In vitro and in vivo demonstration of risperidone implants in mice.
BACKGROUND
Non-adherence with medication is a critical limitation in current long-term treatment of schizophrenia and a primary factor in poor quality-of-life outcomes. However, few treatments have addressed this shortcoming using an implantable drug delivery approach. The goal of this study was to provide in vitro and in vivo proof of concept for a long-term implantable risperidone delivery system in mice.


METHODS
Implantable formulations of risperidone were created using the biodegradable polymer Poly Lactic co Glycolic Acid (PLGA) combined with various drug loads. Implant bioactivity was tested using in vitro release and stability studies, as well as in vivo pharmacokinetic and behavioral studies in mice.


RESULTS
The pattern of risperidone release is influenced by various parameters, including polymer composition and drug load. In vitro measures demonstrate that risperidone is stable in implants under physiological conditions. Behavioral measures demonstrate the bioactivity of risperidone implants delivering 3 mg/kg/day in mice, while pharmacokinetic analyses indicate that reversibility is maintained throughout the delivery interval.


CONCLUSIONS
The current report suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications based on in vivo animal studies and pharmacokinetics. Implantable medications demonstrated here can last two months or longer while maintaining coherence and removability past full release, suggesting a potential paradigm shift in the long-term treatment of schizophrenia.
Rabin
C
C
Stanley Center for Experimental Therapeutics, Division of Neuropsychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia 19104, United States.
Liang
Y
Y
Ehrlichman
R S
RS
Budhian
A
A
Metzger
K L
KL
Majewski-Tiedeken
C
C
Winey
K I
KI
Siegel
S J
SJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001672:Biocompatible Materials; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D015195:Drug Design; D004343:Drug Implants / Q000493:pharmacokinetics* / Q000494:pharmacology; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D019344:Lactic Acid; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010349:Patient Compliance; D011091:Polyesters; D011100:Polyglycolic Acid; D011108:Polymers; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D018967:Risperidone / Q000493:pharmacokinetics* / Q000494:pharmacology; D012559:Schizophrenia / Q000188:drug therapy
D001672:Biocompatible Materials; D004343:Drug Implants; D011091:Polyesters; D011108:Polymers; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); D018967:Risperidone