Hydroxyapatite sodium hyaluronate injection gel and preparation method thereof

Abstract

The invention relates to the technical field of injection gel, and particularly discloses hydroxyapatite sodium hyaluronate injection gel and a preparation method thereof. The hydroxyapatite sodium hyaluronate injection gel is prepared from the following raw materials: hydroxyapatite sodium hyaluronate composite gel and a sodium hyaluronate anesthetic mixed solution, the hydroxyapatite and sodium hyaluronate composite gel is prepared from the following raw material components in parts by weight: 100 to 500 parts of hydroxyapatite microspheres, 8 to 24 parts of cross-linked sodium hyaluronate and 8 to 24 parts of collagen, the sodium hyaluronate anesthetic mixed solution is prepared from the following raw material components in parts by weight: 0.5 to 1.5 parts of sodium hyaluronate dry powder and 1 to 5 parts of anesthetic.

Description

Technical Field

[0001] The present application relates to the technical field of injectable gels, and in particular to a hydroxyapatite sodium hyaluronate injectable gel and a preparation method thereof. Background Art

[0002] As we age and are affected by the external environment, collagen in the skin gradually disappears, elastic fibers gradually age, and the moisture and subcutaneous fat of the skin decrease, causing the skin to sag and form wrinkles. Injection beauty is the process of injecting skin fillers with cosmetic wrinkle removal effects into the dermis or subcutaneous tissue to eliminate or reduce wrinkles and sagging of the skin. Commonly used skin fillers with cosmetic wrinkle removal effects include hyaluronic acid, collagen, etc. The preparation of fillers with only one active substance has problems such as unsatisfactory effects or short shelf life. Therefore, it is urgent to develop a product with good effects and long duration of action. Summary of the invention

[0003] In order to improve the effect and duration of action of the injection gel, the present application provides a hydroxyapatite sodium hyaluronate injection gel and a preparation method thereof.

[0004] In the first aspect, the present application provides a hydroxyapatite sodium hyaluronate injection gel, which adopts the following technical solution: A hydroxyapatite sodium hyaluronate injection gel, wherein the raw materials of the injection gel include hydroxyapatite sodium hyaluronate composite gel and a sodium hyaluronate anesthetic mixed solution; the raw materials of the hydroxyapatite sodium hyaluronate composite gel include the following components in parts by weight: 100-500 parts of hydroxyapatite microspheres, 8-24 parts of cross-linked sodium hyaluronate, and 8-24 parts of collagen; the raw materials of the sodium hyaluronate anesthetic mixed solution include the following components in parts by weight: 0.5-1.5 parts of sodium hyaluronate dry powder and 1-5 parts of anesthetic.

[0005] By adopting the above technical solution, sodium hyaluronate dry powder is used as a filling material to achieve an immediate filling effect, and the anesthetic can reduce pain during injection; cross-linked sodium hyaluronate is used to wrap the hydroxyapatite microspheres, so that the hydroxyapatite microspheres can be evenly dispersed, reducing the occurrence of precipitation; collagen can replenish the collagen lost in the skin, and hydroxyapatite microspheres can continuously stimulate the production of collagen, thereby improving the effect of the injection gel and prolonging the action time.

[0006] In a specific embodiment, the preparation method of the cross-linked sodium hyaluronate comprises the following steps: The sodium hyaluronate dry powder and the cross-linking agent are stirred and mixed evenly, and a cross-linking reaction is carried out under alkaline conditions. After the reaction is completed, dialyzation and granulation are carried out to obtain cross-linked sodium hyaluronate.

[0007] 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.

[0008] In a specific embodiment, the dialysis is performed using a dialysate, the dialysate is a phosphate buffer, the pH of the dialysate is 6.8-7.6, and the osmotic pressure is 270-350 mOsmol / L.

[0009] By adopting the above technical solution, the pH and osmotic pressure of the dialysate are further limited, the dialysis effect can be improved, and thus the quality of the cross-linked sodium hyaluronate is improved.

[0010] In a specific embodiment, the collagen includes one or more of recombinant humanized type I collagen, recombinant humanized type III collagen, recombinant humanized type IV collagen, recombinant humanized type V collagen, and recombinant humanized type XI collagen.

[0011] In a specific embodiment, the method for preparing hydroxyapatite microspheres comprises the following steps: The hydroxyapatite powder and the modifier are stirred and mixed evenly, and reacted at 40-60° C. for 8-12 hours to obtain hydroxyapatite microspheres; wherein the weight ratio of the hydroxyapatite powder to the modifier is 1:(2-3).

[0012] In a specific embodiment, the modifier includes a mixture of carboxybetaine and sulfobetaine, and the weight ratio of carboxybetaine to sulfobetaine is 1:(0.1-0.3).

[0013] By adopting the above technical scheme, hydroxyapatite is modified by using a composite modifier composed of carboxybetaine and sulfobetaine, and the obtained hydroxyapatite microspheres not only have good dispersibility but also have good biocompatibility.

[0014] In a second aspect, the present application provides a method for preparing a hydroxyapatite sodium hyaluronate injection gel, which adopts the following technical solution: A method for preparing sodium hydroxyapatite hyaluronate injection gel comprises the following steps: Prepare collagen solution: Under a laminar flow hood, weigh collagen and dissolve it in water for injection, stir until completely dissolved and filter to obtain collagen solution; Preparation of hydroxyapatite sodium hyaluronate composite gel: adding hydroxyapatite microspheres to collagen solution, and obtaining absorption liquid after complete absorption; adding the absorption liquid to cross-linked sodium hyaluronate, stirring and mixing evenly, and vacuum drying to obtain hydroxyapatite sodium hyaluronate composite gel; Prepare sodium hyaluronate anesthetic mixed solution: add sodium hyaluronate dry powder and anesthetic into buffer solution and stir to mix evenly to obtain sodium hyaluronate anesthetic mixed solution; Compounding: Add the hydroxyapatite sodium hyaluronate compound gel into the sodium hyaluronate anesthetic mixture, stir and mix evenly to obtain an injectable gel.

[0015] By adopting the above technical scheme, collagen is first dissolved with injection water to obtain a collagen solution, and then hydroxyapatite microspheres are added to obtain an absorption liquid, and then the absorption liquid is added to cross-linked sodium hyaluronate, stirred, and vacuum-dried to obtain a hydroxyapatite sodium hyaluronate composite gel; sodium hyaluronate dry powder and anesthetics are added to a buffer solution and stirred to obtain a sodium hyaluronate anesthetic mixed solution, and finally mixed and compounded with the hydroxyapatite sodium hyaluronate composite gel to obtain an injection gel with better effect.

[0016] In a specific embodiment, in the step of preparing the collagen solution, filtration is performed using a 0.22 um aqueous filter membrane.

[0017] In a specific embodiment, in the compounding step, the weight ratio of the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture is 1:(9-11).

[0018] By adopting the above technical solution, the ratio of the hydroxyapatite sodium hyaluronate composite gel and the sodium hyaluronate anesthetic mixed solution is further limited, which can improve the effect of the final injection gel.

[0019] In summary, the present application includes at least one of the following beneficial technical effects: In the present application, sodium hyaluronate dry powder is used as a filling material, which has an immediate filling effect, and the anesthetic can reduce pain during injection; cross-linked sodium hyaluronate is used to wrap the hydroxyapatite microspheres, so that the hydroxyapatite microspheres can be evenly dispersed, reducing the occurrence of precipitation, and making it easier for doctors to push the gel during the actual injection process; collagen can replenish the collagen lost by the skin, and hydroxyapatite microspheres can continuously stimulate the production of collagen, thereby improving the effect of the injection gel and prolonging the action time; In the present application, a composite modifier composed of carboxybetaine and sulfobetaine is used to modify hydroxyapatite, and the obtained hydroxyapatite microspheres not only have good dispersibility but also have good biocompatibility; The method of the present application first dissolves collagen with water for injection to obtain a collagen solution, then adds hydroxyapatite microspheres to obtain an absorption liquid, and then adds the absorption liquid to cross-linked sodium hyaluronate, stirs, and vacuum-dries to obtain a hydroxyapatite sodium hyaluronate composite gel; sodium hyaluronate dry powder and an anesthetic are added to a buffer solution and stirred to obtain a sodium hyaluronate anesthetic mixed solution, and finally mixed and compounded with the hydroxyapatite sodium hyaluronate composite gel to obtain an injection gel with better effect. DETAILED DESCRIPTION

[0020] The present application is further described in detail below with reference to the embodiments.

[0021] All raw materials in the embodiment can be obtained commercially. Among them, 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. 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; collagen includes but is not limited to a mixture of one or more of recombinant type I humanized collagen, recombinant type III humanized collagen, recombinant type IV humanized collagen, recombinant type V humanized collagen, and recombinant type XI humanized collagen, and in this application, a mixture of recombinant type I humanized collagen and recombinant type III humanized collagen is preferred. Preparation Example

[0022] Preparation Example 1 Preparation Example 1 provides a method for preparing cross-linked sodium hyaluronate, comprising the following steps: The sodium hyaluronate powder and the cross-linking agent are stirred and mixed evenly, and a cross-linking reaction is carried out under alkaline conditions of pH=13-14. After the reaction is completed, dialyzate is used for granulation to obtain cross-linked sodium hyaluronate; wherein the weight ratio of the sodium hyaluronate powder and the cross-linking agent is 1:0.1; the cross-linking agent is 1,4-butanediol diglycidyl ether; the dialysate is a phosphate buffer solution, the dialysate pH is 6.8, and the osmotic pressure is 270mOsmol / L.

[0023] Preparation Example 2 Preparation Example 2 provides a method for preparing cross-linked sodium hyaluronate, comprising the following steps: Sodium hyaluronate dry powder and cross-linking agent are stirred and mixed evenly, and cross-linking reaction is carried out under alkaline conditions of pH=13-14. After the reaction is completed, dialyzate is used for granulation to obtain cross-linked sodium hyaluronate; wherein the weight ratio of sodium hyaluronate dry powder and cross-linking agent is 1:0.1; the cross-linking agent is 1,4-butanediol diglycidyl ether; the dialysate is phosphate buffer, the dialysate pH is 7.2, and the osmotic pressure is 310mOsmol / L.

[0024] Preparation Example 3 Preparation Example 3 provides a method for preparing cross-linked sodium hyaluronate, comprising the following steps: The sodium hyaluronate powder and the cross-linking agent are stirred and mixed evenly, and a cross-linking reaction is carried out under alkaline conditions of pH=13-14. After the reaction is completed, dialyzate is used for granulation to obtain cross-linked sodium hyaluronate; wherein the weight ratio of the sodium hyaluronate powder and the cross-linking agent is 1:0.1; the cross-linking agent is 1,4-butanediol diglycidyl ether; the dialysate is a phosphate buffer solution, the dialysate pH is 7.6, and the osmotic pressure is 350mOsmol / L.

[0025] Preparation Example 4 Preparation Example 4 provides a method for preparing hydroxyapatite microspheres, comprising the following steps: The hydroxyapatite powder and the modifier are stirred and mixed evenly, and reacted at 50°C for 10 hours to obtain hydroxyapatite microspheres with a particle size of 0.1-100 μm; wherein the weight ratio of the hydroxyapatite powder to the modifier is 1:2.5; the modifier includes a mixture of carboxybetaine and sulfobetaine, and the weight ratio of the carboxybetaine to the sulfobetaine is 1:0.2.

[0026] Preparation Example 5 Preparation Example 5 provides a method for preparing hydroxyapatite microspheres, comprising the following steps: The hydroxyapatite powder and the modifier are stirred and mixed evenly, and reacted at 60° C. for 10 hours to obtain hydroxyapatite microspheres with a particle size of 0.1-100 μm; wherein the weight ratio of the hydroxyapatite powder to the modifier is 1:2.5; and the modifier is carboxybetaine.

[0027] Preparation Example 6 Preparation Example 6 provides a method for preparing hydroxyapatite microspheres, comprising the following steps: The hydroxyapatite powder and the modifier are stirred and mixed evenly, and reacted at 40°C for 10 hours to obtain hydroxyapatite microspheres with a particle size of 0.1-100 μm; wherein the weight ratio of the hydroxyapatite powder to the modifier is 1:2.5; and the modifier is sulfobetaine. Example

[0028] Example 1 Example 1 provides a method for preparing a hydroxyapatite sodium hyaluronate injection gel, comprising the following steps: Preparation of collagen solution: Under a laminar flow hood, weigh 8 g of collagen and dissolve it in 1 L of water for injection. Stir until completely dissolved and filter with a 0.22 um aqueous filter membrane to obtain a collagen solution; wherein the collagen is a mixture of recombinant humanized type I collagen and recombinant humanized type III collagen, and the weight ratio of recombinant humanized type I collagen to recombinant humanized type III collagen is 1:2; Preparation of hydroxyapatite sodium hyaluronate composite gel: adding 100g of hydroxyapatite microspheres to the collagen solution, and obtaining an absorption liquid after complete absorption; adding the absorption liquid to 8g of the cross-linked sodium hyaluronate in Preparation Example 1, stirring and mixing evenly, and drying at a vacuum degree of -0.09 kPa and 35° C. for 5.5 hours to obtain a hydroxyapatite sodium hyaluronate composite gel; wherein the particle size of the hydroxyapatite microspheres is 0.1-100 μm; Preparation of sodium hyaluronate anesthetic mixed solution: add 0.5g sodium hyaluronate dry powder and 1g anesthetic into an appropriate amount of buffer solution and stir to mix evenly, so that the sodium hyaluronate dry powder and anesthetic components swell to obtain a sodium hyaluronate anesthetic mixed solution; wherein the anesthetic is lidocaine; Compounding: Add the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture, stir and mix evenly to obtain an injectable gel; wherein the weight ratio of the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture is 1:9.

[0029] Example 2 Example 2 provides a method for preparing a hydroxyapatite sodium hyaluronate injection gel, comprising the following steps: Preparation of collagen solution: Under a laminar flow hood, weigh 16 g of collagen and dissolve it in 1 L of water for injection, stir until completely dissolved, and filter with a 0.22 um aqueous filter membrane to obtain a collagen solution; wherein the collagen is a mixture of recombinant humanized type I collagen and recombinant humanized type III collagen, and the weight ratio of recombinant humanized type I collagen to recombinant humanized type III collagen is 1:2; Preparation of hydroxyapatite sodium hyaluronate composite gel: adding 300g of hydroxyapatite microspheres to the collagen solution, and obtaining an absorption liquid after complete absorption; adding the absorption liquid to 16g of the cross-linked sodium hyaluronate in Preparation Example 1, stirring and mixing evenly, and drying at a vacuum degree of -0.09kPa and 35°C for 5.5h to obtain a hydroxyapatite sodium hyaluronate composite gel; wherein the particle size of the hydroxyapatite microspheres is 0.1-100μm; Preparation of sodium hyaluronate anesthetic mixed solution: add 1g sodium hyaluronate dry powder and 3g anesthetic into an appropriate amount of buffer solution and stir to mix evenly, so that the sodium hyaluronate dry powder and anesthetic components swell to obtain a sodium hyaluronate anesthetic mixed solution; wherein the anesthetic is lidocaine; Compounding: Add the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture, stir and mix evenly to obtain an injectable gel; wherein the weight ratio of the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture is 1:9.

[0030] Example 3 Example 3 provides a method for preparing sodium hydroxyapatite hyaluronate injection gel, comprising the following steps: Preparation of collagen solution: Under a laminar flow hood, weigh 24 g of collagen and dissolve it in 1 L of water for injection, stir until completely dissolved, and filter with a 0.22 um aqueous filter membrane to obtain a collagen solution; wherein the collagen is a mixture of recombinant humanized type I collagen and recombinant humanized type III collagen, and the weight ratio of recombinant humanized type I collagen to recombinant humanized type III collagen is 1:2; Preparation of hydroxyapatite sodium hyaluronate composite gel: adding 500g of hydroxyapatite microspheres to the collagen solution, and obtaining an absorption liquid after complete absorption; adding the absorption liquid to 24g of the cross-linked sodium hyaluronate in Preparation Example 1, stirring and mixing evenly, and drying at a vacuum degree of -0.09kPa and 35°C for 5.5h to obtain a hydroxyapatite sodium hyaluronate composite gel; wherein the particle size of the hydroxyapatite microspheres is 0.1-100μm; Preparation of sodium hyaluronate anesthetic mixed solution: 1.5 g of sodium hyaluronate dry powder and 5 g of anesthetic are added to an appropriate amount of buffer solution and stirred to mix evenly, so that the sodium hyaluronate dry powder and anesthetic components swell to obtain a sodium hyaluronate anesthetic mixed solution; wherein the anesthetic is lidocaine; Compounding: Add the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture, stir and mix evenly to obtain an injectable gel; wherein the weight ratio of the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture is 1:9.

[0031] The difference between Example 4 and Example 2 is that the cross-linked sodium hyaluronate is the cross-linked sodium hyaluronate in Preparation Example 2; the remaining steps are consistent with Example 2.

[0032] The difference between Example 5 and Example 2 is that the cross-linked sodium hyaluronate is the cross-linked sodium hyaluronate in Preparation Example 3; the remaining steps are consistent with Example 2.

[0033] The difference between Example 6 and Example 4 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres prepared in Preparation Example 4; the remaining steps are consistent with those of Example 4.

[0034] The difference between Example 7 and Example 4 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres in Preparation Example 5; the remaining steps are consistent with Example 4.

[0035] The difference between Example 8 and Example 4 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres in Preparation Example 6; the remaining steps are consistent with Example 4.

[0036] The difference between Example 9 and Example 6 is that the collagen is recombinant type I humanized collagen; the remaining steps are consistent with Example 6.

[0037] The difference between Example 10 and Example 6 is that the collagen is recombinant type III humanized collagen; the remaining steps are consistent with Example 6.

[0038] The difference between Example 11 and Example 6 is that in the compounding step, the weight ratio of the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture is 1:10; the remaining steps are consistent with Example 6.

[0039] The difference between Example 12 and Example 6 is that in the compounding step, the weight ratio of the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture is 1:11; the remaining steps are consistent with Example 6. Comparative Example 1

[0040] Comparative Example 1 provides a method for preparing an injectable cosmetic plastic surgery material, comprising the following steps: The collagen sponge was crushed into powder using a crusher, the speed of the crusher was set to 7000 rpm, and the time was set to 2 s to obtain collagen powder; The spherical hydroxyapatite powder with a particle size of 30 μm and the collagen powder prepared in the above steps are sterilized by cobalt 60 irradiation to ensure that the raw materials are sterile; Remove the parts of the reactor that come into contact with the product, wrap them together with the scissors, tweezers, wrenches, etc. used in the preparation, attach moist heat sterilization indicator stickers, place them in a steam sterilizer, and sterilize them at 120℃ for 30 minutes; 40 g of sterilized collagen powder and 1000 mL of sterile water for injection were added to the reactor in batches alternately in 4 times until the addition was completed, the reactor was sealed, stirring was started, the speed was 120 r / min, and the reaction was stirred for 24 hours. At the same time, the UV lamp and high-efficiency air conditioner on the operating table were turned on to obtain a gel that was visually uniform and had no stratification, precipitation, suspension, etc.; Open the top cover or the feeding port of the reactor, add 180 g of hydroxyapatite microspheres into the gel, and stir for 2 hours to obtain an injectable cosmetic plastic surgery material.

[0041] Effect: The materials in the embodiments and comparative examples were tested according to GB / T16886.6-2022, and the average score differences at 4 weeks, 8 weeks, 16 weeks, 32 weeks, 38 weeks, 57 weeks and 90 weeks were obtained. The smaller the average score difference, the better the effect of the injection gel.

[0042] Table 1 Test results of injection gel

[0043] Combining Example 1 and Comparative Example 1, the effect of the injection gel in Example 1 is better and the action time is longer. It can be seen that the injection gel in the present application, sodium hyaluronate dry powder is used as a filling material, which has an immediate filling effect, and the cross-linked sodium hyaluronate wraps the hydroxyapatite microspheres, so that the hydroxyapatite microspheres can be evenly dispersed, allowing the doctor to push more smoothly during the injection process; collagen can replenish the collagen lost in the skin, and hydroxyapatite microspheres can continuously stimulate the production of collagen, thereby improving the effect of the injection gel and prolonging the action time.

[0044] In combination with Examples 1-3, the effect of the injection gel in Example 2 is the best. It can be seen that when preparing the injection gel, increasing the amount of raw materials used will increase the effect of the injection gel first and then decrease.

[0045] Combining Example 2, Example 4 and Example 5, the effect of the injection gel in Example 4 is the best. It can be seen that when preparing cross-linked sodium hyaluronate, the dialysis conditions in Preparation Example 2 are the best, so the quality of the obtained cross-linked sodium hyaluronate is the best.

[0046] Combining Example 4 and Example 6, the effect of the injection gel in Example 6 is better. It can be seen that when preparing the hydroxyapatite sodium hyaluronate composite gel, the hydroxyapatite microspheres are selected from hydroxyapatite microspheres modified by a modifier, and the hydroxyapatite is modified by a composite modifier composed of carboxybetaine and sulfobetaine, so that the hydroxyapatite microspheres not only have good dispersion properties, but also have good biocompatibility, thereby further improving the effect of the injection gel.

[0047] Combined with Examples 6-8, the effect of the injection gel in Example 6 is the best. It can be seen that when the hydroxyapatite microspheres are modified by a modifier, the modifier is preferably a mixture of carboxybetaine and sulfobetaine, which has a better modification effect on the hydroxyapatite microspheres.

[0048] In combination with Example 6, Example 9 and Example 10, the effect of the injection gel in Example 6 is the best. It can be seen that when preparing the collagen solution, the collagen is preferably a mixture of recombinant type I humanized collagen and recombinant type III humanized collagen, so that the effect of the injection gel is better.

[0049] In combination with Example 6, Example 11 and Example 12, the effect of the injection gel in Example 11 is the best. It can be seen that when the hydroxyapatite sodium hyaluronate composite gel and the sodium hyaluronate anesthetic mixture are compounded, the ratio of the hydroxyapatite sodium hyaluronate composite gel and the sodium hyaluronate anesthetic mixture in Example 11 is optimal, thereby obtaining a better effect of the injection gel.

[0050] 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. Hydroxyapatite sodium hyaluronate injection gel, characterized by: The raw materials of the injection gel include hydroxyapatite sodium hyaluronate composite gel and sodium hyaluronate anesthetic mixed solution; the raw materials of the hydroxyapatite sodium hyaluronate composite gel include the following components in parts by weight: 100-500 parts of hydroxyapatite microspheres, 8-24 parts of cross-linked sodium hyaluronate, and 8-24 parts of collagen; the raw materials of the sodium hyaluronate anesthetic mixed solution include the following components in parts by weight: 0.5-1.5 parts of sodium hyaluronate dry powder and 1-5 parts of anesthetic; the preparation method of the cross-linked sodium hyaluronate includes the following steps: stirring and mixing the sodium hyaluronate dry powder and the cross-linking agent evenly, and performing a cross-linking reaction under alkaline conditions, After the reaction is completed, dialysis and granulation are carried out to obtain cross-linked sodium hyaluronate; the collagen includes a mixture of recombinant type I humanized collagen and recombinant type III humanized collagen; the preparation method of the hydroxyapatite microspheres includes the following steps: stirring and mixing the hydroxyapatite powder and the modifier evenly, reacting at 40-60°C for 8-12h to obtain hydroxyapatite microspheres; wherein the weight ratio of the hydroxyapatite powder to the modifier is 1: (2-3), the modifier includes a mixture of carboxybetaine and sulfobetaine, and the weight ratio of carboxybetaine to sulfobetaine is 1: (0.1-0.3).

2. The sodium hydroxyapatite hyaluronate injection 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 sodium hydroxyapatite hyaluronate injection gel according to claim 1, characterized in that: The dialysis is performed using a dialysate, which is a phosphate buffer solution, with a pH of 6.8-7.6 and an osmotic pressure of 270-350 mOsmol / L.

4. A method for preparing the sodium hydroxyapatite hyaluronate injection gel according to any one of claims 1 to 3, characterized in that: The following steps are involved: Prepare collagen solution: Under a laminar flow hood, weigh collagen and dissolve it in water for injection, stir until completely dissolved and filter to obtain collagen solution; Preparation of hydroxyapatite sodium hyaluronate composite gel: adding hydroxyapatite microspheres to the collagen solution, and obtaining an absorption liquid after complete absorption; adding the absorption liquid to the cross-linked sodium hyaluronate, stirring and mixing evenly, and vacuum drying to obtain the hydroxyapatite sodium hyaluronate composite gel; Prepare sodium hyaluronate anesthetic mixed solution: add sodium hyaluronate dry powder and anesthetic into buffer solution and stir to mix evenly to obtain sodium hyaluronate anesthetic mixed solution; Compounding: Add the hydroxyapatite sodium hyaluronate compound gel into the sodium hyaluronate anesthetic mixture, stir and mix evenly to obtain an injectable gel.

5. The method for preparing a sodium hydroxyapatite hyaluronate injection gel according to claim 4, characterized in that: In the step of preparing the collagen solution, filtration is performed using a 0.22 um aqueous filter membrane.

6. The method for preparing a sodium hydroxyapatite hyaluronate injection gel according to claim 4, characterized in that: In the compounding step, the weight ratio of the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture is 1:(9-11).

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