterial is used.
2, the syringeability of material
Sample is filled in the 1mL syringe, during experiment, installs the 27G entry needle, simulate actual service condition.Promote pushing ram with constant driving velocity 30mm/min, the sample in the syringe is pushed out via syringe needle.Obtain the pushing force curve.
As seen from the figure, in certain compression displacement, the compressive load variation range of injectable hyaluronic acid--Human-like Collagen composite aquogel is between 5-8N, the rangeability of compressive load is very little, the high low head that pushing force is described is less, show that sample dispersion is even, injection comparatively easily and convenient, and the grain diameter of explanation injectable hyaluronic acid-Human-like Collagen composite aquogel homogeneous comparatively.
3, the size distribution of gel
Get jel product 0.5g, add 0.2% toluidine blue-ethanolic soln dyeing 1min, then centrifuging and taking precipitates, add 1mL distilled water and leave standstill 1min, abandon supernatant liquor after centrifugal, add 95% ethanol 5mL color separation 5min, the more centrifugal ethanol of abandoning, add the dilution of 1mL physiological saline, under 100 times of opticmicroscopes, observe counting, measure particle diameter.
4, hyaluronic acid contents is measured in the gel
Get product 0.5g, add 4.6M HCl hydrolysis 2h in 70 ℃ of water-baths, the solution constant volume adopts the carbazole method to measure wherein glucuronic acid content, thereby can obtain hyaluronic acid contents (A) in the 100mL volumetric flask.
5, the resistance to enzymolysis performance measurement of gel
Get gel 0.5g, add 3mg/mL hyaluronic acid enzyme solution 0.5mL, 37 ℃ of following hydrolysis 15h, 0.22 get 0.5mL filtrate behind the μ m membrane filtration, be settled to 50mL, the carbazole method is measured wherein uronic acid concentration, thereby obtain hyaluronic acid contents (B), the resistance to enzymolysis performance B/A value representation of gel.The results are shown in Table 1.
Table 1 gel determination result
By data in the table as can be seen, under same processing condition, preparing resulting hyaluronic acid derivatives and hyaluronic acid-collagen protein plural gel size distribution is more or less the same, but hyaluronic acid contents is different in the product, and the resistance to enzymolysis performance of hyaluronic acid derivatives is obviously poor than hyaluronic acid-collagen protein plural gel, illustrates that hyaluronic acid-collagen protein plural gel retention time in vivo can obviously prolong.
6, the residual mensuration of linking agent in the jel product
Adopt the residual quantity of linking agent in the fluorescence spectrophotometry gel, the results are shown in Table 2.
The residual quantity of linking agent in table 2 gel
Because linking agent has low toxicity, so the linking agent residual quantity must be up to standard in the product.The linking agent residual quantity can not be higher than 2 μ g/g in the regulation gel, by data in the table as can be known, when crosslinker concentration was low, it was below the mark directly by washing the linking agent residual quantity to be dropped to, but when improving crosslinker concentration, the washing effect can not be up to standard, therefore we combine with the High Temperature High Pressure distillation method, can remove residual cross-linker in the gel significantly, thereby it are better to obtain biocompatibility, toxicity is lower, is applicable to that soft tissue is filled or the hydrogel material of tissue repair.
It is cited that content of the present invention is not limited to embodiment, and the conversion of any equivalence that those of ordinary skills take technical solution of the present invention by reading specification sheets of the present invention is claim of the present invention and contains.
Claims (8)
1. the preparation method of injection hyaluronic acid-collagen protein composite aquogel is characterized in that:
Realized by following steps:
Step 1: hyaluronate sodium is dissolved in the basic solution, stirs it is dissolved fully, make that hyaluronic mass concentration is 6%-20% in the mixing solutions;
Step 2: add collagen protein, making the mass concentration of collagen protein in the mixing solutions is 1-6%, stirs;
Step 3: add linking agent, the mass concentration that makes linking agent in the mixing solutions is 1-10%, temperature of reaction 30-60 ℃, and reaction times 1-14 hour;
Step 4: remove residual cross-linker;
Step 5: the product that obtains in physiological saline balance 3-6 hour;
Step 6: the centrifugal physiological saline of removing, products therefrom is pulverized the formation particle.
2. the preparation method of a kind of injection hyaluronic acid according to claim 1-collagen protein composite aquogel is characterized in that:
In the step 1, the molecular weight of hyaluronate sodium is 50-300 ten thousand.
3. the preparation method of a kind of injection hyaluronic acid according to claim 1 and 2-collagen protein composite aquogel is characterized in that:
In the step 1, basic solution is selected from sodium hydroxide, potassium hydroxide, sodium carbonate solution, and the molecular volume mark is 0.02-2 mol/L.
4. the preparation method of a kind of injection hyaluronic acid according to claim 3-collagen protein composite aquogel is characterized in that:
In the step 2, collagen protein is selected from total length collagen protein, collagen polypeptide, the gelatin that extracts from animal tissues; Or the recombined collagen, the Human-like Collagen that adopt gene engineering method to produce.
5. the preparation method of a kind of injection hyaluronic acid according to claim 4-collagen protein composite aquogel is characterized in that:
In the step 3, linking agent is selected from ethylene glycol diglycidylether, 1,4-butanediol diglycidyl ether, glycol ether diglycidylether, polyethyleneglycol diglycidylether, polypropylene glycol diglycidyl ether, 1,6-hexanediol diglycidyl ether, 1,2,7,8-diepoxy octane, divinylsulfone.
6. according to the preparation method of a kind of injection hyaluronic acid-collagen protein composite aquogel described in the claim 5, it is characterized in that:
In the step 4, the method for removing residual cross-linker is selected from washing, organic solvent cleaning, High Temperature High Pressure distillation.
7. the preparation method of a kind of injection hyaluronic acid according to claim 6-collagen protein composite aquogel is characterized in that:
In the step 6, pulverization process is selected from extruding, grinding, cutting mode.
8. injection hyaluronic acid-collagen protein composite aquogel that preparation method as claimed in claim 1 makes.
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