罗哌卡因乳酸羟基乙酸共聚物纳米粒制备及动物体内的缓释

Poly(lactid-co-glycolide) nanoparticles loaded with ropivacaine: preparation and in vivo release in animals

背景:课题组前期进行了罗哌卡因乳酸羟基乙酸共聚物微球合成工艺及其药物动力学的研究,并证实其有效性,但因颗粒较大,限制其在注射方面的应用,且存在对组织的刺激等不良反应。目的:采用乳剂-扩散溶剂挥发法制备罗哌卡因乳酸羟基乙酸共聚物纳米粒,研究其粉粒学特征、体内释药特性及组织毒性。方法:以乳酸羟基乙酸共聚物为载体,采用乳剂-扩散溶剂挥发法制备罗哌卡因乳酸羟基乙酸共聚物微球并加以研磨过滤,计算纳米粒的粒径、药物包封率、载药量及形态等参数。选取100只昆明小鼠(南方医科大学动物实验中心提供),随机分为实验组和对照,将罗哌卡因-乳酸羟基乙酸纳米粒悬浮液注射入实验组小鼠颈部皮下,对照组小鼠给予等剂量0.5%盐酸罗哌卡因。分别于药物注射后30 min及1,2,3,6,10,18,24,36,48 h进行血药浓度监测,观察体内释药情况,对注射部位及全身主要脏器进行病理学检查以检测其组织学毒性。结果与结论:(1)制备的罗哌卡因-乳酸羟基乙酸纳米粒,粒径为(73.5±16.7) nm,载药量为(6.07±0.22)%,包封率为(62.73±4.83)%;(2)动物体内实验结果显示:实验组小鼠与对照组相比,血药浓度明显降低(P=0.00)。对照组药物留置时间约6h,实验组药物留置时间约48h,药物持续缓释;(3)实验组小鼠药物注射局部组织仅见轻微炎症反应,每组小鼠均未见组织细胞坏死及全身主要脏器的病理学改变;(4)结果提示,罗哌卡因乳酸羟基乙酸纳米粒可以成功制备,动物体内具有明显的缓释性,组织器官毒性小。

BACKGROUND:Synthesis of ropivacaine-loaded poly(lactid-co-glycolide)copolymer microsphere and its pharmacokinetics have been studied preliminarily,and we have confirmed its effectiveness.However,its large size and tissue simulation limit its application.OBJECTIVE:To prepare poly(lactid-co-glycolide)nanoparticles loaded with ropivacaine and to study their particle characteristics,in vivo release characteristics and toxicity.METHODS:Poly(lactid-co-glycolide)nanoparticles loaded with ropivacaine were prepared with poly(lactid-co-glycolide)as carriers by the water-in-oil-in-water emulsion solvent evaporation method.The micromeritic characteristics of the nanoparticles,such as the particle size,loading and entrapment efficiency were taken as parameters for evaluating.One hundred Kunming mice provided by the Laboratory Animal Centre of Southern Medical University in China were randomized into experimental and control groups,and then were subcutaneously injected with poly(lactid-co-glycolide)nanoparticles loaded with ropivacaine and0.5%ropivacaine,respectively.Blood concentration monitoring was performed at30minutes,1,2,3,6,10,18,24,36and48hours after administration.Drug release was observed in vivo,and pathological examinations were performed on the injection site and main body organs to study its tissue toxicity.RESULTS AND CONCLUSION:The poly(lactid-co-glycolide)nanoparticles loaded with ropivacaine were prepared.The average particle size was(73.5±16.7)nm,the drug loading efficiency was(6.07±0.22)%,and the encapsulation efficiency was(62.73±4.83)%.The blood drug concentration in the experimental group was significantly lower than that in the control group(P=0.00).The drug retention time in the control and experimental groups was6and48hours,respectively,indicating the drug release sustained.The mice in the experimental group appeared with mild inflammation in the injection site,and no obvious pathological changes in major organs or necrotic cells occurred.To conclude,poly(lactid-co-glycolide)nanoparticles loaded with ropivacaine can be successfully prepared,and can achieve sustained-release in animals,and have low toxicity.