PHA polyurethane microspheres, preparation method therefor, and use thereof

Abstract

The present disclosure relates to a method for preparing PHA polyurethane microspheres, specifically comprising the following steps: feeding polyhydroxyalkanoate diol and diisocyanate at a molar ratio of 1:(1.2-1.6) and performing a reaction, and performing complete polymerization under the condition of adding a catalytic amount of a first catalyst to obtain a first reaction product; adding a long-chain extender and dihydroxyalkanoic acid to the first reaction product to perform a complete reaction to obtain a second reaction product, wherein the molar ratio of the long-chain extender to dihydroxyalkanoic acid is 10-13:1, and isocyanate groups in the system can be completely reacted; adding water to the second reaction product and stirring to obtain an aqueous PHA polyurethane solution having a solid content of 25-40%; and dropwise adding the aqueous PHA polyurethane solution to a CaCl2 solution having a certain concentration to obtain PHA polyurethane microspheres.

Description

A PHA polyurethane microsphere, its preparation method and application

[0001] This disclosure claims priority to Chinese Patent Application No. 2024118632989, filed on December 17, 2024, entitled "A PHA Polyurethane Microsphere and its Preparation Method and Application", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to the field of functional polymer materials, and in particular to a PHA polyurethane microsphere, its preparation method, and its application. Background Technology

[0003] The continuous improvement of medical standards is inseparable from the rapid development of medical materials. Since the application of microencapsulation technology to drug formulations in the field of microcapsules in the 1970s, microcapsules prepared using biopolymer materials have achieved rapid development and widespread application in fields such as biomedicine and genetic engineering. A microcapsule is a closed micro-container with a core-shell structure, which has the same release mechanism as a capsule: the drug is encapsulated within it and released through diffusion or degradation of the carrier.

[0004] Polyhydroxyalkanoates (PHAs) are a class of natural polymeric biomaterials. They are intracellular polyesters synthesized by microorganisms and possess advantages such as economical and environmentally friendly preparation, biodegradability, and good biocompatibility. Therefore, PHAs are considered biomaterials with enormous potential, and PHA-based biomaterials have wide applications in drug delivery carriers, bioscaffolds, tissue engineering, bone graft substitutes, wound dressings, antibacterial membranes, medical implants, and hemostatic agents, making them one of the most ideal biomedical materials available today.

[0005] Polyurethane, as a synthetic polymer, can be used as a biomaterial for implantation in the human body, possessing excellent biological and mechanical properties, and has been extensively studied in drug release applications. For example, Liu Yuhong et al. prepared polyurethane microcapsules using 2,4-toluene diisocyanate, diphenylmethane diisocyanate, and lignin as raw materials, and studied the factors affecting drug release using nifedipine as a mimic drug. Lin Song synthesized polyurethane microcapsules using polyethylene glycol, polycaprolactone, isophorone diisocyanate, and dimethylolpropionic acid as a chain extender, and studied their biodegradability. Mohajnlnad et al. synthesized a series of polyurethane microspheres with different particle sizes by changing the ratio of raw materials to chain extender, using diphenylmethane diisocyanate and multifunctional polyurethane polyols as raw materials, PVP as a dispersant, and ethylenediamine as a chain extender.

[0006] Currently, there is no polyurethane microsphere that combines excellent toughness and degradation rate. Summary of the Invention

[0007] This disclosure provides a PHA polyurethane microsphere, its preparation method, and its application, which possesses both excellent toughness and degradation rate.

[0008] The first aspect of this disclosure provides a method for preparing PHA polyurethane microspheres, specifically including the following steps:

[0009] Polyhydroxy fatty acid ester diol and diisocyanate are fed in a molar ratio of 1:(1.2~1.6) and reacted. Under the condition of adding a first catalyst at a certain amount, polymerization is completed to obtain the first reactant. The molecular weight of the polyhydroxy fatty acid ester diol is 1200~3500.

[0010] A chain extender and a dihydroxyalkyl acid are added to the first reactant, and the reaction is completed to obtain the second reactant. The molar ratio of the chain extender to the dihydroxyalkyl acid is 10~13:1, and the isocyanate groups in the system are completely reacted.

[0011] Add water to the second reactant and stir to obtain a PHA polyurethane aqueous solution with a solid content of 25-40%.

[0012] The PHA polyurethane aqueous solution was added dropwise into a precipitating solution of a certain concentration to obtain PHA polyurethane microspheres.

[0013] As a preferred technical solution, the molecular weight of the polyhydroxyalkanoate diol is 1500~2500.

[0014] As a preferred technical solution, the chain extender is a polyether polyol or a polyester polyol.

[0015] As a preferred technical solution, the dihydroxyalkyl acid is dimethylolpropionic acid or dimethylolbutyric acid.

[0016] As a preferred technical solution, the first catalyst is dibutyltin dilaurate or tin isooctanoate.

[0017] As a preferred technical solution, the diisocyanate is an aliphatic diisocyanate.

[0018] As a preferred technical solution, the precipitating solution is a calcium chloride solution, a magnesium chloride solution, or an aluminum sulfate solution, with a concentration of 4-8 wt%.

[0019] As a preferred technical solution, the preparation method of the polyhydroxy fatty acid ester diol is as follows: the polyhydroxy fatty acid ester, diol, second catalyst and solvent are mixed, the reaction temperature is 42~48℃, the reaction time is 1~5 hours, vacuum polycondensation is performed for 1~3.5 hours, and the polyhydroxy fatty acid ester diol is obtained after purification and drying.

[0020] As a preferred technical solution, the preparation method of the polyhydroxy fatty acid ester diol is as follows: the polyhydroxy fatty acid ester and solvent are mixed at a mass ratio of 1:8~12, heated to 43~47℃, and a diol with a molar amount of 4~6 times that of the polyhydroxy fatty acid ester and a catalyst amount are added. After reacting for 2~4 hours, vacuum polycondensation is carried out for 1~2.5 hours, and the polyhydroxy fatty acid ester diol is obtained after purification and drying.

[0021] As a preferred technical solution, the diol is at least one selected from propylene glycol, butanediol, and hexanediol. Preferably, the diol is succinic acid.

[0022] As a preferred technical solution, the second catalyst is at least one selected from p-toluenesulfonic acid, tetrabutyl titanate, and tetraisopropyl titanate. Preferably, the second catalyst is tetrabutyl titanate.

[0023] As a preferred technical solution, PHA polyurethane microspheres have a microsphere diameter ≤75nm, a degradation rate ≥85Wt% / 90days, an elongation at break of 44~70%, and a tensile strength of 0.9~1.5MPa.

[0024] The second aspect of this disclosure provides a PHA polyurethane microsphere prepared according to the above method.

[0025] This disclosure provides a third aspect regarding the application of PHA polyurethane microspheres in drug-loaded microspheres and cosmetic fillers.

[0026] Details of one or more embodiments of this disclosure, relative to conventional technologies, are set forth in the following description. Other features, objects, and advantages of the invention will become apparent from the specification and claims.

[0027] The PHA polyurethane microspheres disclosed herein are produced by polymerizing polyhydroxy fatty acid ester diols and diisocyanates of specific molecular weights in a specific ratio, followed by the addition of a specific ratio of chain extender and dihydroxyalkyl acid for end-capping, and finally by using a condensed phase separation method in Ca... 2+ PHA polyurethane microspheres were obtained through cross-linking. The polyurethane microspheres obtained in this disclosure are uniform in size and have a moderate particle size. Compared with pure PHA microspheres, they are more tough and suitable for applications in multiple fields such as drug delivery and cosmetic fillers. Embodiments of the present invention

[0028] To make the technical solutions and advantages of this disclosure clearer, the embodiments of this disclosure will be described in further detail below.

[0029] For simplicity, this paper only explicitly discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form an undefined range; and any lower limit can be combined with other lower limits to form an undefined range, just as any upper limit can be combined with any other upper limit to form an undefined range. Furthermore, although not explicitly stated, every point or individual value between the endpoints of a range is included within that range. Therefore, each point or individual value can serve as its own lower or upper limit and be combined with any other point or individual value, or with other lower or upper limits, to form an undefined range.

[0030] In this description, it should be noted that, unless otherwise stated, "above" and "below" include the stated number, and "multiple" in "one or more" means two or more.

[0031] The foregoing description of this application is not intended to describe every disclosed implementation or method. Instead, the following description provides more specific examples of exemplary embodiments. Throughout the application, guidance is provided through a series of embodiments that can be used in various combinations. The examples listed are representative only and should not be construed as exhaustive.

[0032] The first aspect of this disclosure provides a method for preparing PHA polyurethane microspheres, specifically including the following steps:

[0033] Polyhydroxy fatty acid ester diol and diisocyanate are fed in a molar ratio of 1:(1.2~1.6) and reacted. Under the condition of adding a first catalyst at a certain amount, polymerization is completed to obtain the first reactant. The molecular weight of the polyhydroxy fatty acid ester diol is 1200~3500.

[0034] A chain extender and a dihydroxyalkyl acid are added to the first reactant, and the reaction is completed to obtain the second reactant. The molar ratio of the chain extender to the dihydroxyalkyl acid is 10~13:1, and the isocyanate groups in the system are completely reacted.

[0035] Add water to the second reactant and stir to obtain a PHA polyurethane aqueous solution with a solid content of 25-40%.

[0036] The PHA polyurethane aqueous solution was added dropwise into a precipitating solution of a certain concentration to obtain PHA polyurethane microspheres.

[0037] In this embodiment, dihydroxyalkyl acid refers to a compound containing two hydroxyl groups and one carboxyl group.

[0038] This embodiment involves reacting a polyhydroxyalkanoate diol of a specific molecular weight with diisocyanate at a molar ratio of 1:(1.2~1.6) to obtain a polyurethane prepolymer with isocyanate ends. A specific proportion of chain extender and dihydroxyalkyl acid are then added for end-capping. The process is then performed using a condensed phase separation method in Ca... 2+ PHA polyurethane microspheres were obtained through cross-linking. The polyurethane microspheres obtained in this embodiment are uniform in size and have a moderate particle size. Compared with pure PHA microspheres, they are more tough and suitable for applications in multiple fields such as drug delivery and cosmetic fillers.

[0039] This embodiment, through formulation design and the use of specific proportions of reactants, enables controllable hard and soft segments of the polyurethane chain, resulting in more resilient polyurethane microspheres. Furthermore, by adjusting the amount of reactants added, the microsphere particle size and degradation rate can be controlled, enabling its application in multiple fields such as drug delivery and cosmetic fillers.

[0040] The PHA polyurethane microspheres prepared in this embodiment have higher polarity than pure PHA microspheres, stronger adhesion to cells, and are less prone to aggregation, making them easier to inject.

[0041] In some embodiments, the polyhydroxyalkanoate diol and diisocyanate are in a molar ratio of 1:(1.3~1.5). According to the embodiments of the present application, polyurethane microspheres prepared using polyhydroxyalkanoate diols in this molecular weight range exhibit higher toughness.

[0042] In some embodiments, the molar ratio of the chain extender to the dihydroxyalkyl acid can be 10:1, 11:1, 12:1, or 13:1. The amount of dihydroxyalkyl acid added also affects the degradation rate; the higher the content of dihydroxyalkyl acid in the formulation, the faster the degradation rate.

[0043] In some embodiments, the molecular weight of the polyhydroxyalkanoate diol is 1500-2500. According to embodiments of the present application, polyurethane microspheres prepared using polyhydroxyalkanoate diols within this molecular weight range have smaller particle sizes and faster degradation rates.

[0044] In some embodiments, the chain extender is a polyether polyol or a polyester polyol. In some embodiments, the chain extender is polyethylene glycol or polypropylene glycol with a molecular weight of 200-1000.

[0045] In some embodiments, the polyhydroxyalkanoate diol is poly(β-hydroxybutyric acid) (PHB). In some embodiments, PHB from blue crystal microorganisms with a molecular weight of 50,000 may be used.

[0046] In some embodiments, the dihydroxyalkyl acid is at least one of dimethylolpropionic acid (DMPA) and dimethylolbutyric acid (DMBA).

[0047] In some embodiments, the first catalyst is dibutyltin dilaurate or tin isooctanoate.

[0048] In some embodiments, the diisocyanate is an aliphatic diisocyanate. In some embodiments, the diisocyanate may be at least one selected from isophorone diisocyanate, 1,6-hexamethylene diisocyanate, and dicyclohexylmethane diisocyanate.

[0049] In some embodiments, the precipitating solution is a calcium chloride solution, a magnesium chloride solution, or an aluminum sulfate solution with a concentration of 4-8 wt%. In some embodiments, the concentration of the precipitating solution is selected as 5-7 wt%. In some embodiments, the precipitating solution is selected as a 6 wt% calcium chloride solution.

[0050] In some embodiments, the polyhydroxy fatty acid ester diol is prepared by mixing polyhydroxy fatty acid ester, diol, second catalyst, and solvent, reacting at 42~48℃ for 1-5 hours, followed by vacuum polycondensation for 1-3.5 hours, and then obtaining the polyhydroxy fatty acid ester diol after purification and drying.

[0051] In some embodiments, the preparation method of the polyhydroxyalkanoate diol is as follows: A polyhydroxyalkanoate and a solvent are mixed at a mass ratio of 1:8 to 12, heated to 43 to 47°C, and a diol with a molar amount of 4 to 6 times that of the polyhydroxyalkanoate and a catalytic amount of catalyst are added. After reacting for 2 to 4 hours, vacuum polycondensation is performed for 1 to 2.5 hours. After purification and drying, the polyhydroxyalkanoate diol is obtained. As a specific example, a polyhydroxyalkanoate and a solvent are mixed at a mass ratio of 1:10, heated to 45°C, and a diol with a molar amount of 5 times that of the polyhydroxyalkanoate and a catalytic amount of catalyst are added. After reacting for 3 hours, vacuum polycondensation is performed for 2 hours. The system is then cooled to room temperature and purified to obtain the polyhydroxyalkanoate diol.

[0052] In some embodiments, the diol is at least one selected from propylene glycol, butanediol, and hexanediol. Preferably, the diol is succinic acid.

[0053] In some embodiments, the second catalyst is at least one selected from p-toluenesulfonic acid, tetrabutyl titanate, and tetraisopropyl titanate. Preferably, the second catalyst is tetrabutyl titanate.

[0054] In some embodiments, the PHA polyurethane microspheres have a microsphere diameter ≤75nm, a degradation rate ≥85Wt% / 90days, an elongation at break of 44~70%, and a tensile strength of 0.9~1.5MPa.

[0055] The second aspect of this embodiment provides a PHA polyurethane microsphere prepared according to the above method.

[0056] The third aspect of this embodiment provides the application of PHA polyurethane microspheres in drug-loaded microspheres and cosmetic fillers.

[0057] In the field of drug-loaded microspheres, the diameter of the microspheres is typically below 65 micrometers, because excessively large microspheres can cause aggregation or precipitation, clogging the needle and reducing drug bioavailability. Therefore, for drug-loaded microspheres, PHA polyurethane microspheres with a diameter ≤65 nm are preferred.

[0058] Preparation Example 1

[0059] PHB (purchased from Blue Crystal Microorganisms, molecular weight 50,000) was dissolved in chloroform at a mass-to-volume ratio of 1:10. The solution was stirred until completely dissolved, filtered under reduced pressure, and the filtrate was transferred to a rotary evaporator. The filtrate was concentrated by rotary evaporation, and the concentrated liquid was poured into ice-cold methanol at 0°C and stirred until precipitation occurred. After vacuum filtration, a yellow flocculent substance was obtained, which was dried under reduced pressure at 40°C to constant weight to obtain purified PHB.

[0060] PHB and chloroform were added to a flask at a mass ratio of 1:10. A condenser and a liquid seal device were attached, and the flask was heated to 45°C in a magnetic stirrer until fully dissolved. Then, 1,4-butanediol (5 times the molar amount of PHB) and tetrabutyl titanate (2 wt‰ of the total mass of the catalyst) were added to initiate an esterification reaction. After 3 hours of reaction, the mixture was subjected to vacuum polycondensation for 1 hour. After the reaction was completed, the system was allowed to cool naturally to room temperature. The solution was then poured into a separatory funnel, washed three times with water, and filtered under reduced pressure to obtain a yellow liquid. The concentrated liquid was obtained by rotary evaporation. The concentrated liquid was added to ice-cold methanol at 0°C and stirred until precipitation occurred. After vacuum filtration, a yellow powder was obtained. The powder was dried under vacuum at 40°C to constant weight to obtain PHB diol with a molecular weight of 1600.

[0061] Preparation Example 2

[0062] This preparation example uses a method similar to that of Preparation Example 1, except that the vacuum polycondensation time is changed from 1 h to 2.5 h, and finally PHB diol with a molecular weight of 2400 is obtained.

[0063] Preparation Example 3

[0064] This preparation example uses a method similar to that of Preparation Example 1, except that the vacuum polycondensation time is changed from 1 h to 3.3 h, and finally PHB diol with a molecular weight of 3500 is obtained.

[0065] Preparation Example 4

[0066] This preparation example uses a method similar to that of Preparation Example 1, except that the vacuum polycondensation time is changed from 1 h to 4 h, and finally PHB diol with a molecular weight of 4500 is obtained.

[0067] Preparation Example 5

[0068] This preparation example uses a method similar to that of Preparation Example 1, except that the vacuum polycondensation time is changed from 1 h to 0.5 h, and finally PHB diol with a molecular weight of 1000 is obtained.

[0069] Example 1

[0070] The PHB diol prepared in Example 1 was reacted with IPDI at a molar ratio of 1:1.4. First, the raw material PHB diol and a catalyst (dibutyltin dilaurate) accounting for 2 wt‰ of the total mass fraction of PHB diol and IPDI were added to a flask and heated and stirred for 30 min at 60°C. After the temperature stabilized, IPDI was added dropwise to the flask at a rate of 1 drop per second using a constant pressure dropping funnel. After the addition was complete, the -NCO content was measured after 2 h of reaction. Once the -NCO content in the reaction system remained constant, 0.37 times the molar amount of PEG-200 and 0.03 times the molar amount of DMPA were added. After the NCO groups disappeared, a neutralizing agent was added, and the mixture was stirred for 30 min to neutralize the PHB polyurethane. Then, the stirring speed was increased to 1000 r / min, and distilled water was added to obtain a PHB polyurethane aqueous solution with a solid content of 25%. This solution was then added dropwise to a 6 wt% CaCl2 solution, and the condensed phase separation method was used to separate the NCO groups from the solids. 2+ PHB polyurethane microspheres were formed under the cross-linking effect, and then removed and dried at room temperature after 24 hours.

[0071] Example 2

[0072] This embodiment uses a method similar to that of Example 1, except that the PHB diol used is the PHB diol prepared in Preparation Example 2. For specific parameters, please refer to Table 1.

[0073] Example 3

[0074] This embodiment uses a method similar to that of Example 1, except that the PHB diol used is the PHB diol prepared in Preparation Example 3. For specific parameters, please refer to Table 1.

[0075] Example 4

[0076] This embodiment uses a method similar to that of Embodiment 1, except that the molar amount of PEG-200 is 0.34 and the molar amount of DMPA is 0.06. For specific parameters, please refer to Table 1.

[0077] Example 5

[0078] This embodiment uses a method similar to that of Embodiment 1, except that the equimolar amount of DMPA is replaced with DMBA. For specific parameters, please refer to Table 1.

[0079] Example 6

[0080] This embodiment uses a method similar to that of Example 1, except that the equimolar amount of PEG-200 is replaced with PPG-200. For specific parameters, please refer to Table 1.

[0081] Comparative Example 1

[0082] This comparative example uses a method similar to that of Example 1, except that the molar amount of PEG-200 is 0.4 and the amount of DMPA added is 0. See Table 1 for specific parameters.

[0083] Comparative Example 2

[0084] This comparative example uses a method similar to that of Example 1, except that the molar amount of PHB diol is 1.37 and the amount of PEG-200 added is 0. For specific parameters, please refer to Table 1.

[0085] Comparative Example 3

[0086] This comparative example uses a method similar to that of Example 1, except that the PHB diol used is the PHB diol prepared in Preparation Example 4. Specific parameters are shown in Table 1.

[0087] Comparative Example 4

[0088] This comparative example uses a method similar to that of Example 1, except that the PHB diol used is the PHB diol prepared in Preparation Example 5. Specific parameters are shown in Table 1.

[0089] Comparative Example 5 (Pure PHB Microspheres)

[0090] Dissolve 1g of PHB (molecular weight 50000) in 20mL of dichloromethane to form the oil phase.

[0091] Add 100 mL of pure water to a 250 mL flask, add 0.5 g of PVA, and stir rapidly until homogeneous. Then add the oil phase solution at room temperature (25°C). Stir at 400 rpm for 20 minutes to disperse the oil phase into uniform oil droplets, maintaining the stirring speed constant. Increase the temperature to 40°C at a rate of 1°C per minute, continue stirring for 2 hours, and then condense 19.5 mL of liquid to recover the liquid. Continue holding the solution at this temperature for 30 minutes. Subsequently, cool the flask to room temperature, and freeze-dry the resulting liquid to remove moisture, thus obtaining PHB microspheres.

[0092] Table 1

[0093]

[0094] Performance testing

[0095] Microsphere size: The diameter of microspheres prepared in different embodiments and comparative examples was measured by scanning electron microscopy.

[0096] Degradation rate: PHB polyurethane microspheres with mass m0 were placed in a 0.1M phosphate buffer solution with pH 7.4 and degraded at 37°C. After 90 days, the microspheres were filtered and the mass m1 of the PHB polyurethane microspheres was measured. Degradation rate = (m0 - m1) / m0.

[0097] Elongation at break and tensile strength: Referring to GB / T 1040.2-2022, waterborne PHB polyurethane microspheres were poured into a mold and placed in an 80℃ oven for 12 hours to obtain a PHB polyurethane film. The polyurethane film was then cut into dumbbell-shaped strips as required by national standards and subjected to tensile testing.

[0098] The performance test results of the polyurethane microspheres in each embodiment and comparative example are summarized in Table 2.

[0099] Table 2

[0100] Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Microsphere Particle Size / μm 55637440625584558150100 Degradation Rate / Wt% / 90days 9592879893859270849685 Elongation at Break / % 57684450556358253570 / Tensile Strength / MPa 1.04 1.23 1.35 0.91 0.98 1.15 1.08 2.31 1.57 0.54 /

[0101] As can be seen from Tables 1 and 2 above, according to the technical solution of the present disclosure, the PHB polyurethane microspheres obtained by the method of the present disclosure meet the following requirements: microsphere diameter ≤75nm, degradation rate ≥85 Wt% / 90days, elongation at break 44~70%, and tensile strength 0.9~1.5 MPa.

[0102] Obviously, the above embodiments of this disclosure are merely examples for clearly illustrating the technical solutions of this disclosure, and are not intended to limit the specific implementation of this disclosure. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the claims of this disclosure should be included within the protection scope of the claims of this disclosure.

Claims

1. A process for the preparation of PHA polyurethane microspheres, characterized in that, Specifically, the steps include the following: Polyhydroxy fatty acid ester diol and diisocyanate are fed in a molar ratio of 1:(1.2~1.6) and reacted. Under the condition of adding a first catalyst at a certain amount, polymerization is completed to obtain the first reactant. The molecular weight of the polyhydroxy fatty acid ester diol is 1200~3500. A chain extender and a dihydroxyalkyl acid are added to the first reactant, and the reaction is completed to obtain the second reactant. The molar ratio of the chain extender to the dihydroxyalkyl acid is 10~13:1, and the isocyanate groups in the system are completely reacted. Add water to the second reactant and stir to obtain a PHA polyurethane aqueous solution with a solid content of 25-40%. The PHA polyurethane aqueous solution was added dropwise into a precipitating solution of a certain concentration to obtain PHA polyurethane microspheres.

2. The method of preparing PHA polyurethane microspheres according to claim 1, characterized in that, The molecular weight of the polyhydroxy fatty acid ester diol is 1500~2500.

3. The method of claim 1, wherein the PHA polyurethane microspheres are prepared by the process comprising: The chain extender is a polyether polyol or a polyester polyol; and / or The dihydroxyalkyl acid is dimethylolpropionic acid or dimethylolbutyric acid; and / or The first catalyst is dibutyltin dilaurate or tin isooctanoate; and / or The diisocyanate is an aliphatic diisocyanate.

4. The method for preparing PHA polyurethane microspheres according to claim 1, characterized in that, The precipitating solution is a calcium chloride solution, a magnesium chloride solution, or an aluminum sulfate solution, with a concentration of 4-8 wt%.

5. The method for preparing PHA polyurethane microspheres according to claim 1, characterized in that, The preparation method of the polyhydroxy fatty acid ester diol is as follows: polyhydroxy fatty acid ester, diol, second catalyst and solvent are mixed, the reaction temperature is 42~48℃, the reaction is carried out for 1-5 hours, vacuum polycondensation is carried out for 1-3.5 hours, and the polyhydroxy fatty acid ester diol is obtained after purification and drying.

6. The method for preparing PHA polyurethane microspheres according to claim 5, characterized in that, The diol is at least one selected from propylene glycol, butanediol, and hexanediol; preferably succinic acid; and / or The second catalyst is at least one of p-toluenesulfonic acid, tetrabutyl titanate, and tetraisopropyl titanate; preferably tetrabutyl titanate.

7. The method for preparing PHA polyurethane microspheres according to claim 5, characterized in that, The preparation method of the polyhydroxy fatty acid ester diol is as follows: Polyhydroxy fatty acid ester and solvent are mixed at a mass ratio of 1:10, heated to 43~47℃, and a diol with a molar amount of 4~6 times that of polyhydroxy fatty acid ester and a catalytic amount of catalyst are added. After reacting for 2~4 hours, vacuum polycondensation is carried out for 1~2.5 hours. After purification and drying, the polyhydroxy fatty acid ester diol is obtained.

8. The method for preparing PHA polyurethane microspheres according to any one of claims 1 to 7, characterized in that, The PHA polyurethane microspheres have a microsphere diameter ≤75nm, a degradation rate ≥85 Wt% / 90days, an elongation at break of 44~70%, and a tensile strength of 0.9~1.5 MPa.

9. A PHA polyurethane microsphere, characterized in that, Prepared by the method according to any one of claims 1 to 8.

10. The application of the PHA polyurethane microspheres according to claim 9 in drug-loaded microspheres and cosmetic fillers.

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