局部麻醉用缓释盐酸布比卡因PLGA微球的制备及特性研究

Preparation and property of bupivacaine hydrochloride PLGA microspheres for local anesthesia

目的:制备盐酸布比卡因聚乳酸聚羟乙酸嵌段共聚物(PLGA)微球,并对其皮下给药和蛛网膜下腔给药后体内药动学、药效学进行评价。方法:微球制备采用乳化溶媒挥发法,用反相HPLC法测定其体内血药浓度,分别以针刺疼痛反应和后肢反应综合评分法评价盐酸布比卡因PLGA微球的麻醉效果,以盐酸布比卡因注射液作为对照。结果:微球的包封率为86.78％,载药量为28.92％,微球平均粒径为85.32μm。相同剂量微球组皮下给药和蛛网膜下腔给药后血药浓度均产生2个峰浓度,两峰浓度值显著低于对照组(P<0.05,P<0.01),微球组不同给药的平均滞留时间(MRT)明显长于对照组(P<0.01)。微球组皮下给药最大麻醉圈直径(4.3 cm)显著小于注射剂对照组(8.3 cm,P<0.01),而微球组局麻持续时间(72 h)较对照组(4 h)明显延长(P<0.01)。微球组蛛网膜下腔给药后不同麻醉阶段的麻醉时间t1(460 min)、t2(307.5 min)、t3(242.5min)以及麻醉有效总时间t(1 010 min)和综合评分S(1 860)值均显著大于注射剂对照组的t1(45 min)、t2(83.8 min)、t3(53min)以及t(181.8 min)和S(328)值(P<0.01)。结论:盐酸布比卡因PLGA微球能显著延长皮下给药和蛛网膜下腔给药的体内驻留时间和局部麻醉时间,降低最大血药浓度,提高用药安全性。

Objective: To design the optimum prescription for bupivacaine hydrochloride PLGA microspheres (Bupi-PL GA-MS) and to evaluate its pharmacokinetics and pharmacodynamics. Methods: Bupi-PLGA-MS was prepared with emulsifying solvent evaporating method. The plasma concentration of bupivacaine was determined by HPLC and the anesthetic outcomes of bupi-PLGA-MS after subcutaneous and spinal administration were evaluated by needling and hindlimb reaction. Bupivacaine injection was taken as control. Results; The drug entrapment was 86. 78% ,drug content was 28. 92% ,and the mean diameter was 85. 32 μm. Two peaks of bupivacaine plasma concentration were found in vivo with bupi-PLGA-MS by subcutaneous and spinal administration respectively,which were significantly lower than that of injection group (P<0. 05,P< 0. 01). The mean reaction time(MRT) of bupi-PLGA-MS was higher than that of injection group (P<0. 01). The biggest anaesthetic circle diameters of bupi-HAS-MS(4. 3 cm) was smaller than that of injection group(8.3 cm,P<0. 01) and anaesthetic time of bupi-HAS-MS was evidently prolonged compared to injection group(P<0. 01). The anaesthetic time of different stages by spinal administration with Bupi-PLGA-MS was prolonged (P < 0. 01) . Conclusion: Bupi-PLGA-MS can prolong MRT and the regional anesthetic time,decrease the maximum drug concentration and increase the safety of administration.