Hydroxyapatite microsphere facial skin filler for injection and preparation method thereof

Abstract

The invention belongs to the technical field of medical cosmetology and plastic surgery, and particularly relates to a hydroxyapatite microsphere facial skin filling agent for injection and a preparation method thereof. Hydroxyapatite microspheres and sodium hyaluronate are uniformly mixed, a cross-linking agent is added, and cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles which take hydroxyapatite microspheres as cores and cross-linked sodium hyaluronate as shells and are of a soft-in-hard structure can be obtained through dialysis and particle grading. The cross-linked sodium hyaluronate is used as a core-shell structure, so that the hydroxyapatite is locked in the cross-linked sodium hyaluronate, agglomeration is effectively avoided, the extrusion resistance can be well reduced by the soft-wrapped-hard core-shell structure, and the propulsive force is smaller. All the components in the hydroxyapatite microsphere facial skin filler for injection have better biocompatibility, so that the rejection of the filler in a body is reduced, and the skin problems of allergy, redness, swelling, small lumps and the like after injection and filling are effectively avoided.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical cosmetic surgery, and in particular relates to an injectable hydroxyapatite microsphere facial skin filler and a preparation method thereof. Background Art

[0002] With the improvement of living standards, people have put forward higher requirements for fighting facial aging, which has triggered a huge demand for injectable medical beauty products. Injection beauty is a type of non-surgical plastic surgery. It uses injection methods to inject biological materials or artificially synthesized materials with good biocompatibility into the dermis or subcutaneous layer, and achieves the purpose of reducing skin wrinkles or plasticity through different mechanisms of action. Sodium hyaluronate is a polysaccharide biomaterial with very good biocompatibility. Its degradation and metabolic process in the body has been clearly studied and it is safe for the human body. It is the preferred material for preparing gel products. Nowadays, gel products have been well known to the public as important products in the field of micro-plastic surgery. There are many injectable gel products on the market. Among them, hyaluronic acid products are widely used by plastic surgery institutions for their good biocompatibility, few side effects after injection, and relatively long-lasting shaping effects.

[0003] Regenerative injectable fillers are popular among consumers because of their principle of inducing collagen production in situ, which makes the filling effect more natural, and they are not easy to shift and last for a long time. Among them, hydroxyapatite injectable fillers represented by Radiesse are the only regenerative injectable fillers that do not promote collagen production through inflammatory response, so their adverse events, especially inflammatory nodules, are the least. However, most of the mainstream hydroxyapatite injections on the market currently use carboxymethyl cellulose (CMC) gel as the matrix material. Due to the high density of hydroxyapatite, it can move and precipitate in the CMC gel after injection, resulting in agglomeration, causing small bumps on the skin surface, thus affecting the aesthetic effect. Summary of the invention

[0004] The present invention aims to overcome the defects of the prior art hydroxyapatite injectable filler that is prone to agglomeration and precipitation after injection, resulting in small bumps on the skin surface, affecting the aesthetic effect and leaving safety hazards. An injectable hydroxyapatite microsphere facial skin filler and a preparation method thereof are provided to overcome the above defects.

[0005] To achieve the above-mentioned purpose, the present invention is implemented by the following technical solutions: An injectable hydroxyapatite microsphere facial skin filler, comprising: Cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles, uncross-linked sodium hyaluronate solution; The cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles are prepared by encapsulating hydroxyapatite microspheres with cross-linked sodium hyaluronate gel; the particle size of the hydroxyapatite microspheres is 20-50 μm.

[0006] After extensive research, the inventors of the present invention have found that after uniformly mixing hydroxyapatite microspheres with sodium hyaluronate, adding a crosslinking agent, and undergoing dialysis and particle classification, a "soft-encapsulated hard" structure of cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles with hydroxyapatite microspheres as the core and cross-linked sodium hyaluronate as the shell can be obtained, so that the hydroxyapatite is locked in the middle of the cross-linked sodium hyaluronate, effectively preventing the generation of agglomeration, and this "soft-encapsulated hard" core-shell structure can well reduce the extrusion resistance and make the propulsion force smaller. The common injections currently on the market that use carboxymethyl cellulose (CMC) as the dispersion medium are prone to physical agglomeration because the hydroxyapatite microspheres can move freely in CMC and the density difference between the two is large.

[0007] As a further preference, the particle size of the hydroxyapatite microspheres is 20-40 μm.

[0008] Preferably, the hydroxyapatite microspheres are solid microspheres or hollow microspheres.

[0009] Preferably, the mass fraction of the cross-linked sodium hyaluronate gel contained in the cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles is 30-60%.

[0010] As further preferred, the mass fraction of the cross-linked sodium hyaluronate gel contained in the cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles is 40-50%.

[0011] Preferably, the mass fraction of hydroxyapatite microspheres contained in the cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles is 40-70%.

[0012] As further preferred, the mass fraction of hydroxyapatite microspheres contained in the cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles is 50-60%.

[0013] Preferably, the content of the uncross-linked sodium hyaluronate solution in the injectable hydroxyapatite microsphere facial dermal filler is 5-30wt%.

[0014] As further preferred, the content of the uncross-linked sodium hyaluronate solution in the injectable hydroxyapatite microsphere facial dermal filler is 5-15 wt %.

[0015] Preferably, the content of cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles in the injectable hydroxyapatite microsphere facial skin filler is 70-95wt%.

[0016] As a further preferred embodiment, the content of cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles in the injectable hydroxyapatite microsphere facial skin filler is 85-95wt%.

[0017] Preferably, the cross-linked sodium hyaluronate gel is prepared by chemically cross-linking sodium hyaluronate and a cross-linking agent; the swelling degree of the cross-linked sodium hyaluronate gel is 35-150.

[0018] As further preferred, the swelling degree of the cross-linked sodium hyaluronate gel is 60-90.

[0019] Preferably, the cross-linking agent is any one of 1,4-butanediol glycidyl ether and divinyl sulfone.

[0020] The preparation method of the injectable hydroxyapatite microsphere facial skin filler as described above comprises the following steps: (S.1) completely dissolving sodium hyaluronate in a sodium hydroxide solution, adding a cross-linking agent and mixing evenly, and then adding hydroxyapatite microspheres and mixing evenly to obtain a mixed solution; (S.2) heating the mixed solution obtained in step (S.1) at a constant temperature and performing a cross-linking reaction, dialyzing the mixed solution after the reaction is complete, removing the dialysate, and obtaining a gel; (S.3) The gel obtained in step (S.2) is freeze-dried to obtain a freeze-dried powder, and then an uncross-linked sodium hyaluronate solution is added and mixed evenly, and then filled and sterilized by wet heat to obtain an injectable hydroxyapatite microsphere facial skin filler.

[0021] Preferably, the mass fraction of the sodium hydroxide solution added in step (S.1) is 0.5-5%.

[0022] Preferably, the reaction temperature for constant temperature heating in step (S.2) is 30-60°C; and the reaction time for the cross-linking reaction is 2-48h.

[0023] Therefore, the present invention has the following beneficial effects: (1) The present invention uniformly mixes hydroxyapatite microspheres with sodium hyaluronate, adds a crosslinking agent, and undergoes dialysis and particle classification to obtain cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles with a "soft-encapsulated hard" structure with hydroxyapatite microspheres as the core and cross-linked sodium hyaluronate as the shell, thereby locking the hydroxyapatite in the middle of the cross-linked sodium hyaluronate, effectively preventing the generation of agglomeration, and this "soft-encapsulated hard" core-shell structure can well reduce extrusion resistance and make the propulsion force smaller; (2) The various components in the injectable hydroxyapatite microsphere facial skin filler of the present invention have good biocompatibility, which helps to reduce the rejection of the filler in the body, thereby effectively avoiding skin problems such as allergies, redness, swelling, and small pimples after injection filling. DETAILED DESCRIPTION

[0024] The present invention is further described below in conjunction with specific embodiments. Those of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work should fall within the scope of protection of the present invention.

[0025] Example 1 This embodiment provides an injectable hydroxyapatite microsphere facial skin filler and a preparation method thereof.

[0026] An injectable hydroxyapatite microsphere facial skin filler, comprising: Cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles, uncross-linked sodium hyaluronate solution; Among them, the cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles are prepared by encapsulating hydroxyapatite microspheres with cross-linked sodium hyaluronate gel; the particle size of the hydroxyapatite microspheres is 20~50μm, and the hydroxyapatite microspheres are solid microspheres or hollow microspheres.

[0027] The preparation method of the injectable hydroxyapatite microsphere facial skin filler as described above comprises the following steps: (S.1) Dissolve 1 g of sodium hyaluronate in 20 g of 1% sodium hydroxide solution, stir until completely dissolved, add 1,4-butanediol glycidyl ether (BDDE) crosslinking agent and mix well, then add 56 g of hydroxyapatite microsphere powder, stir well to obtain a mixed solution; (S.2) placing the mixed solution obtained in step (S.1) in a 30°C constant temperature water bath, heating for 48 hours and performing a cross-linking reaction, dialyzing the mixed solution in a dialysate until equilibrium (i.e., dialyzing until the mass no longer increases), removing the dialysate, and obtaining a gel; (S.3) The gel obtained in step (S.2) is freeze-dried using a freeze dryer to obtain a freeze-dried powder. The freeze-dried powder is then mixed evenly with 50 mL of a 2 mg / mL uncross-linked sodium hyaluronate solution, and then filled into a prefilled syringe and sterilized by wet heat to obtain an injectable hydroxyapatite microsphere facial skin filler.

[0028] After adding an equal amount of water to the prefilled syringe and letting it stand, it was observed that hydroxyapatite and cross-linked sodium hyaluronate were not separated. Further test results showed that the push force of the injectable hydroxyapatite microsphere facial skin filler in a 1mL glass syringe was 10N, the swelling degree was 70, the viscosity modulus was 99Pa, and the elastic modulus was 720Pa.

[0029] Example 2 The difference between this embodiment and embodiment 1 is that: A method for preparing an injectable hydroxyapatite microsphere facial skin filler, wherein in step (S.1), a sodium hydroxide solution with a concentration of 1% is replaced with a sodium hydroxide solution with a concentration of 5%; 1,4-butanediol glycidyl ether (BDDE) crosslinking agent is replaced with divinyl sulfone (DVS); 56g of hydroxyapatite microsphere powder is replaced with 33g of hydroxyapatite microsphere powder; in step (S.2), heating in a 30°C constant temperature water bath for 48h is replaced with heating in a 60°C constant temperature water bath for 2h; in step (S.3), a non-crosslinked sodium hyaluronate solution with a concentration of 2mg / mL is replaced with a non-crosslinked sodium hyaluronate solution with a concentration of 1mg / mL. The rest is the same as in Example 1.

[0030] After adding an equal amount of water to the prefilled syringe and letting it stand, it was observed that hydroxyapatite and cross-linked sodium hyaluronate were not separated. Further test results showed that the push force of the injectable hydroxyapatite microsphere facial skin filler in a 1mL glass syringe was 11N, the swelling degree was 40, the viscosity modulus was 120Pa, and the elastic modulus was 600Pa.

[0031] Example 3 The difference between this embodiment and embodiment 1 is that: A method for preparing an injectable hydroxyapatite microsphere facial skin filler, wherein in step (S.1), 20g of 1% sodium hydroxide solution is replaced with 50g of 5% sodium hydroxide solution; 56g of hydroxyapatite microsphere powder is replaced with 116g of hydroxyapatite microsphere powder; in step (S.2), heating in a 30°C constant temperature water bath for 48h is replaced with heating in a 49°C constant temperature water bath for 3h; in step (S.3), uncrosslinked sodium hyaluronate solution with a concentration of 2mg / mL is replaced with uncrosslinked sodium hyaluronate solution with a concentration of 3mg / mL. The rest is the same as in Example 1.

[0032] After adding an equal amount of water to the prefilled syringe and letting it stand, it was observed that hydroxyapatite and cross-linked sodium hyaluronate were not separated. Further test results showed that the push force of the injectable hydroxyapatite microsphere facial skin filler in a 1mL glass syringe was 12N, the swelling degree was 130, the viscosity modulus was 90Pa, and the elastic modulus was 820Pa.

[0033] Example 4 The difference between this embodiment and embodiment 1 is that: A hydroxyapatite microsphere facial skin filler for injection, wherein the particle size of the hydroxyapatite microsphere is 20-40 μm. Other aspects are the same as those in Example 1.

[0034] A method for preparing an injectable hydroxyapatite microsphere facial skin filler, wherein in step (S.1), 1 g of sodium hyaluronate is dissolved in 50 g of a 0.5% sodium hydroxide solution; 117 g of hydroxyapatite microsphere powder is added; in step (S.2), the mixed solution obtained in step (S.1) is placed in a 45°C constant temperature water bath for heating for 25 h and undergoing a cross-linking reaction; in step (S.3), the freeze-dried powder is uniformly mixed with 70 mL of a 5.7 mg / mL uncross-linked sodium hyaluronate solution to finally obtain an injectable hydroxyapatite microsphere facial skin filler. The rest is the same as in Example 1.

[0035] After adding an equal amount of water to the prefilled syringe and letting it stand, it was observed that hydroxyapatite and cross-linked sodium hyaluronate were not separated. Further test results showed that the push force of the injectable hydroxyapatite microsphere facial skin filler in a 1mL glass syringe was 15N, the swelling degree was 150, the viscosity modulus was 80Pa, and the elastic modulus was 650Pa.

[0036] Comparative Example 1 The difference between this comparative example and Example 1 is: A method for preparing an injectable hydroxyapatite microsphere facial skin filler, wherein no hydroxyapatite microsphere powder is added in step (S.1); in step (S.3), the freeze-dried powder is mixed evenly with 50 mL of a 2 mg / mL non-cross-linked sodium hyaluronate solution by mixing the freeze-dried powder evenly with 56 g of hydroxyapatite microsphere powder and 50 mL of a 2 mg / mL non-cross-linked sodium hyaluronate solution; and finally a mixture of cross-linked sodium hyaluronate gel and hydroxyapatite microspheres is obtained. The rest is the same as in Example 1.

[0037] After adding an equal amount of water to the prefilled syringe and letting it stand, it was observed that hydroxyapatite and cross-linked sodium hyaluronate were clearly separated. Further test results showed that the pushing force of the mixture of cross-linked sodium hyaluronate gel and hydroxyapatite microspheres in a 1mL glass syringe was 16N, the swelling degree was 70, the viscosity modulus was 80Pa, and the elastic modulus was 500Pa.

[0038] Comparative Example 2 The difference between this comparative example and Example 1 is: A method for preparing an injectable hydroxyapatite microsphere facial skin filler, wherein in step (S.1), a sodium hydroxide solution with a concentration of 1% is replaced with a sodium hydroxide solution with a concentration of 5%; 1,4-butanediol glycidyl ether (BDDE) crosslinking agent is replaced with divinyl sulfone (DVS); hydroxyapatite microsphere powder is not added; in step (S.2), heating in a 30°C constant temperature water bath for 48 hours is replaced with heating in a 60°C constant temperature water bath for 2 hours; in step (S.3), mixing the lyophilized powder with 50 mL of a non-crosslinked sodium hyaluronate solution with a concentration of 2 mg / mL is replaced with mixing the lyophilized powder with 33 g of hydroxyapatite microsphere powder and 50 mL of a non-crosslinked sodium hyaluronate solution with a concentration of 1 mg / mL; finally, a mixture of crosslinked sodium hyaluronate gel and hydroxyapatite microspheres is obtained. Others are the same as in Example 1.

[0039] After adding an equal amount of water to the prefilled syringe and letting it stand, it was observed that hydroxyapatite and cross-linked sodium hyaluronate were clearly separated. Further test results showed that the pushing force of the mixture of cross-linked sodium hyaluronate gel and hydroxyapatite microspheres in a 1mL glass syringe was 15N, the swelling degree was 40, the viscosity modulus was 110Pa, and the elastic modulus was 420Pa.

[0040] Comparative Example 3 The difference between this comparative example and Example 1 is: A method for preparing an injectable hydroxyapatite microsphere facial skin filler, wherein in step (S.1), 20g of a 1% sodium hydroxide solution is replaced with 50g of a 5% sodium hydroxide solution; no hydroxyapatite microsphere powder is added; in step (S.2), heating in a 30°C constant temperature water bath for 48h is replaced with heating in a 49°C constant temperature water bath for 3h; in step (S.3), mixing the lyophilized powder with 50mL of a 2mg / mL uncrosslinked sodium hyaluronate solution is replaced with mixing the lyophilized powder with 116g of hydroxyapatite microsphere powder and 50mL of a 3mg / mL uncrosslinked sodium hyaluronate solution; finally, a mixture of crosslinked sodium hyaluronate gel and hydroxyapatite microspheres is obtained. Others are the same as in Example 1.

[0041] After adding an equal amount of water to the prefilled syringe and letting it stand, it was observed that hydroxyapatite and cross-linked sodium hyaluronate were clearly separated. Further test results showed that the pushing force of the mixture of cross-linked sodium hyaluronate gel and hydroxyapatite microspheres in a 1mL glass syringe was 20N, the swelling degree was 130, the viscosity modulus was 80Pa, and the elastic modulus was 620Pa.

[0042]

Performance test and result analysis

[0043] The pushing force test method is as follows: Place a 1 mL glass syringe containing injectable hydroxyapatite microsphere facial dermal filler or a mixture of cross-linked sodium hyaluronate gel and hydroxyapatite microspheres on the pushing force measuring instrument, push the push rod at a speed of 30 mm / min, and record the pushing force value within a pushing displacement of 15 mm.

[0044] The swelling test method is as follows: Take a 500-mesh sieve (8cm×8cm square, folded into a 4cm×4cm×2cm square slot) and put it in a drying oven, and cool it down to constant weight at 80℃, which is recorded as m0. Accurately weigh 0.3g of injection filler and place it on a 500-mesh sieve, place the sieve in an evaporating dish, and add 30mL of 0.9% sodium chloride solution at one time to completely soak the sample. After the gel is fully swollen for 120 minutes, take out the sieve and the sample together, and use filter paper to absorb the liquid at the bottom and around the sieve until there is no wet mark on the filter paper. The weight is recorded as m1. Then, put the sieve in a drying oven and cool it down to constant weight at 80℃, which is recorded as m2. The calculation formula is as follows: Swelling degree = (m1-m2) / (m2-m0).

[0045] Among them, in the above formula: m0——mass of screen after constant weight, g; m1——mass of the screen after swelling with injection filler gel, g; m2——The mass of the screen plus the injection filler gel after drying, g.

[0046] The rheological properties test method is as follows: The test was carried out at (25±2)°C using a rheometer at a frequency of 0.01 Hz to 100 Hz and a shear strain of 1%, and the logarithm of the viscous modulus (G″) and the elastic modulus (G′) and the logarithmic coordinates of the frequency were plotted.

[0047] From the analysis of the test results, it can be seen that when the hydroxyapatite is completely wrapped in the cross-linked sodium hyaluronate gel, the hydroxyapatite and the cross-linked sodium hyaluronate will not be delaminated, thereby effectively solving the risk of hydroxyapatite microspheres easily forming physical nodules due to agglomeration. In addition, due to the special "soft-encapsulated hard" core-shell structure of the injectable hydroxyapatite microsphere facial skin filler of the present invention, the injection process is more flexible, which helps to reduce the risk of needle blockage. The pushing force of the injectable hydroxyapatite microsphere facial skin filler prepared in Examples 1 to 3 is lower than that of the mixture of cross-linked sodium hyaluronate gel and hydroxyapatite microspheres prepared in Comparative Examples 1 to 3.

[0048] The above description is only a detailed description of the preferred embodiments and principles of the present invention. For ordinary technicians in this field, according to the ideas provided by the present invention, there will be changes in the specific implementation methods, and these changes should also be regarded as the protection scope of the present invention.

Claims

1. A hydroxyapatite microsphere facial skin filler for injection, characterized in that: include: Cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles, uncross-linked sodium hyaluronate solution; The cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles are prepared by encapsulating hydroxyapatite microspheres with cross-linked sodium hyaluronate gel; the particle size of the hydroxyapatite microspheres is 20-50 μm.

2. The hydroxyapatite microsphere facial skin filler for injection according to claim 1, characterized in that: The mass fraction of the cross-linked sodium hyaluronate gel contained in the cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles is 30-60%.

3. The injectable hydroxyapatite microsphere facial skin filler according to claim 1, characterized in that: The mass fraction of hydroxyapatite microspheres contained in the cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles is 40-70%.

4. The injectable hydroxyapatite microsphere facial skin filler according to claim 1, characterized in that: The content of uncross-linked sodium hyaluronate solution contained in the injectable hydroxyapatite microsphere facial dermal filler is 5-30wt%.

5. The hydroxyapatite microsphere facial skin filler for injection according to claim 1, characterized in that: The content of cross-linked sodium hyaluronate-hydroxyapatite core-shell structure microsphere particles contained in the injectable hydroxyapatite microsphere facial skin filler is 70~95wt%.

6. The injectable hydroxyapatite microsphere facial skin filler according to claim 1, characterized in that: The cross-linked sodium hyaluronate gel is prepared by chemically cross-linking sodium hyaluronate and a cross-linking agent; the swelling degree of the cross-linked sodium hyaluronate gel is 35-150.

7. The injectable hydroxyapatite microsphere facial skin filler according to claim 6, characterized in that: The cross-linking agent is any one of 1,4-butanediol glycidyl ether and divinyl sulfone.

8. A method for preparing an injectable hydroxyapatite microsphere facial skin filler according to any one of claims 1 to 7, characterized in that: The following steps are involved: (S.1) completely dissolving sodium hyaluronate in a sodium hydroxide solution, adding a cross-linking agent and mixing evenly, and then adding hydroxyapatite microspheres and mixing evenly to obtain a mixed solution; (S.2) heating the mixed solution obtained in step (S.1) at a constant temperature and performing a cross-linking reaction, dialyzing the mixed solution after the reaction is complete, removing the dialysate, and obtaining a gel; (S.3) The gel obtained in step (S.2) is freeze-dried to obtain a freeze-dried powder, and then an uncross-linked sodium hyaluronate solution is added and mixed evenly, and then filled and sterilized by wet heat to obtain an injectable hydroxyapatite microsphere facial skin filler.

9. The method for preparing the injectable hydroxyapatite microsphere facial skin filler according to claim 8, characterized in that: The mass fraction of the sodium hydroxide solution added in step (S.1) is 0.5-5%.

10. The method for preparing the injectable hydroxyapatite microsphere facial skin filler according to claim 8, characterized in that: The reaction temperature for constant temperature heating in step (S.2) is 30-60°C; the reaction time for the cross-linking reaction is 2-48h.