Intramuscular administration of paliperidone palmitate extended-release injectable microsuspension induces a subclinical inflammatory reaction modulating the pharmacokinetics in rats.
The present study aims at elucidating the intricate nature of the drug release and absorption following intramuscular (i.m.) injection of sustained-release prodrug nanocrystals/microcrystals. A paliperidone palmitate (PPP) long-acting suspension was characterized with regard to particle size (Dv,50 = 1.09 μm) and morphology prior to i.m. injection in rats. The local disposition was rigorously investigated by means of (immuno)histochemistry and transmission electron microscopy while the concurrent multiphasic pharmacokinetics was linked to the microanatomy. A transient (24 h) trauma-induced inflammation promptly evolved into a subclinical but chronic granulomatous inflammatory reaction initiated by the presence of solid material. The dense inflammatory envelope (CD68(+) macrophages) led to particle agglomeration with subsequent drop in dissolution rate beyond 24 h postinjection. This was associated with a decrease in apparent paliperidone (PP) absorption (near-zero order) until 96 h and a delayed time of occurrence of observed maximum drug plasma concentration (168 h). The infiltrating macrophages phagocytosed large fractions of the depot, thereby influencing the (pro)drug release. Radial angiogenesis (CD31(+)) was observed throughout the inflammatory rim from 72 h onwards and presumably contributed to the sustained systemic PP concentrations by maintaining a sufficient absorptive capacity. No solid-state transitions of the retrieved formulation were recorded with X-ray diffraction analysis. In summary, the initial formulation-driven prodrug (PPP) dissolution and drug (PP) absorption were followed by a complex phase determined by the relative contribution of formulation factors and dynamic physiological variables.
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven 3000, Belgium.
Nicolas
N
Darville
Drug Safety Sciences, Janssen Research & Development, a division of Janssen Pharmaceutica NV.
Marjolein
M
van Heerden
Drug Safety Sciences, Janssen Research & Development, a division of Janssen Pharmaceutica NV.
An
A
Vynckier
Drug Safety Sciences, Janssen Research & Development, a division of Janssen Pharmaceutica NV.
Marc
M
De Meulder
Drug Safety Sciences, Janssen Research & Development, a division of Janssen Pharmaceutica NV.
Patrick
P
Sterkens
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven 3000, Belgium.
Pieter
P
Annaert
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven 3000, Belgium. Electronic address: Guy.VandenMooter@pharm.kuleuven.be.
Guy
G
Van den Mooter
D000818:Animals; D003692:Delayed-Action Preparations; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007273:Injections, Intramuscular; D007555:Isoxazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles; D000068882:Paliperidone Palmitate; D010168:Palmitates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010316:Particle Size; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D013499:Surface Properties; D013535:Suspensions; D014018:Tissue Distribution
D003692:Delayed-Action Preparations; D007555:Isoxazoles; D010168:Palmitates; D011355:Prodrugs; D013535:Suspensions; D000068882:Paliperidone Palmitate
biocompatibility; disposition; histopathology; inflammation; muscle; nanoparticles; paliperidone palmitate; pharmacokinetics; prodrugs; sustained release