中国组织工程研究

中国组织工程研究 ›› 2023, Vol. 27 ›› Issue (16): 2510-2517.doi: 10.12307/2023.161

• 药物控释材料 drug delivery materials • 上一篇    下一篇

星点设计-效应面法优化万古霉素-聚富马酸丙二醇酯/聚乳酸-羟基乙酸共聚物微球的制备工艺

王江华1，2，尹东锋1，2，滕   勇1，2，乌日开西·艾依提3，王晓锋2，马热艳木·艾尼3，蒋厚峰3，帕提古丽·艾合麦提3，王  晶3   

  1. 1新疆医科大学，新疆维吾尔自治区乌鲁木齐市  830000；2中国人民解放军新疆军区总医院，新疆维吾尔自治区乌鲁木齐市  830000；3新疆大学，新疆维吾尔自治区乌鲁木齐市  830000
  • 收稿日期:2022-01-30 接受日期:2022-04-18 出版日期:2023-06-08 发布日期:2022-11-10
  • 通讯作者: 尹东锋，博士，主任药师，新疆医科大学，新疆维吾尔自治区乌鲁木齐市 830000；中国人民解放军新疆军区总医院药剂科，新疆乌鲁木齐市 830000 滕勇，博士，主任医师，新疆医科大学，新疆维吾尔自治区乌鲁木齐市 830000；中国人民解放军新疆军区总医院脊柱外科，新疆乌鲁木齐市 830000
  • 作者简介:王江华，女，汉族，在读硕士，主要从事药物制剂新剂型研究。
  • 基金资助:
    新疆维吾尔自治区区域协同创新专项(科技援疆)计划(2019E0277)；项目负责人：滕勇

Optimization of the preparation process of vancomycin-poly(propylene fumarate)/poly(lactic-co-glycolic acid) microspheres by star point design-response surface method

Wang Jianghua1, 2, Yin Dongfeng1, 2, Teng Yong1, 2, Wurikaixi·Aiyiti3, Wang Xiaofeng2, Mareyanmu·Aini3, Jiang Houfeng3, Patiguli·Aihemaiti3, Wang Jing3   

  1. 1Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China; 2General Hospital of Xinjiang Military Region of the Chinese People’s Liberation Army, Urumqi 830000, Xinjiang Uygur Autonomous Region, China; 3Xinjiang University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
  • Received:2022-01-30 Accepted:2022-04-18 Online:2023-06-08 Published:2022-11-10
  • Contact: Yin Dongfeng, PhD, Chief pharmacist, Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China; General Hospital of Xinjiang Military Region of the Chinese People’s Liberation Army, Urumqi 830000, Xinjiang Uygur Autonomous Region, China Teng Yong, PhD, Chief physician, Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China; General Hospital of Xinjiang Military Region of the Chinese People’s Liberation Army, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
  • About author:Wang Jianghua, Master candidate, Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China; General Hospital of Xinjiang Military Region of the Chinese People’s Liberation Army, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
  • Supported by:
    Regional Collaborative Innovation Special Program of Xinjiang Uygur Autonomous Region (Science and Technology Assistance to Xinjiang), No. 2019E0277 (to TY)

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摘要：


文题释义：

聚富马酸丙二醇酯：是一种用于骨修复的新型可注射医用生物材料，为不饱和线性聚酯，其聚合物是通过主链上碳碳双键交联，两侧各有一个酯基，通过水解其酯键降解，在体内可降解生成富马酸和丙二醇，降解产物可通过正常新陈代谢排出体外，且对体内系统如 pH 值等没有影响，通过控制其分子质量可得可控降解释放度。已有研究将聚富马酸丙二醇酯用于骨组织工程、药物输送、医疗缝线、基因载体、心脏组织、眼科、神经组织工程等领域。
聚乳酸-羟基乙酸共聚物：是一种由乳酸和羟基乙酸按一定比例聚合而成的生物可降解高分子材料，具有良好的生物相容性和成囊成膜性能，已被FDA批准为药用辅料，目前被广泛用于缓控释给药系统研究，已有多种聚乳酸-羟基乙酸共聚物载药微球上市。现有研究证实，通过改变其相对分子质量或聚合物中乳酸与羟基乙酸的比例，能调节聚乳酸-羟基乙酸共聚物的理化性质，进而控制其降解速率，满足不同的临床用药需求。

背景：万古霉素为骨髓炎治疗首选抗生素之一，局部给药不仅能发挥其抗菌作用，而且还能大幅减少全身不良反应。
目的：优选万古霉素-聚富马酸丙二醇酯/聚乳酸-羟基乙酸共聚物微球的制备工艺，并考察其体外释放行为及细胞毒性。
方法：采用复乳溶剂挥发法(W1/O/W2)制备万古霉素-聚富马酸丙二醇酯/聚乳酸-羟基乙酸共聚物微球，以微球的包封率和载药量为评价指标，应用星点设计-效应面法考察聚富马酸丙二醇酯和聚乳酸-羟基乙酸共聚物质量比、聚富马酸丙二醇酯和聚乳酸-羟基乙酸共聚物与万古霉素的质量比、二氯甲烷浓度对制备工艺的影响，对结果进行多元线性回归和二项式拟合，效应面法优选最佳工艺条件，测量微球的粒径、ζ电位、体外释放行为及细胞毒性。
结果与结论：①成功制备了微球，优选聚合物微球的最佳制备工艺为：聚富马酸丙二醇酯与聚乳酸-羟基乙酸共聚物的质量比=2.41、聚富马酸丙二醇酯/聚乳酸-羟基乙酸共聚物与药物质量比=3.56、CH2Cl2浓度为129.73 g/L，实测平均包封率为83.38%，与预测值相比偏差为0.63%；实测平均载药量为18.19%，与预测值相比偏差为0.55%；②最佳工艺制得微球的平均粒径为103.902 μm，ζ电位为-21.5 mV；微球体外3 d后累计释药量为(22.90±0.55)%，28 d后累计释放量达(43.57±1.02)%，28 d后微球释药明显增快，42 d时累计释放量为(97.89±1.39)%；微球细胞毒性分级为1级；③星点设计-效应面法优化微球制备工艺预测性良好，所优化的制备工艺重现性好、简单易行，所制备的微球具有较好的体外缓释特性和生物相容性。
https://orcid.org/0000-0003-4837-2113(王江华)

关键词: 万古霉素, 聚乳酸-羟基乙酸共聚物, 聚富马酸丙二醇酯, 微球, 复乳溶剂挥发法, 星点设计-效应面法, 体外释药, 细胞毒性

Abstract: BACKGROUND: Vancomycin is one of the first-choice antibiotics for osteomyelitis. Local administration can not only exert its antibacterial effect, but also greatly reduce systemic adverse reactions. 
OBJECTIVE: To optimize the preparation process of hydrochloric acid vancomycin-poly(propylene fumarate)/poly(lactic-co-glycolic acid) microspheres, and examine its in vitro release behavior and cytotoxicity. 
METHODS: The hydrochloric acid vancomycin-poly(propylene fumarate)/poly(lactic-co-glycolic acid) microspheres were prepared by the double emulsion solvent evaporation method (W1/O/W2). The encapsulation efficiency and drug loading capacity of microspheres were used as evaluation indicators. The effects of mass ratio of poly(propylene fumarate) and poly(lactic-co-glycolic acid), mass ratio of poly(propylene fumarate) and poly(lactic-co-glycolic acid) to vancomycin and dichloromethane concentration of oil phase poly(propylene fumarate) and poly(lactic-co-glycolic acid) on the preparation process were investigated by star point design-response surface method. The results were analyzed by multiple linear regression and binomial fitting. The effect surface method was used to optimize the optimal process conditions. The particle size of microspheres, the ζ potential, in vitro release behavior, and the cytotoxicity were measured. 
RESULTS AND CONCLUSION: (1) The hydrochloric acid vancomycin-poly(propylene fumarate)/poly(lactic-co-glycolic acid) microspheres were successfully prepared, and the optimal preparation process of the polymer microspheres was as follows: poly(propylene fumarate): poly(lactic-co-glycolic acid) mass ratio=2.41; poly(propylene fumarate)/poly(lactic-co-glycolic acid):pharmaceutical mass ratio=3.56; CH2Cl2 concentration of poly(propylene fumarate)/poly(lactic-co-glycolic acid)=129.73 g/L; the measured average encapsulation efficiency was 83.38%; deviation of 0.63% compared to predicted value; the measured average drug loading was 18.19%; deviation of 0.55% compared to predicted value. (2) The average particle size of the microspheres was 103.902 μm. The ζ potential was -21.5 mV. The cumulative release of the microspheres prepared with the optimal formulation was (22.90±0.55)% after 3 days, and the cumulative drug release reached (43.57±1.02)% after 28 days. After 28 days, the drug release of microspheres increased significantly, and the cumulative release amount was (97.89±1.39)% at 42 days. CTS classification was grade 1. (3) The microsphere preparation process optimized by the star point design-response surface method has good predictability. The optimized preparation process has good reproducibility, is simple and easy to implement, and the prepared microspheres have good in vitro sustained-release properties and biocompatibility. 

Key words: vacomycin, poly(lactic-co-glycolic acid), poly(propylene fumarate), microspheres, emulsion solvent evaporation method, star point design-response surface method, in vitro drug release, cytotoxicity

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