Composite gel for injection and preparation method and application thereof

Abstract

The present invention provides a composite gel for injection, a preparation method and application thereof, wherein the composite gel for injection comprises hyaluronic acid gel and hydroxyapatite; the hydroxyapatite is a porous spherical structure or a porous near-spherical structure; the particle size distribution of the hydroxyapatite is as follows: the volume of particles less than 25 μm accounts for 0-10%, the volume of particles 25-30 μm accounts for 10-20%, the volume of particles 30-35 μm accounts for 20-30%, the volume of particles 35-40 μm accounts for 20-30%, the volume of particles 40-45 μm accounts for 10-20%, the volume of particles greater than 45 μm accounts for 0-10%, and the total volume of each component accounts for 100%. The composite gel for injection has a small injection extrusion force, a high degree of fusion with the skin, is not easy to deform and shift, and has a high cosmetic effect. At the same time, the composite gel for injection has a small side effect, can effectively reduce inflammation caused by injection, and the composite gel for injection has a moderate degradation rate, and there will be no situation where the degradation rate is inconsistent with the actual aging rate, resulting in an unsightly face.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical materials, and in particular relates to a composite gel for injection, a preparation method and an application thereof. Background Art

[0002] Hydrogels have similarities with natural extracellular matrix (ECM), and thus exhibit biocompatibility, biodegradability, and special viscoelasticity, making them biomaterials for tissue engineering. Among them, injectable hydrogels have become a research hotspot in the field of biomaterials due to their unique performance advantages. Compared with traditional hydrogels, injectable hydrogels have good fluidity. Injectable hydrogels can be directly injected into wounds in the form of solutions and formed in situ. Their excellent fluidity significantly improves the application efficacy of hydrogels in the biomedical field.

[0003] Most of the injectable hydrogels currently on the market are hyaluronic acid-based hydrogels, and their application range is largely in the field of beauty, for wrinkle removal and plastic surgery. This plastic surgery technology uses non-animal stable hyaluronic acid gel cultivated by bacterial fermentation. The hyaluronic acid gel is injected into the dermis wrinkles and depressions, or the areas where plumpness is desired, as a filler to achieve the effect of wrinkle removal and facial modification. It can immediately remove wrinkles and change the appearance. Hyaluronic acid gel originally exists in the dermis of human skin in a gelatinous form. It is responsible for storing water, increasing skin volume, and making the skin look full, plump, and elastic. However, hyaluronic acid gel disappears with age, causing the skin to lose its ability to store water, gradually become dull and aged, and form fine wrinkles.

[0004] Pure hyaluronic acid-based hydrogels have problems such as poor mechanical properties. Although many existing technologies have improved the mechanical properties of hyaluronic acid-based hydrogels by adding appropriate inorganic particles, the inorganic particles cannot be effectively and evenly dispersed in the hydrogel during mixing, resulting in poor cosmetic effects of the hydrogel, low fusion with the skin, easy deformation and displacement, large side effects, large extrusion force, and easy inflammation. Summary of the invention

[0005] In order to solve the problems and deficiencies in the prior art, the present invention provides a composite gel for injection, a preparation method and an application thereof. The composite gel for injection has a small injection extrusion force, a high degree of fusion with the skin, is not easy to deform and shift, and has a high cosmetic effect. At the same time, the composite gel for injection has a small side effect, can effectively reduce inflammation caused by injection, and the composite gel for injection has a moderate degradation rate, and there will be no situation where the degradation rate is inconsistent with the actual aging rate, resulting in an unsightly face.

[0006] According to the first aspect of the present invention, there is provided a composite gel for injection, comprising hyaluronic acid gel and hydroxyapatite; the hydroxyapatite is a porous spherical structure or a porous near-spherical structure; the particle size distribution of the hydroxyapatite is as follows: the volume proportion of particles less than 25 μm is 0-10%, the volume proportion of particles 25-30 μm is 10-20%, the volume proportion of particles 30-35 μm is 20-30%, the volume proportion of particles 35-40 μm is 20-30%, the volume proportion of particles 40-45 μm is 10-20%, the volume proportion of particles greater than 45 μm is 0-10%, and the total proportion of each component is 100%.

[0007] The composite gel for injection provided by the present invention is used in combination with hyaluronic acid gel (HA gel, cross-linked) and hydroxyapatite (HAP), wherein the hydroxyapatite used has a specific particle size distribution. First, the particle size of hydroxyapatite is mainly concentrated in the size range of 25 to 45 μm (only a relatively small part of the particle size is less than 25 μm and greater than 45 μm). This size is the best size to avoid macrophage phagocytosis. Too small particles are easily phagocytosed, resulting in a significant effect duration reduction and possible increased inflammation. Too large particles will accumulate (nodule formation), lack lateral tissue diffusion, and may inhibit ideal cell proliferation. Second, in the particle size distribution of hydroxyapatite, a certain proportion is found in multiple small particle size ranges, so that the size distribution of hydroxyapatite in the entire range will not be too concentrated, which is beneficial to improving the dispersion stability of hydroxyapatite in hyaluronic acid gel, optimizing the mechanical properties of the composite gel, and prolonging the duration of the significant effect of the composite gel. In addition, the use of hydroxyapatite with such a particle size distribution in combination with hyaluronic acid gel has little side effects and can effectively reduce inflammation caused by injection. The degradation rate of the injectable composite gel is moderate, and the degradation rate will not be inconsistent with the actual aging rate, resulting in unsightly faces.

[0008] In the current prior art, the hydroxyapatite often used has a particle size that is too concentrated within a certain range. Usually, gel carriers such as hyaluronic acid gel degrade in 1 to 6 months, after which hydroxyapatite begins to play a role. Hydroxyapatite is gradually degraded into fragments under the mediation of macrophages, releasing calcium and phosphate ions. If the particle size distribution of hydroxyapatite is too concentrated in a smaller numerical range, this may cause the product to degrade intensively at a certain time point, affecting the flatness of the face. And the hydroxyapatite used in the present invention is a porous structure, and the hydroxyapatite with a porous structure is more easily dragged by the hyaluronic acid gel and easier to inject. Because in the prior art, in many cases, in order to avoid hydroxyapatite deposition, a hyaluronic acid gel with high viscosity is used, and a hyaluronic acid gel with high viscosity is not easy to inject. At the same time, the hydroxyapatite with a porous structure has a moderate degradation time, keeps the degradation rate consistent with the actual aging rate, and avoids the situation where it causes unsightly faces. The solid structure hydroxyapatite used in the prior art has a long degradation time, and the degradation speed is likely to be inconsistent with the actual aging speed, resulting in an unsightly face, deteriorating the effect of the gel, and more likely to cause inflammation and other problems. In addition, the solid structure hydroxyapatite is not easy to interact with fibroblasts, while the present invention has a porous structure, which is easy to interact with fibroblasts, thereby promoting collagen regeneration.

[0009] Preferably, the porosity of hydroxyapatite is 15-95%. Ensuring that the porosity of hydroxyapatite is within a certain range is beneficial to making hydroxyapatite have a larger specific surface area, so that its surface has a certain degree of active groups, which is easier to be dragged by the hyaluronic acid gel and not easy to deposit, thereby improving its dispersion stability in the hyaluronic acid gel and promoting the effect of the composite gel. On the other hand, it is avoided that the porosity is too high, which causes the mechanical strength of hydroxyapatite itself to decrease, and it is unstable during the mixing process or the use process, which deteriorates the continuous effect of hydroxyapatite.

[0010] Preferably, the porosity of hydroxyapatite is 60-90%. Furthermore, hydroxyapatite within the above porosity range can better balance its dispersion stability in the hyaluronic acid gel and its own mechanical strength, so that the composite gel has a more suitable degradation time, can maintain facial beauty for a longer time, and promote the longer-term use of the composite gel.

[0011] Preferably, the mass proportion of hyaluronic acid gel in the composite gel for injection is 30-70%; the mass proportion of hydroxyapatite in the composite gel for injection is 5-60%. Controlling the mass proportion of hyaluronic acid gel and hydroxyapatite in the composite gel can effectively promote the synergistic effect of the two, so that the two substances can further improve the effect of the composite gel and prolong the action time of the composite gel while giving full play to their respective advantages. And under the above mass proportion, the dispersion stability and promotion effect of hydroxyapatite in the gel are better, because if there is too little hydroxyapatite, it is not conducive to improving the mechanical properties and effect of the composite gel, and if there is too much hydroxyapatite, it is easy to deposit and aggregate, which is not conducive to dispersion stability, nor is it conducive to improving the mechanical properties and effect of the composite gel. Similarly, if there is too little hyaluronic acid gel, it is not enough to drag the hydroxyapatite, resulting in the sedimentation of hydroxyapatite; and if there is too much hyaluronic acid gel, the overall mechanical properties of the composite gel decrease, and the facial lifting effect becomes worse; therefore, these two situations are not conducive to improving the mechanical properties and effect of the composite gel.

[0012] Preferably, the mass proportion of hyaluronic acid gel in the composite gel for injection is 40-70%; the mass proportion of hydroxyapatite in the composite gel for injection is 10-50%. Furthermore, when the mass proportion of hyaluronic acid gel and hydroxyapatite is within the above range, the mechanical properties, effect and duration of the composite gel can be better balanced.

[0013] Preferably, the above-mentioned composite gel for injection further includes alcohol and anesthetic; the mass proportion of alcohol in the composite gel for injection is 0.5-10%; the mass proportion of anesthetic in the composite gel for injection is 0.1-0.5%.

[0014] Preferably, the alcohol includes at least one of glycerol and propylene glycol.

[0015] Preferably, the anesthetic comprises at least one of lidocaine and lidocaine hydrochloride.

[0016] Preferably, the composite gel for injection also includes other cross-linked or non-cross-linked polymer gels, and the mass proportion of other cross-linked or non-cross-linked polymer gels in the composite gel for injection is 0 to 20%; other cross-linked or non-cross-linked polymer gels include at least one of sodium hyaluronate, cellulose, dextran, and polymethyl methacrylate (PMMA).

[0017] In addition, the above-mentioned composite gel for injection may also include a certain amount of vitamins and antioxidants; adding them according to specific circumstances will not affect the performance of the composite gel for injection.

[0018] According to the second aspect of the present invention, there is provided a method for preparing the above-mentioned composite gel for injection, characterized in that it comprises the following steps: S1. preparing an alkaline solution of sodium hyaluronate, adding hydroxyapatite in multiple times, each adding amount being 0.5 to 20% of the total mass of hydroxyapatite, and the total adding amount being 0.5 to 70% of the total mass of hydroxyapatite, and then continuing to add a cross-linking agent thereto for reaction to obtain a first gel; S2. placing the prefabricated gel in a first buffer solution for dialyzing and granulation to obtain a second gel; S3. adding hydroxyapatite to the second gel in multiple times for mixing, each adding amount being 0.5 to 20% of the total mass of hydroxyapatite, and controlling the amount added in the latter time to be greater than the amount added in the previous time until the addition is completed; S4. adding alcohol, anesthetic, and a second buffer solution to the material obtained in S3 to obtain a composite gel for injection. In the preparation method of the composite gel for injection provided by the present invention, hydroxyapatite is added in multiple times before cross-linking in S1, and hydroxyapatite is added in multiple times after cross-linking in S3, and the amount of the latter addition is guaranteed to be greater than the amount of the previous addition. Compared with adding once or multiple times before or after cross-linking, it can promote the full mixing of hydroxyapatite in the hyaluronic acid gel, improve the overall dispersion stability of the composite gel, effectively play the joint role of hydroxyapatite and hyaluronic acid gel, and improve the mechanical properties, effect and action time of the composite gel. At the same time, it can also ensure that the hydroxyapatite can be dispersed evenly and stably in the hyaluronic acid gel in a relatively short time, thereby improving production efficiency.

[0019] Preferably, in S1, the crosslinking agent includes at least one of epoxides, halogenated alcohols, and divinyl sulfone; the epoxide includes at least one of 1,4-butanediol diglycidyl ether, 1-(2,3-epoxypropyl)2,3-epoxycyclohexane, 1,2-ethylene glycol diglycidyl ether, and 1,2,7,8-diepoxyoctane.

[0020] Preferably, the cross-linking reaction temperature in S1 is 20-60° C. and the time is 3-8 hours.

[0021] Preferably, in S2, the first buffer solution includes at least one of a sodium phosphate salt solution, a potassium phosphate salt solution, a sodium hydroxide solution, a potassium hydroxide solution, and a sodium chloride solution.

[0022] Preferably, in S3, during the mixing process, the stirring speed is 100 to 2000 rpm, and the stirring time is 5 to 120 min.

[0023] Preferably, in S1, the specific operation of preparing the sodium hyaluronate alkaline solution is: dissolving the sodium hyaluronate in the alkaline solution; the alkaline solution includes at least one of a sodium hydroxide solution, a potassium hydroxide solution, and a quaternary ammonium base solution).

[0024] Preferably, in S4, the second buffer solution includes at least one of a sodium phosphate salt solution, a potassium phosphate salt solution, a sodium hydroxide solution, a potassium hydroxide solution, and a sodium chloride solution.

[0025] Preferably, other cross-linked or non-cross-linked polymer gels, such as sodium hyaluronate, cellulose, dextran, and polymethyl methacrylate (PMMA), can also be added to S4.

[0026] In summary, the composite gel for injection provided by the present invention effectively improves the dispersion stability of hydroxyapatite in hyaluronic acid gel by strictly controlling the particle size distribution of the hydroxyapatite used, and further optimizes the mechanical properties of the composite gel, and prolongs the duration of the significant effect of the composite gel. The composite gel for injection has a small injection extrusion force, a high degree of fusion with the skin, is not easy to deform and shift, and has a high cosmetic effect. At the same time, the composite gel for injection has few side effects, can effectively reduce inflammation caused by injection, and the composite gel for injection has a moderate degradation rate, and there will be no situation where the degradation rate is inconsistent with the actual aging rate, resulting in an unsightly face. DETAILED DESCRIPTION

[0027] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only embodiments of a part of the present invention, rather than all embodiments.

[0028] Example 1

[0029] The composite gel for injection of this embodiment was prepared according to the following steps:

[0030] S1. Prepare a sodium hyaluronate alkaline solution, add hydroxyapatite in multiple times, each adding amount is 0.5-20% of the total mass of hydroxyapatite, and the total amount added is 30% of the total mass of hydroxyapatite, and then continue to add a cross-linking agent thereto for reaction to obtain a first gel; wherein the specific operation of preparing the sodium hyaluronate alkaline solution is to dissolve sodium hyaluronate in an alkaline solution, wherein the alkaline solution includes at least one of a sodium hydroxide solution, a potassium hydroxide solution, and a quaternary ammonium base solution; the specific reaction conditions for adding the cross-linking agent for reaction are a temperature of 20° C. and a reaction time of 6 hours;

[0031] S2. The preformed gel is dialyzed in a first buffer solution, granulated, and a second gel is obtained; the first buffer solution comprises at least one of a sodium phosphate salt solution, a potassium phosphate salt solution, a sodium hydroxide solution, a potassium hydroxide solution, and a sodium chloride solution;

[0032] S3. Add hydroxyapatite to the second gel in multiple times and mix, with the amount added each time being 0.5-20% of the total amount of hydroxyapatite, and control the amount added in the latter time to be greater than the amount added in the previous time until the addition is completed; during the mixing process, the stirring speed is 750rpm, and the stirring time is 60min; hydroxyapatite is a porous spherical structure or a porous nearly spherical structure, and the particle size distribution of hydroxyapatite is as follows: the volume proportion of particles less than 25μm is 4%, the volume proportion of particles 25-30μm is 16%, the volume proportion of particles 30-35μm is 30%, the volume proportion of particles 35-40μm is 30%, the volume proportion of particles 40-45μm is 16%, and the volume proportion of particles greater than 45μm is 4%. The porosity of hydroxyapatite is 60-90%;

[0033] S4. Add alcohol, anesthetic and second buffer to the material obtained in S3 to obtain a composite gel for injection; the alcohol includes at least one of glycerol and propylene glycol; the anesthetic includes at least one of lidocaine and lidocaine hydrochloride; the second buffer includes at least one of sodium phosphate salt solution, potassium phosphate salt solution, sodium hydroxide solution, potassium hydroxide solution and sodium chloride solution.

[0034] In the above S4, other cross-linked or non-cross-linked polymer gels, vitamins and antioxidants may also be added. The cross-linked or non-cross-linked polymer gels include at least one of sodium hyaluronate, cellulose, dextran and polymethyl methacrylate (PMMA).

[0035] In the above-mentioned preparation of the composite gel for injection, the added amount of each material is calculated by mass fraction as follows: second gel 60%, hydroxyapatite 30%, alcohol 3%, anesthetic 0.3%, second buffer 3%, other cross-linked or non-cross-linked polymer gel 3%, vitamin 0.2%, antioxidant 0.5%.

[0036] Example 2

[0037] In the process of preparing the composite gel for injection of this embodiment, the difference from that of embodiment 1 is that the porosity of the hydroxyapatite used in S3 is 30-60%. The rest of the operations are the same as those of embodiment 1.

[0038] Example 3

[0039] In the process of preparing the composite gel for injection of this embodiment, the difference from that of embodiment 1 is that the porosity of the hydroxyapatite used in S3 is 15-60%. The rest of the operations are the same as those of embodiment 1.

[0040] Example 4

[0041] In the process of preparing the composite gel for injection of this embodiment, the difference from that of embodiment 1 is that the porosity of the hydroxyapatite used in S3 is 25-65%. The rest of the operations are the same as those of embodiment 1.

[0042] Example 5

[0043] In the process of preparing the composite gel for injection of this embodiment, the difference from that of embodiment 1 is that the porosity of the hydroxyapatite used in S3 is 40-80%. The rest of the operations are the same as those of embodiment 1.

[0044] Example 6

[0045] The process of preparing the composite gel for injection of this embodiment is different from that of embodiment 1 in that, in preparing the composite gel for injection, the amount of the second gel and hydroxyapatite added are 50% and 40% respectively, calculated by mass fraction. The rest of the operations are the same as those of embodiment 1.

[0046] Example 7

[0047] The process of preparing the composite gel for injection of this embodiment is different from that of embodiment 1 in that, in preparing the composite gel for injection, the amount of the second gel and hydroxyapatite added are 40% and 50% respectively, calculated by mass fraction. The rest of the operations are the same as those of embodiment 1.

[0048] Example 8

[0049] The process of preparing the composite gel for injection of this embodiment is different from that of embodiment 1 in that, in preparing the composite gel for injection, the amount of the second gel and hydroxyapatite added are 30% and 60% respectively according to the mass fraction. The rest of the operations are the same as those of embodiment 1.

[0050] Example 9

[0051] The process of preparing the composite gel for injection of this embodiment is different from that of embodiment 1 in that, in preparing the composite gel for injection, the amount of the second gel and hydroxyapatite used is 35% and 55% respectively, calculated by mass fraction. The rest of the operations are the same as those of embodiment 1.

[0052] Comparative Example 1

[0053] In the process of preparing the composite gel for injection of this comparative example, the difference from Example 1 is that the particle size distribution of the hydroxyapatite used in S3 is as follows: the volume proportion of particles less than 25 μm is 2%, the volume proportion of particles 25 to 30 μm is 8%, the volume proportion of particles 30 to 35 μm is 70%, the volume proportion of particles 35 to 40 μm is 12%, the volume proportion of particles 40 to 45 μm is 5%, and the volume proportion of particles greater than 45 μm is 3%. The remaining operations are consistent with Example 1.

[0054] Comparative Example 2

[0055] In the process of preparing the composite gel for injection of this comparative example, the difference from Example 1 is that the particle size distribution of the hydroxyapatite used in S3 is as follows: the volume proportion of particles less than 25 μm is 2%, the volume proportion of particles 25 to 30 μm is 5%, the volume proportion of particles 30 to 35 μm is 5%, the volume proportion of particles 35 to 40 μm is 75%, the volume proportion of particles 40 to 45 μm is 10%, and the volume proportion of particles greater than 45 μm is 3%. The remaining operations are consistent with Example 1.

[0056] Comparative Example 3

[0057] In the process of preparing the composite gel for injection of this comparative example, the difference from Example 1 is that the particle size distribution of the hydroxyapatite used in S3 is as follows: 10-13 μm accounts for 16% by volume, 13-16 μm accounts for 34% by volume, 16-20 μm accounts for 34% by volume, and 20-24 μm accounts for 16% by volume. The rest of the operations are the same as in Example 1.

[0058] Comparative Example 4

[0059] In the process of preparing the composite gel for injection of this comparative example, the difference from Example 1 is that the particle size distribution of the hydroxyapatite used in S3 is as follows: 47-50 μm accounts for 19% by volume, 50-54 μm accounts for 31% by volume, 54-60 μm accounts for 31% by volume, and 60-65 μm accounts for 19% by volume. The rest of the operations are the same as in Example 1.

[0060] Comparative Example 5

[0061] In the process of preparing the composite gel for injection of this comparative example, the difference from Example 1 is that when hydroxyapatite is added to S3, the first addition is more than 20%, specifically 23%, and each subsequent addition is more than the previous addition. The rest of the operations are the same as in Example 1.

[0062] Comparative Example 6

[0063] In the process of preparing the composite gel for injection of this comparative example, the difference from Example 1 is that hydroxyapatite is not added to S3 in multiple times but is directly added at one time. The rest of the operations are the same as those in Example 1.

[0064] Test Case

[0065] 1. Experimental Construction Method

[0066] The composite gel for injection prepared in the above examples and comparative examples was subjected to performance tests of dispersion stability, average pushing force, elastic modulus and viscous modulus. The specific test methods are as follows:

[0067] (1) Dispersion stability: Centrifuge at 2040 g for 5 min and observe the gel separation. At the same time, use a universal material testing machine to test the pushing force, and further judge by the change of the pushing force.

[0068] (2) Average pushing force: At room temperature, install the prefilled syringe with the matching core rod and injection needle, expel a small amount of air from the front end, and install it on a universal material testing machine. Perform a pushing force test at a speed of 30 mm / min and a distance of full scale, and record the average pushing force.

[0069] (3) Viscoelasticity: The elastic modulus and viscous modulus were measured using a rheometer at a frequency of 1 Hz.

[0070] 2. Experimental results

[0071] The relevant performance test results of the composite gel for injection prepared in the above examples and comparative examples are shown in Table 1.

[0072] Table 1 Test results of relevant properties of the composite gel for injection prepared in the examples and comparative examples

[0073]

[0074]

[0075] As can be seen from Table 1, the composite gel for injection provided by the present invention can still maintain a good state under certain centrifugal conditions, and the gel material does not separate. Moreover, the average pushing force of the composite gel for injection of the present invention does not change much after centrifugation, that is, it has high stability, and the average pushing force is small, and it is easy to inject. At the same time, it also has good mechanical properties, a high elastic modulus, and a moderate viscosity modulus. It can achieve a degradation rate consistent with the actual aging rate, keep the face beautiful for a long time, and is an excellent composite gel for injection. Specific reference examples 1 to 9.

[0076] In Comparative Examples 1 and 2, the particle size distribution of hydroxyapatite is too concentrated in the range of 30-35 μm and 35-40 μm, respectively, which will lead to poor dispersibility of hydroxyapatite in the gel and concentrated degradation of the gel product at a certain point in time, which is not conducive to ensuring the stability of the gel product. As a result, the elastic modulus and viscous modulus of the gel products in Comparative Examples 1 and 2 are reduced, which is not conducive to the long-term use of the gel product.

[0077] In Comparative Examples 3 and 4, the particle size ranges of hydroxyapatite are 10-24 μm and 47-65 μm, respectively, that is, the particle size ranges are too small and too large, respectively, which will also lead to concentrated degradation of the gel product, and are not conducive to the dispersion of hydroxyapatite particles, the dispersion stability of hydroxyapatite particles in the gel, resulting in a decrease in the elastic modulus and viscosity modulus of the gel product, and is not conducive to the long-term use of the gel product. At the same time, in Comparative Example 4, due to the excessively large particle size of hydroxyapatite, the pushing force is large and it is not easy to inject.

[0078] In Comparative Example 5, when hydroxyapatite is added to S3, the first addition is more than 20%, specifically 23%, and each subsequent addition is more than the previous addition. In Comparative Example 6, hydroxyapatite is added to S3 at one time. All of the above operations will result in the hydroxyapatite being unable to be fully dispersed in the gel, resulting in stratification after centrifugation and unstable gel state.

[0079] Further comparing Example 1 with Examples 2 to 5, the variables are mainly the porosity of the hydroxyapatite used, wherein the porosity of hydroxyapatite in Example 1 is 60-90%, the porosity of hydroxyapatite in Example 2 is 30-60%, the porosity of hydroxyapatite in Example 3 is 15-60%, the porosity of hydroxyapatite in Example 4 is 25-65%, and the porosity of hydroxyapatite in Example 5 is 40-80%. From the relevant performance results of the products, the gel product in Example 1 has the smallest average pushing force, and the elastic modulus and viscosity modulus are relatively high, and the product has the best comprehensive performance. This shows that the porosity of hydroxyapatite has a certain influence on the various properties of the composite gel, and these properties will affect the use effect and service life of the gel product. Therefore, it is necessary to control the porosity of hydroxyapatite within a certain range to be more conducive to improving the various performances of the gel product.

[0080] Further comparing Example 1 with Examples 6 to 9, the variables are mainly the amount of the second gel and hydroxyapatite used, wherein the amount of the second gel and hydroxyapatite added in Example 1 is 60% and 30% respectively, the amount of the second gel and hydroxyapatite added in Example 6 is 50% and 40% respectively, the amount of the second gel and hydroxyapatite added in Example 7 is 40% and 50% respectively, the amount of the second gel and hydroxyapatite added in Example 8 is 30% and 60% respectively, and the amount of the second gel and hydroxyapatite added in Example 9 is 35% and 55% respectively. From the relevant performance results of the products, the gel product in Example 1 has the smallest average pushing force, and the elastic modulus and viscosity modulus are relatively high, and the product has the best comprehensive performance. This shows that the amount of the second gel and hydroxyapatite used has a certain influence on the various properties of the composite gel. When the amount of the second gel and hydroxyapatite added is 30% and 60% respectively, it is more conducive to the role of these two materials and promotes the improvement of product performance.

[0081] The above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention is described in detail with reference to the above embodiments, ordinary technicians in the relevant field should understand that the technical solutions of the present invention can be modified or equivalently replaced, but these modifications or replacements are all within the protection scope of the present invention.

Claims

1. A composite gel for injection, characterized in that: Includes hyaluronic acid gel, hydroxyapatite; The hydroxyapatite is a porous spherical structure or a porous nearly spherical structure; The particle size distribution of the hydroxyapatite is as follows: the volume proportion of particles less than 25 μm is 0-10%, the volume proportion of particles 25-30 μm is 10-20%, the volume proportion of particles 30-35 μm is 20-30%, the volume proportion of particles 35-40 μm is 20-30%, the volume proportion of particles 40-45 μm is 10-20%, the volume proportion of particles greater than 45 μm is 0-10%, and the total proportion of each component is 100%; The mass proportion of the hyaluronic acid gel in the composite gel for injection is 30-60%; The mass percentage of the hydroxyapatite in the composite gel for injection is 30-60%; The preparation method of the composite gel for injection comprises the following steps: S1. preparing a sodium hyaluronate alkaline solution, adding the hydroxyapatite in multiple times, with each addition amount being 0.5 to 20% of the total mass of the hydroxyapatite, and the total addition amount being 0.5 to 70% of the total mass of the hydroxyapatite, and then continuing to add a crosslinking agent thereto for reaction to obtain a first gel; S2. dialyzing the first gel in a first buffer solution and granulating the gel to obtain a second gel; S3. Adding the hydroxyapatite to the second gel in multiple times and mixing, each adding amount is 0.5 to 20% of the total mass of the hydroxyapatite, and controlling the amount added in the latter time to be greater than the amount added in the previous time, until the addition is completed; S4. Add alcohol, anesthetic, and a second buffer to the material obtained in S3 to obtain the composite gel for injection.

2. The composite gel for injection as claimed in claim 1, characterized in that: The porosity of the hydroxyapatite is 15-95%.

3. The composite gel for injection as claimed in claim 2, characterized in that: The porosity of the hydroxyapatite is 60-90%.

4. The composite gel for injection as claimed in claim 1, characterized in that: It also includes alcohol and anesthetics; The alcohol accounts for 0.5 to 10% by weight in the composite gel for injection; The mass proportion of the anesthetic in the composite gel for injection is 0.1-0.5%.

5. The method for preparing the composite gel for injection as claimed in claim 1, characterized in that: In S1, the cross-linking agent includes at least one of epoxide, halogenated alcohol, and divinyl sulfone; The epoxide includes at least one of 1,4-butanediol diglycidyl ether, 1(2,3-epoxypropyl)2,3-epoxycyclohexane, 1,2-ethylene glycol diglycidyl ether, and 1,2,7,8-diepoxyoctane.

6. The method for preparing the composite gel for injection as claimed in claim 1, characterized in that: In S2, the first buffer solution includes at least one of a sodium phosphate salt solution, a potassium phosphate salt solution, a sodium hydroxide solution, a potassium hydroxide solution, and a sodium chloride solution.

7. The method for preparing the composite gel for injection as claimed in claim 1, characterized in that: In S3, during the mixing process, the stirring speed is 100 to 2000 rpm, and the stirring time is 5 to 120 min.

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