Injectable cross-linked hyaluronic acid hydroxyapatite gel and preparation method thereof

Abstract

The present application relates to the technical field of injectable gels, and specifically discloses an injectable cross-linked hyaluronic acid hydroxyapatite gel and a preparation method thereof. An injectable cross-linked hyaluronic acid hydroxyapatite gel comprises a modified sodium hyaluronate hydroxyapatite microsphere gel and a sodium hyaluronate hydroxyapatite microsphere mixed solution, wherein the raw materials of the modified sodium hyaluronate hydroxyapatite microsphere gel comprise the following components in parts by weight: 40 to 70 parts of hydroxyapatite microspheres, 1 to 3 parts of hyaluronic acid, 0.1 to 0.2 parts of a cross-linking agent, and 30 to 40 parts of a lidocaine solution; the raw materials of the sodium hyaluronate hydroxyapatite microsphere mixed solution comprise the following components in parts by weight: 15 to 25 parts of hydroxyapatite microspheres and 0.5 to 1.5 parts of sodium hyaluronate dry powder.

Description

Technical Field

[0001] The present application relates to the technical field of injectable gels, and in particular to an injectable cross-linked hyaluronic acid hydroxyapatite gel and a preparation method thereof. Background Art

[0002] Hydroxyapatite is an inorganic component with good biocompatibility and biodegradability. After a period of time, hydroxyapatite microspheres are implanted in the body. The microsphere particles degrade into calcium and phosphate and are excreted through the renal system, providing longer bioabsorbability for injectable implant products dermal fillers. Due to good biocompatibility, the microspheres are wrapped by the body's natural reaction, leading to the growth of connective tissue. Autologous connective tissue replaces the volume lost during the degradation of the HA gel carrier within a few months. However, during the storage of the gel, hydroxyapatite will deposit over time and even phase separation will occur. During use, the needle will be blocked due to uneven distribution, affecting the doctor's injection operation. Summary of the invention

[0003] In order to reduce the deposition of hydroxyapatite, the present application provides an injectable cross-linked hyaluronic acid hydroxyapatite gel and a preparation method thereof.

[0004] In the first aspect, the present application provides an injectable cross-linked hyaluronic acid hydroxyapatite gel, which adopts the following technical solution:

[0005] An injectable cross-linked hyaluronic acid hydroxyapatite gel comprises a modified sodium hyaluronate hydroxyapatite microsphere gel and a sodium hyaluronate hydroxyapatite microsphere mixed solution. The raw materials of the modified sodium hyaluronate hydroxyapatite microsphere gel comprise the following components in parts by weight: 40-70 parts of hydroxyapatite microspheres, 1-3 parts of hyaluronic acid, 0.1-0.2 parts of a cross-linking agent, and 30-40 parts of a lidocaine solution; the raw materials of the sodium hyaluronate hydroxyapatite microsphere mixed solution comprise the following components in parts by weight: 15-25 parts of hydroxyapatite microspheres and 0.5-1.5 parts of sodium hyaluronate dry powder.

[0006] By adopting the above technical scheme, part of the hydroxyapatite microspheres are added together with the hyaluronic acid to carry out cross-linking in the modified sodium hyaluronate hydroxyapatite microsphere gel when the hyaluronic acid is cross-linked, so that the hydroxyapatite microspheres are evenly distributed and not easy to precipitate, but at this time, not many hydroxyapatite microspheres are wrapped; the sodium hyaluronate hydroxyapatite microsphere mixture composed of hydroxyapatite microspheres and sodium hyaluronate dry powder plays a lubricating role, and then it is mixed with the modified sodium hyaluronate hydroxyapatite microsphere gel, and a secondary reaction is carried out, so that more hydroxyapatite microspheres can be wrapped, thereby reducing the occurrence of precipitation of hydroxyapatite microspheres.

[0007] In a specific embodiment, the particle size of the hydroxyapatite microspheres is 0.1-100 microns.

[0008] By adopting the above technical solution, the particle size of the hydroxyapatite microspheres is further limited, so that the hydroxyapatite microspheres can be better dispersed in the gel.

[0009] In a specific embodiment, the cross-linking agent includes one or more of 1,4-butanediol diglycidyl ether, polyethylene glycol diglycidyl ether, and ethylene glycol diglycidyl ether.

[0010] In a specific embodiment, the mass concentration of the lidocaine solution is 5-7 mg / ml.

[0011] In a specific embodiment, the method for preparing hydroxyapatite microspheres comprises the following steps:

[0012] The hydroxyapatite powder is mixed with the organic acid solution to obtain a mixed solution; the mixed solution is stirred and dispersed at 450-550 r / min and 100-120° C. for 30-40 minutes, filtered, and vacuum dried to obtain hydroxyapatite microspheres.

[0013] By adopting the above technical scheme, hydroxyapatite is modified with organic acid, and the carboxylic acid groups in the organic acid chelate with the calcium ions on the surface of hydroxyapatite, changing the charge properties and steric hindrance of the hydroxyapatite surface, thereby improving the dispersion performance and stability of hydroxyapatite, and can further reduce the occurrence of precipitation of hydroxyapatite microspheres.

[0014] In a specific embodiment, the organic acid is a mixture of citric acid and oxalic acid.

[0015] In a specific embodiment, the concentration of citric acid in the organic acid solution is 0.1 mol / L, and the concentration of oxalic acid is 0.05 mol / L.

[0016] By adopting the above technical solution, using a composite organic acid composed of citric acid and oxalic acid and limiting the concentrations of citric acid and oxalic acid, the modification effect on hydroxyapatite can be improved, thereby further improving the performance of the prepared hydroxyapatite microspheres.

[0017] In a second aspect, the present application provides a method for preparing an injectable cross-linked hyaluronic acid hydroxyapatite gel, which adopts the following technical solution:

[0018] A method for preparing an injectable cross-linked hyaluronic acid hydroxyapatite gel comprises the following steps:

[0019] Preparation of modified sodium hyaluronate hydroxyapatite microsphere gel: firstly, hydroxyapatite microspheres, hyaluronic acid and a cross-linking agent are stirred under alkaline conditions to perform a cross-linking reaction, then dialyzed with a dialysate, and lidocaine solution is added at the same time, stirred and mixed uniformly to obtain a modified sodium hyaluronate hydroxyapatite microsphere gel;

[0020] Preparation of sodium hyaluronate hydroxyapatite microsphere mixed solution: adding hydroxyapatite microspheres and sodium hyaluronate dry powder into a buffer solution, stirring and mixing evenly to obtain a sodium hyaluronate hydroxyapatite microsphere mixed solution;

[0021] Compounding: Add the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixture, stir, and boil at 120-122° C. for 25-35 minutes. Finally, oscillate the obtained product discontinuously for 18-22 hours to obtain an injectable cross-linked hyaluronic acid hydroxyapatite gel.

[0022] By adopting the above technical scheme, hydroxyapatite microspheres and hyaluronic acid are first cross-linked, and the hydroxyapatite microspheres are partially wrapped to obtain modified sodium hyaluronate hydroxyapatite microsphere gel; then, the hydroxyapatite microspheres and sodium hyaluronate dry powder are added to the buffer solution and stirred to obtain a sodium hyaluronate hydroxyapatite microsphere mixed solution; finally, the modified sodium hyaluronate hydroxyapatite microsphere gel is added to the sodium hyaluronate hydroxyapatite microsphere mixed solution, stirred, boiled, and oscillated to obtain an injectable cross-linked hyaluronic acid hydroxyapatite gel with good stability.

[0023] In a specific embodiment, in the step of preparing the modified sodium hyaluronate hydroxyapatite microsphere gel, the dialysate includes a phosphate buffer solution with a pH of 6.8-7.6 and an osmotic pressure of 270-350m0sm / L.

[0024] By adopting the above technical solution, the pH and osmotic pressure of the dialysate are further limited, the osmotic effect can be improved, and thus the quality of the prepared modified sodium hyaluronate hydroxyapatite microsphere gel is improved.

[0025] In a specific embodiment, in the compounding step, the weight ratio of the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixed solution is 1:(9-11).

[0026] By adopting the above technical solution, the ratio of the modified sodium hyaluronate hydroxyapatite microsphere gel and the sodium hyaluronate hydroxyapatite microsphere mixed solution is further limited, so that the hydroxyapatite microspheres can be better wrapped, thereby improving the stability of the final gel.

[0027] In summary, the present application includes at least one of the following beneficial technical effects:

[0028] In the modified sodium hyaluronate hydroxyapatite microsphere gel of the present application, part of the hydroxyapatite microspheres are added together for cross-linking when the hyaluronic acid is cross-linked, and the hydroxyapatite microspheres are evenly distributed and not easy to precipitate, but at this time, not many hydroxyapatite microspheres are wrapped; the sodium hyaluronate hydroxyapatite microsphere mixed liquid composed of hydroxyapatite microspheres and sodium hyaluronate dry powder plays a lubricating role, and then it is mixed with the modified sodium hyaluronate hydroxyapatite microsphere gel, and reacted for a second time, so that more hydroxyapatite microspheres can be wrapped, thereby reducing the occurrence of precipitation of hydroxyapatite microspheres;

[0029] In the present application, organic acid is used to modify hydroxyapatite, and the carboxylic acid groups in the organic acid chelate with calcium ions on the surface of hydroxyapatite to change the charge properties and steric hindrance of the surface of hydroxyapatite, thereby improving the dispersion performance and stability of hydroxyapatite, and further reducing the occurrence of precipitation of hydroxyapatite microspheres;

[0030] The method of the present application first cross-links hydroxyapatite microspheres and hyaluronic acid, partially encapsulates the hydroxyapatite microspheres, and obtains modified sodium hyaluronate hydroxyapatite microsphere gel; then, adds hydroxyapatite microspheres and sodium hyaluronate dry powder into a buffer solution, stirs, and obtains a sodium hyaluronate hydroxyapatite microsphere mixed solution; finally, adds the modified sodium hyaluronate hydroxyapatite microsphere gel into the sodium hyaluronate hydroxyapatite microsphere mixed solution, stirs, boils, and oscillates, and obtains an injectable cross-linked hyaluronic acid hydroxyapatite gel with good stability. DETAILED DESCRIPTION

[0031] The present application is further described in detail below in conjunction with embodiments.

[0032] All raw materials in the embodiment can be obtained commercially. The CAS number of sodium hyaluronate dry powder is 9067-32-7; the raw materials of phosphate buffer include disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, and water for injection, and disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride are provided by Sinopharm Chemical Reagent Co., Ltd.; the cross-linking agent includes but is not limited to a mixture of one or more of 1,4-butanediol diglycidyl ether, polyethylene glycol diglycidyl ether, and ethylene glycol diglycidyl ether, and 1,4-butanediol diglycidyl ether is preferred in this application.

[0033] Preparation Example 1

[0034] Preparation Example 1 provides a method for preparing hydroxyapatite microspheres, comprising the following steps:

[0035] Dissolving citric acid and oxalic acid in water for injection to obtain an organic acid solution, wherein the concentration of citric acid in the organic acid solution is 0.1 mol / L, and the concentration of oxalic acid is 0.05 mol / L;

[0036] The hydroxyapatite powder is mixed with an organic acid solution to obtain a mixed solution; the mixed solution is stirred and dispersed at 450 r / min and 120° C. for 40 minutes, filtered, and vacuum dried at 60° C. for 10 hours to obtain hydroxyapatite microspheres with a particle size of 0.1-100 microns; wherein 1 L of organic acid solution is added to every 100 g of hydroxyapatite powder in the mixed solution.

[0037] Preparation Example 2

[0038] Preparation Example 2 provides a method for preparing hydroxyapatite microspheres, comprising the following steps:

[0039] Dissolving citric acid and oxalic acid in water for injection to obtain an organic acid solution, wherein the concentration of citric acid in the organic acid solution is 0.1 mol / L, and the concentration of oxalic acid is 0.05 mol / L;

[0040] The hydroxyapatite powder is mixed with an organic acid solution to obtain a mixed solution; the mixed solution is stirred and dispersed at 500 r / min and 110° C. for 35 minutes, filtered, and vacuum dried at 60° C. for 10 hours to obtain hydroxyapatite microspheres with a particle size of 0.1-100 microns; wherein 1L of organic acid solution is added to every 100g of hydroxyapatite powder in the mixed solution.

[0041] Preparation Example 3

[0042] Preparation Example 3 provides a method for preparing hydroxyapatite microspheres, comprising the following steps:

[0043] Dissolving citric acid and oxalic acid in water for injection to obtain an organic acid solution, wherein the concentration of citric acid in the organic acid solution is 0.1 mol / L, and the concentration of oxalic acid is 0.05 mol / L;

[0044] The hydroxyapatite powder is mixed with an organic acid solution to obtain a mixed solution; the mixed solution is stirred and dispersed at 550 r / min and 100° C. for 30 minutes, filtered, and vacuum dried at 60° C. for 10 hours to obtain hydroxyapatite microspheres with a particle size of 0.1-100 microns; wherein 1 L of organic acid solution is added to every 100 g of hydroxyapatite powder in the mixed solution.

[0045] Preparation Example 4

[0046] Preparation Example 4 provides a method for preparing hydroxyapatite microspheres, comprising the following steps:

[0047] Dissolving citric acid in water for injection to obtain an organic acid solution, wherein the concentration of citric acid in the organic acid solution is 0.15 mol / L;

[0048] The hydroxyapatite powder is mixed with an organic acid solution to obtain a mixed solution; the mixed solution is stirred and dispersed at 500 r / min and 110° C. for 35 minutes, filtered, and vacuum dried at 60° C. for 10 hours to obtain hydroxyapatite microspheres with a particle size of 0.1-100 microns; wherein 1L of organic acid solution is added to every 100g of hydroxyapatite powder in the mixed solution.

[0049] Preparation Example 5

[0050] Preparation Example 5 provides a method for preparing hydroxyapatite microspheres, comprising the following steps:

[0051] Dissolving oxalic acid in water for injection to obtain an organic acid solution, wherein the concentration of oxalic acid in the organic acid solution is 0.15 mol / L;

[0052] The hydroxyapatite powder is mixed with an organic acid solution to obtain a mixed solution; the mixed solution is stirred and dispersed at 500 r / min and 110° C. for 35 minutes, filtered, and vacuum dried at 60° C. for 10 hours to obtain hydroxyapatite microspheres with a particle size of 0.1-100 microns; wherein 1L of organic acid solution is added to every 100g of hydroxyapatite powder in the mixed solution. Example

[0053] Example 1 provides a method for preparing an injectable cross-linked hyaluronic acid hydroxyapatite gel, comprising the following steps:

[0054] Preparation of modified sodium hyaluronate hydroxyapatite microsphere gel: first, 40 kg of hydroxyapatite microspheres, 1 kg of hyaluronic acid, and 0.1 kg of a cross-linking agent are stirred under alkaline conditions of pH = 13-14 to perform a cross-linking reaction, and then dialyzed using a dialysate, and 30 kg of a lidocaine solution with a mass concentration of 6 mg / ml is added, and stirred and mixed evenly to obtain a modified sodium hyaluronate hydroxyapatite microsphere gel; wherein the dialysate is a phosphate buffer solution with a pH of 6.8 and an osmotic pressure of 270 m0sm / L; the particle size of the hydroxyapatite microspheres is 0.1-100 microns; and the cross-linking agent is 1,4-butanediol diglycidyl ether;

[0055] Preparation of sodium hyaluronate hydroxyapatite microsphere mixed solution: 15 kg of hydroxyapatite microspheres and 0.5 kg of sodium hyaluronate dry powder are added to an appropriate amount of buffer solution, and stirred to mix evenly, so that the hydroxyapatite microspheres and sodium hyaluronate dry powder components swell to obtain a sodium hyaluronate hydroxyapatite microsphere mixed solution; wherein the buffer solution is a phosphate buffer solution, pH=6.8;

[0056] Compounding: Add the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixture, stir, and boil at 120°C for 35 minutes. Finally, oscillate the obtained product discontinuously for 18 hours to obtain an injectable cross-linked hyaluronic acid hydroxyapatite gel; wherein the weight ratio of the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixture is 1:9. Example

[0057] The difference between Example 2 and Example 1 is that the modified sodium hyaluronate hydroxyapatite microsphere gel is prepared by first stirring 55 kg of hydroxyapatite microspheres, 2 kg of hyaluronic acid, and 0.15 kg of a cross-linking agent under alkaline conditions of pH = 13-14 to perform a cross-linking reaction, then dialyzing with a dialysate, and adding 35 kg of a lidocaine solution with a mass concentration of 6 mg / ml, stirring and mixing to obtain a modified sodium hyaluronate hydroxyapatite microsphere gel;

[0058] Preparation of sodium hyaluronate hydroxyapatite microsphere mixed solution: add 20 kg of hydroxyapatite microspheres and 1 kg of sodium hyaluronate dry powder into an appropriate amount of buffer solution, stir and mix evenly to allow the hydroxyapatite microspheres and sodium hyaluronate dry powder components to swell, and obtain a sodium hyaluronate hydroxyapatite microsphere mixed solution; the remaining steps are consistent with Example 1. Example

[0059] The difference between Example 3 and Example 1 is that the modified sodium hyaluronate hydroxyapatite microsphere gel is prepared by first stirring 70 kg of hydroxyapatite microspheres, 3 kg of hyaluronic acid, and 0.2 kg of a cross-linking agent under alkaline conditions of pH = 13-14 to perform a cross-linking reaction, then dialyzing with a dialysate, and adding 40 kg of a lidocaine solution with a mass concentration of 6 mg / ml, stirring and mixing to obtain a modified sodium hyaluronate hydroxyapatite microsphere gel;

[0060] Preparation of sodium hyaluronate hydroxyapatite microsphere mixed solution: add 25 kg of hydroxyapatite microspheres and 1.5 kg of sodium hyaluronate dry powder into an appropriate amount of buffer solution, stir and mix evenly to allow the hydroxyapatite microspheres and sodium hyaluronate dry powder components to swell, and obtain a sodium hyaluronate hydroxyapatite microsphere mixed solution; the remaining steps are consistent with Example 1. Example

[0061] The difference between Example 4 and Example 2 is that, compounding: adding the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixture, stirring, and boiling at 121° C. for 30 minutes, and finally oscillating the obtained product discontinuously for 20 hours to obtain an injectable cross-linked hyaluronic acid hydroxyapatite gel; the remaining steps are consistent with Example 2. Example

[0062] The difference between Example 5 and Example 2 is that, compounding: adding the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixture, stirring, and boiling at 122°C for 25 minutes, and finally oscillating the obtained product discontinuously for 22 hours to obtain an injectable cross-linked hyaluronic acid hydroxyapatite gel; the remaining steps are consistent with Example 2. Example

[0063] The difference between Example 6 and Example 4 is that the dialysate is a phosphate buffer solution with a pH of 7.2 and an osmotic pressure of 310 m0sm / L; the remaining steps are consistent with Example 4. Example

[0064] The difference between Example 7 and Example 4 is that the dialysate is a phosphate buffer solution with a pH of 7.6 and an osmotic pressure of 350 m0sm / L; the remaining steps are consistent with Example 4. Example

[0065] The difference between Example 8 and Example 6 is that in the compounding step, the weight ratio of the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixed solution is 1:10; the remaining steps are consistent with Example 6. Example

[0066] The difference between Example 9 and Example 6 is that in the compounding step, the weight ratio of the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixed solution is 1:11; the remaining steps are consistent with Example 6. Example

[0067] The difference between Example 10 and Example 8 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres in Preparation Example 1; the remaining steps are consistent with Example 8. Example

[0068] The difference between Example 11 and Example 8 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres in Preparation Example 2; the remaining steps are consistent with Example 8. Example

[0069] The difference between Example 12 and Example 8 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres in Preparation Example 3; the remaining steps are consistent with Example 8. Example

[0070] The difference between Example 13 and Example 8 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres in Preparation Example 4; the remaining steps are consistent with Example 8. Example

[0071] The difference between Example 14 and Example 8 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres in Preparation Example 5; the remaining steps are consistent with Example 8.

[0072] Comparative Example 1

[0073] Comparative Example 1 provides a method for preparing an injectable cross-linked hyaluronic acid hydroxyapatite gel, comprising the following steps:

[0074] Preparation of modified sodium hyaluronate hydroxyapatite microsphere gel: first, 40 kg of hydroxyapatite microspheres, 1 kg of hyaluronic acid, and 0.1 kg of cross-linking agent are stirred under alkaline conditions of pH = 13-14 to carry out a cross-linking reaction, then dialyzed with a dialysate, and 30 kg of lidocaine solution with a mass concentration of 6 mg / ml is added, and stirred and mixed evenly to obtain a cross-linked hyaluronic acid hydroxyapatite gel; wherein the dialysate is a phosphate buffer solution with a pH of 6.8 and an osmotic pressure of 270 m0sm / L; the particle size of the hydroxyapatite microspheres is 0.1-100 microns; and the cross-linking agent is 1,4-butanediol diglycidyl ether.

[0075] Aging resistance: The gels in the examples and comparative examples were placed in an environment of 60±2°C for accelerated aging, which lasted for 6 months.

[0076] Acute systemic toxicity test: After the test sample was extracted with the extract composed of sodium chloride injection and sesame oil, 5 mice were used for each extract, and the polar extract or polar solvent control solution was injected into the mouse body by subcutaneous injection, and the polar extract or non-polar solvent control solution was injected into the mouse body by subcutaneous injection. After the injection, the mouse was observed for immediate response (within 30 minutes), 4h, 24h, 48h, and 72h to observe the animal behavior characteristics, and the animal weight was recorded at the time of injection and 24h, 48h, and 72h after injection. Under the conditions of this test, the sample extract did not induce acute systemic toxicity in mice, and the test sample met the test requirements.

[0077] Stability: Measure the weight of the gel as a. After the gel is left to stand for 14 days, measure the weight of hydroxyapatite released from the gel as b. Calculate the hydroxyapatite release rate c = b / a*100%. The smaller the release rate c, the better the stability of the gel.

[0078] Table 1 Gel test results

[0079] sample Release rate c (%) Example 1 3.21 Example 2 3.13 Example 3 3.17 Example 4 3.01 Example 5 3.09 Example 6 2.78 Example 7 2.82 Example 8 2.21 Example 9 2.50 Example 10 1.68 Embodiment 11 1.23 Example 12 1.39 Example 13 1.91 Embodiment 14 1.99 Comparative Example 1 15.02

[0080] In combination with Examples 1-3 and Comparative Example 1, the stability of the gel in Examples 1-3 is good. It can be seen that using the preparation method in the present application, the hyaluronic acid is first cross-linked with part of the hydroxyapatite microspheres, and then the hydroxyapatite microspheres, sodium hyaluronate dry powder, and buffer solution are stirred and mixed evenly to form a sodium hyaluronate hydroxyapatite microsphere mixed solution, which has a good lubricating effect, and after mixing it with the modified sodium hyaluronate hydroxyapatite microsphere gel, it can react a second time to encapsulate more hydroxyapatite microspheres, thereby improving the stability of the obtained gel.

[0081] Combining Example 2, Example 4 and Example 5, the stability of the gel in Example 4 is the best. It can be seen that when the sodium hyaluronate hydroxyapatite microsphere gel and the sodium hyaluronate hydroxyapatite microsphere mixed solution are compositely modified, the boiling conditions in Example 4 are the best, so that the stability of the gel in Example 4 is the best.

[0082] Combining Example 4, Example 6 and Example 7, the stability of the gel in Example 6 is the best. It can be seen that when preparing the modified sodium hyaluronate hydroxyapatite microsphere gel, the dialysis conditions in Example 6 are the best, and thus the stability of the gel in Example 6 is the best.

[0083] In combination with Example 6, Example 8 and Example 9, the stability of the gel in Example 8 is the best. It can be seen that when the sodium hyaluronate hydroxyapatite microsphere gel and the sodium hyaluronate hydroxyapatite microsphere mixed solution are composite-modified, the amount of the sodium hyaluronate hydroxyapatite microsphere mixed solution used is increased, and the stability of the obtained gel shows a trend of first increasing and then decreasing.

[0084] Combining Example 8 with Examples 10-12, the stability of the gel in Examples 10-12 is better, which shows that when preparing the gel, the hydroxyapatite microspheres are selected from hydroxyapatite microspheres modified with organic acids, which can further improve the stability of the gel.

[0085] Combining Example 11, Example 13 and Example 14, the stability of the gel in Example 11 is the best. It can be seen that when the hydroxyapatite microspheres are modified, the organic acid in the organic acid solution is preferably a composite organic acid composed of citric acid and oxalic acid, which can further improve the stability of the gel.

[0086] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. An injectable cross-linked hyaluronic acid hydroxyapatite gel, characterized in that: The invention comprises a modified sodium hyaluronate hydroxyapatite microsphere gel and a sodium hyaluronate hydroxyapatite microsphere mixed solution, wherein the weight ratio of the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixed solution is 1:(9-11); the modified sodium hyaluronate hydroxyapatite microsphere gel is obtained by cross-linking, and the raw materials thereof comprise the following components in parts by weight: 40-70 parts of hydroxyapatite microspheres, 1-3 parts of hyaluronic acid, 0.1-0.2 parts of a cross-linking agent, and 30-40 parts of a lidocaine solution; the raw materials of the sodium hyaluronate hydroxyapatite microsphere mixed solution comprise the following components in parts by weight: 15-25 parts of hydroxyapatite microspheres, and 0.5-1.5 parts of sodium hyaluronate dry powder; the particle size of the hydroxyapatite microspheres is 0.1-100 microns; the preparation method of the hydroxyapatite microspheres comprises the following steps: Mixing hydroxyapatite powder with an organic acid solution to obtain a mixed solution; stirring and dispersing the mixed solution at 450-550 r / min and 100-120° C. for 30-40 minutes, filtering, and vacuum drying to obtain hydroxyapatite microspheres; the organic acid is a mixture of citric acid and oxalic acid; The injectable cross-linked hyaluronic acid hydroxyapatite gel is compounded by modified sodium hyaluronate hydroxyapatite microsphere gel and a sodium hyaluronate hydroxyapatite microsphere mixed solution, and the specific steps are: adding the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixed solution, stirring, boiling, and finally discontinuously oscillating the obtained product to obtain the injectable cross-linked hyaluronic acid hydroxyapatite gel.

2. The injectable cross-linked hyaluronic acid hydroxyapatite gel according to claim 1, characterized in that: The cross-linking agent includes one or more of 1,4-butanediol diglycidyl ether, polyethylene glycol diglycidyl ether, and ethylene glycol diglycidyl ether.

3. The injectable cross-linked hyaluronic acid hydroxyapatite gel according to claim 1, characterized in that: The mass concentration of the lidocaine solution is 5-7 mg / ml.

4. The injectable cross-linked hyaluronic acid hydroxyapatite gel according to claim 1, characterized in that: The concentration of citric acid in the organic acid solution is 0.1 mol / L, and the concentration of oxalic acid is 0.05 mol / L.

5. A method for preparing the injectable cross-linked hyaluronic acid hydroxyapatite gel according to any one of claims 1 to 4, characterized in that: The following steps are involved: Preparation of modified sodium hyaluronate hydroxyapatite microsphere gel: firstly, hydroxyapatite microspheres, hyaluronic acid and a cross-linking agent are stirred under alkaline conditions to perform a cross-linking reaction, then dialyzed with a dialysate, and lidocaine solution is added at the same time, stirred and mixed uniformly to obtain a modified sodium hyaluronate hydroxyapatite microsphere gel; Preparation of sodium hyaluronate hydroxyapatite microsphere mixed solution: adding hydroxyapatite microspheres and sodium hyaluronate dry powder into a buffer solution, stirring and mixing evenly to obtain a sodium hyaluronate hydroxyapatite microsphere mixed solution; Compounding: Add the modified sodium hyaluronate hydroxyapatite microsphere gel to the sodium hyaluronate hydroxyapatite microsphere mixture, stir, and boil at 120-122° C. for 25-35 minutes. Finally, oscillate the obtained product discontinuously for 18-22 hours to obtain an injectable cross-linked hyaluronic acid hydroxyapatite gel.

6. The method for preparing an injectable cross-linked hyaluronic acid hydroxyapatite gel according to claim 5, characterized in that: In the step of preparing the modified sodium hyaluronate hydroxyapatite microsphere gel, the dialysate includes a phosphate buffer solution with a pH of 6.8-7.6 and an osmotic pressure of 270-350m0sm / L.