CN112480440A - Preparation method of single-phase cross-linked sodium hyaluronate gel - Google Patents
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Abstract
The invention discloses a preparation method of single-phase cross-linked sodium hyaluronate gel, belonging to the technical field of medicine preparation. The preparation method comprises the following steps: preparing a NaOH mixed solution containing a cross-linking agent, preparing a sodium hyaluronate solution, adding the NaOH mixed solution into the sodium hyaluronate solution, uniformly stirring, and performing constant-temperature water bath to obtain sodium hyaluronate gel; cutting the sodium hyaluronate gel into small pieces, adding a hydrochloric acid PBS solution, and dialyzing in the PBS solution to obtain cross-linked phase sodium hyaluronate; mixing the cross-linked sodium hyaluronate with the non-cross-linked sodium hyaluronate solution, degassing, filling, and sterilizing. The preparation method disclosed by the invention not only can effectively reduce manual operation in the production process and reduce the risk of cross contamination, but also can avoid generating byproducts and effectively reduce bubbles generated during filling, thereby effectively ensuring the quality of the sodium hyaluronate gel.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation method of single-phase cross-linked sodium hyaluronate gel.
Background
Hyaluronic acid is an important component of human and animal skin, vitreous body, joint lubricating fluid and cartilage tissue, is formed by repeatedly connecting (1-beta-4) D-glucuronic acid and (1-beta-3) N-acetyl-D-glucosamine disaccharide units, and is widely used in repair surgery, eye surgery or as a cosmetic product to fill wrinkles. The hyaluronic acid has good physical and chemical properties and biocompatibility. However, it is degraded rapidly in vivo by the enzymatic action of hyaluronidase, has a short residence time, and requires repeated injections to achieve therapeutic efficacy. The cross-linked hyaluronic acid is a polymer gel obtained by cross-linking and modifying hyaluronic acid by a cross-linking agent, can make up for the defects of short retention time and the like of hyaluronic acid, and has good biocompatibility and effect.
At present, the existing preparation process of sodium hyaluronate generally comprises the following steps: the problems of crosslinking reaction-swelling-dialysis-filling-sterilization are mainly as follows: byproducts are easily generated in the cross-linking process, bubbles are easily generated in the filling process, the gel property is easily influenced, and the quality control is unstable, so that the product quality is seriously influenced.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the preparation method of the single-phase cross-linked sodium hyaluronate gel, which not only can effectively reduce manual operation in the production process and reduce the risk of cross contamination, but also can avoid generating byproducts and effectively reduce bubbles generated during filling, thereby effectively ensuring the quality of the sodium hyaluronate gel.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a preparation method of single-phase cross-linked sodium hyaluronate gel comprises the following steps:
s1, adding the cross-linking agent and the NaOH solution into a centrifugal tube according to the mass ratio of 1:8-1:10, introducing nitrogen into the centrifugal tube, and uniformly mixing in a centrifugal machine to obtain the NaOH mixed solution containing the cross-linking agent for later use;
s2, mixing sodium hyaluronate with a NaOH solution with the pH value of more than 13 according to the mass ratio of 1:6-1:8, stirring and dissolving, and placing the mixture in a three-dimensional mixer to mix for 1-2 hours to obtain a sodium hyaluronate solution;
s3, adding all the NaOH mixed solution prepared in the step S1 into the sodium hyaluronate solution, uniformly mixing, introducing nitrogen, and carrying out thermostatic water bath at 45-55 ℃ for 2-3h to obtain sodium hyaluronate gel;
s4, cutting the sodium hyaluronate gel into small pieces, adding a hydrochloric acid PBS solution, placing the small pieces in a three-dimensional mixer, mixing for 24-36h, stirring uniformly to be pasty, filling the pasty pieces into a dialysis bag, and placing the dialysis bag in a flowing pure PBS solution at 2-8 ℃ for dialysis for 30-36h to obtain cross-linked phase sodium hyaluronate;
s5, uniformly mixing the cross-linked sodium hyaluronate with the non-cross-linked sodium hyaluronate solution according to the mass ratio of 8:1-9:1, degassing, filling and sterilizing to obtain the sodium hyaluronate.
In a preferred embodiment of the present invention, the molecular weight of the sodium hyaluronate used in step S2 is 2.1 to 2.7 MDa.
As a preferred embodiment of the present invention, the molecular weight of the sodium hyaluronate used in the non-crosslinked phase sodium hyaluronate solution is 3.0 MDa.
As a preferred embodiment of the invention, the hydrochloric acid PBS solution consists of hydrochloric acid and PBS; wherein, the adding amount of the hydrochloric acid is calculated by the adding amount and concentration of the sodium hydroxide to obtain the theoretical required amount of neutralization to neutrality; the PBS is prepared from disodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate and sodium chloride.
As a preferred embodiment of the present invention, the crosslinking agent is 1, 4-butanediol diglycidyl ether (BDDE).
As a preferred embodiment of the present invention, the step S2 includes the following steps: and (2) mixing sodium hyaluronate with a NaOH solution with the pH value of more than 13 in a polytetrafluoroethylene cup with a cover according to the mass ratio of 1:6-1:8, stirring to dissolve, covering the cup cover, and then placing the cup cover in a three-dimensional mixer to mix for 1-2 hours to obtain the sodium hyaluronate solution.
In a preferred embodiment of the present invention, in the step S4, the PBS solution is replaced 5 to 6 times during the dialysis process.
As a preferred embodiment of the present invention, step S5 is to perform degassing treatment using a stainless steel degassing tank, connect the stainless steel degassing tank and a filling machine through a silicone tube, fill the gel in the degassing tank into a glass syringe through the filling machine by using vacuum, and place the glass syringe in a steam air sterilization cabinet for sterilization by rapid temperature increase and decrease.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method provided by the invention has the advantages that the time of the whole manual operation step is not more than 1h, the manual operation in the production process can be effectively reduced, and the risk of cross contamination is reduced; on the other hand, by introducing nitrogen to protect the ring-opening reaction of the cross-linking agent BDDE, byproducts generated in the cross-linking process can be avoided, a degassing tank and a filling machine are connected through a silicone tube, no bubble is generated during filling, terminal sterilization is performed by using a rapid temperature rise and drop mode, pressure compensation is performed in the sterilization process, so that the rubber plug displacement is prevented, the influence of the sterilization process on the gel property is reduced, and the quality of the sodium hyaluronate gel is effectively ensured. In conclusion, the preparation method provided by the invention has the advantages of fewer process steps, easiness in operation and short period, can effectively improve the quality of gel products, and is suitable for large-scale industrial production.
Drawings
FIG. 1 is a graph comparing the modulus of elasticity of example 1 of the present invention with that of a conventional product.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments.
A preparation method of single-phase cross-linked sodium hyaluronate gel comprises the following steps:
s1, adding the cross-linking agent BDDE and the NaOH solution into a centrifugal tube according to the mass ratio of 1:8-1:10, introducing nitrogen into the centrifugal tube, and uniformly mixing the mixture in the centrifugal tube to obtain the NaOH mixed solution containing the cross-linking agent BDDE for later use;
s2, mixing sodium hyaluronate with a NaOH solution with the pH value of more than 13 in a polytetrafluoroethylene cup with a cover according to the mass ratio of 1:6-1:8, stirring to dissolve, covering the cup cover, and mixing in a three-dimensional mixer for 1-2 hours to obtain a sodium hyaluronate solution; wherein the molecular weight of the sodium hyaluronate is 2.1-2.7 MDa;
s3, adding the NaOH mixed solution prepared in the step S1 into the sodium hyaluronate solution, uniformly mixing, introducing nitrogen, covering a cup cover after the air in the cup is completely replaced by the nitrogen, and carrying out constant-temperature water bath at 45-55 ℃ for 2-3 hours to obtain sodium hyaluronate gel;
s4, cutting the sodium hyaluronate gel into small pieces, adding a hydrochloric acid PBS solution, placing the small pieces in a three-dimensional mixing machine, mixing for 24-36h, stirring uniformly to be pasty, placing the pasty pieces in a dialysis bag, placing the dialysis bag in a flowing pure PBS solution at 2-8 ℃ for dialysis for 30-36h, and replacing the PBS solution for 5-6 times in the dialysis process to obtain cross-linked phase sodium hyaluronate; the hydrochloric acid PBS solution consists of hydrochloric acid and PBS, and the addition amount of the hydrochloric acid is calculated according to the addition amount and concentration of sodium hydroxide to obtain the theoretical required amount of neutralization to neutrality, namely the amounts of the hydrochloric acid and the sodium hydroxide are equal; the PBS is prepared from disodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate and sodium chloride; preferably, the composition of PBS is as follows: na (Na)2HPO4·12H2O 0.555g、NaH2PO4·H20.039g of O and 9g of NaCl are added with water to 1000 mL;
s5, uniformly mixing the cross-linked sodium hyaluronate with the non-cross-linked sodium hyaluronate solution with the molecular weight of 3.0MDa according to the mass ratio of 8:1-9:1, degassing by adopting a stainless steel degassing tank, connecting the stainless steel degassing tank with a filling machine through a silicone tube, filling the gel in the degassing tank into a glass syringe by utilizing vacuum through the filling machine, and placing the glass syringe in a steam air sterilization cabinet for sterilization by adopting rapid temperature rise and fall.
Example 1:
a preparation method of single-phase cross-linked sodium hyaluronate gel comprises the following steps:
s1, adding 700 mu L of cross-linking agent BDDE and 5g of NaOH solution into a centrifugal tube, introducing nitrogen into the centrifugal tube, and uniformly mixing in the centrifugal tube to obtain a NaOH mixed solution containing the cross-linking agent BDDE for later use;
s2, dissolving 10g of sodium hyaluronate powder with the molecular weight of 2.1MDa in 90g of 0.3mol/L sodium hydroxide solution in a PTFE beaker, and stirring and dissolving the solution on a three-dimensional mixer at the rotating speed of 70 rpm;
s3, adding the NaOH mixed solution after fully stirring and dissolving, injecting nitrogen into the cup after uniformly stirring, immediately covering the cup cover, transferring the cup cover to a constant-temperature water bath, and preserving the temperature at 45 ℃ for 3 hours to obtain sodium hyaluronate gel;
s4, cutting the gel into small pieces of 0.5 multiplied by 0.5cm, adding 9g of 3mol/L hydrochloric acid and 160g of PBS solution, placing the small pieces on a three-dimensional mixer, mixing for 6 hours at a rotating speed of 70rpm, after that, refining the gel by using a 80-mesh screen, uniformly stirring, filling the gel into a dialysis bag of 8000Da-12000Da, placing the dialysis bag in the PBS solution flowing at the temperature of 20 ℃ for dialysis, replacing the dialysate once every 6 hours, weighing, and ending the dialysis until the mass of the gel reaches about 500 g;
s5, adding 50g of sodium hyaluronate PBS solution with the content of 20mg/ml, and uniformly stirring; stirring, filling 2/3 with the syringe filling amount in a 60ml disposable plastic syringe, placing in a degasser for degassing for 5 minutes, filling in a 1ml syringe after the degassing is finished, placing in a high-temperature steam sterilization cabinet, and sterilizing at 129 ℃ for 3 minutes to obtain a sample A.
Example 2:
a preparation method of single-phase cross-linked sodium hyaluronate gel comprises the following steps:
s1, adding 700 mu L of cross-linking agent BDDE and 5g of NaOH solution into a centrifugal tube, introducing nitrogen into the centrifugal tube, and uniformly mixing in the centrifugal tube to obtain a NaOH mixed solution containing the cross-linking agent BDDE for later use;
s2, dissolving 10g of sodium hyaluronate powder with the molecular weight of 2.5MDa in 90g of 0.3mol/L sodium hydroxide solution in a PTFE beaker, and stirring and dissolving the solution on a three-dimensional mixer at the rotating speed of 70 rpm;
s3, adding the NaOH mixed solution after fully stirring and dissolving, injecting nitrogen into the cup after uniformly stirring, immediately covering the cup cover, transferring the cup cover to a constant-temperature water bath, and keeping the temperature of the cup in the constant-temperature water bath for 2 hours at 50 ℃ to obtain sodium hyaluronate gel;
s4, cutting the gel into small pieces of 0.5 multiplied by 0.5cm, adding 9g of 3mol/L hydrochloric acid and 160g of PBS solution, placing the small pieces on a three-dimensional mixer, mixing for 6 hours at a rotating speed of 70rpm, after that, refining the gel by using a 80-mesh screen, uniformly stirring, filling the gel into a dialysis bag of 8000Da-12000Da, placing the dialysis bag in the PBS solution flowing at the temperature of 20 ℃ for dialysis, replacing the dialysate once every 6 hours, weighing, and ending the dialysis until the mass of the gel reaches about 500 g;
s5, adding 50g of sodium hyaluronate PBS solution with the content of 20mg/ml, and uniformly stirring; stirring, filling 2/3 with the syringe filling amount in a 60ml disposable plastic syringe, placing in a degasser for degassing for 5 minutes, filling in a 1ml syringe after the degassing is finished, placing in a high-temperature steam sterilization cabinet, and sterilizing at 129 ℃ for 3 minutes to obtain a sample B.
Example 3:
a preparation method of single-phase cross-linked sodium hyaluronate gel comprises the following steps:
s1, adding 750 mu L of cross-linking agent BDDE and 5g of NaOH solution into a centrifugal tube, introducing nitrogen into the centrifugal tube, and uniformly mixing in the centrifugal tube to obtain a NaOH mixed solution containing the cross-linking agent BDDE for later use;
s2, dissolving 10g of sodium hyaluronate powder with the molecular weight of 2.5MDa in 90g of 0.3mol/L sodium hydroxide solution in a PTFE beaker, and stirring and dissolving the solution on a three-dimensional mixer at the rotating speed of 70 rpm;
s3, adding the NaOH mixed solution after fully stirring and dissolving, injecting nitrogen into the cup after uniformly stirring, immediately covering the cup cover, transferring the cup cover to a constant-temperature water bath, and keeping the temperature of the cup in the constant-temperature water bath for 2 hours at 50 ℃ to obtain sodium hyaluronate gel;
s4, cutting the gel into small pieces of 0.5 multiplied by 0.5cm, adding 9g of 3mol/L hydrochloric acid and 160g of PBS solution, placing the small pieces on a three-dimensional mixer, mixing for 6 hours at a rotating speed of 70rpm, after that, refining the gel by using a 80-mesh screen, uniformly stirring, filling the gel into a dialysis bag of 8000Da-12000Da, placing the dialysis bag in the PBS solution flowing at the temperature of 20 ℃ for dialysis, replacing the dialysate once every 6 hours, weighing, and ending the dialysis until the mass of the gel reaches about 500 g;
s5, adding 50g of sodium hyaluronate PBS solution with the content of 20mg/ml, and uniformly stirring; stirring, filling 2/3 with the syringe filling amount in a 60ml disposable plastic syringe, placing in a degasser for degassing for 5 minutes, filling in a 1ml syringe after the degassing is finished, placing in a high-temperature steam sterilization cabinet, and sterilizing at 129 ℃ for 3 minutes to obtain a sample C.
Performance comparison experiment:
comparison of swelling degree and elastic modulus
The results of measuring the swelling degree and the elastic modulus for each of the samples obtained in examples 1 to 3 are shown in Table 1.
TABLE 1 results of testing swelling degree and elastic modulus in examples 1 to 3
| Sample (I) | Degree of swelling | Modulus of elasticity (@1Hz) |
| Example 1 | 31 | 295Pa |
| Example 2 | 26 | 353Pa |
| Example 3 | 21 | 412Pa |
The lower the swelling degree, the higher the crosslinking degree of the product can be reflected laterally, the higher the elastic modulus, the stronger the external force influence resistance of the product is reflected, the better the supporting effect in vivo is, the too high elastic modulus is not suitable, and the too high elastic modulus can influence the naturalness of the injected face. Therefore, the results in Table 1 show that example 2 has a better elastic modulus and swelling degree.
Second, in vitro degradation experiment
In-vitro enzyme degradation tests are carried out on the samples prepared in the examples 1-3 at 37 ℃ by using 5U/mL hyaluronidase, the enzymolysis degrees at different time points are detected and recorded until the samples are completely degraded, so as to compare the in-vitro degradation performance of the samples prepared in the examples 1-3, and the enzymolysis degrees are reflected by detecting the concentration of glucuronic acid in the enzymolysis liquid at different time points.
Uniformly converting the content of glucuronic acid detected in the enzymolysis solution into the content of sodium hyaluronate to obtain G0Taking a sample as a blank, taking a sample subjected to enzymolysis for 24h as a point of complete enzymolysis, and calculating the sodium hyaluronate content of the enzymolysis liquid obtained at each time point and enzymolysis for 24h and G according to the following formula0The relationship of the contents in the sample tube gives the degree of enzymolysis at each time point, and the results are shown in table 2.
In the above formula: rho is the mass concentration value of sodium hyaluronate in a sample, mg/ml; c1The content of glucuronic acid in the sample tube is μ g/ml; m is the mass of the cross-linked sodium hyaluronate gel, g; m is1Adding amount of the enzymolysis liquid; rho1The density of the cross-linked sodium hyaluronate gel is 1.01 g/ml;
in the formula, rho is the mass concentration value of sodium hyaluronate in a sample, mg/ml; rho0Is G0The mass concentration value of the sodium hyaluronate in the sample tube is mg/ml; rho24Is the mass concentration value of the sodium hyaluronate in the sample tube after 24 hours of enzymolysis, namely mg/ml.
TABLE 2 examples 1-3 in vitro degradation test results
The results in Table 2 show that example 3 has the best resistance to enzymatic hydrolysis, reflecting the best in vivo maintenance, and example 1 has the worst resistance to enzymatic hydrolysis, reflecting the poorer in vivo maintenance. Example 2 has better resistance to enzymatic hydrolysis and better elastic modulus and swelling, so the sample prepared in example 2 has the best quality.
Third, comparison experiment with existing product
The experiment for comparing the elastic modulus of the single-phase product under Huaxi biological flag is a comparative example 1, the single-phase product under Aire Jian flag is a comparative example 2, and the experiment is carried out with the example 2 of the invention: using a swept mode under rotational rheometer oscillation test, from 0.08Hz to 5Hz and the corresponding elastic modulus G' was recorded, the results are shown in fig. 1.
The results in FIG. 1 show that: the elasticity modulus of the sodium hyaluronate gel prepared in the embodiment 2 of the invention is higher than that of the sodium hyaluronate gel prepared in the comparative examples 1 and 2, so that the sodium hyaluronate gel prepared in the embodiment 2 has more excellent physical properties, and meanwhile, the gel prepared in the invention has better shaping effect, maintaining effect and external force resistance.
In conclusion, the sodium hyaluronate gel prepared by the preparation method provided by the invention has better elastic modulus and swelling degree and good enzymolysis resistance. The preparation method provided by the invention has the advantages of few process steps, easiness in operation and short period, can effectively improve the quality of gel products, and is suitable for large-scale industrial production.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (8)
1. A preparation method of single-phase cross-linked sodium hyaluronate gel is characterized by comprising the following steps: the method comprises the following steps:
s1, adding the cross-linking agent and the NaOH solution into a centrifugal tube according to the mass ratio of 1:8-1:10, introducing nitrogen into the centrifugal tube, and uniformly mixing in a centrifugal machine to obtain the NaOH mixed solution containing the cross-linking agent for later use;
s2, mixing sodium hyaluronate with a NaOH solution with the pH value of more than 13 according to the mass ratio of 1:6-1:8, stirring and dissolving, and placing the mixture in a three-dimensional mixer to mix for 1-2 hours to obtain a sodium hyaluronate solution;
s3, adding all the NaOH mixed solution prepared in the step S1 into the sodium hyaluronate solution, uniformly mixing, introducing nitrogen, and carrying out thermostatic water bath at 45-55 ℃ for 2-3h to obtain sodium hyaluronate gel;
s4, cutting the sodium hyaluronate gel into small pieces, adding a hydrochloric acid PBS solution, placing the small pieces in a three-dimensional mixer, mixing for 24-36h, stirring uniformly to be pasty, filling the pasty pieces into a dialysis bag, and placing the dialysis bag in a flowing pure PBS solution at 2-8 ℃ for dialysis for 30-36h to obtain cross-linked phase sodium hyaluronate;
s5, uniformly mixing the cross-linked sodium hyaluronate with the non-cross-linked sodium hyaluronate solution according to the mass ratio of 8:1-9:1, degassing, filling and sterilizing to obtain the sodium hyaluronate.
2. The method of preparing a single-phase cross-linked sodium hyaluronate gel according to claim 1, characterized in that: the molecular weight of the sodium hyaluronate used in the step S2 is 2.1-2.7 MDa.
3. The method of preparing a single-phase cross-linked sodium hyaluronate gel according to claim 1, characterized in that: the molecular weight of the sodium hyaluronate used in the non-crosslinked sodium hyaluronate solution is 3.0 MDa.
4. The method of preparing a single-phase cross-linked sodium hyaluronate gel according to claim 1, characterized in that: the hydrochloric acid PBS solution consists of hydrochloric acid and PBS; wherein the PBS is prepared from disodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate and sodium chloride.
5. The method of preparing a single-phase cross-linked sodium hyaluronate gel according to claim 1, characterized in that: the cross-linking agent is 1, 4-butanediol diglycidyl ether.
6. The method of preparing a single-phase cross-linked sodium hyaluronate gel according to claim 1, characterized in that: the specific steps of step S2 are as follows: and (2) mixing sodium hyaluronate with a NaOH solution with the pH value of more than 13 in a polytetrafluoroethylene cup with a cover according to the mass ratio of 1:6-1:8, stirring to dissolve, covering the cup cover, and then placing the cup cover in a three-dimensional mixer to mix for 1-2 hours to obtain the sodium hyaluronate solution.
7. The method of preparing a single-phase cross-linked sodium hyaluronate gel according to claim 1, characterized in that: and in the step S4, the PBS solution is replaced for 5-6 times in the dialysis process.
8. The method of preparing a single-phase cross-linked sodium hyaluronate gel according to claim 1, characterized in that: and step S5, degassing by using a stainless steel degassing tank, connecting the stainless steel degassing tank with a filling machine by using a silicone tube, filling gel in the degassing tank into a glass syringe by using vacuum through the filling machine, placing the glass syringe into a steam air sterilization cabinet, and sterilizing by adopting rapid temperature rise and fall.
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| CN114349977A (en) * | 2022-01-08 | 2022-04-15 | 王苗苗 | Sodium hyaluronate linear crosslinking method |
| CN114621501A (en) * | 2022-03-30 | 2022-06-14 | 浙江景嘉医疗科技有限公司 | Sodium hyaluronate gel and preparation method and application thereof |
| CN114732939A (en) * | 2022-04-20 | 2022-07-12 | 埃伦宝音 | Hyaluronic acid thread and preparation method and application thereof |
| CN116212108A (en) * | 2023-04-18 | 2023-06-06 | 杭州科腾生物制品有限公司 | Double-layer crosslinked gel containing lidocaine and preparation method and application thereof |
| CN117659439A (en) * | 2023-12-12 | 2024-03-08 | 陕西康润惠泽科技有限公司 | Preparation method of cross-linked hyaluronic acid gel for injection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108250457A (en) * | 2017-05-08 | 2018-07-06 | 上海利康瑞生物工程有限公司 | Controllable two-phase cross-linking sodium hyaluronate gel of a kind of shear viscosity and preparation method thereof and preparation |
| CN108395552A (en) * | 2017-12-15 | 2018-08-14 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of single-phase cross-linking sodium hyaluronate gel |
| CN108774329A (en) * | 2018-06-13 | 2018-11-09 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of medical cross-linking sodium hyaluronate gel |
-
2020
- 2020-11-30 CN CN202011378636.1A patent/CN112480440A/en active Pending
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2021
- 2021-06-03 CH CH00643/21A patent/CH718108B1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108250457A (en) * | 2017-05-08 | 2018-07-06 | 上海利康瑞生物工程有限公司 | Controllable two-phase cross-linking sodium hyaluronate gel of a kind of shear viscosity and preparation method thereof and preparation |
| CN108395552A (en) * | 2017-12-15 | 2018-08-14 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of single-phase cross-linking sodium hyaluronate gel |
| CN108774329A (en) * | 2018-06-13 | 2018-11-09 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of medical cross-linking sodium hyaluronate gel |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114349977A (en) * | 2022-01-08 | 2022-04-15 | 王苗苗 | Sodium hyaluronate linear crosslinking method |
| CN114349977B (en) * | 2022-01-08 | 2024-05-03 | 杭州科腾生物制品有限公司 | Linear crosslinking method of sodium hyaluronate |
| CN114621501A (en) * | 2022-03-30 | 2022-06-14 | 浙江景嘉医疗科技有限公司 | Sodium hyaluronate gel and preparation method and application thereof |
| CN114621501B (en) * | 2022-03-30 | 2023-02-17 | 浙江景嘉医疗科技有限公司 | Sodium hyaluronate gel and preparation method and application thereof |
| CN114732939A (en) * | 2022-04-20 | 2022-07-12 | 埃伦宝音 | Hyaluronic acid thread and preparation method and application thereof |
| CN116212108A (en) * | 2023-04-18 | 2023-06-06 | 杭州科腾生物制品有限公司 | Double-layer crosslinked gel containing lidocaine and preparation method and application thereof |
| CN116212108B (en) * | 2023-04-18 | 2023-10-20 | 杭州科腾生物制品有限公司 | Double-layer crosslinked gel containing lidocaine and preparation method and application thereof |
| CN117659439A (en) * | 2023-12-12 | 2024-03-08 | 陕西康润惠泽科技有限公司 | Preparation method of cross-linked hyaluronic acid gel for injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CH718108A2 (en) | 2022-05-31 |
| CH718108B1 (en) | 2022-11-30 |
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