CN114917399A

CN114917399A - Three kinds of polymer microsphere and its preparation method and application

Info

Publication number: CN114917399A
Application number: CN202210670450.6A
Authority: CN
Inventors: 黄潇楠; 李嘉伟; 马鑫博
Original assignee: Capital Normal University
Current assignee: Capital Normal University
Priority date: 2022-06-14
Filing date: 2022-06-14
Publication date: 2022-08-19

Abstract

The invention discloses microspheres of three high polymer materials and a preparation method and application thereof. Adopts inverse emulsion polymerization method, and has simple and controllable process. The obtained microspheres are small-particle-size polyvinyl alcohol microspheres. Sodium alginate microspheres and gelatin microspheres. The three microspheres can be cross-linked and polymerized by taking sodium polyacrylate as an expanding agent to obtain microspheres with small particle size, the particle size distribution is 5-10 mu m, the particle size uniformity is good, the sphericity and the surface smoothness are high, the biocompatibility and the stability are good, the transitional cross-linking is avoided, the dispersibility is good, the overall process is simple and controllable, the cost is low, the industrial production is facilitated, and the sodium polyacrylate can replace various imported and domestic expensive embolic agent products. Meanwhile, the microsphere can be respectively and simultaneously carried with a developing agent and an antitumor agent, has higher drug loading capacity and stable drug release curve, meets the use requirement of fine blood vessels in the embolization treatment, expands the application range of the embolization treatment, and meets the clinical requirement and reduces the treatment cost of patients because different microspheres are degradable and non-degradable.

Description

Three kinds of polymer microsphere and its preparation method and application

Technical Field

The invention relates to the fields of biomedicine and high polymer materials, in particular to three types of high polymer microspheres and a preparation method and application thereof.

Background

With the development of clinical medical technology, transcatheter vascular embolization has been more and more widely applied in the field of interventional radiotherapy due to its advantages of minimally invasive, whole-course image guidance, selective target vessel insertion technology, accurate positioning, and the like. The principle of transcatheter vascular embolization is that by means of high-definition medical image equipment, an artificially-synthesized embolizing material loaded with antitumor drug is injected into blood vessel via catheter to make blood vessel be blocked so as to block blood supply of blood vessel to tumor portion, and release antitumor drug to make tumor be withered and necrotized. The key to transcatheter vascular embolization is the selection of an appropriate medicated embolizing agent.

The microsphere type embolic agent is the most widely applied in clinical application at present. The existing microspheres can be classified into albumin microspheres, gelatin microspheres, starch microspheres, polylactic acid microspheres, chitosan microspheres, sodium alginate microspheres, polyvinyl alcohol microspheres, ethyl cellulose microspheres and the like according to the material matrix. However, these microspheres have various defects that limit their clinical use, for example, some microspheres have irregular shapes and non-uniform sizes, which may cause side effects such as drifting, blood vessel blockage, and mis-embolism during the interventional operation, and damage to normal tissues. Some microspheres have smooth surfaces, regular shapes and uniform sizes, are very good in hydrophilicity and suspension property and are easy to guide along with blood flow, but the elasticity and the flexibility of the microspheres are very poor, the conductivity is not good, the microspheres are difficult to deform and smoothly pass through a micro catheter and can quickly recover to the original state, so that incomplete embolism of blood vessels is caused, the expansion coefficient of some microspheres is too large, the size of the microspheres is difficult to select when the microspheres are applied, the visibility of X-ray perspective is avoided, the use effect is very unsatisfactory, and the clinical interventional therapy requirement cannot be met. In addition, in recent years, the use of drug-loaded embolization microspheres is favored, and some of the existing microspheres cannot be combined with chemotherapeutic drugs or have low drug-loading rate, so that the clinical application is limited.

The literature search finds that the currently researched drug-loaded polymer microspheres comprise polyvinyl alcohol microspheres, gelatin microspheres, sodium alginate microspheres and the like. Particularly, the drug-loaded polymer microsphere is modified mostly, so that the drug-loaded polymer microsphere can be slowly released while the drug loading rate and the drug loading rate are increased.

Based on the above defects of microspheres made of different materials, polymer microspheres represented by polyvinyl alcohol have been widely used and modified gradually due to their smooth surface, uniform size, perfect spherical shape, good biocompatibility and suspension property, and good elasticity and flexibility. The small-particle-size modified polyvinyl alcohol microspheres which have the excellent characteristics and meet the actual use requirements are not realized in the prior art and are also urgently needed for embolism treatment.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides three preparation methods of polymer microspheres.

In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows: the preparation method of the three polymer microspheres comprises the following steps:

s1, preparing a water phase: preparing a polyvinyl alcohol aqueous solution with the mass fraction of 5% and a sodium polyacrylate aqueous solution with the mass fraction of 0.1% at normal temperature and normal pressure, mixing the polyvinyl alcohol aqueous solution and the sodium polyacrylate aqueous solution according to the volume ratio of 7: 3-9: 1, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to obtain a water phase 1; preparing a sodium alginate aqueous solution with the mass fraction of 1% and a gelatin aqueous solution with the mass fraction of 10%, mixing the sodium alginate aqueous solution and the gelatin aqueous solution according to the volume ratio of 7: 3-9: 1, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to form a water phase 2; preparing 10% gelatin aqueous solution by mass, and taking 5-15mL as a water phase 3;

s2, preparing an oil phase: adding 2.0g of span 80 into 100mL of liquid paraffin under normal temperature and pressure, and uniformly stirring, wherein 30-70 mL of span is taken as an oil phase;

s3, crosslinking reaction: under normal temperature and normal pressure, preparing 50 mass percent glutaraldehyde aqueous solution and 1mol/L hydrochloric acid, dropwise adding a water phase 1 (water phase 2) into an oil phase under the stirring condition of 300-500 rpm, heating to 40-60 ℃ after all the water phase is dropwise added, heating for 30-120 min, keeping stirring and temperature, dropwise adding 1mL glutaraldehyde aqueous solution, waiting for 5-30 min, dropwise adding 1mL hydrochloric acid, and waiting for 30-120 min; (preparing 50 mass percent of glutaraldehyde aqueous solution under normal temperature and pressure, dropwise adding a water phase 3 into an oil phase under the stirring condition of 300-500 rpm, heating to 40-60 ℃ for 10-30 min after all the water phase is dropwise added, keeping stirring, placing into an ice water bath for 20-40 min, dropwise adding 1mL of glutaraldehyde aqueous solution, and waiting for 10-30 min)

S4, preparation of microspheres: and standing the reaction liquid, fully cooling, absorbing upper-layer liquid, repeatedly washing the residual substances with petroleum ether, adding cold ethanol, uniformly stirring, carrying out suction filtration, collecting powder obtained by suction filtration, and fully drying to obtain three types of polymer microspheres. Preferably, in step S2, the liquid paraffin may be replaced by white oil or vegetable oil, and the span 80 may be replaced by span 60.

Preferably, the petroleum ether in the step S3 may be replaced with hot water or ethanol.

The small-particle-size polyvinyl alcohol microspheres obtained by the preparation method based on the three polymer microspheres have the whole particle size distribution of 1-100 mu m; the obtained high-load sodium alginate microspheres are characterized in that: the total particle size distribution is 50-500 μm; the obtained developable medicine-carrying gelatin microsphere is characterized in that: the total particle size distribution is 1 to 100 μm.

More than 80% of polyvinyl alcohol microspheres with small particle size obtained by the preparation method of the three polymer microspheres have particle size distribution centered at 5-10 mu m; the obtained high-load sodium alginate microspheres are characterized in that: more than 75% of the particle size distribution is concentrated in 100-200 μm; the obtained developable medicine-carrying gelatin microsphere is characterized in that: more than 80% of the particle size distribution is concentrated in 25 to 50 μm.

Based on the application of the three polymer microspheres, the preparation method is used for preparing the developing microspheres in transcatheter arterial chemoembolization treatment, and comprises the following steps:

and (3) adding 0.25-1 g of barium sulfate into the water phase obtained in the step S1 of the preparation method of the three polymer microspheres, uniformly stirring, and taking the mixture as the water phase to continue the steps S2, S3 and S4 to obtain the developing microspheres.

Preferably, the barium sulfate can be replaced by ferroferric oxide, Gd-DTPA, Mn-DPDP, AMI-25, Resovist, UCNP or iodine preparations.

Based on the application of the three polymer microspheres, the preparation method is used for preparing the drug-loaded microspheres in transcatheter arterial chemoembolization, and comprises the following steps:

adding 0.05-0.2 g of doxorubicin into the water phase obtained in the step S1 of the preparation method of the three polymer microspheres, uniformly stirring, and taking the mixture as the water phase to continue the steps S2, S3 and S4 to obtain the drug-loaded microspheres.

Preferably, the doxorubicin may be replaced with curcumin, bleomycin, mitoxantrone hydrochloride, epirubicin, pirarubicin, oxaliplatin, cisplatin, vincristine, mitomycin or irinotecan.

Due to the application of the technical scheme, compared with the prior art, the invention has the following beneficial effects:

the invention adopts the inverse emulsion polymerization method, and the process is simple and controllable. The first small-particle-size polyvinyl alcohol microspheres are prepared by cross-linking and polymerizing acetal with sodium polyacrylate as an expanding agent and glutaraldehyde as a cross-linking agent, the particle size distribution of all the particles is controlled to be 1-100 mu m, the particle size distribution of the main particles is 5-10 mu m, the particle size uniformity is good, the sphericity and the surface smoothness are high, the biocompatibility and the stability are good, the transitional cross-linking is avoided, the dispersibility is good, a developer and an antitumor agent can be carried respectively and simultaneously, the drug-loading rate and the drug-release curve are high, the use requirements of fine blood vessels in embolization treatment are met, the application range of embolization treatment is expanded, and the unexpected excellent effect is generated; the second high-load sodium alginate microsphere has narrow particle size distribution, high sphericity, strong size and shape uniformity, smooth surface, good dispersibility, capability of respectively and simultaneously coating a plurality of developers and anti-tumor drugs, higher load capacity, simple and controllable integral process, low cost, easy and accurate control, contribution to industrial production, capability of replacing various imported and domestic expensive embolic agent products, capability of providing acceptable excellent embolic agent for treating cancer for patients and capability of reducing the pain and economic burden of patients; the third type of developable drug-loaded gelatin microspheres have the advantages that through concise process flow and proper parameter control, the amino group of lysine in gelatin and the aldehyde group in glutaraldehyde are subjected to Schiff base reaction, and crosslinking polymerization is carried out to obtain the developable drug-loaded gelatin microspheres, the particle size distribution is narrow, the sphericity is high, the product uniformity is strong, the industrial production is easy, the natural gelatin material consisting of amino acid not only endows the microspheres with better water absorption, but also can be used for carrying a developer and an antitumor drug respectively and simultaneously, has higher drug-loading rate and stable drug-release curve, and can be completely degraded within 10-30 days.

Drawings

FIG. 1 is a surface topography of three polymeric microspheres obtained in example 1 under a scanning electron microscope low power lens.

FIG. 2 is a surface topography of three polymeric microspheres obtained in example 1 under a scanning electron microscope high power mirror.

Fig. 3 is a table showing the recorded calculation of the water absorption measurement of the drug-loaded microspheres obtained in example 4.

FIG. 4 is a line graph showing the relationship of drug release rate measurement of drug-loaded microspheres obtained in example 4.

Detailed Description

The present invention will be further described in detail with reference to the following specific examples:

example 1

The polyvinyl alcohol microspheres with small particle size are prepared by the following steps:

s1, preparation of a water phase: preparing a polyvinyl alcohol aqueous solution with the mass fraction of 5% and a sodium polyacrylate aqueous solution with the mass fraction of 0.1% at normal temperature and normal pressure, mixing the polyvinyl alcohol aqueous solution and the sodium polyacrylate aqueous solution according to the volume ratio of 8:2, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to obtain a water phase 1; preparing 1% of sodium alginate aqueous solution and 10% of gelatin aqueous solution by mass, mixing the sodium alginate aqueous solution and the gelatin aqueous solution according to the volume ratio of 8:2, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to be used as a water phase 2; preparing 10% gelatin aqueous solution by mass fraction, and taking 10mL as a water phase 3;

s2, preparing an oil phase: adding 2.0g of span 80 into 100mL of liquid paraffin at normal temperature and normal pressure, and uniformly stirring, wherein 50mL of span is taken as an oil phase;

s3, crosslinking reaction: preparing 50% glutaraldehyde aqueous solution and 1mol/L hydrochloric acid at normal temperature and normal pressure, dropwise adding 1/2 aqueous phase into oil phase under the stirring condition of 350rpm, heating to 50 ℃ for 30min after all the aqueous phase is dropwise added, keeping stirring and temperature, dropwise adding 1mL glutaraldehyde aqueous solution, waiting for 10min, dropwise adding 1mL hydrochloric acid, and waiting for 60 min; (at normal temperature and pressure, preparing 50% glutaraldehyde water solution by mass fraction, dropwise adding water phase 3 into oil phase under 350rpm stirring condition, dropwise adding water phase, heating to 60 deg.C for 10min, stirring, placing into ice water bath for 20min, dropwise adding 1mL glutaraldehyde water solution, and waiting for 10 min.)

S4, preparation of microspheres: and standing the reaction liquid, fully cooling, absorbing upper-layer liquid, repeatedly washing the residual substances with petroleum ether, adding cold ethanol, uniformly stirring, carrying out suction filtration, collecting powder obtained by suction filtration, and fully drying to obtain three types of polymer microspheres.

Example 2

Three types of polymer microspheres were prepared as follows:

s1, preparation of a water phase: preparing a polyvinyl alcohol aqueous solution with the mass fraction of 5% and a sodium polyacrylate aqueous solution with the mass fraction of 0.1% at normal temperature and normal pressure, mixing the polyvinyl alcohol aqueous solution and the sodium polyacrylate aqueous solution according to the volume ratio of 7:3, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to obtain a water phase 1; preparing a sodium alginate aqueous solution with the mass fraction of 1% and a gelatin aqueous solution with the mass fraction of 10%, mixing the sodium alginate aqueous solution and the gelatin aqueous solution according to the volume ratio of 7:3, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to be used as a water phase 2; preparing 10% gelatin water solution by mass fraction, and taking 8mL as a water phase 3;

S4, preparation of microspheres: and standing the reaction liquid, fully cooling, sucking and removing the upper layer liquid, repeatedly washing the residual substances by using petroleum ether, adding cold ethanol, uniformly stirring, carrying out suction filtration, collecting powder obtained by suction filtration, and fully drying to obtain the three types of polymer microspheres.

Example 3

Three types of polymer microspheres are prepared as follows:

s1, preparing a water phase: preparing a polyvinyl alcohol aqueous solution with the mass fraction of 5% and a sodium polyacrylate aqueous solution with the mass fraction of 0.1% at normal temperature and normal pressure, mixing the polyvinyl alcohol aqueous solution and the sodium polyacrylate aqueous solution according to the volume ratio of 9:1, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to obtain a water phase 1; preparing a sodium alginate aqueous solution with the mass fraction of 1% and a gelatin aqueous solution with the mass fraction of 10%, mixing the sodium alginate aqueous solution and the gelatin aqueous solution according to the volume ratio of 9:1, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to be used as a water phase 2; preparing 10% gelatin water solution by mass fraction, and taking 12mL as a water phase 3;

s3, preparing 50% glutaraldehyde water solution and 1mol/L hydrochloric acid at normal temperature and normal pressure, dropwise adding 1/2 water phase into the oil phase under the stirring condition of 350rpm, heating to 50 ℃ after all the water phase is dropwise added, heating for 30min, keeping stirring and temperature, dropwise adding 1mL glutaraldehyde water solution, waiting for 10min, dropwise adding 1mL hydrochloric acid, and waiting for 60 min; (at normal temperature and pressure, preparing 50% glutaraldehyde water solution by mass fraction, dropwise adding water phase 3 into oil phase under 350rpm stirring condition, dropwise adding water phase, heating to 60 deg.C for 10min, stirring, placing into ice water bath for 20min, dropwise adding 1mL glutaraldehyde water solution, and waiting for 10 min.)

S4, preparing microspheres: and standing the reaction liquid, fully cooling, sucking and removing the upper layer liquid, repeatedly washing the residual substances by using petroleum ether, adding cold ethanol, uniformly stirring, carrying out suction filtration, collecting powder obtained by suction filtration, and fully drying to obtain the three types of polymer microspheres.

The three polymer microspheres obtained in example 1 were characterized and analyzed as follows:

observation of feature and size

Adding 1mL of microsphere powder into 1mL of absolute ethyl alcohol, performing ultrasonic treatment for 1min, dripping the obtained liquid on conductive adhesive, observing the microsphere morphology by using a scanning electron microscope after air drying, and counting the particle size distribution, wherein the microspheres are round spheres with higher sphericity and smoother in surface by combining the graph 1 and the graph 2, and the particle size distribution of all the polyvinyl alcohol microsphere powder is 1-100 microns by calculation and statistics, and more than 90% of the particle size distribution is concentrated in 5-10 microns; the particle size distribution of all the high-load sodium alginate microspheres is 50-500 microns, and the particle size distribution of more than 75% and even higher proportion is concentrated in 100-200 microns; the whole particle size distribution of the gelatin microsphere powder is 1-100 mu m, and more than 90% of the particle size distribution is concentrated in 25-50 mu m;

through full experimental summary, the particle size distribution of all the polyvinyl alcohol microsphere powder obtained by the three embodiments and all the technical schemes in the scope of the invention is 1-100 μm, and more than 90% of the particle size distribution is concentrated in 5-10 μm; the particle size distribution of all the high-load sodium alginate microspheres is 50-500 mu m, and the particle size distribution of more than 75% and even higher is concentrated in 100-200 mu m; the whole particle size distribution of the gelatin microsphere powder is 1-100 mu m, and more than 90% of the particle size distribution is concentrated in 25-50 mu m; have a higher sphericity and a smoother surface.

The small-particle-size polyvinyl alcohol microspheres obtained by the three embodiments and all technical schemes in the scope of the invention can be used for preparing developing microspheres in transcatheter arterial chemoembolization treatment, and the preparation method comprises the following steps:

Wherein, the developing agent barium sulfate can be replaced by ferroferric oxide, Gd-DTPA, Mn-DPDP, AMI-25, Resovist, UCNP or iodine preparation.

The microspheres obtained by the three embodiments and all technical schemes in the scope of the invention can also be used for preparing drug-loaded microspheres in transcatheter arterial chemoembolization, and the preparation method comprises the following steps:

adding 0.05-0.2 g of doxorubicin into the water phase obtained in the step S1 of the microsphere preparation method, uniformly stirring, and then taking the mixture as the water phase to continue the steps S2, S3 and S4 to obtain the drug-loaded microsphere.

Wherein, the drug doxorubicin can be replaced by curcumin, bleomycin, mitoxantrone hydrochloride, epirubicin, pirarubicin, oxaliplatin, cisplatin, vincristine, mitomycin or irinotecan.

Example 4

The drug-loaded microsphere is prepared by the following steps:

s1, preparation of a water phase: preparing a polyvinyl alcohol aqueous solution with the mass fraction of 5% and a sodium polyacrylate aqueous solution with the mass fraction of 0.1% at normal temperature and normal pressure, mixing the polyvinyl alcohol aqueous solution and the sodium polyacrylate aqueous solution according to the volume ratio of 7: 3-9: 1, adding 0.1g of doxorubicin into the mixed solution with the volume of 10mL, and uniformly stirring the mixed solution to obtain a water phase 1; preparing a sodium alginate aqueous solution with the mass fraction of 1% and a gelatin aqueous solution with the mass fraction of 10%, mixing the sodium alginate aqueous solution and the gelatin aqueous solution according to the volume ratio of 7: 3-9: 1, adding 0.1g of doxorubicin into the mixed solution with the volume of 10mL, and uniformly stirring the mixed solution to obtain a water phase 2; preparing 10% gelatin water solution by mass fraction, adding 0.1g doxorubicin into 5-15mL of the gelatin water solution, and uniformly stirring to obtain a water phase 3;

s2, preparing an oil phase: under normal temperature and normal pressure, 2.0g of span 80 is added into 100mL of liquid paraffin and stirred evenly, and 50mL is taken as oil phase;

s3, crosslinking reaction: under normal temperature and normal pressure, preparing 50 mass percent of glutaraldehyde aqueous solution and 1mol/L hydrochloric acid, dropwise adding 1/2 water phase into the oil phase under the stirring condition of 350rpm, heating to 50 ℃ for 30min after all the water phase is dropwise added, keeping stirring and temperature, dropwise adding 1mL of glutaraldehyde aqueous solution, waiting for 10min, dropwise adding 1mL of hydrochloric acid, and waiting for 60 min; (at normal temperature and pressure, preparing 50% glutaraldehyde water solution by mass fraction, dropwise adding water phase 3 into oil phase under 350rpm stirring condition, dropwise adding water phase, heating to 60 deg.C for 10min, stirring, placing into ice water bath for 20min, dropwise adding 1mL glutaraldehyde water solution, and waiting for 10 min.)

S4, preparation of microspheres: and standing the reaction liquid, fully cooling, sucking the upper layer liquid, repeatedly washing the residual substance with petroleum ether, adding cold ethanol, uniformly stirring, carrying out suction filtration, collecting the powder obtained by suction filtration, and fully drying to obtain the drug-loaded microspheres.

The drug-loaded microspheres obtained in example 4 were characterized and analyzed as follows:

topography observation

Adding 1mL of microsphere powder into 1mL of absolute ethyl alcohol, performing ultrasonic treatment for 1min, dripping the obtained liquid on conductive adhesive, air-drying, and observing the microsphere morphology by using a scanning electron microscope, wherein the difference between the sphericity and the surface smoothness of the drug-loaded microsphere is small compared with that of the original microsphere as shown in figure 4;

water absorption measurement

0.03g of microsphere powder is taken out and added into 1mL of ultrapure water for soaking for 24h for three times, the dry-wiping weighing mass of unabsorbed water is recorded as m according to a formula

The water absorption and average values of the three samples were calculated, and the results are shown in fig. 3.

Determination of drug Release Rate

Preparing a series of doxorubicin standard solutions with concentration gradient, respectively testing the absorbances of the doxorubicin standard solutions at 480nm, drawing a doxorubicin standard concentration curve, adding 0.05g of microsphere powder into 2mL of ultrapure water, placing the ultrapure water in a water bath at 37 ℃ to simulate the internal environment temperature of a human body, carrying out ultraviolet absorbance test every two hours, recording the absorbance at 480nm, converting the absorbance into release concentration according to the standard concentration curve, and drawing a time relation curve of the release concentration, wherein in the three drug-loaded microspheres, as shown in fig. 4, the drug release speed of the sodium alginate microspheres is far higher than that of the other two, and the release dosage of the gelatin microspheres is slightly different from that of the PVA microspheres, so that the gelatin microspheres are slightly higher than that of the PVA microspheres; the medicine release speed is faster in the first 2 hours after entering the human embolism position, and the medicine release speed is obviously slowed down and kept relatively stable after 2 hours.

In the four embodiments and all technical solutions within the scope of the present invention, the liquid paraffin in step S2 may be replaced by white oil or vegetable oil, span 80 may be replaced by span 60, and the petroleum ether in step S3 may be replaced by hot water or ethanol.

The microspheres, the drug-loaded microspheres and the developing microspheres obtained by the four embodiments and all technical schemes in the scope of the invention can be used for preparing developing drug-loaded microspheres, developers and/or drugs can be added into the water phase in the step S1, and also can be added into liquid used for swelling the microspheres before use, and only the microspheres are required to be fully absorbed by the developers and/or the drugs.

The raw material dosage, tool selection and operation of the invention adopt small-batch preparation which is biased to the laboratory environment, and the invention can adopt chemical equipment with higher automation degree and more accurately controlled chemical process to realize large-batch, pollution-free, high-efficiency and yield industrial production in the clean and sterile medical instrument production plant environment.

The innovation of the invention is as follows: the invention adopts an inverse emulsion polymerization method, has simple and controllable process, good particle size uniformity, high sphericity and surface smoothness, good biocompatibility and stability, avoids transitional crosslinking, has good dispersibility, can be used for carrying a developer and an antitumor drug respectively and simultaneously, has higher drug-loading rate and stable drug-release curve, meets the use requirement of fine blood vessels in embolization treatment, expands the application range of embolization treatment, and produces unexpected excellent effect.

The above-mentioned embodiments are only for illustrating the technical idea and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention by this, and all equivalent changes or modifications made according to the spirit of the present invention should be covered in the protection scope of the present invention.

Claims

1. The preparation method of the three polymer microspheres is characterized by comprising the following steps: the method comprises the following steps:

s1, preparing a water phase: preparing a polyvinyl alcohol aqueous solution with the mass fraction of 5% and a sodium polyacrylate aqueous solution with the mass fraction of 0.1% at normal temperature and normal pressure, mixing the polyvinyl alcohol aqueous solution and the sodium polyacrylate aqueous solution according to the volume ratio of 7: 3-9: 1, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to obtain a water phase 1; preparing a sodium alginate aqueous solution with the mass fraction of 1% and a gelatin aqueous solution with the mass fraction of 10%, mixing the sodium alginate aqueous solution and the gelatin aqueous solution according to the volume ratio of 7: 3-9: 1, wherein the volume of the mixed solution is 10mL, and uniformly stirring the mixed solution to obtain a water phase 2; preparing 10% gelatin water solution by mass fraction, and taking 5-15mL as a water phase 3;

s2, preparing an oil phase: under normal temperature and normal pressure, adding 2.0g of span 80 into 100mL of liquid paraffin, and uniformly stirring, wherein 30-70 mL of span is taken as an oil phase;

S4, preparing microspheres: and standing the reaction liquid, fully cooling, absorbing upper-layer liquid, repeatedly washing the residual substances with petroleum ether, adding cold ethanol, uniformly stirring, carrying out suction filtration, collecting powder obtained by suction filtration, and fully drying to obtain three types of polymer microspheres.

2. The method for preparing three kinds of polymer microspheres according to claim 1, wherein: in the step S2, the liquid paraffin may be replaced by white oil or vegetable oil, and the span 80 may be replaced by span 60.

3. The method for preparing three kinds of polymer microspheres according to claim 1, wherein: the petroleum ether in step S3 may be replaced with hot water or ethanol.

4. The polyvinyl alcohol microspheres with small particle size obtained by the method for preparing three kinds of polymer microspheres according to any one of claims 1 to 3, wherein the method comprises the following steps: the total particle size distribution is 1-100 μm; the obtained high-load sodium alginate microspheres are characterized in that: the total particle size distribution is 50-500 μm; the obtained developable medicine-carrying gelatin microsphere is characterized in that: the total particle size distribution is 1 to 100 μm.

5. The polyvinyl alcohol microspheres with small particle size obtained by the method for preparing three kinds of polymer microspheres according to any one of claims 1 to 3, wherein the method comprises the following steps: more than 80% of the particle size distribution is concentrated in 5-10 μm; the obtained high-load sodium alginate microspheres are characterized in that: more than 75% of the particle size distribution is concentrated in 100-200 μm; the obtained developable medicine-carrying gelatin microsphere is characterized in that: more than 80% of the particle size distribution is concentrated in 25 to 50 μm.

6. The use of three polymeric microspheres according to any one of claims 4 to 5, for preparing a contrast microsphere for transcatheter arterial chemoembolization, the preparation method comprising the steps of:

and (3) adding 0.25-1 g of barium sulfate into the water phase obtained in the step S1 of the preparation method of the polymer microsphere, uniformly stirring, and taking the mixture as the water phase to continue the steps S2, S3 and S4 to obtain the developing microsphere.

7. The application of the three polymer microspheres according to claim 6, wherein the barium sulfate can be replaced by ferroferric oxide, Gd-DTPA, Mn-DPDP, AMI-25, Resovist, UCNP or iodine preparation.

8. The application of the three polymer microspheres according to any one of claims 4 to 5, which is used for preparing the drug-loaded microspheres in transcatheter arterial chemoembolization, and the preparation method comprises the following steps:

in the preparation method of the three polymer microspheres, 0.05-0.2 g of doxorubicin is added into the water phase obtained in the step S1, and the mixture is uniformly stirred and then used as the water phase to continue the steps S2, S3 and S4, so that the drug-loaded microspheres can be obtained.

9. The use of the three polymeric microspheres according to claim 8, wherein the doxorubicin is replaced with curcumin, bleomycin, mitoxantrone hydrochloride, epirubicin, pirarubicin, oxaliplatin, cisplatin, vincristine, mitomycin or irinotecan.