Injection filling composition containing hydroxyapatite as well as preparation and application of injection filling composition

Abstract

The invention discloses an injection filling composition containing hydroxyapatite as well as preparation and application of the injection filling composition. The injection filling composition containing hydroxyapatite comprises a matrix and hydroxyapatite microspheres, the matrix comprises cross-linked hyaluronic acid gel particles and free hyaluronic acid substances; the content of hyaluronic acid substances in the matrix is 14-25mg / g, and the mass ratio of the hyaluronic acid substances to the free hyaluronic acid substances in the cross-linked hyaluronic acid gel particles is 1: (0.03-0.18); the particle size D90 of the cross-linked hyaluronic acid gel particles is 200 to 350 [mu] m; the elastic modulus (G) of the cross-linked hyaluronic acid gel particles at a frequency of 1 Hz is 270-600 Pa. The prepared injection filling composition is moderate in pushing force, the injection difficulty is reduced, and the problems of inflammatory reaction or abnormal upheaval and the like are avoided. The viscoelasticity of the injection filling composition is also moderate, and the injection filling composition has an ideal and natural supporting effect on the skin.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical aesthetics, in particular to a hydroxyapatite-containing injection filling composition, and preparation and application thereof. BACKGROUND

[0002] Hydroxyapatite is the main inorganic component of human bones and teeth, i.e. an inherent inorganic component of the human body, and thus has good biocompatibility, no immunogenicity, and extremely rare allergic reactions, and the degradation products are calcium and phosphate ions, which can be normally utilized and discharged by the human body, and no exogenous substance remains. Based on the above-mentioned advantages of hydroxyapatite, it is widely used in the fields of medicine and medical aesthetics.

[0003] In the field of medical aesthetics, hydroxyapatite can be made into microspheres, and then compounded with a sodium carboxymethylcellulose gel or a hyaluronic acid gel matrix to prepare an injection filling material for facial filling. Due to the physical properties of the hydroxyapatite microspheres, after being injected into the upper layer of the periosteum, the hydroxyapatite microspheres can form a solid support structure, immediately increasing the tissue volume and filling the facial depression. The hydroxyapatite microspheres will slowly degrade at the filling site and stimulate the regeneration of autologous collagen, thereby gradually replacing the implanted material and achieving a more natural and long-lasting rejuvenation effect. However, the uniformity and stability of the dispersion of the hydroxyapatite microspheres in the matrix have always been a difficult problem in the field that needs to be solved. If the dispersion stability and uniformity are not ideal, it will cause problems such as needle blockage during injection, not only increasing the difficulty of injection for doctors, but also leading to uneven filling, abnormal local bulging, or local inflammatory reactions, and also increasing the pain during injection, which brings a bad experience to the beauty seekers.

[0004] Therefore, there is an urgent need in the field to develop a hydroxyapatite microsphere-containing injection filling composition with immediate filling effect, ideal support performance, moderate pushing force, high safety in use, and the like. SUMMARY

[0005] The technical problem to be solved by the present application is to overcome the defects that the support effect is not ideal when the content of hydroxyapatite microspheres in the existing injection filling material is low, and the uniformity and stability of the dispersion of the microspheres in the matrix are poor when the content of hydroxyapatite microspheres is high, resulting in needle blockage, poor use safety and unsatisfactory filling effect. The present application provides an injection filling composition containing a matrix and hydroxyapatite microspheres. By specially selecting the matrix, the ideal support effect on the microspheres can still be ensured when the content of hydroxyapatite microspheres is high, and the uniform and stable dispersion of the hydroxyapatite microspheres in the preparation is promoted. The hydroxyapatite microspheres and the specific matrix can be uniformly mixed by simple mechanical stirring method, the mechanical damage to the hydroxyapatite microspheres is reduced during the preparation process, the content of fine particles in the injection filling composition is reduced, and the occurrence of inflammatory reaction is effectively avoided. Moreover, the injection filling composition has moderate pushing force, which reduces the difficulty of injection for doctors and avoids problems such as inflammatory reaction caused by injection operation or abnormal bulging caused by excessive local injection; the viscoelasticity of the injection filling composition is moderate, and the skin has ideal and natural support effect.

[0006] The present application solves the above technical problems through the following technical solutions.

[0007] The present application provides an injection filling composition containing hydroxyapatite, which comprises a matrix and hydroxyapatite microspheres; the matrix comprises cross-linked hyaluronic acid gel particles and free hyaluronic acid substances;

[0008] In the present application, the content of hyaluronic acid substances in the matrix is 14-25 mg / g, the mass ratio of the hyaluronic acid substances in the cross-linked hyaluronic acid gel particles to the free hyaluronic acid substances is 1:(0.03-0.18), the particle size D90 of the cross-linked hyaluronic acid gel particles is 200-350 μm, and the elastic modulus G' of the cross-linked hyaluronic acid gel particles at a frequency of 1 Hz is 270-600 Pa.

[0009] In some embodiments, the content of hyaluronic acid substances in the matrix is 14-19 mg / g, for example, 14 mg / g, 14.25 mg / g, 14.5 mg / g, 14.75 mg / g, 15 mg / g, 16 mg / g, 17 mg / g, 18 mg / g, 19 mg / g, 20 mg / g, 21 mg / g, 22 mg / g, 23 mg / g, 24 mg / g or 25 mg / g. In the present application, the content of hyaluronic acid substances in the matrix is calculated based on the feeding amount, that is, the sum of the content of hyaluronic acid substances in the cross-linked hyaluronic acid gel particles and the content of free hyaluronic acid substances is calculated based on the feeding amount.

[0010] In some embodiments, the mass of the hyaluronic acid substance in the crosslinked hyaluronic acid gel particles and the mass of the free hyaluronic acid substance are in a ratio of 1: (0.03-0.15), for example, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.11, 1:0.12, 1:0.13, 1:0.14, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19, or 1:0.2.

[0011] In some embodiments, the weight average molecular weight of the free hyaluronic acid substance is 10-200 kDa, preferably 10-140 kDa, more preferably 110-140 kDa, for example, 130 kDa.

[0012] In some embodiments, the free hyaluronic acid substance is a hyaluronic acid salt, preferably at least one selected from the group consisting of sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, and zinc hyaluronate.

[0013] In some embodiments, the crosslinked hyaluronic acid gel particles have a particle size D10 of 50-110 μm, preferably 80-105 μm.

[0014] In some embodiments, the crosslinked hyaluronic acid gel particles have a particle size D50 of 120-190 μm, preferably 130-185 μm.

[0015] In some embodiments, the crosslinked hyaluronic acid gel particles have a particle size D90 of 210-330 μm, preferably 220-320 μm.

[0016] In some embodiments, the crosslinked hyaluronic acid gel particles have an elastic modulus G' of 285-530 Pa, preferably 350-530 Pa, for example, 270 Pa, 300 Pa, 350 Pa, 400 Pa, 450 Pa, 500 Pa, 550 Pa, or 600 Pa at a frequency of 1 Hz.

[0017] In some embodiments, the crosslinked hyaluronic acid gel particles have a viscous modulus G'' of 20-65 Pa, preferably 25-60 Pa, for example, 20 Pa, 25 Pa, 30 Pa, 35 Pa, 40 Pa, 45 Pa, 50 Pa, 55 Pa, 60 Pa, or 65 Pa at a frequency of 1 Hz.

[0018] In some embodiments, the crosslinked hyaluronic acid gel particles have a loss tangent tan δ of 0.1-0.5 at a frequency of 1 Hz. -1The shear viscosity η at a shear rate is 60-300 Pa·s, preferably 70-220 Pa·s, for example, 60 Pa·s, 80 Pa·s, 100 Pa·s, 120 Pa·s, 140 Pa·s, 160 Pa·s, 180 Pa·s, 200 Pa·s, 220 Pa·s, 240 Pa·s, 260 Pa·s, 280 Pa·s or 300 Pa·s.

[0019] In some embodiments, the mass ratio of the matrix and the hydroxyapatite microspheres is 1:(0.3-1.5), preferably 1:(0.3-1.2), more preferably 1:(0.4-1), for example, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5.

[0020] In some embodiments, the particle size of the hydroxyapatite microspheres is 20-60 μm, preferably 25-45 μm.

[0021] In some embodiments, the matrix further comprises a buffering agent and / or an anesthetic agent.

[0022] The buffering agent is a buffering agent acceptable in the medical and cosmetic fields for adjusting the pH value and the osmotic pressure of the system, preferably a phosphate buffer, more preferably a mixture of a dihydrogen phosphate and a dihydrogen phosphate.

[0023] Preferably, the dihydrogen phosphate is selected from sodium dihydrogen phosphate and / or potassium dihydrogen phosphate.

[0024] Preferably, the dihydrogen phosphate is selected from sodium dihydrogen phosphate and / or potassium dihydrogen phosphate.

[0025] The anesthetic agent is selected from at least one of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine and bupivacaine.

[0026] The mass percentage of the anesthetic agent in the matrix is 0.1%-0.6%.

[0027] The amount of the buffering agent can be conventional in the art, and is generally used to adjust the pH value of the hydroxyapatite-containing injection filling composition to 6-8, and / or to adjust the osmotic pressure of the hydroxyapatite-containing injection filling composition to isotonicity.

[0028] In some embodiments, the preparation method of the crosslinked hyaluronic acid gel particles comprises the following steps: mixing a crosslinking agent, a hyaluronic acid substance and an alkaline aqueous solution, performing a crosslinking reaction, sieving and granulating to obtain the crosslinked hyaluronic acid gel particles.

[0029] The cross-linking hyaluronic acid gel particles are prepared by adding a cross-linking agent to a hyaluronic acid substance in an alkaline aqueous solution, and the cross-linking agent is a cross-linking agent containing at least two epoxy groups, preferably a cross-linking agent containing two epoxy groups, and more preferably selected from at least one of 1,4-butanediol diglycidyl ether, ethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, and poly(dimethylsiloxane) diglycidyl ether.

[0030] The cross-linking hyaluronic acid gel particles are prepared by adding a cross-linking agent to a hyaluronic acid substance in an alkaline aqueous solution, and the hyaluronic acid substance is a hyaluronic acid salt, preferably selected from at least one of sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, and zinc hyaluronate.

[0031] The cross-linking hyaluronic acid gel particles are prepared by adding a cross-linking agent to a hyaluronic acid substance in an alkaline aqueous solution, and the hyaluronic acid substance has a weight average molecular weight of 80-250 kDa, preferably 100-220 kDa, and more preferably 130-200 kDa.

[0032] The cross-linking hyaluronic acid gel particles are prepared by adding a cross-linking agent to a hyaluronic acid substance in an alkaline aqueous solution, and the alkaline aqueous solution is selected from at least one of a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution, a sodium carbonate aqueous solution, and a sodium bicarbonate aqueous solution.

[0033] The cross-linking hyaluronic acid gel particles are prepared by adding a cross-linking agent to a hyaluronic acid substance in an alkaline aqueous solution, and the water in the alkaline aqueous solution is selected from at least one of deionized water, distilled water, purified water, and water for injection.

[0034] The cross-linking hyaluronic acid gel particles are prepared by adding a cross-linking agent to a hyaluronic acid substance in an alkaline aqueous solution, and the mass percentage of the alkaline substance in the alkaline aqueous solution is 0.8%-2%, preferably 0.8%-1.5%, such as 0.8%, 0.9%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, or 2%.

[0035] The cross-linking hyaluronic acid gel particles are prepared by adding a cross-linking agent to a hyaluronic acid substance in an alkaline aqueous solution, and the volume of the cross-linking agent added per unit volume of the alkaline aqueous solution is 8-15 μL / mL, preferably 10-13 μL / mL, such as 8 μL / mL, 9 μL / mL, 10 μL / mL, 11 μL / mL, 12 μL / mL, 12.5 μL / mL, 13 μL / mL, 14 μL / mL, or 15 μL / mL.

[0036] The cross-linking hyaluronic acid gel particles are prepared by adding a cross-linking agent to a hyaluronic acid substance in an alkaline aqueous solution, and the mass of the hyaluronic acid substance added per unit volume of the alkaline aqueous solution is 0.08-0.13 g / mL, preferably 0.1-0.125 g / mL.

[0037] In the preparation of the cross-linked hyaluronic acid gel particles, the mixing comprises the following steps: mixing the cross-linking agent with the alkaline aqueous solution to obtain material A; and mixing the material A with the hyaluronic acid substance.

[0038] Preferably, the first mixing and / or the second mixing is carried out under stirring.

[0039] Preferably, the first mixing and / or the second mixing is carried out for a time period sufficient to mix the components uniformly.

[0040] Preferably, the cross-linking reaction is carried out at a temperature of 20-50°C.

[0041] Preferably, the cross-linking reaction is carried out for a time period of 2-32h.

[0042] In a preferred embodiment, the cross-linking reaction comprises the following steps: carrying out a first cross-linking at 40-50°C for 3-8h, and carrying out a second cross-linking at 20-25°C for 10-24h.

[0043] Preferably, the first cross-linking is carried out at a temperature of 40-45°C.

[0044] Preferably, the first cross-linking is carried out for a time period of 3-6h, such as 4h.

[0045] Preferably, the first cross-linking is carried out under static condition.

[0046] Preferably, the second cross-linking is carried out for a time period of 10-15h, such as 12h.

[0047] Preferably, the second cross-linking is carried out under static condition.

[0048] Preferably, the cross-linking reaction is further followed by a step of dialysis and / or dilution. According to the prior art, the purpose of the dialysis is to remove the residual cross-linking agent and / or cross-linking agent derivative in the system.

[0049] Preferably, the washing solution used in the dialysis and / or the dilution liquid used in the dilution is a salt solution, preferably a phosphate buffer.

[0050] Preferably, the osmotic pressure of the washing solution and / or the dilution liquid is 200-400mOsm / L, more preferably 220-320mOsm / L, such as 250mOsm / L.

[0051] Preferably, the pH value of the washing solution and / or the dilution liquid is 6.0-8.0, such as 7.

[0052] Preferably, the mass ratio of the washing solution to the cross-linked reaction gel is conventional in the art, preferably (20-200): 1.

[0053] The total dialysis time is 1-96 hours, preferably 8-72 hours.

[0054] The dialysis can be performed in a dialysis bag.

[0055] The concentration of the hyaluronic acid substance in the diluted system is 14-22 mg / g, preferably 15-20 mg / g.

[0056] In the preparation of the cross-linked hyaluronic acid gel particles, the mesh size of the sieve used in the sieving and granulating is 200-500 mesh.

[0057] In the preparation of the cross-linked hyaluronic acid gel particles, the sieving and granulating is performed 2-5 times.

[0058] In a preferred embodiment, the sieving and granulating includes the following steps: sieving and granulating 1-2 times using a 200-300 mesh sieve, and then sieving and granulating 1-2 times using a 400-500 mesh sieve.

[0059] The application also provides a method for preparing a sterile injection filling composition, which includes the following steps: mixing the hydroxyapatite-containing injection filling composition as described above, and sterilizing.

[0060] In some embodiments, the mixing method is mechanical stirring, and the stirring speed is 50-400 rpm.

[0061] In some embodiments, the sterilization method is moist heat sterilization.

[0062] The temperature of the moist heat sterilization is 110-140°C, for example 121°C.

[0063] The time of the moist heat sterilization is 10-40 minutes, preferably 10-20 minutes, for example 12 minutes or 15 minutes.

[0064] The application also provides a sterile injection filling composition prepared by the method for preparing a sterile injection filling composition as described above.

[0065] In some embodiments, the elastic modulus G' of the sterile injection filling composition at a frequency of 1 Hz is 700-5000 Pa, preferably 740-4500 Pa.

[0066] In some embodiments, the sterile injection filling composition has a viscous modulus G`` of 65-1400 Pa, preferably 70-1250 Pa at a frequency of 1 Hz.

[0067] In some embodiments, the sterile injection filling composition has a shear viscosity η of 100-300 Pa·s, preferably 110-260 Pa·s at a shear rate. -1 In some embodiments, the sterile injection filling composition has a shear viscosity η of 100-300 Pa·s, preferably 110-260 Pa·s at a shear rate.

[0068] In some embodiments, the sterile injection filling composition has a push force of 10-35 N, for example 10 N, 12 N, 14 N, 16 N, 18 N, 20 N, 22 N, 24 N, 26 N, 28 N, 30 N, 32 N, 34 N or 35 N when a 27G needle is used.

[0069] The application also provides a use of the sterile injection filling composition as described above in the preparation of a medical or cosmetic product.

[0070] In some embodiments, the medical or cosmetic product comprises a filling and shaping product.

[0071] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined in any manner, thereby obtaining preferred examples of the application.

[0072] The reagents and raw materials used in the application are commercially available.

[0073] The positive progress of the application is that, by specially selecting the matrix, the ideal support effect on the microspheres can be ensured even when the content of the hydroxyapatite microspheres is high, so as to promote the uniform and stable dispersion of the hydroxyapatite microspheres in the preparation. The hydroxyapatite microspheres and the specific matrix can be uniformly mixed by simple mechanical stirring method, the damage to the hydroxyapatite microspheres is reduced during the preparation process, the content of the small particles in the injection filling composition is reduced, and the inflammatory reaction is reduced. Moreover, the injection filling composition prepared has moderate push force, which reduces the injection difficulty of the doctor and avoids problems such as inflammatory reaction or abnormal bulging due to excessive local injection; the viscoelasticity is moderate, and the skin has an ideal and natural support effect. BRIEF DESCRIPTION OF DRAWINGS

[0074] Figure 1 The state diagram of the sterile injection filling composition prepared in Example 1 is shown in the figure;

[0075] Figure 2 The state diagram of the sterile injection filling composition prepared in Example 1 after centrifugation is shown in the figure;

[0076] Figure 3 The state diagram of the sterile injection filling composition prepared in Comparative Example 1 after centrifugation is shown in the figure;

[0077] Figure 4A state diagram of the sterile injection filling composition prepared for Comparative Example 2 is shown in FIG. 1.

[0078] Figure 5 A state diagram of the sterile injection filling composition after centrifugation prepared for Comparative Example 5 is shown in FIG. 5. DETAILED DESCRIPTION

[0079] The present application is further illustrated by the following examples without thereby limiting the present application to the examples described. The experimental methods in the following examples, for which specific conditions are not indicated, are selected according to the conventional methods and conditions, or according to the product instructions.

[0080] The reagents and raw materials used in the following examples are commercially available, and the purity of the reagents used is injection grade.

[0081] (1) The particle size test method of the following cross-linked hyaluronic acid gel particles is as follows:

[0082] The particle size distribution of the cross-linked hyaluronic acid gel particles is measured by taking an appropriate amount of the upper transparent gel particles in the measuring cell after centrifugation at 15000 rpm for 15 min with 0.9% sodium chloride as the dispersant, stirring at an appropriate speed (1500-2000 revolutions per minute), and measuring according to the Particle Size and Particle Size Distribution Determination Method (Chinese Pharmacopoeia 2020 Edition Part Four General Rule 0982) Third Method (Malvern Mastersizer 3000), so that the detector light shielding rate is within the range of 5%-20%, the particle refractive index is 1.33, the particle absorption rate is 0.01, the analysis model is general, and the average value is taken by continuous measurement for 3 times.

[0083] (2) The test method of the elastic modulus G` and the viscous modulus G`` of the following sample to be tested

[0084] Dynamic frequency scanning is performed using a rheometer, the test temperature is set to 25°C, the frequency variation range is 0.1-10 Hz, the shear strain is 0.5%, and the number of sampling points is 10 for each order of magnitude. The values of the elastic modulus G` and the viscous modulus G`` at 1 Hz are compared.

[0085] (3) The test method of the shear viscosity η of the following sample to be tested

[0086] Shear rate scanning is performed using a rheometer, the detection temperature is set to 25°C, the shear rate range is 0.1-100 s -1 , the gap is set to 0.3 mm, the scanning time is 3 min, and the number of sampling points is 20 for each order of magnitude, and the shear viscosity value under the shear rate condition of 1 s -1 is taken.

[0087] (4) The preparation method of the cross-linked hyaluronic acid gel particles in the following examples or comparative examples is as follows:

[0088] Cross-linked hyaluronic acid gel particles A: 100 μL of 1,4-butanediol diglycidyl ether was measured and added to 9 mL of 1 wt% sodium hydroxide aqueous solution to obtain material A, 1 g of sodium hyaluronate with a weight average molecular weight of 130 WD a was added to material A, and after uniform mixing, a one-time cross-linking reaction was carried out at 40°C for 4 h under static conditions, and then a two-time cross-linking reaction was carried out at 25°C for 12 h under static conditions; the gel prepared after the two-time cross-linking reaction was cut into small pieces; the cut gel was washed by dialysis using a phosphate buffer with an osmotic pressure of 250 mOsm / L and a pH of 7, and the washed gel was diluted to obtain a gel with a sodium hyaluronate concentration of 20 mg / g; the diluted gel was sieved twice using a 200-mesh sieve, and then sieved twice using a 500-mesh sieve to obtain cross-linked hyaluronic acid gel particles A. The shear viscosity of the cross-linked hyaluronic acid gel particles A under the condition of a shear rate of 1 s -1 -1 was 149.6 Pa·s, the elastic modulus G' at 1 Hz was 290.0 Pa, the viscous modulus G'' was 28.28 Pa, the particle size D10 was 82.9 μm, the particle size D50 was 142 μm, and the particle size D90 was 245 μm.

[0089] Cross-linked hyaluronic acid gel particles B: Compared with the preparation method of cross-linked hyaluronic acid gel particles A, the only difference is that the amount of sodium hydroxide aqueous solution is adjusted from 9 mL to 8.5 mL, and other condition parameters are the same, to obtain cross-linked hyaluronic acid gel particles B. The shear viscosity of the cross-linked hyaluronic acid gel particles B under the condition of a shear rate of 1 s -1 -1 was 200.3 Pa·s, the elastic modulus G' at 1 Hz was 367.6 Pa, the viscous modulus G'' was 26.12 Pa, the particle size D10 was 88.4 μm, the particle size D50 was 140 μm, and the particle size D90 was 227 μm.

[0090] Cross-linked hyaluronic acid gel particles C: Compared with the preparation method of cross-linked hyaluronic acid gel particles A, the only difference is that the amount of sodium hydroxide aqueous solution is adjusted from 9 mL to 8 mL, and other condition parameters are the same, to obtain cross-linked hyaluronic acid gel particles C. The shear viscosity of the cross-linked hyaluronic acid gel particles C under the condition of a shear rate of 1 s -1 -1 was 114.2 Pa·s, the elastic modulus G' at 1 Hz was 497.7 Pa, the viscous modulus G'' was 39.68 Pa, the particle size D10 was 87.4 μm, the particle size D50 was 149 μm, and the particle size D90 was 258 μm.

[0091] Cross-linked hyaluronic acid gel particles D: compared with the preparation method of cross-linked hyaluronic acid gel particles C, the only difference is that the concentration of the aqueous sodium hydroxide solution is adjusted from 1wt% to 1.2wt%, and other condition parameters are the same, and cross-linked hyaluronic acid gel particles D are prepared. Among them, the shear viscosity of cross-linked hyaluronic acid gel particles D is 200.3Pa·s under the condition of shear rate 1s -1 , the elastic modulus G` is 408.1Pa at 1Hz, the viscous modulus G`` is 25.93Pa, the particle size D10 is 90μm, D50 is 156μm, and D90 is 258μm.

[0092] Cross-linked hyaluronic acid gel particles E: compared with the preparation method of cross-linked hyaluronic acid gel particles C, the only difference is that the sieving method for granulation is different, and the specific adjustment is to sieve the diluted gel twice with a 200 mesh sieve, and then sieve once with a 500 mesh sieve, and other condition parameters are the same, and cross-linked hyaluronic acid gel particles E are prepared. Among them, the shear viscosity of cross-linked hyaluronic acid gel particles E is 124.4Pa·s under the condition of shear rate 1s -1 , the elastic modulus G` is 520.1Pa at 1Hz, the viscous modulus G`` is 40.68Pa, the particle size D10 is 101μm, D50 is 177μm, and D90 is 314μm.

[0093] Cross-linked hyaluronic acid gel particles F: compared with the preparation method of cross-linked hyaluronic acid gel particles E, the only difference is that when the washed gel is diluted, the gel is configured to have a sodium hyaluronate concentration of 15mg / g, and other condition parameters are the same, and cross-linked hyaluronic acid gel particles F are prepared. Among them, the shear viscosity of cross-linked hyaluronic acid gel particles F is 74.19Pa·s under the condition of shear rate 1s -1 , the elastic modulus G` is 436.0Pa at 1Hz, the viscous modulus G`` is 57.6Pa, the particle size D10 is 92.8μm, D50 is 168μm, and D90 is 309μm.

[0094] Cross-linked hyaluronic acid gel particles G: compared with the preparation method of cross-linked hyaluronic acid gel particles F, the only difference is that the sodium hyaluronate with a weight average molecular weight of 130WDa is replaced by sodium hyaluronate with a weight average molecular weight of 200WDa, and other condition parameters are the same, and cross-linked hyaluronic acid gel particles G are prepared. Among them, the shear viscosity of cross-linked hyaluronic acid gel particles G is 83.3Pa·s under the condition of shear rate 1s -1 , the elastic modulus G` is 470.0Pa at 1Hz, the viscous modulus G`` is 44.51Pa, the particle size D10 is 101μm, D50 is 180μm, and D90 is 327μm.

[0095] Cross-linked hyaluronic acid gel particles H: the difference compared with the preparation method of cross-linked hyaluronic acid gel particles D is that the amount of aqueous sodium hydroxide solution is adjusted from 8 mL to 5 mL, the amount of BDDE is adjusted from 100 μL to 15 μL, and other condition parameters are the same, and cross-linked hyaluronic acid gel particles H are prepared. Among them, the shear viscosity of cross-linked hyaluronic acid gel particles H under the condition of shear rate 1 s -1 -1 is 102.4 Pa·s, the elastic modulus G` at 1 Hz is 168.3 Pa, the viscous modulus G`` is 30.25 Pa, the particle size D10 is 124 μm, D50 is 210 μm, and D90 is 388 μm.

[0096] Cross-linked hyaluronic acid gel particles I: the difference compared with the preparation method of cross-linked hyaluronic acid gel particles C is that when the washed gel is diluted, the gel with a sodium hyaluronate concentration of 13 mg / g is configured, and other condition parameters are the same, and cross-linked hyaluronic acid gel particles I are prepared. Among them, the shear viscosity of cross-linked hyaluronic acid gel particles I under the condition of shear rate 1 s -1 -1 is 60.4 Pa·s, the elastic modulus G` at 1 Hz is 414.4 Pa, the viscous modulus G`` is 66.78 Pa, the particle size D10 is 113 μm, D50 is 209 μm, and D90 is 264 μm.

[0097] Cross-linked hyaluronic acid gel particles J: the difference compared with the preparation method of cross-linked hyaluronic acid gel particles C is that the sieving granulation method is different, specifically, the sieving granulation of the diluted gel is performed twice with a 200 mesh sieve, and then sieving granulation is performed twice with a 300 mesh sieve, and other condition parameters are the same, and cross-linked hyaluronic acid gel particles J are prepared. Among them, the shear viscosity of cross-linked hyaluronic acid gel particles J under the condition of shear rate 1 s -1 -1 is 115.5 Pa·s, the elastic modulus G` at 1 Hz is 511.1 Pa, the viscous modulus G`` is 34.03 Pa, the particle size D10 is 104 μm, D50 is 201 μm, and D90 is 422 μm.

[0098] (5) The hydroxyapatite microspheres used in the following examples and comparative examples have a particle size D90 of 25-45 μm, and are Dingan® / DinganTec® hydroxyapatite microspheres for surgical implants purchased from Suzhou Dingan Technology Co., Ltd.

[0099] Examples 1-13 and Comparative Examples 1-5

[0100] Example 1: The cross-linked hyaluronic acid gel particles A, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres at a mass ratio of 1 : 1, the mixing was carried out under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 ℃ for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0101] Example 2: The cross-linked hyaluronic acid gel particles B, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres at a mass ratio of 1 : 1, the mixing was carried out under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 ℃ for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0102] Example 3: The cross-linked hyaluronic acid gel particles C, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres at a mass ratio of 1 : 0.83, the mixing was carried out under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 ℃ for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0103] Example 4: The cross-linked hyaluronic acid gel particles C, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres at a mass ratio of 1 : 0.91, the mixing was carried out under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 ℃ for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0104] Example 5: The cross-linked hyaluronic acid gel particles C, free sodium hyaluronate (weight average molecular weight 30 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres at a mass ratio of 1 : 0.91, the mixing was carried out under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 ℃ for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0105] Example 6: The cross-linked hyaluronic acid gel particles C, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 : 1 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121°C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0106] Example 7: The cross-linked hyaluronic acid gel particles D, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 : 0.43 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121°C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0107] Example 8: The cross-linked hyaluronic acid gel particles E, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 : 1 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121°C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0108] Example 9: The cross-linked hyaluronic acid gel particles F, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 : 0.43 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121°C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0109] Example 10: The cross-linked hyaluronic acid gel particles F, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 : 0.67 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121°C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0110] Example 11: The cross-linked hyaluronic acid gel particles F, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 :0.67 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 °C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0111] Example 12: The cross-linked hyaluronic acid gel particles F, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 :0.67 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 °C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0112] Example 13: The cross-linked hyaluronic acid gel particles G, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 :0.43 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 °C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0113] Comparative Example 1: The cross-linked hyaluronic acid gel particles H, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 :1 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 °C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0114] Comparative Example 2: The cross-linked hyaluronic acid gel particles I, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres in a mass ratio of 1 :0.43 under mechanical stirring, the stirring speed was 200 rpm, after uniform mixing, it was sterilized by moist heat at 121 °C for 12 min to prepare a sterile injection filling composition, the specific parameters of cross-linked HA are shown in Table 1 below.

[0115] Comparative Example 3: The cross-linked hyaluronic acid gel particles J, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres at a mass ratio of 1:1 under mechanical stirring, the stirring speed was 200 rpm, and after uniform mixing, the sterile injection filling composition was prepared by moist heat sterilization at 121°C for 12 min, and the specific parameters of the cross-linked HA are shown in Table 1 below.

[0116] Comparative Example 4: The cross-linked hyaluronic acid gel particles C and phosphate buffer were mixed to prepare a matrix, without adding free sodium hyaluronate; the matrix was mixed with hydroxyapatite microspheres at a mass ratio of 1:0.29 under mechanical stirring, the stirring speed was 200 rpm, and after uniform mixing, the sterile injection filling composition was prepared by moist heat sterilization at 121°C for 12 min, and the specific parameters of the cross-linked HA are shown in Table 1 below.

[0117] Comparative Example 5: The cross-linked hyaluronic acid gel particles C, free sodium hyaluronate (weight average molecular weight 130 WD a) and phosphate buffer were mixed to prepare a matrix; the matrix was mixed with hydroxyapatite microspheres at a mass ratio of 1:0.43 under mechanical stirring, the stirring speed was 200 rpm, and after uniform mixing, the sterile injection filling composition was prepared by moist heat sterilization at 121°C for 12 min, and the specific parameters of the cross-linked HA are shown in Table 1 below.

[0118] Table 1

[0119]

[0120] Note: In Table 1, "cross-linked HA" refers to cross-linked hyaluronic acid gel particles; "free HA" refers to free sodium hyaluronate.

[0121] Effect Example 1

[0122] The shear viscosity, elastic modulus, viscous modulus, push force and stability of the sterile injection filling compositions prepared in the above examples and comparative examples were tested, and the results are shown in Table 2.

[0123] The detection method of shear viscosity, elastic modulus and viscous modulus is described above.

[0124] Push force test method: Take one sample after filling, install a 27G (0.4*12mm) needle of Terumo, exhaust the air bubbles at the needle, and place it in the detector of the universal tensile tester, and test at a speed of 30mm / min to test the maximum push force.

[0125] Stability study method: the sterile injection filling composition prepared in the above examples or comparative examples was centrifuged in a centrifuge tube at 5000 rpm for 7 min, and the dispersion of the hydroxyapatite microspheres in the system was observed. The results are shown in the accompanying drawings.

[0126] Table 2

[0127]

[0128] In Table 2, " / " represents not tested.

[0129] According to the results in Table 2, the sterile injection filling composition prepared in the examples has moderate viscoelasticity and small pushing force. The microspheres and the matrix can be mixed uniformly using a small stirring speed, and the microspheres have good dispersion stability in the matrix. The state diagram of the sterile injection filling composition prepared in Example 1 is shown in Figure 1 , and the state diagram after centrifugation (5000 rpm, 7 min) is shown in Figure 2 . Neither of them is stratified, and the hydroxyapatite is uniformly and stably dispersed in the matrix. The stability study results of the sterile injection filling compositions prepared in other examples are the same as those of Example 1.

[0130] According to the results of Comparative Example 1, when the elastic modulus of the cross-linked hyaluronic acid gel particles is less than the limited range of the present application and the particle size is greater than the limited range of the present application, the support effect on the hydroxyapatite microspheres is poor, and obvious stratification occurs after centrifugation (5000 rpm, 7 min). The results are shown in Figure 3 .

[0131] According to the results of Comparative Example 2, the content of HA in the matrix has a great influence on the stability of the product. When the content of HA is less than the limited range of the present application, obvious stratification occurs in the product after moist heat sterilization, and the results are shown in Figure 4 . Obvious stratification occurs after centrifugation. It can be seen that the stability of the cross-linked hyaluronic acid gel particles and the support effect on the hydroxyapatite microspheres are both poor.

[0132] According to the results of Comparative Example 3, the particle size of the cross-linked hyaluronic acid gel particles has a great influence on the pushing force of the product. When the particle size is large, the pushing force is significantly increased. This is not conducive to the operation of the doctor during injection, and is prone to cause inflammation and local abnormal elevation.

[0133] According to the results of Comparative Example 4 and Comparative Example 5, the amount of free hyaluronic acid added also has a great influence on the product performance. When the content of free hyaluronic acid is low or no free hyaluronic acid is added, it will lead to too high a pushing force, which is not conducive to the operation of the doctor during injection, and is easy to cause inflammation and local abnormal uplift and other problems. When the content of free hyaluronic acid is high, it will affect the stability of the product. Even if a small amount of hydroxyapatite microspheres is added, the stability of the product cannot be guaranteed. After centrifugation (5000 rpm, 7 min), stratification occurs. The results are shown in Table 1. Figure 5 .

[0134] Finally, it should be noted that the terms "comprising", "containing" or any other similar term in the present application are intended to cover non-exclusive inclusion, so that the process, method, article or device including a series of elements not only includes those elements, but also includes other elements not explicitly listed or inherent to such process, method, article or device.

[0135] Although the present application has been disclosed by the description of the specific embodiments of the present application above, it should be understood that those skilled in the art can design various modifications, improvements or equivalents of the present application within the spirit and scope of the appended claims. These modifications, improvements or equivalents should also be considered to be included in the scope of protection required by the present application.

Claims

1. A hydroxyapatite-containing injection filler composition, characterized in that, It includes a matrix and hydroxyapatite microspheres; the matrix includes cross-linked hyaluronic acid gel particles and free hyaluronic acid-like substances; The matrix contains 14-25 mg / g of hyaluronic acid, and the mass ratio of hyaluronic acid in the cross-linked hyaluronic acid gel particles to that of free hyaluronic acid is 1:(0.03-0.18). The particle size D90 of the cross-linked hyaluronic acid gel particles is 200-350 μm, and the elastic modulus G' of the cross-linked hyaluronic acid gel particles at a frequency of 1 Hz is 270-600 Pa.

2. The injection filling composition according to claim 1, characterized in that, The injection filling composition satisfies at least one of the following conditions (1) to (14): (1) The content of hyaluronic acid in the matrix is ​​14~19 mg / g; (2) The mass ratio of hyaluronic acid in the cross-linked hyaluronic acid gel particles to the mass ratio of free hyaluronic acid is 1:(0.03~0.15). (3) The weight-average molecular weight of the free hyaluronic acid is 10~200 WDa; (4) The free hyaluronic acid-like substance is hyaluronic acid salt; (5) The particle size D10 of the cross-linked hyaluronic acid gel particles is 50~110μm; (6) The particle size D50 of the cross-linked hyaluronic acid gel particles is 120~190μm; (7) The particle size D90 of the cross-linked hyaluronic acid gel particles is 210~330μm; (8) The elastic modulus G` of the cross-linked hyaluronic acid gel particles at a frequency of 1 Hz is 285~530 Pa; (9) The cross-linked hyaluronic acid gel particles have a viscosity modulus G`` of 20~65 Pa at a frequency of 1 Hz; (10) The cross-linked hyaluronic acid gel particles in 1s -1 The shear viscosity η at the shear rate is 60~300 Pa·s; (11) The mass ratio of the matrix to the hydroxyapatite microspheres is 1:(0.3~1.5). (12) The particle size of the hydroxyapatite microspheres is 20~60μm; (13) The matrix also includes a buffer and / or an anesthetic; (14) The preparation method of the cross-linked hyaluronic acid gel particles includes the following steps: mixing the cross-linking agent, hyaluronic acid and alkaline aqueous solution, performing a cross-linking reaction, sieving and granulating to obtain the cross-linked hyaluronic acid gel particles.

3. The injection filling composition according to claim 2, characterized in that, The injection filling composition satisfies at least one of the following conditions (1) to (13): (1) The weight-average molecular weight of the free hyaluronic acid is 10~140WDa, preferably 110~140WDa; (2) The free hyaluronic acid substance is selected from at least one of sodium hyaluronate, potassium hyaluronate, calcium hyaluronate and zinc hyaluronate; (3) The particle size D10 of the cross-linked hyaluronic acid gel particles is 80~105μm; (4) The particle size D50 of the cross-linked hyaluronic acid gel particles is 130~185μm; (5) The particle size D90 of the cross-linked hyaluronic acid gel particles is 220~320μm; (6) The elastic modulus G` of the cross-linked hyaluronic acid gel particles at a frequency of 1 Hz is 350~530 Pa; (7) The cross-linked hyaluronic acid gel particles have a viscosity modulus G`` of 25~60 Pa at a frequency of 1 Hz; (8) The cross-linked hyaluronic acid gel particles in 1s -1 The shear viscosity η at the shear rate is 70~220 Pa·s; (9) The mass ratio of the matrix to the hydroxyapatite microspheres is 1:(0.3~1.2), preferably 1:(0.4~1). (10) The particle size of the hydroxyapatite microspheres is 25~45μm; (11) The buffer is a phosphate buffer, preferably a mixture of dihydrogen phosphate and dihydrogen phosphate; preferably, the dihydrogen phosphate is selected from disodium hydrogen phosphate and / or dipotassium hydrogen phosphate; preferably, the dihydrogen phosphate is selected from sodium dihydrogen phosphate and / or potassium dihydrogen phosphate. (12) The anesthetic agent is selected from at least one of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine and bupivacaine; (13) The anesthetic agent accounts for 0.1% to 0.6% of the mass of the matrix.

4. The injection filling composition according to claim 2 or 3, characterized in that, The preparation method of the cross-linked hyaluronic acid gel particles satisfies at least one of the following conditions (1) to (14): (1) The crosslinking agent is a crosslinking agent containing at least two epoxy groups; (2) The hyaluronic acid-like substance is a hyaluronic acid salt; (3) The weight-average molecular weight of the hyaluronic acid-like substances is 80WDa~250WDa; (4) The alkaline aqueous solution is selected from at least one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution and sodium bicarbonate aqueous solution; (5) The water in the alkaline aqueous solution is selected from at least one of deionized water, distilled water, purified water and water for injection; (6) The mass percentage of alkaline substances in the alkaline aqueous solution is 0.8%~2%; (7) The volume of the crosslinking agent added per unit volume of the alkaline aqueous solution is 8~15 μL / mL; (8) The mass of the hyaluronic acid substance added per unit volume of the alkaline aqueous solution is 0.08~0.13 g / mL; (9) The mixing includes the following steps: mixing the crosslinking agent with the alkaline aqueous solution once to obtain material A; mixing material A with the hyaluronic acid substance a second time; (10) The temperature of the crosslinking reaction is 20~50℃; (11) The cross-linking reaction takes 2 to 32 hours; (12) The crosslinking reaction further includes dialysis and / or dilution steps; (13) The mesh size of the sieve used for granulation is 200-500 mesh; (14) The number of times the granulation is sieved is 2 to 5.

5. The injection filling composition according to claim 4, characterized in that, The preparation method of the cross-linked hyaluronic acid gel particles satisfies at least one of the following conditions (1) to (11): (1) The crosslinking agent is a crosslinking agent containing two epoxy groups, preferably selected from at least one of 1,4-butanediol diglycidyl ether, ethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether and poly(dimethylsiloxane) diglycidyl ether; (2) The hyaluronic acid substance is selected from at least one of sodium hyaluronate, potassium hyaluronate, calcium hyaluronate and zinc hyaluronate; (3) The weight-average molecular weight of the hyaluronic acid-like substance is 100WDa~220WDa, preferably 130~200WDa; (4) The mass percentage of alkaline substances in the alkaline aqueous solution is 0.8%~1.5%; (5) The volume of the crosslinking agent added per unit volume of the alkaline aqueous solution is 10~13 μL / mL; (6) The mass of the hyaluronic acid substance added per unit volume of the alkaline aqueous solution is 0.1~0.125 g / mL; (7) The crosslinking reaction includes the following steps: performing a first crosslinking at 40~50℃ for 3~8h, and then performing a second crosslinking at 20~25℃ for 10~24h; preferably, the temperature of the first crosslinking is 40~45℃; preferably, the time of the first crosslinking is 3~6h; preferably, the first crosslinking is performed under static conditions; preferably, the time of the second crosslinking is 10~15h; preferably, the second crosslinking is performed under static conditions. (8) The cleaning solution and / or the diluent used for dialysis is a salt solution; preferably, the osmotic pressure of the cleaning solution and / or the diluent is 200~400 mOsm / L, more preferably 220~320 mOsm / L; preferably, the pH value of the cleaning solution and / or the diluent is 6.0~8.0; (9) The total dialysis time is 1 to 96 hours, preferably 8 to 72 hours; (10) The concentration of hyaluronic acid in the diluted system is 14~22 mg / g, preferably 15~20 mg / g; (11) The sieving and granulation includes the following steps: sieving and granulating with a 200-300 mesh screen 1-2 times, and then sieving and granulating with a 400-500 mesh screen 1-2 times.

6. A method for preparing a sterile injection filling composition, characterized in that, The process includes the following steps: mixing the injection filling composition as described in any one of claims 1 to 5 and sterilizing it.

7. The method for preparing the sterile injection filling composition according to claim 6, characterized in that, The preparation method satisfies the following conditions (1) and / or (2): (1) The mixing method is mechanical stirring, and the stirring speed is 50~400 rpm; (2) The sterilization method is moist heat sterilization, the temperature of moist heat sterilization is 110~140℃, and the time of moist heat sterilization is 10~40min.

8. A sterile injection filling composition, characterized in that, It is prepared by the preparation method as described in claim 6 or 7.

9. The sterile injection filling composition according to claim 8, characterized in that, The sterile injection filling composition satisfies at least one of the following conditions (1) to (4): (1) The elastic modulus G` of the sterile injection filling composition at a frequency of 1 Hz is 700~5000 Pa, preferably 740~4500 Pa; (2) The viscous modulus G`` of the sterile injection filling composition at a frequency of 1 Hz is 65~1400 Pa, preferably 70~1250 Pa; (3) The sterile injection filling composition is in 1s -1 The shear viscosity η at the shear rate is 100~300 Pa·s, preferably 110~260 Pa·s; (4) The extrusion force of the sterile injection filling composition using a 27G needle is 10~35N.

10. The use of a sterile injection filling composition as described in claim 8 or 9 in the preparation of medical or cosmetic products; preferably, the medical or cosmetic products include filling and shaping products.

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