A kind of hydroxyapatite sodium hyaluronate injection gel and preparation method thereof

Abstract

This application relates to the technical field of injectable gels, specifically disclosing a hydroxyapatite sodium hyaluronate injectable gel and a preparation method thereof. The hydroxyapatite sodium hyaluronate injectable gel comprises raw materials including a hydroxyapatite sodium hyaluronate composite gel and a sodium hyaluronate anesthetic mixture. The raw materials for the hydroxyapatite sodium hyaluronate composite gel include the following components in parts by weight: 100-500 parts hydroxyapatite microspheres, 8-24 parts cross-linked sodium hyaluronate, and 8-24 parts collagen. The raw materials for the sodium hyaluronate anesthetic mixture include the following components in parts by weight: 0.5-1.5 parts sodium hyaluronate dry powder and 1-5 parts 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] With aging and the influence of the external environment, the skin gradually loses collagen, elastic fibers age, and moisture and subcutaneous fat decrease, causing skin sagging and wrinkles. Injectable cosmetic treatments involve injecting wrinkle-removing dermal fillers into the dermis or subcutaneous tissue to eliminate or reduce wrinkles and sagging. Commonly used wrinkle-removing dermal fillers include hyaluronic acid and collagen. Fillers formulated with only one active substance can be ineffective or have a short shelf life. Therefore, there is an urgent need to develop products with improved efficacy and long-lasting effects. Summary of the Invention

[0003] In order to improve the effect and duration 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:

[0005] 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 mixture; 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 mixture include the following components in parts by weight: 0.5-1.5 parts of sodium hyaluronate dry powder and 1-5 parts of anesthetic.

[0006] 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 wraps 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.

[0007] In a specific embodiment, the preparation method of the cross-linked sodium hyaluronate comprises the following steps:

[0008] 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, the mixture is dialyzed and granulated to obtain cross-linked sodium hyaluronate.

[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 dialysis is performed using a dialysate, which is a phosphate buffer solution, having a pH of 6.8-7.6 and an osmotic pressure of 270-350 mOsmol / L.

[0011] 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.

[0012] 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.

[0013] In a specific embodiment, the method for preparing the hydroxyapatite microspheres comprises the following steps:

[0014] The hydroxyapatite powder and the modifier are stirred and mixed uniformly, 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).

[0015] 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).

[0016] By adopting the above technical solution and using a composite modifier composed of carboxybetaine and sulfobetaine to modify hydroxyapatite, the obtained hydroxyapatite microspheres not only have good dispersibility but also have good biocompatibility.

[0017] In a second aspect, the present application provides a method for preparing a hydroxyapatite sodium hyaluronate injection gel, which adopts the following technical solution:

[0018] A method for preparing sodium hydroxyapatite hyaluronate injection gel comprises the following steps:

[0019] 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.

[0020] 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;

[0021] Prepare sodium hyaluronate anesthetic mixture: add sodium hyaluronate dry powder and anesthetic into buffer solution and stir to mix evenly to obtain sodium hyaluronate anesthetic mixture;

[0022] Compounding: Add the hydroxyapatite sodium hyaluronate composite gel into the sodium hyaluronate anesthetic mixture, stir and mix evenly to obtain the injection gel.

[0023] By adopting the above technical solution, collagen is first dissolved with injection water to obtain a collagen solution, and then hydroxyapatite microspheres are added to obtain an absorption liquid. The absorption liquid is then added to cross-linked sodium hyaluronate, stirred, and vacuum-dried to obtain a hydroxyapatite sodium hyaluronate composite gel; sodium hyaluronate dry powder and anesthetic are added to a buffer solution and stirred to obtain a sodium hyaluronate anesthetic mixture, and finally mixed and compounded with the hydroxyapatite sodium hyaluronate composite gel to obtain an injection gel with better effect.

[0024] In a specific embodiment, in the step of preparing the collagen solution, filtration is performed using a 0.22 um aqueous filter membrane.

[0025] 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).

[0026] By adopting the above technical solution, the ratio of the hydroxyapatite sodium hyaluronate composite gel and the sodium hyaluronate anesthetic mixture is further limited, which can improve the effect of the final injection gel.

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

[0028] In this 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 collagen lost in the skin, and hydroxyapatite microspheres can continuously stimulate collagen production, thereby improving the effect of the injection gel and prolonging the duration of action;

[0029] In this 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;

[0030] 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 mixture, and finally mixed and compounded with the hydroxyapatite sodium hyaluronate composite gel to obtain an injectable gel with better effect. DETAILED DESCRIPTION

[0031] The present application is further described in detail below with reference to the embodiments.

[0032] All raw materials in the examples can be obtained commercially. Sodium hyaluronate dry powder has a CAS number of 9067-32-7. The raw materials for the 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. Cross-linking agents include, but are 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 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, and in this application, a mixture of recombinant humanized type I collagen and recombinant humanized type III collagen is preferred.

[0033] Preparation Example

[0034] Preparation Example 1

[0035] Preparation Example 1 provides a method for preparing cross-linked sodium hyaluronate, comprising the following steps:

[0036] Sodium hyaluronate dry powder and a 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, dialyzation is carried out with a dialysate and granulation is performed to obtain cross-linked sodium hyaluronate; wherein the weight ratio of sodium hyaluronate dry powder to 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.

[0037] Preparation Example 2

[0038] Preparation Example 2 provides a method for preparing cross-linked sodium hyaluronate, comprising the following steps:

[0039] Sodium hyaluronate dry powder and a 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, dialyzation is carried out with a dialysate and granulation is performed to obtain cross-linked sodium hyaluronate; wherein the weight ratio of sodium hyaluronate dry powder to 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 7.2, and the osmotic pressure is 310mOsmol / L.

[0040] Preparation Example 3

[0041] Preparation Example 3 provides a method for preparing cross-linked sodium hyaluronate, comprising the following steps:

[0042] Sodium hyaluronate dry powder and a 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, dialyzation is carried out with a dialysate and granulation is performed to obtain cross-linked sodium hyaluronate; wherein the weight ratio of sodium hyaluronate dry powder to 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.

[0043] Preparation Example 4

[0044] Preparation Example 4 provides a method for preparing hydroxyapatite microspheres, comprising the following steps:

[0045] 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; 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.

[0046] Preparation Example 5

[0047] Preparation Example 5 provides a method for preparing hydroxyapatite microspheres, comprising the following steps:

[0048] 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.

[0049] Preparation Example 6

[0050] Preparation Example 6 provides a method for preparing hydroxyapatite microspheres, comprising the following steps:

[0051] 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

[0052] Example 1

[0053] Example 1 provides a method for preparing a hydroxyapatite sodium hyaluronate injection gel, comprising the following steps:

[0054] Prepare 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, then filter through a 0.22 μm aqueous filter membrane to obtain a collagen solution. The collagen solution is a mixture of recombinant humanized type I collagen and recombinant humanized type III collagen, with a weight ratio of recombinant humanized type I collagen to recombinant humanized type III collagen of 1:2.

[0055] Preparation of hydroxyapatite sodium hyaluronate composite gel: adding 100 g of hydroxyapatite microspheres to a collagen solution, and after complete absorption, obtaining an absorption liquid; adding the absorption liquid to 8 g of the cross-linked sodium hyaluronate prepared in Preparation Example 1, stirring and mixing, and drying at a vacuum degree of -0.09 kPa and 35° C. for 5.5 h to obtain a hydroxyapatite sodium hyaluronate composite gel; wherein the particle size of the hydroxyapatite microspheres is 0.1-100 μm;

[0056] Prepare a sodium hyaluronate anesthetic mixture: add 0.5g of sodium hyaluronate dry powder and 1g of anesthetic to an appropriate amount of buffer and stir to mix evenly, so that the sodium hyaluronate dry powder and anesthetic components swell to obtain a sodium hyaluronate anesthetic mixture; wherein the anesthetic is lidocaine;

[0057] 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.

[0058] Example 2

[0059] Example 2 provides a method for preparing a hydroxyapatite sodium hyaluronate injection gel, comprising the following steps:

[0060] Prepare 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, then filter through a 0.22 μm aqueous filter membrane to obtain a collagen solution; the collagen solution is a mixture of recombinant humanized type I collagen and recombinant humanized type III collagen, with a weight ratio of recombinant humanized type I collagen to recombinant humanized type III collagen of 1:2.

[0061] Preparation of a hydroxyapatite-sodium hyaluronate composite gel: 300 g of hydroxyapatite microspheres were added to a collagen solution, and after complete absorption, an absorption solution was obtained; the absorption solution was added to 16 g of the cross-linked sodium hyaluronate prepared in Preparation Example 1, stirred and mixed uniformly, and dried at a vacuum degree of -0.09 kPa and 35° C. for 5.5 h to obtain a hydroxyapatite-sodium hyaluronate composite gel; wherein the particle size of the hydroxyapatite microspheres was 0.1-100 μm;

[0062] Prepare a sodium hyaluronate anesthetic mixture: add 1g of sodium hyaluronate dry powder and 3g of anesthetic to an appropriate amount of buffer and stir to mix evenly, so that the sodium hyaluronate dry powder and anesthetic components swell to obtain a sodium hyaluronate anesthetic mixture; wherein the anesthetic is lidocaine;

[0063] 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.

[0064] Example 3

[0065] Example 3 provides a method for preparing a hydroxyapatite sodium hyaluronate injection gel, comprising the following steps:

[0066] Prepare 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, then filter through a 0.22 μm aqueous filter membrane to obtain a collagen solution; the collagen solution is a mixture of recombinant humanized type I collagen and recombinant humanized type III collagen, with a weight ratio of recombinant humanized type I collagen to recombinant humanized type III collagen of 1:2.

[0067] Preparation of a hydroxyapatite-sodium hyaluronate composite gel: 500 g of hydroxyapatite microspheres were added to a collagen solution, and after complete absorption, an absorption solution was obtained; the absorption solution was added to 24 g of the cross-linked sodium hyaluronate prepared in Preparation Example 1, stirred and mixed uniformly, and dried at a vacuum degree of -0.09 kPa and 35° C. for 5.5 h to obtain a hydroxyapatite-sodium hyaluronate composite gel; wherein the particle size of the hydroxyapatite microspheres was 0.1-100 μm;

[0068] Prepare a sodium hyaluronate anesthetic mixture: add 1.5g of sodium hyaluronate dry powder and 5g of anesthetic to an appropriate amount of buffer and stir to mix evenly, so that the sodium hyaluronate dry powder and anesthetic components swell to obtain a sodium hyaluronate anesthetic mixture; wherein the anesthetic is lidocaine;

[0069] 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.

[0070] The difference between Example 4 and Example 2 is that the cross-linked sodium hyaluronate is the cross-linked sodium hyaluronate prepared in Preparation Example 2; the remaining steps are consistent with those of Example 2.

[0071] The difference between Example 5 and Example 2 is that the cross-linked sodium hyaluronate is the cross-linked sodium hyaluronate prepared in Preparation Example 3; the remaining steps are consistent with those of Example 2.

[0072] 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.

[0073] The difference between Example 7 and Example 4 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres prepared in Preparation Example 5; the remaining steps are consistent with those of Example 4.

[0074] The difference between Example 8 and Example 4 is that the hydroxyapatite microspheres are the hydroxyapatite microspheres prepared in Preparation Example 6; the remaining steps are consistent with those of Example 4.

[0075] The difference between Example 9 and Example 6 is that the collagen is recombinant humanized type I collagen; the remaining steps are consistent with Example 6.

[0076] The difference between Example 10 and Example 6 is that the collagen is recombinant humanized type III collagen; the remaining steps are consistent with Example 6.

[0077] 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.

[0078] 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

[0079] Comparative Example 1 provides a method for preparing an injectable cosmetic plastic surgery material, comprising the following steps:

[0080] The collagen sponge was crushed into powder using a grinder with the speed of the grinder set to 7000 rpm and the time set to 2 s to obtain collagen powder;

[0081] The spherical hydroxyapatite powder with a particle size of 30 μm and the collagen powder prepared in the above steps were sterilized by cobalt 60 irradiation to ensure the sterility of the raw materials;

[0082] 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, and place them in a steam sterilizer for moist heat sterilization at 120℃ for 30 minutes;

[0083] 40 g of sterilized collagen powder and 1000 mL of sterile water for injection were added alternately to the reactor in 4 portions until the addition was complete. The reactor was sealed and stirred at 120 r / min for 24 hours while turning on the UV lamp and high-efficiency air conditioner on the operating table to obtain a gel that was visually uniform and free of stratification, precipitation, and suspension.

[0084] Open the top cover or feeding port of the reactor, add 180 g of hydroxyapatite microspheres to the gel, and stir for 2 hours to obtain an injectable cosmetic plastic surgery material.

[0085] Effect: The materials in the examples and comparative examples were tested in accordance with 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.

[0086] Table 1 Test results of injection gel

[0087]

[0088] Combining Example 1 and Comparative Example 1, the injection gel in Example 1 has a better effect and a longer duration of action. It can be seen that the injection gel in this application uses sodium hyaluronate dry powder as a filling material, which has an immediate filling effect. 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 duration of action.

[0089] 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.

[0090] Combining Examples 2, 4, and 5, the injection gel in Example 4 has the best effect. This shows that when preparing cross-linked sodium hyaluronate, the dialysis conditions in Preparation Example 2 are optimal, and thus the obtained cross-linked sodium hyaluronate has the best quality.

[0091] 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 with a modifier, and the hydroxyapatite is modified by using a composite modifier composed of carboxybetaine and sulfobetaine, so that the hydroxyapatite microspheres not only have better dispersion properties, but also have better biocompatibility, thereby further improving the effect of the injection gel.

[0092] 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.

[0093] 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 injection gel has a better effect.

[0094] 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 is compounded with the sodium hyaluronate anesthetic mixture, 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.

[0095] 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 non-creative modifications to the present embodiment as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A hydroxyapatite sodium hyaluronate injection gel, characterized by: The raw materials of the injection gel include hydroxyapatite sodium hyaluronate composite gel and sodium hyaluronate anesthetic mixture; 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 mixture 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, carrying out a cross-linking reaction under alkaline conditions, dialyzing after the reaction, and granulating to obtain cross-linked sodium hyaluronate; the dialysis is carried out using a dialysate, and the dialysis The dialysate is a phosphate buffer solution, the pH of the dialysate is 6.8-7.6, and the osmotic pressure is 270-350 mOsmol / L; the collagen comprises a mixture of recombinant humanized type I collagen and recombinant humanized type III collagen; the preparation method of the hydroxyapatite microspheres comprises the following steps: stirring and uniformly mixing hydroxyapatite powder and a modifier, and reacting 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), the modifier comprises a mixture of carboxybetaine and sulfobetaine, and the weight ratio of carboxybetaine to sulfobetaine is 1:(0.1-0.3); the preparation method of the injectable 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 through a 0.22 μm aqueous filter membrane to obtain the 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 mixture: add sodium hyaluronate dry powder and anesthetic into buffer solution and stir to mix evenly to obtain sodium hyaluronate anesthetic mixture; Compounding: Add the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture, stir and mix evenly to obtain an injectable gel; the weight ratio of the hydroxyapatite sodium hyaluronate composite gel to the sodium hyaluronate anesthetic mixture is 1: (9-11).

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.

Images