Injectable polyurethane microsphere as well as preparation method and application thereof

Abstract

The invention provides an injectable polyurethane microsphere as well as a preparation method and application thereof. Wherein the polyurethane is a polymerization product of polylactic acid polyol and bio-based isocyanate. The injectable polyurethane microsphere is smooth in surface, relatively small and uniform in particle size, good in dispersity, easy to inject, easy to disperse and relatively small in adverse reaction when being used as a facial filling agent.

Description

Technical Field

[0001] The invention relates to the technical field of biomedical materials, and in particular to an injectable polyurethane microsphere and a preparation method and application thereof. Background Art

[0002] Bio-based polyurethane materials have excellent biocompatibility, degradability and controllable structural properties. Polyurethane synthesized from polylactic acid polyol and lysine diisocyanate will first decompose into polylactic acid and lysine. Lysine can be absorbed by the human body, while polylactic acid is subsequently decomposed into CO2 and H2O, which can be absorbed by the body or excreted through metabolism. This degradable and absorbable material has no side effects on the human body and is widely used in biological tissue engineering, orthopedic repair and fixation materials, drug delivery, etc., but it is still a blank in terms of facial filling materials.

[0003] Microspheres refer to a microparticle dispersion system formed by a high molecular polymer carrier, with a particle size generally ranging from 0.01 to 300 μm. They are often used in biomedicine. On the one hand, they can encapsulate drugs to achieve sustained release, controlled release, and targeted drug delivery, thereby improving drug stability, reducing adverse drug reactions, and reducing drug side effects. On the other hand, they can be used to fill bone defect areas. Due to the small particle size of the microspheres and their good fluidity, cells can easily pass through the tiny gaps between the microspheres, which is beneficial to the formation of new blood vessels and promotes cell migration and adhesion, proliferation, and differentiation on the surface of the microspheres.

[0004] As we age, the collagen fibrils that provide strength become fragmented and fibroblast connections weaken, leading to sagging skin and loss of youthful skin. Fillers can provide a more youthful appearance by providing volume support. With the growing demand for medical beauty, scientists have invented many types of facial fillers to meet people's facial rejuvenation needs, such as collagen, hyaluronic acid, polylactic acid, etc. However, due to the poor biocompatibility of these materials, the human body absorbs them too quickly and needs to be filled repeatedly, or due to the complex manufacturing process and poor product dispersion, filling leads to subcutaneous redness or nodules. Summary of the invention

[0005] The purpose of the present invention is to overcome the shortcomings of the prior art and provide an injectable polyurethane microsphere and a preparation method and application thereof.

[0006] In a first aspect, the present invention provides an injectable polyurethane microsphere, wherein the polyurethane is a polymerization product of polylactic acid polyol and bio-based isocyanate.

[0007] The invention adopts bio-based isocyanate as raw material to prepare polyurethane, and the raw material is simple, easily available and biodegradable.

[0008] The polyurethane microspheres of the present invention are complete in morphology, independent of each other, have no agglomeration phenomenon, and have good biocompatibility, and can meet injection requirements.

[0009] In some embodiments, the polylactic acid polyol is prepared by ring-opening polymerization of lactide and a polyol under the action of a catalyst.

[0010] In some embodiments, the polyol includes 1,4-butanediol.

[0011] In some embodiments, the catalyst comprises stannous octoate.

[0012] In some embodiments, the weight average molecular weight of the polylactic acid polyol is 1000-3000 g / mol.

[0013] In some embodiments, the particle size of the polyurethane microspheres is 20-70 μm, for example, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm or any value therebetween.

[0014] In some embodiments, the particle size of the polyurethane microspheres is ≤60 μm.

[0015] In some embodiments, the polyurethane microspheres have a particle size of 20-60 μm.

[0016] If the particle size is too large, the absorption rate of the injectable polyurethane microspheres of the present application will be too low. If the particle size is too small, the injectable polyurethane microspheres will agglomerate, which is not conducive to injection and dispersion.

[0017] In some embodiments, the weight average molecular weight of the polyurethane is 10000-70000 g / mol, for example, 10000 g / mol, 15000 g / mol, 20000 g / mol, 25000 g / mol, 30000 g / mol, 35000 g / mol, 40000 g / mol, 45000 g / mol, 50000 g / mol, 55000 g / mol, 60000 g / mol, 65000 g / mol, 70000 g / mol or any value therebetween. The higher the weight average molecular weight of the polyurethane, the less likely it is to degrade.

[0018] In some embodiments, the weight average molecular weight of the polyurethane is 20,000-70,000 g / mol.

[0019] In some embodiments, the weight average molecular weight of the polyurethane is 20,000-50,000 g / mol.

[0020] In some embodiments, the bio-based isocyanate includes L-lysine diisocyanate.

[0021] In a second aspect, the present invention provides a method for preparing injectable polyurethane microspheres, comprising the following steps:

[0022] (1) subjecting the polyurethane solution to a membrane emulsification reaction in a dispersant solution and shearing the solution to form an emulsion;

[0023] (2) subjecting the emulsion to a curing reaction and then drying to obtain polyurethane microspheres.

[0024] In the present application, polyurethane is directly dissolved in a solvent to form a polyurethane solution, and then the polyurethane solution is passed through a microporous membrane of a membrane emulsifier for membrane emulsification reaction, thereby obtaining a monodisperse polyurethane emulsion. Compared with the prior art, in which a polyurethane emulsion is first obtained and then the solvent is volatilized to obtain polyurethane microspheres, the polyurethane in the present application only needs to be dissolved in a solvent to form a polyurethane solution, and no pre-emulsification treatment is required, which is not only simple to operate, but also reduces the impact on the microsphere formation effect caused by uneven pre-emulsification.

[0025] Furthermore, the present application controls the particle size of the polyurethane microspheres by controlling the pore size of the microporous membrane used in the membrane emulsification reaction, so that the particle size is within a range that is conducive to injection and dispersion.

[0026] In some embodiments, the polyurethane solution is a mixture of polyurethane and an organic solvent.

[0027] In some embodiments, the organic solvent includes one or more of dichloromethane, chloroform, or ethyl acetate.

[0028] In some embodiments, the concentration of the polyurethane solution is 0.01-3wt%; for example, 0.05wt%, 0.07wt%, 0.09wt%, 0.11wt%, 0.13wt%, 0.15wt%, 0.17wt%, 0.19wt%, 0.25wt%, 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3wt% or any value therebetween.

[0029] In some embodiments, the concentration of the polyurethane solution is 0.01-1 wt %.

[0030] In some embodiments, the concentration of the polyurethane solution is 0.01-0.5 wt %.

[0031] In some embodiments, the dispersant in the dispersant solution includes sodium dodecyl sulfate and / or polyvinyl alcohol.

[0032] In some embodiments, the solvent in the dispersant solution is deionized water.

[0033] In some embodiments, the concentration of the dispersant solution is 0.05-10wt%, for example, 0.1wt%, 0.5wt%, 0.9wt%, 1.3wt%, 1.7wt%, 2.1wt%, 2.5wt%, 2.9wt%, 3.5wt%, 4.5wt%, 5.5wt%, 6.5wt%, 7.5wt%, 8.5wt%, 9.5wt% or any value therebetween.

[0034] In some embodiments, the concentration of the dispersant solution is 0.05-2 wt %.

[0035] In some embodiments, the concentration of the dispersant solution is 0.1-1 wt %.

[0036] In some embodiments, the membrane emulsification reaction is performed in a membrane emulsifier.

[0037] In some embodiments, the pressurizing gas of the membrane emulsifier comprises nitrogen.

[0038] In some embodiments, the pressurized gas of the membrane emulsifier includes high-purity nitrogen, and the purity of the high-purity nitrogen is above 99%, preferably 99.9992%.

[0039] In some embodiments, the pressure of the membrane emulsifier is 0.001-0.020 MPa, for example, 0.005 MPa, 0.007 MPa, 0.009 MPa, 0.011 MPa, 0.013 MPa, 0.015 MPa, 0.017 MPa, 0.019 MPa or any value therebetween.

[0040] In some embodiments, the shearing comprises magnetic stirring.

[0041] In some embodiments, the shear rate is 600-1500 r / min, for example, 600 r / min, 700 r / min, 800 r / min, 900 r / min, 1000 r / min, 1200 r / min, 1400 r / min or any value therebetween.

[0042] In some embodiments, the shearing time is 5-60 min, for example, 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min, 60 min or any value therebetween.

[0043] In some embodiments, the solidification step includes: removing the solvent in the emulsion.

[0044] In some embodiments, the solvent in the emulsion is removed by magnetic stirring.

[0045] In some embodiments, the speed of the magnetic stirring is 600 r / min-1500 r / min, for example, 700 r / min, 900 r / min, 1000 r / min, 1100 r / min, 1200 r / min, 1300 r / min, 1400 r / min, 1500 r / min or any value therebetween.

[0046] In some embodiments, the magnetic stirring time is 12-24 h, for example, 14 h, 16 h, 18 h, 20 h, 22 h, 24 h or any value therebetween.

[0047] In some embodiments, after removing the solvent from the emulsion, the method further comprises the steps of washing, precipitation and centrifugation.

[0048] In some embodiments, the detergent used in the washing is ultrapure water.

[0049] In some embodiments, the centrifugal rotation speed is 1000-10000 r / min; for example, 1500 r / min, 2500 r / min, 3500 r / min, 4500 r / min, 5500 r / min, 6500 r / min, 7500 r / min or any value therebetween.

[0050] In some embodiments, the centrifugation time is 1-30 min, for example, 1 min, 5 min, 10 min, 15 min, 20 min, 25 min, 30 min or any value therebetween.

[0051] In some embodiments, the drying can be freeze-drying.

[0052] In a third aspect, the present invention provides a facial filler, comprising the polyurethane microspheres described in the first aspect of the present invention or the polyurethane microspheres prepared by the preparation method described in the second aspect of the present invention.

[0053] Bio-based polyurethane has high biocompatibility and will decompose into lysine and lactic acid in the human body, but the decomposition rate is lower than other filling materials, and the decomposition products are not only non-toxic but also can stimulate the formation of new facial tissue, thereby prolonging the filling time and achieving a therapeutic effect. Therefore, the microsphere filler made of bio-based polyurethane is a new and good facial filling material.

[0054] The polyurethane microspheres of the present invention are different from conventional facial fillers. Since the microspheres are prepared by a membrane emulsification method, the microspheres have a smooth surface, controllable particle size, good dispersibility, and can avoid the occurrence of adverse reactions such as subcutaneous nodules or redness and swelling. In addition, the microspheres prepared by a membrane emulsification method can realize the idea of ​​industrial mass production, thereby industrializing the preparation of polyurethane microspheres.

[0055] In a fourth aspect, the present invention provides a use of the facial filler according to the third aspect of the present invention in facial repair.

[0056] In some embodiments, the facial filler is directly implanted under the dermis as a facial filling material at a part of the face that needs repair.

[0057] In some embodiments, the method of implanting comprises injection.

[0058] Compared with the prior art, the present invention has the following beneficial effects:

[0059] (1) The polyurethane microspheres of the present invention have a smooth surface, a small and uniform particle size, good dispersibility, and are easy to inject. They are easy to disperse and have few adverse reactions when used as facial fillers.

[0060] (2) The decomposition rate of the polyurethane microspheres of the present invention is lower than that of other filling materials, and the decomposition products are not only non-toxic but also can stimulate the formation of new facial tissue, thereby extending the filling time and achieving a therapeutic effect;

[0061] (3) The preparation method of the polyurethane microspheres of the present invention is simple and easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 This is a microscope image of the polyurethane microspheres prepared in Example 5 of the present invention;

[0063] Figure 2 This is a SEM image of the polyurethane microspheres prepared in Example 5 of the present invention;

[0064] Figure 3 This is an infrared spectrum of the polyurethane microspheres prepared in Example 5 of the present invention;

[0065] Figure 4 The figures are dispersion states of the polyurethane microspheres prepared in Examples 1 and 5 of the present invention after standing for different periods of time. DETAILED DESCRIPTION

[0066] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments and drawings. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation to the present invention.

[0067] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0068] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments and equipment used in the following examples, etc., can all be purchased on the market or can be obtained by existing methods; the reagent amounts, unless otherwise specified, are the reagent amounts used in conventional experimental operations; the experimental methods, unless otherwise specified, are all conventional methods.

[0069] The particle size of the polyurethane microspheres prepared in the embodiment of the present invention is 20-70 μm.

[0070] The polyurethane in the embodiment of the present invention is prepared by polylactic acid polyol and bio-based isocyanate, wherein the bio-based polyurethane is L-lysine diisocyanate, and the polylactic acid polyol is prepared by ring-opening polymerization of lactide and 1,4-butanediol under the catalysis of stannous octoate, and its weight average molecular weight is 2000g / mol as measured by GPC.

[0071] The polyvinyl alcohol used in the embodiment of the present invention is P832103 polyvinyl alcohol 224 type, cas: 9002-89-5, alcoholysis degree: 87.0-89.0 mol%, viscosity: 40.0-48.0 mPa.s, purchased from MacLean Reagent Network.

[0072] The membrane emulsification reaction of the present invention is carried out in a membrane emulsifier, and the membrane emulsifier needs to utilize pressurized gas (such as nitrogen) to pressurize and extrude the polyurethane solution to form final emulsion droplets.

[0073] Example 1

[0074] Preparation of injectable polyurethane microspheres

[0075] A) dissolving polyurethane in an organic solvent to obtain a polyurethane solution;

[0076] The polyurethane is synthesized from polylactic acid polyol and bio-based isocyanate; the weight average molecular weight of the polyurethane is 20000 g / mol, the organic solvent is dichloromethane; the concentration of the polyurethane solution is 0.05wt%;

[0077] B) preparing a dispersant solution;

[0078] The dispersant is polyvinyl alcohol; the concentration of the dispersant solution is 0.25wt%;

[0079] C) passing the polyurethane solution through a membrane emulsifier, performing membrane emulsification and shearing in a dispersant to obtain an emulsion;

[0080] The pressurized gas of the membrane emulsifier includes high-purity nitrogen, and the gauge pressure of the membrane emulsifier is 0.005MPa; the shearing is magnetic stirring, the magnetic stirring rate is 1000r / min, and the shearing time is 30min;

[0081] D) stirring the emulsion continuously to remove the solvent, and freeze-drying the emulsion to obtain polyurethane microspheres.

[0082] In step D), the method for removing the solvent is specifically: subjecting the emulsion to magnetic stirring; the speed of the magnetic stirring is 1000 r / min; the time of the magnetic stirring is 24 h;

[0083] In step D), after removing the solvent, the method further comprises: washing, precipitating and centrifuging the emulsion after the solvent is removed; the washing detergent is ultrapure water; the centrifugal speed is 8000 r / min; and the centrifugal time is 5 minutes.

[0084] Example 2

[0085] Preparation of injectable polyurethane microspheres

[0086] A) dissolving polyurethane in an organic solvent to obtain a polyurethane solution;

[0087] The polyurethane is synthesized from polylactic acid polyol and bio-based isocyanate; the weight average molecular weight of the polyurethane is 20000 g / mol, the organic solvent is dichloromethane; the concentration of the polyurethane solution is 0.1 wt%;

[0088] B) preparing a dispersant solution,

[0089] The dispersant is polyvinyl alcohol; the concentration of the dispersant solution is 0.25wt%;

[0090] C) passing the polyurethane solution through a membrane emulsifier, performing membrane emulsification and shearing in a dispersant to obtain an emulsion;

[0091] The pressurized gas of the membrane emulsifier includes high-purity nitrogen, and the gauge pressure of the membrane emulsifier is 0.005MPa; the shearing is magnetic stirring, the magnetic stirring rate is 1000r / min, and the shearing time is 30min;

[0092] D) stirring the emulsion continuously to remove the solvent, and freeze-drying the emulsion to obtain polyurethane microspheres.

[0093] In step D), the method for removing the solvent is specifically: subjecting the emulsion to magnetic stirring; the speed of the magnetic stirring is 1000 r / min; the time of the magnetic stirring is 24 h;

[0094] In step D), after removing the solvent, the method further comprises: washing, precipitating and centrifuging the emulsion after the solvent is removed; the washing detergent is ultrapure water; the centrifugal speed is 8000 r / min; and the centrifugal time is 5 minutes.

[0095] Example 3

[0096] Preparation of injectable polyurethane microspheres

[0097] A) dissolving polyurethane in an organic solvent to obtain a polyurethane solution;

[0098] The polyurethane is synthesized from polylactic acid polyol and bio-based isocyanate; the weight average molecular weight of the polyurethane is 50,000 g / mol; the organic solvent is dichloromethane; and the concentration of the polyurethane solution is 0.2 wt%.

[0099] B) preparing a dispersant solution,

[0100] The dispersant includes polyvinyl alcohol; the concentration of the dispersant solution is 0.5wt%;

[0101] C) passing the polyurethane solution through a membrane emulsifier, performing membrane emulsification and shearing in a dispersant to obtain an emulsion;

[0102] The pressurized gas of the membrane emulsifier includes high-purity nitrogen, and the gauge pressure of the membrane emulsifier is 0.008 MPa; the shearing is magnetic stirring, the magnetic stirring rate is 1000 r / min, and the shearing time is 30 min;

[0103] D) stirring the emulsion continuously to remove the solvent, and freeze-drying the emulsion to obtain polyurethane microspheres.

[0104] In step D), the method for removing the solvent is specifically: subjecting the emulsion to magnetic stirring; the speed of the magnetic stirring is 1000 r / min; and the time of the magnetic stirring is 24 h.

[0105] In step D), after removing the solvent, the method further comprises: washing, precipitating and centrifuging the emulsion after the solvent is removed; the washing detergent is ultrapure water; the centrifugal speed is 8000 r / min; and the centrifugal time is 5 minutes.

[0106] Example 4

[0107] Preparation of injectable polyurethane microspheres

[0108] A) dissolving polyurethane in an organic solvent to obtain a polyurethane solution;

[0109] The polyurethane is synthesized from polylactic acid polyol and bio-based isocyanate; the weight average molecular weight of the polyurethane is 50,000 g / mol; the organic solvent is dichloromethane; and the concentration of the polyurethane solution is 0.25 wt%.

[0110] B) preparing a dispersant solution,

[0111] The dispersant is polyvinyl alcohol; the concentration of the dispersant solution is 0.5wt%;

[0112] C) passing the polyurethane solution through a membrane emulsifier, performing membrane emulsification and shearing in a dispersant to obtain an emulsion;

[0113] The pressurized gas of the membrane emulsifier includes high-purity nitrogen, and the gauge pressure of the membrane emulsifier is 0.010 MPa; the shearing is magnetic stirring, the magnetic stirring rate is 1000 r / min, and the shearing time is 30 min;

[0114] D) stirring the emulsion continuously to remove the solvent, and freeze-drying the emulsion to obtain polyurethane microspheres.

[0115] In step D), the method for removing the solvent is specifically: subjecting the emulsion to magnetic stirring; the speed of the magnetic stirring is 1000 r / min; and the time of the magnetic stirring is 24 h.

[0116] In step D), after removing the solvent, the method further comprises: washing, precipitating and centrifuging the emulsion after the solvent is removed; the washing detergent is ultrapure water; the centrifugal speed is 8000 r / min; and the centrifugal time is 5 minutes.

[0117] Example 5

[0118] Preparation of injectable polyurethane microspheres

[0119] A) dissolving polyurethane in an organic solvent to obtain a polyurethane solution;

[0120] The polyurethane is synthesized from polylactic acid polyol and bio-based isocyanate; the weight average molecular weight of the polyurethane is 50000 g / mol; the organic solvent is dichloromethane; and the concentration of the polyurethane solution is 0.3 wt%.

[0121] B) preparing a dispersant solution,

[0122] The dispersant is polyvinyl alcohol; the concentration of the dispersant solution is 0.25 wt %.

[0123] C) passing the polyurethane solution through a membrane emulsifier, performing membrane emulsification and shearing in a dispersant to obtain an emulsion;

[0124] The pressurized gas of the membrane emulsifier includes high-purity nitrogen, and the gauge pressure of the membrane emulsifier is 0.010 MPa; the shearing is magnetic stirring, the magnetic stirring rate is 1000 r / min, and the shearing time is 30 min.

[0125] D) stirring the emulsion continuously to remove the solvent, and freeze-drying the emulsion to obtain polyurethane microspheres.

[0126] In step D), the method for removing the solvent is specifically: subjecting the emulsion to magnetic stirring; the speed of the magnetic stirring is 1000 r / min; and the time of the magnetic stirring is 12 h.

[0127] In step D), after removing the solvent, the method further comprises: washing, precipitating and centrifuging the emulsion after the solvent is removed; the washing detergent is ultrapure water; the centrifugal speed is 8000 r / min; and the centrifugal time is 5 minutes.

[0128] Figure 1 This is a microscope picture of the polyurethane microspheres prepared in Example 5. It can be seen that the particle size of the polyurethane microspheres is 25-60 μm and is uniform. There is no adhesion between the microspheres, and the unitary and dispersible properties are good.

[0129] Figure 2 This is the SEM image of the polyurethane microspheres prepared in Example 5. It can be seen that the surface of the polyurethane microspheres is smooth, the microspheres are uniform and have a uniform particle size.

[0130] The present invention performs infrared spectrum analysis on the polyurethane microspheres prepared in Example 5. Figure 3 The infrared spectrum of the polyurethane microspheres prepared in Example 5 of the present invention is shown in FIG. Figure 3 The infrared absorption spectrum of polyurethane microspheres shows that 3425 cm -1 The broad peak is the stretching vibration absorption peak of NH in the carbamate structure, 1084 cm -1 Nearby is the typical ether bond characteristic peak. 1758cm -1 The absorption peak near 1593cm is the stretching vibration peak of C=O in the urethane group, and -1 The absorption peak is the stretching vibration peak of β-diketone, 1365cm -1 The micro-crystallization peak of carbamate appeared at 2050-2700 cm -1The characteristic absorption peaks of the isocyanate group in the region basically disappear, which indicates that the isocyanate in the polyurethane system has completely participated in the reaction. The appearance or disappearance of these characteristic peaks indicates that the material synthesized in this example is polyurethane.

[0131] Comparative Example 1

[0132] Preparation of polylactic acid microspheres.

[0133] A) dissolving polylactic acid in an organic solvent to obtain a polylactic acid solution;

[0134] The polylactic acid is prepared by ring-opening polymerization of lactide and 1,4-butanediol; the weight average molecular weight of the polylactic acid is 2000 g / mol; the organic solvent is dichloromethane; the concentration of the polylactic acid solution is 0.05 wt%.

[0135] B) preparing a dispersant solution,

[0136] The dispersant is polyvinyl alcohol; the concentration of the dispersant solution is 0.25 wt %.

[0137] C) passing the polylactic acid solution through a membrane emulsifier, performing membrane emulsification and shearing in a dispersant to obtain an emulsion;

[0138] The pressurized gas of the membrane emulsifier includes high-purity nitrogen, and the gauge pressure of the membrane emulsifier is 0.005 MPa; the shearing is magnetic stirring, the magnetic stirring rate is 1000 r / min, and the shearing time is 30 min.

[0139] D) stirring the emulsion continuously to remove the solvent, and then freeze-drying to obtain polylactic acid microspheres.

[0140] In step D), the method for removing the solvent is specifically: subjecting the emulsion to magnetic stirring; the speed of the magnetic stirring is 1000 r / min; and the time of the magnetic stirring is 24 h.

[0141] In step D), after removing the solvent, the method further comprises: washing, precipitating and centrifuging the emulsion after the solvent is removed; the washing detergent is ultrapure water; the centrifugal speed is 8000 r / min; and the centrifugal time is 5 minutes.

[0142] Application Example 1 Comparison of degradation weight loss rates

[0143] 10.0 g of each of the polyurethane microspheres in Examples 1-5 and the microspheres prepared in Comparative Example 1 were weighed and placed in a buffer solution with a pH of 7.4, and a degradation experiment was carried out in a constant temperature incubator at 37°C. The microspheres were taken out at regular intervals, and the remaining mass of the microspheres was weighed after centrifugation, washing, and freeze-drying. The specific results are shown in Table 1.

[0144] Table 1

[0145] Group 60 days 120 days 180 days Example 1 7.88g 6.27g 4.96g Example 2 7.96g 6.71g 5.03g Example 3 8.06g 6.87g 5.66g Example 4 8.29g 6.94g 5.76g Example 5 8.34g 7.17g 6.26g Comparative Example 1 7.65g 5.13g 2.31g

[0146] The values ​​in Table 1 are the residual mass of microspheres. It can be seen from the data in Table 1 that the degradation rates of Examples 1 and 2 are significantly faster than those of Examples 3, 4, and 5, from which we can know that the higher the molecular weight of the polyurethane, the less likely it is to degrade. Moreover, the degradation rate of polyurethane microspheres with large molecular weight is relatively stable, and such polyurethane microspheres are better for drug sustained release or filling. The degradation rate of the polylactic acid microspheres in Comparative Example 1 is significantly faster than that in the examples, which shows that the polyurethane microspheres in the present invention are significantly better than polylactic acid microspheres for drug sustained release or filling.

[0147] Application Example 2: Absorbability Comparison

[0148] A disposable 1mL syringe with a needle with an inner diameter of 0.5mm and a length of 19.7mm (i.e., a commonly used 1mL syringe gun tip) is used as the injection rate detection device, and 1mL of microsphere dispersion (microsphere dry weight is 0.1g, denoted as M0) is used as the experimental sample. Weigh 0.1g of the polyurethane microspheres prepared in Examples 1 to 5 and the microspheres prepared in Comparative Example 1, respectively, disperse them in 1mL of distilled water, and place them in a glass bottle. After rapid mixing, a microsphere dispersion is formed. Use a 1mL syringe to draw 1mL of the dispersion, and freeze-dry the microspheres absorbed in the syringe respectively; the absorbability is expressed as the percentage of the mass of the microspheres absorbed in the syringe (M1) to the total mass of the microspheres (M0), and the absorbability is calculated as (M1 / M0)×100%. The specific results are shown in Table 2.

[0149] Table 2

[0150] Group Absorbability % Example 1 90 Example 2 89 Example 3 91 Example 4 87 Example 5 88 Comparative Example 1 89

[0151] From the results in Table 2, it can be seen that the microspheres prepared in Examples 1-5 have good absorbability and can be used for injection.

[0152] Application Example 3 Comparison of protein adsorption

[0153] When biomaterials come into contact with the physiological environment, they need good cell adhesion to avoid being rejected in the body and producing serious side effects. A very important point in cell adhesion is that a large amount of protein adheres to the cell surface, and protein adsorption is an important driving force for cell adhesion.

[0154] With BSA protein concentration as the horizontal axis and BSA absorbance as the vertical axis, a BSA protein growth curve was drawn, a BSA solution was prepared, its absorbance was measured, and the polyurethane microspheres were incubated with the BSA solution. After incubation for 5 hours, the absorbance of the BSA solution was measured again, and the concentration after incubation was calculated. The concentration difference before and after incubation indicated that the BSA protein was adsorbed by the polyurethane microspheres. The specific adsorption results are shown in Table 3.

[0155] Table 3

[0156] Group BAS adsorption (ug / g) Example 1 3600 Example 2 3400 Example 3 3000 Example 4 3300 Example 5 3100

[0157] From the results in Table 3, it can be seen that the higher the BSA adsorption value, the better the protein adsorption. The adsorption values ​​of Examples 1-5 are all above 3000 μg / g, indicating that the polyurethane microspheres prepared by the method of the present invention have excellent cell adhesion and can be used for the preparation of drug sustained-release microspheres, and thus applied to injection solutions.

[0158] Application Example 4: Dispersion Comparison of Polyurethane Microspheres

[0159] 0.5 g of polyurethane microspheres of Examples 1 and 5 and 5 mL of deionized water were added to two glass bottles respectively, and the mixture was shaken vigorously and then allowed to stand. The dispersion state of the polyurethane microspheres at different standing times was observed. The results are shown in Figure 4 .

[0160] Depend on Figure 4 It can be seen that the dispersion state of the polyurethane microspheres gradually decreases with the increase of time, and the overall dispersion time can be maintained for 20 minutes.

[0161] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. An injectable polyurethane microsphere, in, The polyurethane is a polymerization product of polylactic acid polyol and bio-based isocyanate.

2. The injectable polyurethane microspheres according to claim 1, It is characterized in that The particle size of the injectable polyurethane microspheres is 20-70 μm, preferably ≤60 μm; and / or The weight average molecular weight of the polyurethane is 10000-70000 g / mol, preferably 20000-70000 g / mol, more preferably 20000-50000 g / mol; and / or The bio-based isocyanate includes L-lysine diisocyanate.

3. A method for preparing the injectable polyurethane microspheres according to claim 1 or 2, comprising the following steps: (1) subjecting the polyurethane solution to a membrane emulsification reaction in a dispersant solution and shearing the solution to form an emulsion; (2) solidifying the emulsion and then drying it to obtain the injectable polyurethane microspheres.

4. The preparation method according to claim 3, It is characterized in that The polyurethane solution is a mixture of polyurethane and an organic solvent; The organic solvent comprises one or more of dichloromethane, chloroform or ethyl acetate; and / or The concentration of the polyurethane solution is 0.01-3wt%; and / or The dispersant in the dispersant solution comprises sodium lauryl sulfate and / or polyvinyl alcohol; and / or The solvent in the dispersant solution is deionized water; and / or The concentration of the dispersant solution is 0.05-10 wt %.

5. The preparation method according to claim 3 or 4, It is characterized in that The membrane emulsification reaction is carried out in a membrane emulsifier. Preferably, the pressurized gas of the membrane emulsifier includes nitrogen, and / or the pressure of the membrane emulsifier is 0.001-0.020 MPa.

6. The preparation method according to any one of claims 3 to 5, It is characterized in that The shearing includes magnetic stirring. Preferably, the shearing rate is 600-1500 r / min, and / or the shearing time is 5-60 min.

7. The preparation method according to any one of claims 3 to 6, It is characterized in that The solidification step comprises: removing the solvent in the emulsion, preferably, removing the solvent in the emulsion by magnetic stirring; preferably, the speed of the magnetic stirring is 600r / min-1500r / min; and / or the time of the magnetic stirring is 12-24h.

8. The preparation method according to claim 7, It is characterized in that After removing the solvent of the emulsion, the steps of washing, precipitation and centrifugation are also included; Preferably, the washing detergent used is ultrapure water; and / or The centrifugal speed is 1000-10000r / min; and / or The centrifugation time is 1-30 min.

9. A facial filler, comprising the polyurethane microspheres according to claim 1 or 2 or the polyurethane microspheres prepared by the preparation method according to any one of claims 3 to 8.

10. Use of the facial filler according to claim 9 in facial repair; Preferably, the facial filler is directly implanted under the dermis as a facial filling material at the part of the face that needs to be repaired; Preferably, the method of implantation comprises injection.

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