Development of near zero-order release PLGA-based microspheres of a novel antipsychotic

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• 作者：Jinlong Zhao¹ ; Lexi Wang¹ ; Chunyu Fan ; Kongtong Yu ; Ximing Liu ; Xiaolei Zhao ; Dan Wang ; Wenhua Liu ; Zhengxing Su ; Fengying Sun ; ^{sunfengying@jlu.edu.cn} ; Youxin Li ; ^{liyouxin@jlu.edu.cn}
• 关键词：Antipsychotic ; Microsphere ; Zero-order release ; PK-PD relationship
• 刊名：International Journal of Pharmaceutics
• 出版年：2017
• 出版时间：10 January 2017
• 年：2017
• 卷：516
• 期：1-2
• 页码：32-38
• 全文大小：846 K
• 卷排序：516

文摘

The novel antipsychotic isoperidone, a prodrug of paliperidone, was designed to improve liposolubility for the development of poly(D,L-lactide-co-glycolide) (PLGA)-based microspheres to achieve near zero-order release behaviour in vivo. Microspheres with a smooth surface were obtained using the oil-in-water emulsion solvent evaporation method and yielded a high encapsulation efficiency of 92%. Pharmacokinetic studies in beagle dogs showed a one-week plateau phase followed by a two-week quasi-zero-order release with no burst release. The in vitro release method with a good in vitro-in vivo correlation was also established. Pharmacodynamic evaluation was performed using the MK-801-induced schizophrenic behavioural mouse model, and the sustained suppressive effect lasted two weeks. The pharmacokinetic-pharmacodynamic (PK-PD) relationship of isoperidone microspheres was compared to that of oral administration of free drug. The results revealed a strong correlation between the plasma drug level and the antipsychotic effect. A stable drug plasma concentration was detected in mice both intraday and interday from 8 to 22 d after a single injection of isoperidone microspheres, and a sustained suppressive effect on the schizophrenic model was also observed. In comparison, the mouse group receiving oral daily administration exhibited more dose-dependent effects, and the pharmacological effect diminished rapidly in conjunction with a reduction of the plasma drug levels 8 h after the last administration of isoperidone on day 3. The above results confirm the superiority of long-acting release over oral administration and indicate a valuable alternative for the clinical treatment of schizophrenia.