阅读说明：本技术 一种多孔微球的制备方法和由此得到的微球栓塞剂及其应用 (Preparation method of porous microspheres, microsphere embolic agent obtained by preparation method and application of microsphere embolic agent ) 是由 郭晓勇 王翔 刘翠钗 于 2021-07-20 设计创作，主要内容包括：本发明涉及一种多孔微球的制备方法,其包括：S1,将乙二醇聚合物和聚乙烯吡咯烷酮溶于纯化水中,搅拌溶解并加入N,N-亚甲基丙烯酰胺,再加入甲基丙烯酸乙酯溶解,以提供水相；S2,将液体石蜡加入至石油醚中,加入四甲基乙二胺,以提供油相；S3,搅拌下,将水相滴加至油相中,快速搅拌1-4h,升温至40-60℃,继续搅拌2-5小时,过滤得多孔微球。本发明还涉及由此得到的微球栓塞剂及其应用。根据本发明的多孔微球的制备方法,通过将水相滴入油相中得到多孔微球,其为表面具有多孔结构的微米级球状结构,从而通过表面的孔隙来“吸附镶嵌”多种小分子例如抗肿瘤药物于微球,从而达到更好的加载药物效果。(The invention relates to a preparation method of porous microspheres, which comprises the following steps: s1, dissolving ethylene glycol polymer and polyvinylpyrrolidone in purified water, stirring to dissolve, adding N, N-methylene acrylamide, adding ethyl methacrylate to dissolve to provide a water phase; s2, adding liquid paraffin to petroleum ether, adding tetramethylethylenediamine to provide an oil phase; s3, dropwise adding the water phase into the oil phase under stirring, rapidly stirring for 1-4h, heating to 40-60 ℃, continuously stirring for 2-5h, and filtering to obtain the porous microspheres. The invention also relates to the microsphere embolic agent obtained thereby and application thereof. According to the preparation method of the porous microsphere, the water phase is dripped into the oil phase to obtain the porous microsphere which is a micron-sized spherical structure with a porous structure on the surface, so that various small molecules such as antitumor drugs are adsorbed and embedded in the microsphere through pores on the surface, and a better drug loading effect is achieved.)

1. A preparation method of porous microspheres is characterized by comprising the following steps:

s1, dissolving ethylene glycol polymer and polyvinylpyrrolidone in purified water, stirring to dissolve, adding N, N-methylene acrylamide, adding ethyl methacrylate to dissolve to provide a water phase;

s2, adding liquid paraffin to petroleum ether, adding tetramethylethylenediamine to provide an oil phase;

s3, dropwise adding the water phase into the oil phase under stirring, rapidly stirring for 1-4h, heating to 40-60 ℃, continuously stirring for 2-5h, and filtering to obtain the porous microspheres.

2. The method of claim 1, wherein the ethylene glycol polymer is polyethylene glycol dipropyl acrylamide, four-arm polyethylene glycol acrylamide and/or eight-arm polyethylene glycol acrylamide.

3. The method according to claim 1, wherein in step S1, the N, N-methylene acrylamide is added and then sonicated for 5 to 15 min.

4. The method of claim 1, wherein in step S2, ultrasonic degassing is performed after adding tetramethylethylenediamine.

5. The preparation method according to claim 1, wherein in the step S3, after the oil phase is cooled to 0 to 10 ℃, sodium stearate and azobisisobutyronitrile are added and stirred for 10 to 30min, and then vacuum pumping is performed for 0.5 to 1h, and then the water phase is added dropwise to the oil phase.

6. The preparation method according to claim 1, wherein in the step S3, the aqueous phase is slowly dropped into half, stirred for 10-30min, then dropped into half of the remaining amount, stirred for 10-30min, heated to 20-30 ℃, the remaining aqueous phase is completely poured into the organic phase, stirred for 0.5-1h, heated to 40-60 ℃ within 20min, continuously stirred for 2-5h, and filtered to obtain the porous microspheres.

7. The method according to claim 6, wherein the rotation speed before the addition of the aqueous phase is 500r/min, and the rotation speed is adjusted to 600r/min after the temperature is raised to 20 to 30 ℃.

8. A microsphere embolization agent according to any one of claims 1 to 7, wherein the microsphere embolization agent is a porous microsphere, which is a micron-sized spherical structure having a porous structure on the surface.

9. Use of a microsphere embolic agent according to claim 8, wherein the surface of the microsphere embolic agent has pores for carrying small molecule drugs.

10. The use according to claim 9, wherein the small molecule drug is doxorubicin, and/or sorafenib.

Technical Field

The invention relates to a carrier tape of a medicament, in particular to a preparation method of porous microspheres, a microsphere embolic agent obtained by the preparation method and application of the microsphere embolic agent.

Background

The existing microsphere embolic agent mainly comprises gelatin microspheres, starch microspheres, sodium alginate, polyvinyl alcohol microspheres and the like, wherein the first three microspheres have no drug carrying performance and are easy to be hydrolyzed and damaged in vivo, the polyvinyl alcohol microspheres can carry drugs, but only part of the drugs with positive charges can be carried, and the drug carrying types of the microspheres are greatly limited.

Disclosure of Invention

In order to solve the problems of limited drug loading types of the microsphere embolic agent in the prior art and the like, the invention provides a preparation method of porous microspheres, the microsphere embolic agent obtained by the preparation method and application thereof.

The preparation method of the porous microspheres comprises the following steps: s1, dissolving ethylene glycol polymer and polyvinylpyrrolidone in purified water, stirring to dissolve, adding N, N-methylene acrylamide, adding ethyl methacrylate to dissolve, and providing a water phase; s2, adding liquid paraffin to petroleum ether, adding tetramethylethylenediamine to provide an oil phase; s3, dropwise adding the water phase into the oil phase under stirring, rapidly stirring for 1-4h, heating to 40-60 ℃, continuously stirring for 2-5h, and filtering to obtain the porous microspheres.

Preferably, the ethylene glycol polymer is polyethylene glycol dipropyl acrylamide, four-arm polyethylene glycol acrylamide and/or eight-arm polyethylene glycol acrylamide.

Preferably, in the step S1, the N, N-methylene acrylamide is added and then ultrasonic treatment is carried out for 5-15 min.

Preferably, in the step S2, after adding tetramethylethylenediamine, ultrasonic degassing is performed.

Preferably, in step S3, after the oil phase is cooled to 0-10 ℃, sodium stearate and azobisisobutyronitrile are added and stirred for 10-30min, and then vacuum pumping is performed for 0.5-1h, and then the water phase is added into the oil phase dropwise.

Preferably, in the step S3, the water phase is slowly dropped into half, stirred for 10-30min, then dropped into half of the remaining amount, stirred for 10-30min, heated to 20-30 ℃, the remaining water phase is completely poured into the organic phase, stirred for 0.5-1h, heated to 40-60 ℃ within 20min, continuously stirred for 2-5h, and filtered to obtain the porous microspheres.

Preferably, the rotation speed before adding the water phase is 500r/min, and the rotation speed is adjusted to 600r/min after the temperature is raised to 20-30 ℃.

The invention also provides the microsphere embolization agent obtained by the preparation method, wherein the microsphere embolization agent is a porous microsphere which is a micron-sized spherical structure with a porous structure on the surface.

The invention also provides application of the microsphere embolic agent, wherein the surface of the microsphere embolic agent is provided with pores for carrying small molecule drugs.

Preferably, the small molecule drug is doxorubicin, and/or sorafenib.

According to the preparation method of the porous microsphere, the water phase is dripped into the oil phase to obtain the porous microsphere which is a micron-sized spherical structure with a porous structure on the surface, so that a plurality of small molecules such as antitumor drugs are adsorbed and inlaid in the microsphere through pores on the surface, and a better drug loading effect is achieved.

Detailed Description

The following provides a detailed description of the preferred embodiments of the present invention.

Example 1

Preparing a water phase: dissolving polyethylene glycol dipropyl acrylamide and polyvinylpyrrolidone in purified water, stirring to dissolve, adding N, N-methylene acrylamide, performing ultrasonic treatment for 10min, and adding ethyl methacrylate to dissolve for later use.

Preparing an oil phase: adding liquid paraffin into petroleum ether, adding tetramethylethylenediamine, ultrasonically degassing, stirring, and cooling to 0-10 deg.C.

Polymerization reaction: cooling the oil phase to 0-10 ℃, adding sodium stearate and azodiisobutyronitrile, stirring for 10-30min, vacuumizing for 0.5-1h by using a vacuum pump at the rotating speed of 500r/min, slowly dropping half of the water phase, stirring for 10-30min, dropping the rest half of the water phase, stirring for 10-30min, heating to 20-30 ℃, adjusting the rotating speed to 600r/min, pouring the rest water phase into the organic phase, stirring for 0.5-1h, heating to 40-60 ℃ within 20min, continuing stirring for 2-5h, adding 1 volume of purified water, stirring for 20min, filtering to obtain spheres, and observing the spheres by using a microscope.

Weighing 1g of microspheres, adding the microspheres into 10mg/ml of adriamycin solution, standing for 10min, and measuring the adriamycin content in the solution, wherein the adriamycin content is reduced by 90 percent compared with the original adriamycin content.

Example 2

Preparing a water phase: dissolving four-arm polyethylene glycol acrylamide and polyvinylpyrrolidone in purified water, stirring to dissolve, adding N, N-methylene acrylamide, performing ultrasonic treatment for 10min, and adding ethyl methacrylate to dissolve for later use.

Preparing an oil phase: adding liquid paraffin into petroleum ether, adding tetramethylethylenediamine, ultrasonically degassing, stirring, and cooling to 0-10 deg.C.

Polymerization reaction: cooling the oil phase to 0-10 ℃, adding sodium stearate and azodiisobutyronitrile, stirring for 10-30min, vacuumizing for 0.5-1h by using a vacuum pump at the rotating speed of 500r/min, slowly dropping half of the water phase, stirring for 10-30min, dropping the rest half of the water phase, stirring for 10-30min, heating to 20-30 ℃, adjusting the rotating speed to 600r/min, pouring the rest water phase into the organic phase, stirring for 0.5-1h, heating to 40-60 ℃ within 20min, continuing stirring for 2-5h, adding 1 volume of purified water, stirring for 20min, filtering to obtain spheres, and observing the spheres by using a microscope.

Weighing 1g of microspheres, adding the microspheres into 10mg/ml of sorafenib solution, standing for 10min, and determining the sorafenib content in the solution, wherein the sorafenib content is reduced by 90% compared with the original content.

Example 3

Preparing a water phase: dissolving eight-arm polyethylene glycol acrylamide and polyvinylpyrrolidone in purified water, stirring to dissolve, adding N, N-methylene acrylamide, performing ultrasonic treatment for 10min, and adding ethyl methacrylate to dissolve for later use.

Preparing an oil phase: adding liquid paraffin into petroleum ether, adding tetramethylethylenediamine, ultrasonically degassing, stirring, and cooling to 0-10 deg.C.

Polymerization reaction: cooling the oil phase to 0-10 ℃, adding sodium stearate and azodiisobutyronitrile, stirring for 10-30min, vacuumizing for 0.5-1h by using a vacuum pump at the rotating speed of 500r/min, slowly dropping half of the water phase, stirring for 10-30min, dropping the rest half of the water phase, stirring for 10-30min, heating to 20-30 ℃, adjusting the rotating speed to 600r/min, pouring the rest water phase into the organic phase, stirring for 0.5-1h, heating to 40-60 ℃ within 20min, continuing stirring for 2-5h, adding 1 volume of purified water, stirring for 20min, filtering to obtain spheres, and observing the spheres by using a microscope.

Weighing 1g of microspheres, adding the microspheres into 10mg/ml of adriamycin solution, standing for 10min, and measuring the adriamycin content in the solution, wherein the adriamycin content is reduced by 90 percent compared with the original adriamycin content.

The above embodiments are merely preferred embodiments of the present invention, which are not intended to limit the scope of the present invention, and various changes may be made in the above embodiments of the present invention. All simple and equivalent changes and modifications made according to the claims and the content of the specification of the present application fall within the scope of the claims of the present patent application. The invention has not been described in detail in order to avoid obscuring the invention.