[关键词]
[摘要]
目的 为解决银杏内酯B(GB)溶解度小、体内消除快、长期放置稳定性差等缺陷,用一种全新的可生物降解的多糖聚合物作为载体材料,将GB制备成具有缓释作用的冻干纳米制剂。方法 采用亲水性聚合物凝聚法制备银杏内酯B纳米粒(GB-NP),以平均粒径和多分散系数(PDI)作为评价指标,采用Design-Expert 8.0软件进行星点设计,考察GB的浓度、GB与聚合物的质量比、聚合物溶液的pH值等因素对评价指标的影响,应用效应面法得到优化的制备工艺,进一步制备成冻干制剂并对其进行体外释放等考察。结果 优化的处方条件:GB质量浓度为1.5 mg/mL、GB与聚合物的质量比为0.1、聚合物溶液pH 5.0。包封率为(99.64±0.45)%,载药量为(9.04±0.04)%,粒径为(192.8±2.8)nm,PDI为0.18±0.03。冻干条件为以1%的甘露醇为冻干保护剂,GB-NP溶液置-80℃预冻12 h,在-40℃、5 kPa(0.05 bar)条件下干燥24 h。GB-NP的体外释放度结果显示,GB原料药1 h累积释药率达到(64.74±3.95)%,而GB-NP 1 h时累积释药率为(36.90±1.41)%。结论 该生物可降解的多糖聚合物可解决GB在水中的溶解度小、不便于制备成静脉注射剂的问题,而且还能使GB-NP具有良好的缓释作用。
[Key word]
[Abstract]
Objective In order to solve the problem of ginkgolide B (GB) for preparing the intravenous injection dosage form, such as it's low solubility, rapid elimination in vivo and poor stability in long-term storage, a novel biodegradable polysaccharide polymer was used as a carrier to encapsulate GB into nanoparticles with sustained-release profile, which then was freeze dried for keep its stability. Methods GB nanoparticles (GB-NP) were prepared by coacervation method with hydrophilicity polymer. The Design-Expert 8.0 software was applied for experimental design. The formulation was finalized by investigating the concentration of GB, the mass ratio of GB to polymer, and the pH of the polymer solution with size and polydispersity indexas the evaluation parameters. The optimum formulation and technique were selected by response surface method. Then the nanoparticle suspension was further freeze dried and in vitro release behavior was tested in PBS containing 30% ethanol. Results The optimum prescription conditions were as follows:the concentration of GB was 1.5 mg/mL, the ratio of GB mass to polymer mass was 0.1 and the polymer solution pH was set at 5.0. The entrapment efficiency was (99.64±0.45)% with the drug loading ratio of (9.04±0.04)%. Average particle size of GB-NP was (192.8±2.8) nm with a preferable PDI of 0.18±0.03. The freeze-drying conditions were described as follows:using 1% mannitol as freeze-drying supporting agent, the solution of GB-NP was pre-frozen for 12 h at -80℃ and dried for 24 h at -40℃. The release behavior of free GB was rapid with the cumulative release rate reaching (64.74±3.95)% during the first hour, while the cumulative release rate of GB in nanoparticles was (36.90±1.41)% during the first hour. Conclusion The GB-NP using this special biodegradable polysaccharide polymer can improve GB's dissolution behavior in water and make GB sustained release in vitro, which is beneficial for preparing GB's intravenous injection dosage form.
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[基金项目]
国家自然科学基金面上项目(81774011);国家自然科学基金面上项目(81202926)