Beauty filling material for injection and preparation method thereof

Abstract

The invention discloses a beautifying filling material for injection, which is prepared from the following components in percentage by mass: 10 to 40 parts of hydroxyapatite microspheres, 60 to 90 parts of gel liquid, 2 to 5 parts of gradient cross-linked modified sodium hyaluronate, 0.5 to 1 part of vitamin E-tea seed oil-panthenol composite microemulsion and 0.5 to 1 part of hyaluronic acid-proline graft copolymer. The preparation method of the beauty filling material for injection comprises the following steps: S1, synthesizing hydroxyapatite; s2, preparation of hydroxyapatite microspheres; and S3, stirring and mixing. The hydroxyapatite microsphere gel disclosed by the invention has a filling system with good biocompatibility and good stability, solves the problem of poor compatibility of a thickening agent and a matrix, can be remained at a plastic part for a long time after being injected, can provide long-acting filling, supporting and improving skin wrinkles in tissues, and also can be used for preparing a medical dressing. Meanwhile, the nourishing, repairing and deep moisturizing functions are provided, the filling and repairing effects are achieved, and facial aging is delayed.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biomedical materials, and particularly relates to a cosmetic filling material for injection and a preparation method thereof. BACKGROUND

[0002] In the field of medical cosmetology, facial soft tissue filling is one of the core means to improve facial aging, and the technical core is to realize facial volume supplement and structure remodeling through the intervention of filling materials. At present, filling materials have evolved from traditional simple physical filling to stimulating tissue regeneration, and regenerative facial soft tissue filling materials have gradually become the mainstream in the market.

[0003] The core advantage of such regenerative materials is that after being injected into the deep layer of the dermis and subcutaneous tissue of the face, they can not only rely on the volume of the material itself to achieve short-term filling, but also continuously stimulate the activity of human fibroblasts and induce the generation of collagen, ultimately forming a volume support structure composed of self-tissue. This mechanism makes the effect more in line with the physiological state, avoids the false face feeling that may occur with traditional materials, and the effect usually lasts for 1-2 years, and some products can even achieve longer duration, significantly reducing the drawbacks of repeated injections required by traditional filling.

[0004] The existing regenerative facial soft tissue filling products on the market mainly use synthetic high molecular materials such as polylactic acid and polycaprolactone as the core component. Although such materials can trigger tissue regeneration through the degradation process, there are natural limitations in biocompatibility with human tissues as artificial synthetic substances. Long-term implantation may cause potential risks such as local foreign body reaction and thickening of the fibrous envelope, and the degradation rate of the material is difficult to accurately match the rhythm of collagen generation, which may cause uneven filling effect and fluctuation in maintenance period in some cases.

[0005] In contrast, hydroxyapatite, as a natural inorganic component of human bone and teeth, has been verified through decades of clinical application for its biocompatibility and safety, and has good affinity with human hard and soft tissues. It is not easy to cause immune rejection after implantation, and can provide a scaffold carrier for fibroblast attachment and proliferation through its unique porous microsphere structure, more efficiently guiding the ordered deposition of collagen. Therefore, it is necessary to propose an injection cosmetic filling material with hydroxyapatite as the core, precise particle size control, excellent dispersibility, and material degradation and tissue regeneration synergy. SUMMARY

[0006] The present application relates to the technical field of biomedical materials, and particularly relates to a cosmetic filling material for injection and a preparation method thereof.

[0007] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows: A cosmetic filling material for injection, consisting of the following components in percentage by mass: 10-40 parts of hydroxyapatite microspheres, 60-90 parts of gel liquid.

[0008] Preferably, the gel liquid is any combination of one or more of cellulose derivatives, chitosan, sodium alginate, polyethylene oxide, polyethylene glycol, which is added to a mixture of injection water and glycerol in proportion, stirred uniformly, and the mixture is placed in a 60℃ oven for 4h to obtain.

[0009] Preferably, it further comprises the following components in percentage by mass: 2-5 parts of gradient cross-linked modified sodium hyaluronate, 0.5-1 part of vitamin E-tea seed oil-panthenol complex microemulsion, 0.5-1 part of hyaluronic acid-proline graft copolymer.

[0010] Preferably, the preparation steps of the gradient cross-linked modified sodium hyaluronate are as follows: The sodium hyaluronate with a molecular weight of 800-1200kDa is divided into two groups A and B with a mass ratio of 7:3; The low cross-linking degree component is prepared by adding 5%-6% glycolaldehyde to group A in an amount of 5%-6% of the mass of group A, at pH 6.5-7.0 and 35-40℃ for 1.5h, and the high cross-linking degree component is prepared by using a mixed cross-linking agent of glycolaldehyde-adipic acid dihydrazide with a mass ratio of 3:1, and the total amount of addition is 7%-8% of the mass of group B, at pH 7.0-7.2 and 40-45℃ for 2.5h; After mixing the two components, ultrasonic dispersion is performed at a power of 300-400W for 10-15min to obtain the gradient cross-linked modified sodium hyaluronate.

[0011] Preferably, the preparation steps of the hyaluronic acid-proline graft copolymer are as follows: Mix the hyaluronic acid with a molecular weight of 100-200kDa and L-proline in a mass ratio of 5:1, add 1-ethyl-carbodiimide hydrochloride solution with a mass concentration of 1%-2%, and the amount of addition is 3 times the mass of the mixture; Stir and react at pH 5.0-5.5 and 30-35℃ for 4-6h, then purify by dialysis for 24h with a molecular weight cutoff of 50kDa, and freeze-dry to obtain a white powder of the graft copolymer.

[0012] Preferably, the preparation steps of the vitamin E-tea seed oil-panthenol complex microemulsion are as follows: Mix vitamin E, tea seed oil, and panthenol in a mass ratio of 3:2:1 as the oil phase; Mix polysorbate 80 with a mass concentration of 10%-15% and glycerol with a mass concentration of 5%-8% in a mass ratio of 2:1 as the water phase; The oil phase is slowly added to the aqueous phase, and the mixture is sheared at 10000-12000 r / min at 40-45℃ for 15-20 min, followed by ultrasonic emulsification at 200-300W for 5-8 min to form a uniform microemulsion with a particle size of 100-300 nm.

[0013] A method for preparing an injectable cosmetic filler material includes the following steps: S1. Hydroxyapatite synthesis: calcium nitrate, diammonium hydrogen phosphate and ammonia are mixed into water for injection and reacted continuously for 24-30 hours at 25-40℃, pH 9.0-10.0 and stirring rate of 200-300 r / min to obtain hydroxyapatite slurry, which is then filtered and washed to obtain hydroxyapatite paste. S2. Preparation of hydroxyapatite microspheres: The slurry is introduced into a spray centrifugal dryer to obtain spherical or near-spherical hydroxyapatite powder; the powder microspheres are calcined at 800-1000℃ to obtain hydroxyapatite microspheres; the hydroxyapatite microspheres are sieved by ultrasonic vibration to obtain hydroxyapatite microspheres with a suitable particle size range of 5-100 micrometers; the sieved microspheres are then calcined at 1100-1300℃ to obtain high-purity hydroxyapatite microspheres with good biocompatibility. S3. Stir and mix: Place the hydroxyapatite microspheres and other components with the gel liquid in a mixer in a certain proportion. The mixer provides a vacuum pressure of 50,000-100,000 Pa. Adjust the speed of the stirring paddle to 30-100 r / min and stir for 60-120 min. The temperature is 25-30℃. The material cylinder rotates and revolves to stir at the same time.

[0014] Preferably, in step S1, the molar ratio of calcium nitrate to diammonium hydrogen phosphate is 5:3, the mass concentration of ammonia water is 25%-28%, and the ammonia water droplet speed is controlled at 1-2 drops / second during the reaction.

[0015] Preferably, in step S2, the inlet air temperature of the spray centrifugal dryer is set to 100-300℃, the outlet air temperature is controlled to 50-150℃, and the centrifugal speed is 10000-30000 r / min.

[0016] The present invention has the following beneficial effects: 1. This invention uses hydroxyapatite microspheres as the core to form a microsphere gel. Compared with traditional filler materials with synthetic polymers such as polylactic acid and polycaprolactone as the core, it has better biocompatibility and no cytotoxicity. After injection, the microspheres are fixed by fibrous tissue and are not easy to move. The gel components gradually degrade and are replaced by human tissue. The microspheres degrade slowly and can be retained for a long time. It can not only improve skin wrinkles through stable support to achieve long-lasting filling, but also simultaneously play a role in nourishing and repairing and deep moisturizing, achieving the dual effect of filling and anti-aging repair, thus delaying the facial aging process. 2. This invention uses a gradient crosslinking process to prepare sodium hyaluronate. By combining components with different degrees of crosslinking, it avoids the defects of traditional single crosslinking products that degrade too quickly or have excessively high mechanical strength. The elastic modulus of the prepared filler material is significantly higher than that of single crosslinking products. This not only prolongs the duration of the filling effect but also ensures the material's flexibility and natural feel, reducing the risk of hardening and foreign body reactions. At the same time, relying on the hyaluronic acid-proline graft copolymer to regulate skin cell activity, it breaks through the limitation of traditional materials that can only fill. By promoting collagen regeneration, it improves aging problems such as collagen loss and decreased elasticity in the dermis, achieving a synergistic effect of filling and anti-aging. 3. This invention utilizes composite microemulsion carrier technology to stabilize active ingredients such as vitamin E and panthenol through high-speed shearing and ultrasonic emulsification, preventing their oxidation and failure or clogging of the needle, and ensuring the effective performance of their antioxidant, repair, and other biological functions. At the same time, it combines vacuum negative pressure and barrel rotation-revolution synergistic stirring process to solve the problem of poor compatibility between thickener and matrix, prevent phase separation, and achieve an instability coefficient within 16 hours that is much lower than that of atmospheric pressure stirring. This ensures smooth injection, reduces accelerated material degradation and tissue irritation risks, and improves the stability and safety of the filling system. Attached Figure Description

[0017] Figure 1 This is a flowchart of the hydroxyapatite slurry synthesis process proposed in this invention; Figure 2 This is a flowchart of the hydroxyapatite microsphere preparation process proposed in this invention; Figure 3 This is an overall appearance diagram of the hydroxyapatite microspheres proposed in this invention; Figure 4 This is an enlarged view of the hydroxyapatite microspheres proposed in this invention; Figure 5 This is a crystallinity analysis diagram of the hydroxyapatite microspheres proposed in this invention; Figure 6 The images show the viscoelasticity analysis of the filler materials in the embodiments and comparative examples proposed in this invention at 25°C and 0.1Hz. Detailed Implementation

[0018] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0019] An injectable cosmetic filler material, by weight percentage, is composed of the following components: 10-40 parts hydroxyapatite microspheres and 60-90 parts gel.

[0020] The gel solution is prepared by adding one or more of cellulose derivatives, chitosan, sodium alginate, polyethylene oxide, and polyethylene glycol in a certain proportion to a mixture of water for injection and glycerin, stirring until homogeneous, and then placing the mixture in a 60°C oven for 4 hours.

[0021] It also includes the following components: 2-5 parts of gradient cross-linked modified sodium hyaluronate, 0.5-1 part of vitamin E-tea seed oil-panthenol composite microemulsion, and 0.5-1 part of hyaluronic acid-proline graft copolymer.

[0022] The preparation steps of gradient crosslinked modified sodium hyaluronate are as follows: Sodium hyaluronate with a molecular weight of 800-1200 kDa was divided into two groups, A and B, with a mass ratio of 7:3. Group A used 5%-6% glyceraldehyde by mass, with the addition amount being 5%-6% of the mass of Group A. The reaction was carried out at pH 6.5-7.0 and 35-40℃ for 1.5 hours to obtain a low cross-linking degree component. Group B used a mixed cross-linking agent of glyceraldehyde and adipic acid dihydrazide, with a mass ratio of glyceraldehyde to adipic acid dihydrazide of 3:1 and a total addition amount of 7%-8% of the mass of Group B. The reaction was carried out at pH 7.0-7.2 and 40-45℃ for 2.5 hours to obtain a high cross-linking degree component. The two components were mixed and then ultrasonically dispersed at a power of 300-400W for 10-15 minutes to obtain gradient crosslinked modified sodium hyaluronate.

[0023] The preparation steps of the hyaluronic acid-proline graft copolymer are as follows: Hyaluronic acid with a molecular weight of 100-200 kDa is mixed with L-proline at a mass ratio of 5:1, and 1-ethyl-carbodiimide hydrochloride solution with a mass concentration of 1%-2% is added, with the amount added being 3 times the mass of the mixture. The reaction was stirred at pH 5.0-5.5 and 30-35℃ for 4-6 hours. After the reaction, the mixture was purified by dialysis for 24 hours, with a molecular weight cutoff of 50 kDa. The resulting white powdered graft copolymer was obtained by freeze drying.

[0024] The preparation steps of the vitamin E-tea seed oil-panthenol complex microemulsion are as follows: Vitamin E, tea seed oil, and panthenol were mixed in a mass ratio of 3:2:1 to form the oil phase. A mixture of 10%-15% polysorbate 80 and 5%-8% glycerol at a mass ratio of 2:1 was prepared as the aqueous phase. The oil phase is slowly added to the aqueous phase, and the mixture is sheared at 10000-12000 r / min at 40-45℃ for 15-20 min, followed by ultrasonic emulsification at 200-300W for 5-8 min to form a uniform microemulsion with a particle size of 100-300 nm.

[0025] A method for preparing an injectable cosmetic filler material includes the following steps: S1. Hydroxyapatite Synthesis: Calcium nitrate, diammonium hydrogen phosphate, and ammonia are mixed into water for injection. The molar ratio of calcium nitrate to diammonium hydrogen phosphate is 5:3, and the mass concentration of ammonia is 25%-28%. During the reaction, the ammonia dripping rate is controlled at 1-2 drops / second. The reaction is continued for 24-30 hours at 25-40℃, pH 9.0-10.0, and a stirring rate of 200-300 r / min to obtain a hydroxyapatite slurry. This slurry is then filtered and washed to obtain a hydroxyapatite paste. The hydroxyapatite paste synthesis process is as follows: Figure 1 As shown, raw materials A, B, and C represent calcium nitrate, diammonium hydrogen phosphate, and ammonia, respectively. S2, preparation of hydroxyapatite microspheres, specific process as follows: Figure 2 As shown, the slurry was introduced into a spray centrifugal dryer. The inlet air temperature of the spray centrifugal dryer was set to 180-220℃, the outlet air temperature was controlled to 80-100℃, and the centrifugal speed was 8000-10000 r / min, to obtain spherical or near-spherical hydroxyapatite powder. The powder microspheres were calcined at 800-1000℃ to obtain hydroxyapatite microspheres. The hydroxyapatite microspheres were then sieved by ultrasonic vibration to obtain hydroxyapatite microspheres with a suitable particle size range of 5-100 micrometers. The sieved microspheres were then calcined at 1100-1300℃ to obtain high-purity hydroxyapatite microspheres with good biocompatibility. The data of the prepared microspheres are as follows: morphology, relatively smooth surface, microspheres are composed of solid spheres; crystallinity, 90-100%; particle size, 5-100 micrometers, average particle size 25-45 micrometers, the specific shape and appearance of the microspheres are as follows. Figure 3 and Figure 4 As shown, the crystallinity is as follows Figure 5 As shown.

[0026] S3. Stirring and mixing: Place the hydroxyapatite microspheres and other components with the gel liquid in a mixer in a certain proportion. The mixer provides a vacuum pressure of 50,000-100,000 Pa. Adjust the speed of the stirring paddle to 30-100 r / min and stir for 60-120 min at a temperature of 25-30℃. The material cylinder rotates and revolves simultaneously to stir. The rotation ensures that the components are stirred evenly, and the revolution generates centrifugal force to detach air bubbles, forming a cosmetic filler material mainly composed of microsphere gel.

[0027] I. Implementation Example Design Example 1

[0028] An injectable cosmetic filler material, by weight percentage, comprises the following components: 20g of hydroxyapatite microspheres and 80g of gel per 100g.

[0029] In this embodiment, the preparation process of hydroxyapatite microspheres strictly followed steps S1 and S2 in the technical solution. The vacuum stirring parameters were 80000 Pa negative pressure, 100 r / min rotation speed, stirring for 120 min, and temperature 30℃. The gel solution was prepared by adding chitosan and polyethylene glycol in a certain proportion to a mixture of water for injection and glycerin, stirring until homogeneous, and then placing the mixture in a 60℃ oven for 4 h. Example 2

[0030] An injectable cosmetic filler material, by weight percentage, comprises the following components: per 100g, 20g of hydroxyapatite microspheres, 75.5g of gel, 3g of gradient cross-linked modified sodium hyaluronate, 0.8g of vitamin E-tea seed oil-panthenol composite microemulsion, and 0.7g of hyaluronic acid-proline graft copolymer.

[0031] In addition to the basic steps, the preparation process in this embodiment involves simultaneously adding gradient crosslinked modified sodium hyaluronate, composite microemulsion, graft copolymer, hydroxyapatite microspheres, and gel to a mixer during the preparation of the filler material. The vacuum stirring parameters are 80,000 Pa negative pressure, 80 r / min rotation speed, stirring for 55 min, and temperature 27°C. The gel is prepared by adding chitosan and polyethylene glycol in a certain proportion to a mixture of water for injection and glycerin, stirring until homogeneous, and then placing the mixture in a 60°C oven for 4 h. Example 3

[0032] An injectable cosmetic filler material is described in this embodiment. The composition is the same as in Example 2, only the content of each component is adjusted. The specific weights of each component per 100g of filler material are as follows: 18g hydroxyapatite microspheres, 78.5g gel, 2.5g gradient cross-linked modified sodium hyaluronate, 0.5g vitamin E-tea seed oil-panthenol composite microemulsion, and 0.5g hyaluronic acid-proline graft copolymer. The gel is prepared by mixing chitosan and polyethylene glycol in a specific ratio with water for injection and glycerin, stirring until homogeneous, and then incubating the mixture in a 60°C oven for 4 hours.

[0033] The preparation process in this embodiment is the same as in embodiment 2, with the vacuum stirring parameters being 80000Pa negative pressure, 80r / min rotation speed, stirring for 55min, and temperature of 27℃.

[0034] II. Proportional Design Comparative Example 1 An injectable cosmetic filler material, using common regenerative facial soft tissue filler products on the market, with polylactic acid, polycaprolactone and other synthetic polymer materials as core components.

[0035] Comparative Example 2 An injectable cosmetic filler material is described. The composition of this comparative example is essentially the same as that of Example 2, except that it does not use gradient cross-linked modified sodium hyaluronate, but instead uses sodium hyaluronate with a single degree of cross-linking, and the composite microemulsion is not ultrasonically emulsified. Specifically, each 100g contains 20g of hydroxyapatite microspheres, 75.5g of gel, 3g of gradient cross-linked modified sodium hyaluronate, 0.8g of vitamin E-tea seed oil-panthenol composite microemulsion, and 0.7g of hyaluronic acid-proline graft copolymer. The gel is prepared by mixing chitosan and polyethylene glycol in a specific ratio with water for injection and glycerin, stirring until homogeneous, and then incubating the mixture in a 60°C oven for 4 hours.

[0036] The preparation process of this comparative example is the same as that of Example 2, except for the sodium hyaluronate and composite microemulsion components.

[0037] Comparative Example 3 An injectable cosmetic filler material, with the same composition as Example 3, specifically comprises: 18g hydroxyapatite microspheres, 78.5g gel, 2.5g gradient cross-linked modified sodium hyaluronate, 0.5g vitamin E-tea seed oil-panthenol composite microemulsion, and 0.5g hyaluronic acid-proline graft copolymer. The gel is prepared by mixing chitosan and polyethylene glycol in a specific ratio with water for injection and glycerin, stirring until homogeneous, and then incubating the mixture in a 60°C oven for 4 hours.

[0038] The difference between the preparation process of this comparative example and that of Example 3 is that the preparation of microsphere gel in step S5 is carried out by atmospheric pressure stirring instead of vacuum stirring, and the stirring speed is only 20 r / min, the stirring time is 45 min, and the synergistic rotation of the barrel is not achieved.

[0039] III. Comparative Test Analysis Comparative Test 1: Stability Analysis of the Gel System Factors such as volume concentration, particle size, particle shape, and particle migration in a dispersion system can all cause changes in the transmittance signal of the sample. For fillers with uniform dispersion and good stability, the particle settling rate is small and stable, and rapid particle aggregation or system flocculation does not occur. Therefore, the change value and rate of change in transmittance are both small. Thus, by recording the transmittance change at a specific excitation wavelength, the state of the dispersion system can be obtained, thereby assessing the stability and dispersion uniformity of the system. A 16-hour test was conducted to monitor the change in sample transmittance over time in real time, and the instability coefficient was calculated. The higher the instability coefficient, the more unstable the sample. Specific recorded data are shown in the table below: Table 1. Data Record of Instability Coefficient Comparison

[0040] Based on the table above, the instability indices of the samples from Examples 1, 2, and 3 remained essentially around 0 within 16 hours, while the instability index of Comparative Example 1 gradually increased in the first 6 hours and stabilized after the 6th hour, remaining at a level significantly higher than that of the three example samples. The comparison between Example 2 and Comparative Example 2 shows that gradient crosslinking modification of sodium hyaluronate imparts a more stable microstructure to the gel. The comparison between Example 3 and Comparative Example 3 shows that vacuum negative pressure stirring combined with rotation and revolution stirring can remove air bubbles from the cosmetic filler material, resulting in uniform dispersion of components and improved stability of the dispersion system.

[0041] Comparative Test 2: Pushing Force Test The cosmetic filler materials prepared in Examples 1 and 2 were used for testing. A 1 ml syringe was used to draw the settled cosmetic filler material, a 27G needle was inserted, and a digital push-pull force testing machine was used to detect the average pushing force required to eject the cosmetic filler material through the injection needle. The specific data are shown in the table below: Table 2. Comparison of Average Pushing Force (N) Data Record Table

[0042] Based on the table above, the average extrusion force of Examples 1, 2, and 3 is basically the same at around 18N, while the average extrusion force of the sample in Comparative Example 1 is more than 10N higher than that of the three examples. This indicates that the gel systems in these examples exhibit better injectability. A comparison between Examples 1 and 2 shows that, with a higher solute content in Example 2, gradient crosslinking of sodium hyaluronate, the composite microemulsion, and the graft copolymer can improve the injection performance of the material.

[0043] Comparative Test 3: Viscoelasticity Test The viscoelasticity of the filler materials in Examples 1-3 and Comparative Examples 1-3 was tested at 25°C and 0.1Hz, and the results were obtained. Figure 6 The elastic modulus G′ of each group was greater than G″, proving that the material has good resistance to deformation and can effectively recover its original shape after stress is applied. Specific recorded data are shown in the table below: Table 3. Comparison of Elastic Modulus G′ (Pa) and Storage Modulus G″ (Pa)

[0044] Based on the above table content, Example 1 will be compared with Example 2, Example 2 with Example 3, Example 1 with Comparative Example 1, Example 2 with Comparative Example 2, and Example 3 with Comparative Example 3.

[0045] The comparison results between Example 1 and Comparative Example 1 show that the elastic modulus of Example 1 is at a higher level than that of Comparative Example 1. This indicates that the filling material prepared in Example 1 has higher strength, proving that the material has good resistance to deformation and can effectively recover its original shape after stress is applied. It is superior to existing commercially available products, has a better effect on filling skin wrinkles, and can promote the rapid repair of the skin lipid film layer.

[0046] The comparison between Example 1 and Example 2 shows that the elastic modulus of Example 2 is at a high level, higher than that of Example 1, which indicates that gradient crosslinked modified sodium hyaluronate can form a stable elastic support network. The comparison between Example 2 and Example 3 shows that the filler material with higher solute content has a higher elastic modulus; The comparison results between Example 2 and Comparative Example 2 show that the elastic modulus of Example 2 is higher than that of Comparative Example 2, proving that gradient cross-linked sodium hyaluronate can form a synergistic effect with the graft copolymer, providing a stable microenvironment for collagen synthesis and achieving a better filling effect. A single cross-linked structure cannot achieve the same effect. The comparison results between Example 3 and Comparative Example 3 show that the elastic modulus of Example 3 is significantly higher than that of Comparative Example 3. This is because the material of Comparative Example 3 contains a large number of air bubbles and uneven mixing, which destroys the structural stability and results in poor resistance to deformation.

[0047] Test 4: Cytotoxicity Test The cosmetic filler material prepared in Example 1 was used for testing. Vigorously growing cells were digested and formulated into 1×10⁻⁶ cells. 5 Cell suspension at 100 μL / mL was added to each well of a 96-well plate and incubated at 37°C for 24 h in 5% CO2. After 24 h, the original culture medium was discarded, and 100 μL of each concentration of sample extract (0.2 g / mL extraction ratio, 37°C for 24 h), negative control, and positive control were added respectively. At least 6 replicates were performed for each group, and the plates were incubated at 37°C for 24 h in 5% CO2. Cell morphology was then observed. All liquid in the 96-well plate was discarded, and 50 μL of MTT solution was added, incubated at 37°C for 2 h. The MTT solution was removed, and 100 μL of isopropanol was added to each well. The plate was titrated by shaking, and the absorbance was measured using a microplate reader to calculate the viability. The results of Example 1 indicate that the filling material has good biocompatibility and does not produce cytotoxicity.

[0048] Table 4 Survival Rate Record Table

[0049] Even formulations containing only basic components exhibit significantly superior biocompatibility, filling stability, injectability, and resistance to deformation compared to traditional commercially available synthetic polymer fillers, demonstrating the core advantages of natural-based materials.

[0050] The addition of three functional components—gradiently crosslinked modified sodium hyaluronate, composite microemulsion, and graft copolymer—combined with a vacuum rotation-revolution stirring process, significantly improves the performance of the filler material across all dimensions, which is the core of this invention's technological breakthrough. The stirring process proposed in this invention—vacuum negative pressure and synergistic rotation-revolution—is a crucial production step to ensure material performance. Even with an optimized full-function formulation, if the process suffers from defects such as incomplete degassing or heterogeneity, the material's filling stability, safety, repair ability, and long-term effectiveness will still be significantly inferior to the optimized process, failing to realize the formulation's optimal potential.

[0051] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. An injectable cosmetic filler material, characterized in that, By mass percentage, it consists of the following components: 10-40 parts hydroxyapatite microspheres, 60-90 parts gel, 2-5 parts gradient crosslinked modified sodium hyaluronate, 0.5-1 part vitamin E-tea seed oil-panthenol composite microemulsion, and 0.5-1 part hyaluronic acid-proline graft copolymer. The preparation steps of the gradient crosslinked modified sodium hyaluronate are as follows: Sodium hyaluronate with a molecular weight of 800-1200 kDa was divided into two groups, A and B, with a mass ratio of 7:

3. Group A used 5%-6% glyceraldehyde by mass, with the addition amount being 5%-6% of the mass of Group A. The reaction was carried out at pH 6.5-7.0 and 35-40℃ for 1.5 hours to obtain a low cross-linking degree component. Group B used a mixed cross-linking agent of glyceraldehyde and adipic acid dihydrazide, with a mass ratio of glyceraldehyde to adipic acid dihydrazide of 3:1 and a total addition amount of 7%-8% of the mass of Group B. The reaction was carried out at pH 7.0-7.2 and 40-45℃ for 2.5 hours to obtain a high cross-linking degree component. The two components were mixed and then ultrasonically dispersed at a power of 300-400W for 10-15 minutes to obtain gradient crosslinked modified sodium hyaluronate. The preparation steps of the vitamin E-tea seed oil-panthenol complex microemulsion are as follows: Vitamin E, tea seed oil, and panthenol were mixed in a mass ratio of 3:2:1 to form the oil phase. A mixture of 10%-15% polysorbate 80 and 5%-8% glycerol at a mass ratio of 2:1 was prepared as the aqueous phase. The oil phase is slowly added to the aqueous phase, and the mixture is sheared at 10000-12000 r / min at 40-45℃ for 15-20 min, followed by ultrasonic emulsification at 200-300W for 5-8 min to form a uniform microemulsion with a particle size of 100-300 nm.

2. The injectable cosmetic filler material according to claim 1, characterized in that, The gel solution is prepared by adding one or more of cellulose derivatives, chitosan, sodium alginate, polyethylene oxide, and polyethylene glycol in a certain proportion to a mixture of water for injection and glycerin, stirring until homogeneous, and then placing the mixture in a 60°C oven for 4 hours.

3. The injectable cosmetic filler material according to claim 1, characterized in that, The preparation steps of the hyaluronic acid-proline graft copolymer are as follows: Hyaluronic acid with a molecular weight of 100-200 kDa is mixed with L-proline at a mass ratio of 5:1, and 1-ethyl-carbodiimide hydrochloride solution with a mass concentration of 1%-2% is added, with the amount added being 3 times the mass of the mixture. The reaction was stirred at pH 5.0-5.5 and 30-35℃ for 4-6 hours. After the reaction, the mixture was purified by dialysis for 24 hours, with a molecular weight cutoff of 50 kDa. The resulting white powdered graft copolymer was obtained by freeze drying.

4. A method for preparing an injectable cosmetic filler material as described in any one of claims 1-3, characterized in that, Includes the following steps: S1. Hydroxyapatite synthesis: calcium nitrate, diammonium hydrogen phosphate and ammonia are mixed into water for injection and reacted continuously for 24-30 hours at 25-40℃, pH 9.0-10.0 and stirring rate of 200-300 r / min to obtain hydroxyapatite slurry, which is then filtered and washed to obtain hydroxyapatite paste. S2. Preparation of hydroxyapatite microspheres: The slurry is introduced into a spray centrifugal dryer to obtain spherical or near-spherical hydroxyapatite powder; the powder microspheres are calcined at 800-1000℃ to obtain hydroxyapatite microspheres; the hydroxyapatite microspheres are sieved by ultrasonic vibration to obtain hydroxyapatite microspheres with a suitable particle size range of 5-100 micrometers; the sieved microspheres are then calcined at 1100-1300℃ to obtain high-purity hydroxyapatite microspheres with good biocompatibility. S3. Stir and mix: Place the hydroxyapatite microspheres and other components with the gel liquid in a mixer in a certain proportion. The mixer provides a vacuum pressure of 50,000-100,000 Pa. Adjust the speed of the stirring paddle to 30-100 r / min and stir for 60-120 min. The temperature is 25-30℃. The material cylinder rotates and revolves to stir at the same time.

5. The method for preparing an injectable cosmetic filler material according to claim 4, characterized in that, In step S1, the molar ratio of calcium nitrate to diammonium hydrogen phosphate is 5:3, the mass concentration of ammonia water is 25%-28%, and the ammonia water droplet speed is controlled at 1-2 drops / second during the reaction.

6. The method for preparing an injectable cosmetic filler material according to claim 4, characterized in that, In step S2, the inlet air temperature of the spray centrifugal dryer is set to 100-300℃, the outlet air temperature is controlled to 50-150℃, and the centrifugal speed is 10000-30000 r / min.

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