EUDRAGIT RS/POLOXAMER 188 NANOCARRIERS LOADED WITH LOPERAMIDE EXERT SUSTAINED CENTRAL EFFECTS, AFTER A SINGLE DOSE ADMINISTRATION, BY ENHANCING LOPERAMIDE AQUEOUS DISPERSION AND REDUCING P-GLYCOPROTEIN-MEDIATED EFFLUX

CATALAN-FIGUEROA, JOHANNA; PONCE BETI MF; CONSTANTIN MF; MONTIVERO, AGUSTÍN. J.; GARCÍA, MAURICIO A.; SILVERO C, M. JAZMÍN; BECERRA, MARÍA CECILIA; GONZALEZ, PABLO M.; MORALES, JAVIER O.; PÉREZ MF

Congreso; NanomedAR 2020; 2020

Brain drug delivery has gathered scientific interest since Central Nervous System (CNS) disorders treatments have limited efficacy due to the Blood Brain Barrier (BBB); thus, drugs with therapeutic potential cannot be used because of pharmacokinetic restrictions. Loperamide is a hydrophobic µ-opioid agonist and P-glycoprotein substrate, with poor gastrointestinal absorption and BBB penetration, that has shown non-µ-receptor-associated neuroprotective properties. Therefore, we have assessed the capacity of Eudragit® RS/Poloxamer 188 (P188) nanocarriers loaded with loperamide (NP-Lop), for crossing the BBB. Methods: NP-Lop effects over P-glycoprotein were evaluated by uptake and transport assays in MDCK-MDR1 cells. Central NP-Lop biodistribution was assessed, after a single-dose administration, by determining: i) supraspinal analgesic effects in naïve rats submitted to the Hot Plate Test (oral and intraperitoneal administration); and ii) advance oxidative protein products (AOPP) in prefrontal cortex (PFC) of rats submitted to traumatic brain injury (TBI) (intravenous administration). Results: NP-Lop increased loperamide uptake 3.1-times, while efflux was decreased 10-times, regarding controls. Likewise, NP-Lop increased analgesia ~20 and 60-fold at 30 min, 2 and 24 h after both, intraperitoneal and oral administration, and reduced AOPP ~6.7-fold, seven days post-TBI. Conclusion: NP-Lop may expand CNS effective treatments by enhancing drugs brain biodistribution as well as gastrointestinal absorption.