CN114917399A - Three kinds of polymer microspheres and their preparation method and application - Google Patents

Abstract

The invention discloses microspheres of three kinds of macromolecular materials and their preparation method and application. Using inverse emulsion polymerization, the process is simple and controllable. The obtained microspheres are small particle size polyvinyl alcohol microspheres. Sodium alginate microspheres and gelatin microspheres. All three kinds of microspheres can use sodium polyacrylate as expansion agent, cross-linking and polymerize to obtain microspheres with small particle size, the particle size distribution is 5-10μm, the particle size uniformity is good, the sphericity and surface smoothness are high, and it has a good biological phase. Capacitance and stability, avoiding transitional cross-linking, good dispersibility, simple and controllable overall process, low cost, favorable for industrial production, and can replace various imported and domestic expensive embolic products. At the same time, it can carry contrast agent and antitumor drug separately and simultaneously, with high drug loading and stable drug release curve, which meets the requirements for the use of tiny blood vessels in embolization therapy, and expands the application range of embolization therapy. Divided into two categories: degradable and non-degradable, to meet clinical needs and reduce patient treatment costs.

Description

Three kinds of polymer microspheres and their preparation method and application

technical field

The invention relates to the fields of biomedicine and polymer materials, in particular to three types of polymer microspheres and their preparation methods and applications.

Background technique

With the development of clinical medical technology, transcatheter vascular embolization has been more and more widely used in the field of interventional radiotherapy due to its advantages of minimally invasiveness, whole-process image guidance, selective target vessel insertion technology, and accurate positioning. The principle of transcatheter vascular embolization is to use high-definition medical imaging equipment to inject synthetic embolic material containing anti-tumor drugs into the blood vessels through the catheter to block the blood vessels, thereby blocking blood supply to the tumor site and releasing anti-tumor drugs. Drugs cause tumor shrinkage and necrosis. The key to transcatheter vascular embolization is to choose an appropriate drug-loaded embolization agent.

The most widely used clinically at present is the microsphere embolic agent. The existing microspheres can be divided into albumin microspheres, gelatin microspheres, starch microspheres, polylactic acid microspheres, chitosan microspheres, sodium alginate microspheres, polyvinyl alcohol microspheres, ethyl cellulose microspheres according to the material matrix. Microspheres etc. However, these microspheres limit their clinical use due to their respective defects. For example, some microspheres are irregular in shape and non-uniform in size, which leads to side effects such as drift, blockage of blood vessels, and false embolization during interventional operations, causing damage to normal tissues. Although some microspheres have smooth surface, regular shape, relatively uniform size, and good hydrophilicity and suspension, they are easy to be guided with blood flow, but the microspheres have poor elasticity and stretchability, poor conductivity, and it is difficult to The deformation can be smoothly passed through the micro-catheter and can be quickly restored to its original state, resulting in incomplete embolization of blood vessels, and some microspheres have too large expansion coefficients, so it is difficult to choose the size of the microspheres during application, and there is no X-ray visibility. , the use effect is very unsatisfactory, and cannot meet the needs of clinical interventional therapy. In addition, in recent years, the use of drug-loaded embolization microspheres has been favored in clinical practice. Some of the existing microspheres cannot be combined with chemotherapeutic drugs or have low drug loading, which limits their clinical application.

The literature search found that the currently researched drug-loaded polymer microspheres include polyvinyl alcohol microspheres, gelatin microspheres and sodium alginate microspheres. Especially for the modification of drug-loaded polymer microspheres, the purpose is to increase the drug-loading amount and drug-loading rate, and at the same time to achieve slow and controlled release.

Based on the defects of the above microspheres of different materials, the polymer microspheres represented by polyvinyl alcohol have smooth surface, uniform size, perfect round spherical shape, good biocompatibility and suspension, and good elasticity and stretchability. , has gradually been widely used and modified. For the embolization of small blood vessels, microspheres with smaller particle size are required. The small-diameter modified polyvinyl alcohol microspheres with the above excellent characteristics and practical requirements have not been realized by the existing technology, and are also urgently needed for embolization therapy. .

SUMMARY OF THE INVENTION

In order to overcome the above-mentioned deficiencies of the prior art, the present invention provides three preparation methods of polymer microspheres.

In order to achieve the above-mentioned purpose, the technical scheme adopted by the present invention to solve the technical problem is: the preparation method of three kinds of polymer microspheres comprises the following steps:

S1. Preparation of water phase: under normal temperature and pressure, prepare 5% polyvinyl alcohol aqueous solution and 0.1% mass fraction sodium polyacrylate aqueous solution, and take the polyvinyl alcohol aqueous solution and the polyvinyl alcohol aqueous solution in the volume ratio of 7:3-9:1. Mix the sodium polyacrylate aqueous solution, the volume of the mixed solution is 10 mL, and stir evenly as water phase 1; configure 1% mass fraction of sodium alginate aqueous solution and 10% mass fraction of gelatin aqueous solution, and take the volume ratio of 7:3 to 9:1. The sodium alginate aqueous solution and the gelatin aqueous solution are mixed, the volume of the mixed solution is 10 mL, and the mixture is stirred evenly as the water phase 2; the gelatin aqueous solution of 10% mass fraction is prepared, and 5-15 mL is taken as the water phase 3;

S2. Preparation of oil phase: under normal temperature and pressure, take 2.0g of Span 80 into 100mL of liquid paraffin and stir evenly, and take 30-70mL as the oil phase;

S3. Cross-linking reaction: under normal temperature and pressure, configure 50% mass fraction of glutaraldehyde aqueous solution and 1 mol/L concentration of hydrochloric acid, and add water phase 1 (water phase 2) dropwise to the oil phase under stirring at 300 to 500 rpm ), the water phase is all dropped in and heated to 40-60°C for 30-120min, keep stirring and temperature, add dropwise 1mL of glutaraldehyde aqueous solution and wait for 5-30min, dropwise add 1mL of hydrochloric acid and wait for 30-120min; (Under normal temperature and pressure, configure 50% mass fraction of glutaraldehyde aqueous solution, add water phase 3 dropwise to the oil phase under stirring at 300 to 500 rpm, and then heat up to 40 to 60 ° C and heat for 10 to 10 30min, keep stirring, put it in an ice-water bath for 20-40min, add 1mL of glutaraldehyde aqueous solution dropwise and wait for 10-30min;)

S4. Preparation of microspheres: the reaction solution is allowed to stand for sufficient cooling, the upper layer liquid is removed and the remaining substances are repeatedly washed with petroleum ether, cold ethanol is added to stir evenly, and suction filtration is carried out, and the powder obtained by suction filtration is collected and fully dried to obtain three high Molecular Microspheres. Preferably, in the step S2, the liquid paraffin can be replaced with white oil or vegetable oil, and the span 80 can be replaced with the span 60.

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

The small particle size polyvinyl alcohol microspheres obtained based on the above-mentioned three preparation methods of polymer microspheres have all particle size distributions of 1 to 100 μm; the obtained high-load sodium alginate microspheres are characterized in that: all particles The particle size distribution is 50-500 μm; the obtained developable drug-loaded gelatin microspheres are characterized in that: the whole particle size distribution is 1-100 μm.

The small particle size polyvinyl alcohol microspheres obtained based on the above three preparation methods of polymer microspheres have more than 80% particle size distribution 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 drug-loaded gelatin microsphere is characterized in that: more than 80% of the particle size distribution is concentrated in 25-50 μm.

Based on the application of the above-mentioned three kinds of polymer microspheres, for the preparation of developing microspheres in transcatheter arterial chemoembolization, the preparation method comprises the following steps:

Add 0.25-1 g of barium sulfate to the water phase in step S1 of the three preparation methods of polymer microspheres, stir evenly and continue steps S2, S3 and S4 as the water phase to obtain developing microspheres.

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

Based on the application of the above-mentioned three kinds of polymer microspheres, for the preparation of drug-loaded microspheres in transcatheter arterial chemoembolization, the preparation method includes the following steps:

Add 0.05-0.2 g of doxorubicin to the aqueous phase in step S1 of the three preparation methods of polymer microspheres, stir evenly, and continue steps S2, S3 and S4 as the aqueous phase to obtain drug-loaded microspheres.

Preferably, the doxorubicin can be replaced with curcumin, bleomycin, mitoxantrone hydrochloride, epirubicin, pirarubicin, oxaliplatin, cisplatin, vincristine, mitox erythromycin or irinotecan.

Due to the application of the above-mentioned technical solutions, the present invention has the following beneficial effects compared with the prior art:

The invention adopts an inverse emulsion polymerization method, and the process is simple and controllable. The first small particle size polyvinyl alcohol microspheres use sodium polyacrylate as expansion agent, glutaraldehyde as crosslinking agent, and acetal crosslinking polymerization to obtain small particle size polyvinyl alcohol microspheres, and the overall particle size distribution is controlled at 1 ~100μm, the main particle size distribution is 5~10μm, good particle size uniformity, high sphericity and surface smoothness, good biocompatibility and stability, avoids excessive cross-linking, good dispersibility, can be separated and At the same time, it is equipped with contrast agent and anti-tumor drug, with high drug loading and stable drug release curve, which meets the requirements for the use of small blood vessels in embolization therapy, expands the application scope of embolization therapy, and produces unpredictable excellent results. The second type of high-load sodium alginate microspheres has narrow particle size distribution, high sphericity, strong size and shape uniformity, smooth surface, good dispersibility, and can be coated with a variety of imaging agents and antitumor drugs separately and simultaneously. High loading, simple and controllable overall process, low cost, easy and precise control, beneficial to industrial production, can replace various imported and domestic expensive embolic products, provide patients with acceptable and excellent embolic agents for cancer treatment, reduce patient The third type of developable drug-loaded gelatin microspheres, through a simple process flow and appropriate parameter control, makes the amine group of lysine in gelatin and the aldehyde group in glutaraldehyde Schiff Alkali reaction, cross-linking polymerization to obtain developable drug-loaded gelatin microspheres, with narrow particle size distribution, high sphericity, strong product uniformity, and easy industrial production. The natural gelatin material composed of amino acids not only endows the microspheres with better water absorption, The imaging agent and the antitumor drug can be loaded separately and simultaneously, with high drug loading and stable drug release curve, and can be completely degraded within 10 to 30 days.

Description of drawings

Fig. 1 is the surface topography of three kinds of polymer microspheres obtained in Example 1 under the low magnification of scanning electron microscope.

FIG. 2 is a surface topography diagram of three kinds of polymer microspheres obtained in Example 1 under a high magnification microscope of a scanning electron microscope.

FIG. 3 is a record calculation table for the determination of the water absorption rate of the drug-loaded microspheres obtained in Example 4. FIG.

FIG. 4 is a graph showing the relationship between the drug-loading microspheres’ drug release rate measurement obtained in Example 4. FIG.

Detailed ways

Below in conjunction with specific embodiment, the content of the present invention is described in further detail:

Example 1

Prepare small particle size polyvinyl alcohol microspheres as follows:

S1. Preparation of water phase: under normal temperature and pressure, prepare 5% polyvinyl alcohol aqueous solution and 0.1% mass fraction sodium polyacrylate aqueous solution, and take the polyvinyl alcohol aqueous solution and sodium polyacrylate aqueous solution in a volume ratio of 8:2 Mixing, the volume of the mixed solution is 10 mL, and stirring is used as water phase 1; 1% aqueous sodium alginate solution and 10% aqueous gelatin solution are prepared, and the aqueous solution of sodium alginate and the aqueous gelatin solution are mixed in a volume ratio of 8:2. , the volume of the mixed solution is 10 mL, and stir evenly as water phase 2; configure 10% mass fraction of gelatin aqueous solution, and take 10 mL as water phase 3;

S2. Preparation of oil phase: under normal temperature and pressure, take 2.0g of Span 80 and add it to 100mL of liquid paraffin and stir evenly, and take 50mL as the oil phase;

S3. Cross-linking reaction: under normal temperature and pressure, configure 50% mass fraction of glutaraldehyde aqueous solution and 1 mol/L hydrochloric acid, add water phase 1/water phase 2 dropwise to the oil phase under stirring at 350 rpm, water After all the phases are added dropwise, the temperature is raised to 50°C and heated for 30min, maintaining stirring and temperature, adding 1mL of glutaraldehyde aqueous solution dropwise and waiting for 10min, adding 1mL hydrochloric acid dropwise and waiting for 60min; (under normal temperature and pressure, configure 50% mass fraction glutaraldehyde aqueous solution, add water phase 3 dropwise to the oil phase under stirring at 350rpm, the water phase is all added dropwise and then heated to 60°C for 10min, keep stirring, put it in an ice-water bath for 20min, dropwise add 1mL pentane Wait 10min after dialdehyde water solution ;)

S4. Preparation of microspheres: the reaction solution is allowed to stand for sufficient cooling, the upper layer liquid is removed and the remaining substances are repeatedly washed with petroleum ether, cold ethanol is added to stir evenly, and suction filtration is carried out, and the powder obtained by suction filtration is collected and fully dried to obtain three high Molecular Microspheres.

Example 2

Three polymer microspheres were prepared as follows:

S1. Preparation of water phase: under normal temperature and pressure, prepare 5% polyvinyl alcohol aqueous solution and 0.1% mass fraction sodium polyacrylate aqueous solution, and take the polyvinyl alcohol aqueous solution and sodium polyacrylate aqueous solution in a volume ratio of 7:3 Mixing, the volume of the mixed solution is 10mL, and stirring is used as water phase 1; configure 1% mass fraction of sodium alginate aqueous solution and 10% mass fraction of gelatin aqueous solution, and mix sodium alginate aqueous solution and gelatin aqueous solution in a volume ratio of 7:3 , the volume of the mixed solution is 10mL, and stir well as water phase 2; configure 10% mass fraction of gelatin aqueous solution, and take 8mL as water phase 3;

S2. Preparation of oil phase: under normal temperature and pressure, take 2.0g of Span 80 and add it to 100mL of liquid paraffin and stir evenly, and take 50mL as the oil phase;

S3. Cross-linking reaction: under normal temperature and pressure, configure 50% mass fraction of glutaraldehyde aqueous solution and 1 mol/L hydrochloric acid, add water phase 1/water phase 2 dropwise to the oil phase under stirring at 350 rpm, water After all the phases are added dropwise, the temperature is raised to 50°C and heated for 30min, maintaining stirring and temperature, adding 1mL of glutaraldehyde aqueous solution dropwise and waiting for 10min, adding 1mL hydrochloric acid dropwise and waiting for 60min; (under normal temperature and pressure, configure 50% mass fraction glutaraldehyde aqueous solution, add water phase 3 dropwise to the oil phase under stirring at 350rpm, the water phase is all added dropwise and then heated to 60°C for 10min, keep stirring, put it in an ice-water bath for 20min, dropwise add 1mL pentane Wait 10min after dialdehyde water solution ;)

S4. Preparation of microspheres: the reaction solution is allowed to stand for sufficient cooling, the upper layer liquid is removed and the remaining substances are repeatedly washed with petroleum ether, cold ethanol is added to stir evenly, and suction filtration is carried out, and the powder obtained by suction filtration is collected and fully dried to obtain three high Molecular Microspheres.

Example 3

Three polymer microspheres were prepared as follows:

S1. Preparation of water phase: under normal temperature and pressure, prepare 5% polyvinyl alcohol aqueous solution and 0.1% mass fraction sodium polyacrylate aqueous solution, and take the polyvinyl alcohol aqueous solution and sodium polyacrylate aqueous solution in a volume ratio of 9:1 Mixing, the volume of the mixed solution is 10 mL, and stirring is used as water phase 1; 1% aqueous solution of sodium alginate and 10% aqueous gelatin are prepared, and the aqueous solution of sodium alginate and aqueous gelatin are mixed in a volume ratio of 9:1. , the volume of the mixed solution is 10mL, stir evenly as water phase 2; configure 10% mass fraction of gelatin aqueous solution, take 12mL as water phase 3;

S2. Preparation of oil phase: under normal temperature and pressure, take 2.0g of Span 80 and add it to 100mL of liquid paraffin and stir evenly, and take 50mL as the oil phase;

S3. Under normal temperature and pressure, configure 50% mass fraction of glutaraldehyde aqueous solution and 1 mol/L concentration of hydrochloric acid, add water phase 1/water phase 2 dropwise to the oil phase under stirring at 350 rpm, and all the water phases are added dropwise. Then heat up to 50°C for 30min, keep stirring and temperature, add 1mL of glutaraldehyde aqueous solution dropwise and wait for 10min, add 1mL of hydrochloric acid dropwise and wait for 60min; (under normal temperature and pressure, configure 50% mass fraction of glutaraldehyde Aqueous solution, add water phase 3 dropwise to the oil phase under stirring at 350 rpm, heat up to 60 °C for 10 min after all the water phase is added dropwise, keep stirring, put it in an ice-water bath for 20 min, add 1 mL of glutaraldehyde aqueous solution dropwise Wait 10mins ;)

S4. Preparation of microspheres: the reaction solution is allowed to stand for sufficient cooling, the upper layer liquid is removed and the remaining substances are repeatedly washed with petroleum ether, cold ethanol is added to stir evenly, and suction filtration is carried out, and the powder obtained by suction filtration is collected and fully dried to obtain three high Molecular Microspheres.

The three kinds of polymer microspheres obtained in Example 1 are characterized and analyzed as follows:

Topography and size observation

Take 1ml of microsphere powder and add 1ml of absolute ethanol to ultrasonic for 1min, drop the obtained liquid on the conductive adhesive, and use scanning electron microscope to observe the morphology of the microspheres and count the particle size distribution after air drying. Combined with Figure 1 and Figure 2, the microspheres show spherical The higher round sphere has a smoother surface. According to the calculation and statistics, the particle size distribution of the polyvinyl alcohol microsphere powder is 1-100 μm, and more than 90% of the particle size distribution is concentrated in 5-10 μm; high-load sodium alginate microspheres The total particle size distribution is 50-500 μm, and more than 75% or even higher proportion of particle size distribution is concentrated in 100-200 μm; the total particle size distribution of gelatin microsphere powder is 1-100 μm, and more than 90% particle size distribution is concentrated in 25-50 μm;

After sufficient experiments, it is concluded that the total particle size distribution of the polyvinyl alcohol microsphere powder obtained by the above three embodiments and all technical solutions within the scope of the present invention is 1-100 μm, and more than 90% of the particle size distribution is concentrated in 5-10 μm; high; The particle size distribution of the loaded sodium alginate microspheres is 50-500 μm, and the particle size distribution of more than 75% or even higher proportion is concentrated in 100-200 μm; the particle size distribution of the gelatin microsphere powder is 1-100 μm, and more than 90% particle size distribution The distribution is concentrated in 25～50μm; all have higher sphericity and smoother surface.

The small particle size polyvinyl alcohol microspheres obtained by the above-mentioned three embodiments and all technical solutions within the scope of the present invention can be used to prepare developing microspheres in transcatheter arterial chemoembolization, and the preparation method includes the following steps:

Add 0.25-1 g of barium sulfate to the water phase in step S1 of the three preparation methods of polymer microspheres, stir evenly and continue steps S2, S3 and S4 as the water phase to obtain developing microspheres.

Among them, the contrast agent barium sulfate can be replaced by ferric oxide, Gd-DTPA, Mn-DPDP, AMI-25, Resovist, UCNP or iodine preparation.

The microspheres obtained by the above three embodiments and all technical solutions within the scope of the present invention can also be used to prepare drug-loaded microspheres in transcatheter arterial chemoembolization, and the preparation method includes the following steps:

Add 0.05-0.2 g of doxorubicin to the water phase in step S1 of the preparation method of microspheres, stir evenly and continue steps S2, S3 and S4 as the water phase to obtain drug-loaded microspheres.

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

Example 4

Prepare drug-loaded microspheres as follows:

S1. Preparation of water phase: under normal temperature and pressure, prepare 5% polyvinyl alcohol aqueous solution and 0.1% mass fraction sodium polyacrylate aqueous solution, and take the polyvinyl alcohol aqueous solution and the polyvinyl alcohol aqueous solution in the volume ratio of 7:3-9:1. Mix the sodium polyacrylate aqueous solution, the volume of the mixed solution is 10mL, add 0.1g of doxorubicin, stir well as water phase 1; configure 1% mass fraction of sodium alginate aqueous solution and 10% mass fraction of gelatin aqueous solution, according to 7:3 The volume ratio of ~9:1 was mixed with sodium alginate aqueous solution and gelatin aqueous solution, the volume of the mixed solution was 10 mL, 0.1 g of doxorubicin was added, and stirred evenly as water phase 2; 10% mass fraction of gelatin aqueous solution was prepared, and 5- Add 0.1g of doxorubicin to 15mL, stir evenly as water phase 3;

S2. Preparation of oil phase: under normal temperature and pressure, take 2.0g of Span 80 and add it to 100mL of liquid paraffin and stir evenly, and take 50mL as the oil phase;

S3. Cross-linking reaction: under normal temperature and pressure, configure 50% mass fraction of glutaraldehyde aqueous solution and 1 mol/L hydrochloric acid, add water phase 1/water phase 2 dropwise to the oil phase under stirring at 350 rpm, water After all the phases are added dropwise, the temperature is raised to 50°C and heated for 30min, maintaining stirring and temperature, adding 1mL of glutaraldehyde aqueous solution dropwise and waiting for 10min, adding 1mL hydrochloric acid dropwise and waiting for 60min; (under normal temperature and pressure, configure 50% mass fraction glutaraldehyde aqueous solution, add water phase 3 dropwise to the oil phase under stirring at 350rpm, the water phase is all added dropwise and then heated to 60°C for 10min, keep stirring, put it in an ice-water bath for 20min, dropwise add 1mL pentane Wait 10min after dialdehyde water solution ;)

S4. Preparation of microspheres: the reaction solution is allowed to stand for sufficient cooling, the upper layer liquid is removed, and the remaining substances are repeatedly washed with petroleum ether, and cold ethanol is added to stir evenly, and then suction filtration is performed. ball.

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

Morphology observation

Take 1ml of microsphere powder and add 1ml of absolute ethanol to ultrasonic for 1min, drop the obtained liquid on the conductive adhesive, and use scanning electron microscope to observe the morphology of the microspheres after air drying. As shown in Figure 4, the drug-loaded microspheres are more spherical than the original microspheres There is little difference between the degree and surface smoothness;

Water Absorption Determination

计算出三次样本的吸水率和平均值，结果如图3所示。Take 0.03g of microsphere powder three times and add 1mL of ultrapure water to soak for 24h, wipe the unabsorbed water dry and record the weight as m. According to the formula

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

Determination of drug release rate

Prepare a series of concentration gradient doxorubicin standard solutions, test their absorbance at 480nm respectively, draw a standard concentration curve of doxorubicin, take 0.05g of microsphere powder and add 2mL of ultrapure water to a 37°C water bath to simulate the human body environment temperature, UV absorbance test was carried out every two hours, the absorbance at 480nm was recorded, and it was converted into the release concentration according to the standard concentration curve, and the curve of its relationship with time was drawn, as shown in Figure 4, among the three drug-loaded microspheres , the release rate of sodium alginate microspheres is much higher than the other two, and the drug release amount of gelatin microspheres and PVA microspheres is similar, the performance of gelatin microspheres is slightly higher than that of PVA microspheres; The drug release rate was faster in one hour, and the drug release rate was obviously slowed down and remained relatively stable after 2 hours.

In the above-mentioned four embodiments and all technical solutions within the scope of the present invention, in step S2, liquid paraffin can be replaced by white oil or vegetable oil, Span 80 can be replaced by Span 60, and sherwood oil can be replaced by hot water or ethanol in step S3.

The microspheres, drug-loaded microspheres and developing microspheres obtained by the above-mentioned four embodiments and all technical solutions within the scope of the present invention can all be prepared to develop drug-loaded microspheres, and the developer and/or the drug can be in the aqueous phase of step S1. It can also be added in the liquid used for swelling the microspheres before use, as long as the microspheres can fully absorb the developer and/or the drug.

The dosage of raw materials, the selection of tools and the operation of the present invention are all inclined to small batch preparation in a laboratory environment, and can be realized by using chemical equipment with a higher degree of automation and a more precise control chemical process in a clean and sterile medical device production workshop environment. High-volume, non-polluting, high-efficiency and high-yield industrial production.

The innovation of the present invention is: the present invention adopts the inverse emulsion polymerization method, the process is simple and controllable, the particle size uniformity is good, the sphericity and the surface smoothness are high, the biocompatibility and stability are good, and the transition is avoided. It is cross-linked and has good dispersibility. It can carry contrast agents and anti-tumor drugs separately and simultaneously. It has high drug loading and stable drug release curve. The range of applications has produced unpredictable and excellent results.

The above-mentioned embodiments are only to illustrate the technical concept and characteristics of the present invention, and their purpose is to enable those who are familiar with the art to understand the content of the present invention and implement it, and cannot limit the scope of protection of the present invention with this, all according to the spirit of the present invention Substantially equivalent changes or modifications should be included within the protection scope of the present invention.

Claims (9)

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;

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, 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.

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