title: Design of a long-term antipsychotic in situ forming implant and its release control method and mechanism.
abstract: Two kinds of in situ forming implants (ISFIs) of atypical antipsychotics, risperidone and its 9-hydroxy active metabolite, paliperidone, using poly(lactide-co-glycolide)(PLGA) as carrier, were investigated. Significant difference was observed in the solution-gel transition mechanism of the two systems: homogeneous system of N-methyl-2-pyrrolidone (NMP) ISFI, in which drug was dissolved, and heterogeneous system of dimethyl sulfoxide (DMSO) ISFI, in which drug was dispersed. Fast solvent extractions were found in both systems, but in comparison with the high drug release rate from homogeneous system of drug/polymer/NMP, a fast solvent extraction from the heterogeneous system of drug/polymer/DMSO was not accompanied by a high drug release rate but a rapid solidification of the implant, which resulted in a high drug retention, well-controlled initial burst and slow release of the drug. In vivo study on beagle dogs showed a more than 3-week sustained release with limited initial burst. Pharmacologic evaluation on optimized paliperidone ISFIs presented a sustained-suppressing effect from 1 day to 38 day on the MK-801 induced schizophrenic behavior mice model. A long sustained-release antipsychotic ISFI of 50% drug loading and controlled burst release was achieved, which indicated a good potential in clinic application.
authors.affiliation: College of Life Science, Jilin University, Qianjin Street No. 2699, Changchun, Jilin Province 130012, China.
authors.forename: Lexi
authors.initials: L
authors.lastname: Wang
authors.forename: Aiping
authors.initials: A
authors.lastname: Wang
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhao
authors.forename: Ximing
authors.initials: X
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Fengying
authors.initials: F
authors.lastname: Sun
authors.forename: Youxin
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D004121:Dimethyl Sulfoxide; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004285:Dogs; D004343:Drug Implants; D005079:Excipients; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005782:Gels; D007555:Isoxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D007700:Kinetics; D019344:Lactic Acid; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D000068882:Paliperidone Palmitate; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D011760:Pyrrolidinones; D012995:Solubility; D012996:Solutions; D012997:Solvents; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D004343:Drug Implants; D005079:Excipients; D018691:Excitatory Amino Acid Antagonists; D005782:Gels; D007555:Isoxazoles; D011743:Pyrimidines; D011760:Pyrrolidinones; D012996:Solutions; D012997:Solvents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016291:Dizocilpine Maleate; C038678:N-methylpyrrolidone; D000068882:Paliperidone Palmitate; D004121:Dimethyl Sulfoxide