title: Baclofen-loaded solid lipid nanoparticles: preparation, electrophysiological assessment of efficacy, pharmacokinetic and tissue distribution in rats after intraperitoneal administration.
abstract: Intrathecal baclofen administration is the reference treatment for spasticity of spinal or cerebral origin, but the risk of infection or catheter dysfunctions are important limits. To explore the possibility of alternative administration routes, we studied a new preparation comprising solid lipid nanoparticles (SLN) incorporating baclofen (baclofen-SLN). We used SLN because they are able to give a sustained release and to target the CNS. Wistar rats were injected intraperitoneally with baclofen-SLN or baclofen solution (baclofen-sol group) at increasing dosages. At different times up to 4 h, efficacy was tested by the H-reflex and two scales evaluating sedation and motor symptoms due to spinal lesions. Rats were killed and baclofen concentration determined in blood and tissues. Physiological solution or unloaded SLN was used as controls. After baclofen-SLN injection, the effect, consisting in a greater and earlier reduction of the H/M ratio than baclofen-sol group and controls, was statistically significant from a dose of 5 mg/kg and was inversely correlated with dose. Clinical effect of baclofen-SLN on both the behavioral scales was greater than that of baclofen-sol and lasted until 4th hour. Compared with baclofen-sol, baclofen-SLN produced significantly higher drug concentrations in plasma from 2nd hour until 4th hour with a linear decrement and in the brain at all times. In conclusion, our study demonstrated the efficacy of a novel formulation of baclofen, which exploits the advantages of SLN preparations. However, for clinical purposes, high baclofen concentrations in brain tissue and sedation may be unwanted effects, requiring further studies and optimization of dosages.
authors.affiliation: Department of Neurology and Neurorehabilitation, San Giuseppe Hospital, Piancavallo (VB), Italy. lorenzo.priano@unito.it
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Priano
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Zara
authors.forename: Nadia
authors.initials: N
authors.lastname: El-Assawy
authors.forename: Stefania
authors.initials: S
authors.lastname: Cattaldo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Muntoni
authors.forename: Eva
authors.initials: E
authors.lastname: Milano
authors.forename: Loredana
authors.initials: L
authors.lastname: Serpe
authors.forename: Claudia
authors.initials: C
authors.lastname: Musicanti
authors.forename: Chantal
authors.initials: C
authors.lastname: Pérot
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Gasco
authors.forename: Giacinta
authors.initials: G
authors.lastname: Miscio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauro
mesh_terms: D000818:Animals; D001418:Baclofen / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001522:Behavior, Animal; D004337:Drug Carriers; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D006181:H-Reflex / Q000502:physiology; D007274:Injections, Intraperitoneal; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry*; D008297:Male; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D009128:Muscle Spasticity / Q000188:drug therapy / Q000473:pathology; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D008055:Lipids; D009125:Muscle Relaxants, Central; D001418:Baclofen