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CN-117398507-B - Porous degradable embolism microsphere and preparation method thereof

CN117398507BCN 117398507 BCN117398507 BCN 117398507BCN-117398507-B

Abstract

The invention discloses a porous degradable embolism microsphere and a preparation method thereof, the porous degradable embolism microsphere comprises the following steps of taking an aqueous solution of a drug as an inner aqueous phase W1, adding a modified PLGA polymer into methylene dichloride, stirring and dissolving at a low temperature to obtain an oil phase, adding a composite emulsifier into the oil phase, adding W1 into the oil phase, carrying out high-shear homogenization to obtain a stable emulsion, slowly adding the stable emulsion into a PVA aqueous solution, fully emulsifying, volatilizing a solvent until the microsphere is completely solidified, and carrying out rapid cooling pre-freezing and freeze-drying after the microsphere is washed with water to form the porous degradable embolism microsphere. The microsphere prepared by the method has a porous structure, uniform particle size distribution, uniform drug distribution and uniform drug release, and higher drug release rate is obtained by modifying PLGA.

Inventors

  • ZHU XIAOMIN
  • WANG NING
  • TANG XUAN
  • LIU YANG
  • ZHANG DAIZHOU
  • ZHU XIAOJIE
  • MENG JIANWEN
  • MA LIXIA
  • LI WENMING
  • DONG HAO
  • CHEN JIANYING
  • Yao Jiechen

Assignees

  • 山东省药学科学院

Dates

Publication Date
20260512
Application Date
20231107

Claims (7)

  1. 1. The preparation method of the porous degradable embolism microsphere is characterized by comprising the following steps of: (1) The preparation method of the inner emulsion comprises the steps of taking aqueous solution or pure water of a water-soluble medicine as W1, weighing a modified PLGA polymer, adding the modified PLGA polymer into dichloromethane, stirring and dissolving the aqueous solution or pure water to obtain an oil phase, adding a composite emulsifier into the oil phase, adding the W1 into the oil phase, and carrying out high-shear homogenization to obtain a stable emulsion; (2) Weighing PVA, adding the PVA into water, heating, stirring and dissolving to obtain uniform PVA aqueous solution, and cooling to obtain a water phase W; (3) Emulsifying and solidifying, namely slowly adding the emulsion obtained in the step (1) into the stirred water phase, fully emulsifying, volatilizing the solvent and completely solidifying the microspheres; (4) Cleaning the microspheres, namely stopping stirring after the microspheres are solidified, filtering, taking the solid microspheres, adding pure water, stirring and cleaning, filtering, and repeatedly washing; (5) Drying the microspheres, namely washing, then rapidly cooling and pre-freezing, and then performing low-temperature vacuum drying to form holes to obtain the porous modified PLGA microspheres.
  2. 2. The preparation method of the porous degradable embolic microsphere according to claim 1, wherein the mass ratio of doxorubicin hydrochloride to pure water is 1:100, the mass ratio of PLGA polymer to dichloromethane is 1:20-1:5, and the mass ratio of oil phase to water phase is 1:10-1:3.
  3. 3. The method for preparing the porous and degradable embolic microsphere according to claim 1, wherein the compound emulsifier in the step (1) is a compound emulsifier of tween 80 and SPAN80, and the mass ratio of tween 80 to SPAN80 is 5:1.
  4. 4. The method for preparing porous and degradable embolic microspheres according to claim 1, wherein the mass ratio of the composite emulsifier to the oil phase in step (1) is 1:100-1:50.
  5. 5. The method for preparing porous and degradable embolic microspheres according to claim 1, wherein the shear rate in step (1) is 6000-10000rpm, the stirring rate in step (2) is 300rpm, and the stirring aqueous phase in step (3) is 250-600rpm.
  6. 6. The method for preparing porous and degradable embolic microspheres according to claim 1, wherein the pre-freezing temperature in step (5) is-80 ℃ and the low temperature is-50 ℃.
  7. 7.A porous degradable embolic microsphere prepared by the method of any one of claims 1-6.

Description

Porous degradable embolism microsphere and preparation method thereof Technical Field The invention belongs to the fields of high polymer materials and biomedical engineering, and in particular relates to a porous degradable embolic microsphere and a preparation method thereof. Background Arterial Chemoembolization (TACE) is a common non-surgical treatment for liver cancer. TACE can be classified into conventional TACE (c-TACE) and drug eluting microsphere TACE (DEB-TACE) according to the embolic agent. C-TACE is the embolism treatment using iodized oil as main component and gelatin sponge granule, blank microsphere or PVA as auxiliary component, and DEB-TACE is the embolism treatment using medicine-eluting microsphere loaded with chemotherapeutic medicine as main component. The drug-loaded microspheres can be loaded with chemotherapeutic drugs such as doxorubicin, irinotecan and the like, and the particle size of the drug-loaded microspheres mainly comprises 70-150 mu m, 100-300 mu m, 300-500 mu m or 500-700 mu m and the like, and the microspheres with different particle sizes are selected according to the tumor size, the blood supply condition and the treatment purpose. The DEB-TACE can embolize the blood supply artery of liver cancer to make the tumor ischemic necrosis, and simultaneously is used as a carrier of a chemotherapeutic medicine, thereby having the advantage of continuously and stably releasing the medicine. The DEB-TACE is mainly DC Bead of Biocompatibles in UK, CALLISPHERE drug-loaded microsphere of Hengrui medical company in China, HEPASPHERE/Quadra Sphere microsphere of BioSphere medical company in U.S. A.A., and the like, and is non-degradable drug-loaded microsphere. The main action mechanism of the drug release microsphere is that positive charge chemotherapeutic drugs such as doxorubicin, irinotecan and the like are loaded by ion exchange before TACE operation, but the drugs containing anionic groups or difficult to dissociate in the structure cannot be loaded, and the drug release microsphere after operation is mainly concentrated three days before operation is finished, so that the effect of long-term stable release cannot be achieved. Biodegradable DEBs have not been seen as commercially available products. Theoretically, biodegradable DEB will only embolize arteries during treatment and release chemotherapeutic drugs to tumors, alleviating post-embolization syndrome, especially long-term syndrome, the quality and mechanical strength of the microspheres will gradually decrease over time, and will be absorbed by surrounding tissues, the vessel will be recanalized after embolization, and taking the cell growth cycle into account, it may be more beneficial to have multiple intermittent embolization of the same lesion, while bioabsorbable microspheres provide a route of administration for subsequent chemotherapy. Disclosure of Invention The invention aims to overcome the technical defects and provide a porous degradable embolism microsphere and a preparation method thereof, the microsphere prepared by the method has a porous structure, uniform particle size distribution, uniform drug distribution and uniform drug release. The invention is realized by the following technical scheme: a preparation method of porous degradable embolism microsphere comprises the following steps: (1) Preparing an inner emulsion, namely taking doxorubicin hydrochloride, adding pure water to dissolve the doxorubicin hydrochloride completely to obtain W1, weighing a modified PLGA polymer, adding the modified PLGA polymer into dichloromethane, stirring and dissolving the modified PLGA polymer to obtain an oil phase, adding a composite emulsifier into the oil phase, adding the W1 into the oil phase, and carrying out high-shear homogenization to obtain a stable emulsion; (2) Weighing PVA, adding the PVA into water, heating, stirring and dissolving to obtain uniform PVA aqueous solution, and cooling to obtain a water phase W; (3) Emulsifying and solidifying, namely slowly adding the emulsion obtained in the step (1) into a water phase stirred at a constant speed, fully emulsifying, volatilizing a solvent and completely solidifying the microspheres; (4) Cleaning the microspheres, namely stopping stirring after the microspheres are solidified, filtering, taking the solid microspheres, adding pure water, stirring and cleaning, filtering, and repeatedly washing; (5) Drying the microspheres, namely pre-freezing the microspheres in a refrigerator after washing, and then carrying out low-temperature vacuum drying by a freeze dryer to obtain the dried PLGA microspheres. Further, the mass ratio of doxorubicin hydrochloride to pure water is 1:100, the mass ratio of modified PLGA polymer to dichloromethane is 1:20-1:5, and the mass ratio of oil phase to water phase is 1:40-1:5. Further, the compound emulsifier in the step (1) is a compound emulsifier of tween 80 and SPAN80, and the mass ratio of tween 80 to SPAN80 is 5:1. Furt