CN-122011346-A - Preparation method of crosslinked polyester microsphere, crosslinked polyester microsphere and application thereof

CN122011346ACN 122011346 ACN122011346 ACN 122011346ACN-122011346-A

Abstract

The invention relates to a preparation method of a crosslinked polyester microsphere, the crosslinked polyester microsphere and application thereof, and belongs to the technical field of biomedical materials. The preparation method of the crosslinked polyester microsphere provided by the invention does not need to introduce other high polymer polyester materials for blending or modify prepolymer so as to improve the molding stability of the microsphere, and the prepared crosslinked polyester microsphere has excellent shape retaining capability and mechanical stability, low inflammatory reaction in biological experiments, good generation of tissue collagen and suitability for soft tissue filling materials.

Inventors

Gu Zhanghao
LI ZHIYUN
SUN WEIWEI
CHEN FEIHAO
CHEN JIANYU
CHEN ZHONGGUANG

Assignees

同光(昆山)生物科技有限公司

Dates

Publication Date: 20260512
Application Date: 20260415

Claims (10)

1. A method for preparing crosslinked polyester microspheres, comprising the steps of: (1) Mixing polybasic acid and polyhydric alcohol, and performing melt polycondensation reaction to obtain polyester prepolymer; (2) Mixing the polyester prepolymer obtained in the step (1) with a solvent A to obtain an oil phase solution A; (3) Mixing the oil phase solution A obtained in the step (2) with the oil phase solution B to obtain a polyester prepolymer emulsion; (4) The polyester prepolymer emulsion obtained in the step (3) is subjected to a thermal crosslinking reaction to obtain the crosslinked polyester microsphere; the polyacid includes a polyacid having a functionality of 2 or a polyacid having a functionality of 3; the polyol comprises a polyol having a functionality of 2 or a polyol having a functionality of 3; When the polyacid is a polyacid having a functionality of 2, the polyol is selected from polyols having a functionality of 3; when the polyacid is a polyacid having a functionality of 3, the polyol is selected from polyols having a functionality of 2.
2. The method of producing crosslinked polyester microspheres according to claim 1, wherein the polybasic acid having a functionality of 2 comprises any one or a combination of at least two of malic acid, sebacic acid, succinic acid, fumaric acid, tartaric acid, or α -ketoglutaric acid; The polybasic acid with the functionality of 3 comprises any one or at least two of citric acid, propane-1, 2, 3-tricarboxylic acid or propylene-1, 2, 3-tricarboxylic acid; The polyol with the functionality of 2 comprises any one or a combination of at least two of ethylene glycol, polyethylene glycol, 1, 3-propylene glycol, 1, 4-butanediol, 1, 8-octanediol, 1, 2-propylene glycol, 1, 2-octanediol, methyl propylene glycol, 1, 5-pentanediol, neopentyl glycol, 1, 2-pentanediol, 1, 6-hexanediol or 1, 2-hexanediol; The polyol with the functionality of 3 comprises any one or a combination of at least two of glycerol, trimethylolpropane, trimethylolethane or hexanetriol; the molar ratio of the polybasic acid to the polyhydric alcohol in the step (1) is 1 (0.5-2); The reaction temperature of the melt polycondensation reaction in the step (1) is 100-200 ℃, and the reaction time of the melt polycondensation reaction is 0.5-5 h.
3. The method for producing crosslinked polyester microspheres according to claim 1, wherein the polyester prepolymer obtained in step (1) has a number average molecular weight of 500 to 12000.
4. The method for producing crosslinked polyester microspheres according to claim 1, wherein the solvent a in step (2) comprises an organic solvent; The organic solvent comprises any one or a combination of at least two of N, N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, diphenyl ether, N-methylpyrrolidone, 1,2,3, 4-tetrahydronaphthalene, dimethylbenzene, toluene or cyclohexanone; The mass ratio of the solvent A to the polyester prepolymer is (0.1-10) 1; the oil phase solution A in the step (2) also comprises a catalyst; The catalyst comprises any one or a combination of at least two of methylbenzenesulfonic acid, thionyl chloride, acetamide, tetrabutyl titanate, sodium methoxide, sodium ethoxide, tetraethyl titanate, tetraisopropyl titanate, boron trifluoride, stannous octoate, stannic chloride, stannous oxalate, stannous chloride, p-toluenesulfonic acid or butylstannoic acid; The mass ratio of the catalyst to the polyester prepolymer is (0.001-0.1): 1.
5. The method for producing crosslinked polyester microspheres according to claim 1, wherein the mass ratio of the oil phase solution a to the oil phase solution B in the step (3) is (0.01 to 0.5): 1; the oil phase solution B comprises a solvent B; The solvent B comprises any one or a combination of at least two of liquid paraffin, white oil, n-hexadecane, n-heptane, isoparaffin, silicone oil or mineral oil; the oil phase solution B also comprises a dispersing agent; The dispersing agent comprises any one or a combination of at least two of sorbitol monooleate, glycerol monooleate, polyisobutylene, polymethacrylate dispersing agent, PVP, PEG-fatty chain copolymer, hydrophobic silica, hydrophobic nano clay or surface modified bioactive glass nano particles; The mass ratio of the solvent B to the dispersing agent in the oil phase solution B is (50-500): 1; The mixing in step (3) is carried out with stirring; the stirring speed is 100-5000 r/min, and the stirring time is 10-60 min.
6. The method for producing crosslinked polyester microspheres according to claim 1, wherein the reaction temperature of the thermal crosslinking reaction in step (4) is 30 to 150 ℃ and the reaction time of the thermal crosslinking reaction is 1 to 200 h; the thermal crosslinking reaction in step (4) is carried out under vacuum environment; the vacuum degree of the vacuum environment is 10-1000 Pa.
7. The method for producing crosslinked polyester microspheres according to claim 1, further comprising a post-treatment step after the thermal crosslinking reaction in step (4); The post-treatment step comprises filtering, washing, drying and sieving.
8. A crosslinked polyester microsphere prepared by the method for preparing a crosslinked polyester microsphere according to any one of claims 1 to 7.
9. The crosslinked polyester microspheres of claim 8 wherein the crosslinked polyester microspheres have a particle size of 0.1 to 150 μm.
10. Use of the crosslinked polyester microspheres of claim 8 or 9 in soft tissue filling materials.

Description

Preparation method of crosslinked polyester microsphere, crosslinked polyester microsphere and application thereof Technical Field The invention relates to the technical field of biomedical materials, in particular to a preparation method of a crosslinked polyester microsphere, the crosslinked polyester microsphere and application thereof. Background With the rapid development of medical beauty technology, the minimally invasive, reversible and injectable soft tissue filling material is widely applied in the fields of facial rejuvenation, contour shaping, tissue volume reconstruction and the like due to the advantages of simple operation, short recovery period, high safety and the like. The medical filling materials commonly used in clinic at present mainly comprise hyaluronic acid filling materials, collagen materials and the like, but the materials have the defects of short filling effect maintenance and insufficient supporting performance. In order to extend the filling effect and improve the tissue supporting property, polymer microspheres have been widely studied as a functional filling component, and a stable spatial scaffold structure is formed in vivo by the microspheres, thereby inducing collagen regeneration and maintaining tissue volume. The common polymer microspheres comprise polylactic acid microspheres or polycaprolactone microspheres, but most of the microspheres are of linear polyester structures, the molecular chains of the microspheres are mainly dependent on physical entanglement to maintain morphological stability, deformation, collapse or breakage are easy to occur under body fluid environment and long-term stress conditions, and continuous and stable tissue support is difficult to provide, meanwhile, the microspheres generally undergo rapid reduction of molecular weight in a bulk phase degradation mode, the mechanical properties are obviously attenuated along with degradation progress, and acidic degradation products are possibly accumulated locally, so that adverse clinical reactions such as inflammatory reaction, nodule or touch hardening are initiated. Compared with linear polyester microspheres, the cross-linked polyester microspheres have the advantages that by introducing a stable three-dimensional cross-linked network structure between molecular chains, the shape retention capacity and mechanical stability of the microspheres are remarkably improved, the integral structure and space supporting function can be maintained even under partial degradation conditions, the mechanical property and viscoelasticity of the cross-linked polyester microspheres can be regulated and controlled through the degree of cross-linking, the cross-linked polyester microspheres are closer to the characteristics of natural soft tissues, and long-term stable filling effect is realized while good injection smoothness is ensured. However, crosslinked polyester materials are difficult to prepare into crosslinked polyester microspheres by conventional microsphere preparation methods, the root cause of which is that such materials typically require the preparation of low molecular weight prepolymers first to meet melt or solution processing operability. However, due to the low molecular weight of the prepolymer, the entanglement of molecular chains in the system is insufficient, and stable solidification and structure maintenance are difficult to realize in the microsphere forming process. For example, the prepolymer number average molecular weight of polycyitrate materials is typically only about 1000-5000, and it is difficult to form morphology-stable microsphere structures alone without further crosslinking or reinforcement. It is often desirable in the art to incorporate other polymeric polyester materials for blending or to chemically modify the prepolymer to improve the molding stability. However, the above-mentioned method inevitably introduces other components into the system, so that it is difficult to obtain crosslinked polyester microspheres having a single component and a pure structure. If the crosslinked polyester material is prepared in advance, the polyester material loses thermoplasticity or solubility due to the formation of a three-dimensional network structure, and the feasibility of microsphere preparation by adopting a conventional melt molding or solution emulsification method is limited. Therefore, how to prepare a crosslinked polyester microsphere with single component, pure structure and excellent shape retention capability and mechanical stability has become a problem to be solved in the prior art. Disclosure of Invention In order to solve the technical problems, the invention relates to a preparation method of a crosslinked polyester microsphere, the crosslinked polyester microsphere and application thereof, wherein other high polymer polyester materials are not required to be introduced for blending or prepolymer is not required to be subjected to chemical modification so as to i