Development of near zero-order release PLGA-based microspheres of a novel antipsychotic.
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 8h 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.
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China.
Jinlong
J
Zhao
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China.
Lexi
L
Wang
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China.
Chunyu
C
Fan
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China.
Kongtong
K
Yu
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China.
Ximing
X
Liu
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China.
Xiaolei
X
Zhao
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China.
Dan
D
Wang
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China.
Wenhua
W
Liu
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China.
Zhengxing
Z
Su
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China. Electronic address: sunfengying@jlu.edu.cn.
Fengying
F
Sun
School of Life Sciences, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province, 130012, China. Electronic address: liyouxin@jlu.edu.cn.
Youxin
Y
Li
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D065546:Drug Liberation; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D008863:Microspheres; D000068882:Paliperidone Palmitate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011355:Prodrugs; D012559:Schizophrenia / Q000188:drug therapy; D012995:Solubility; D013997:Time Factors
D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011355:Prodrugs; C000618188:isoperidone; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016291:Dizocilpine Maleate; D000068882:Paliperidone Palmitate
Antipsychotic; Microsphere; PK-PD relationship; Zero-order release