Baclofen-loaded solid lipid nanoparticles: Preparation, electrophysiological assessment of efficacy, pharmacokinetic and tissue distribution in rats after intraperitoneal administration

• Published in: European journal of pharmaceutics and biopharmaceutics 2011-09, Vol.79 (1), p.135-141
• Main Authors: Priano, Lorenzo, Zara, Gian Paolo, El-Assawy, Nadia, Cattaldo, Stefania, Muntoni, Elisabetta, Milano, Eva, Serpe, Loredana, Musicanti, Claudia, Pérot, Chantal, Gasco, Maria Rosa, Miscio, Giacinta, Mauro, Alessandro
• Format: Article
• Language: English
• Subjects: Animals; Baclofen; Baclofen - administration & dosage; Baclofen - chemistry; Baclofen - pharmacokinetics; Baclofen - pharmacology; Behavior, Animal; Drug Carriers; Drug Compounding; Drug Delivery Systems; Drug Evaluation, Preclinical; H-reflex; H-Reflex - physiology; Injections, Intraperitoneal; Intraperitoneal; Lipids - administration & dosage; Lipids - chemistry; Male; Muscle Relaxants, Central - administration & dosage; Muscle Relaxants, Central - chemistry; Muscle Relaxants, Central - pharmacokinetics; Muscle Relaxants, Central - pharmacology; Muscle Spasticity - drug therapy; Muscle Spasticity - pathology; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Rats; Rats, Wistar; Solid lipid nanoparticles; Spasticity; Tissue Distribution
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2011.02.009

We studied efficacy, pharmacokinetic and tissue distribution of baclofen incorporated in solid lipid nanoparticles (SLN), after intraperitoneal administration in rats. SLN are able to give a sustained release and targeting the CNS. Our study demonstrated prolonged efficacy of this novel formulation of baclofen, even if high baclofen concentrations in brain tissue and sedation require optimization of dosages for clinical purposes. 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.