Design, optimization and pharmacokinetic evaluation of Piribedil loaded solid lipid nanoparticles dispersed in nasal in situ gelling system for effective management of Parkinson's disease

Piribedil (PBD) is an anti-Parkinson's drug that gained interest recently due to its unique pharmacological profile. But its clinical use is severely limited by drug delivery issues like high dosing frequency (up to 5 tablets/day), low oral bioavailability (<10%), severe GI side-effects, etc. In this work, we have developed solid lipid nanoparticles (PBD-SLNs) to access the nose to brain pathways for direct uptake of PBD. PBD-SLNs were optimized using design of experiments approach to a mean particle size of 358 nm, and drug loading of 15%. The optimized PBD-SLNs were found to be nearly spherical in shape and showed good stability. Further, the SLNs were loaded in thermoresponsive Methyl Cellulose in situ gel (PBD-SLN-ISG) to delay mucociliary clearance upon intranasal administration in rats. Intranasal administration at the olfactory region was achieved with a cannulamicrotip setup. In vivo pharmacokinetic studies showed that PBD-SLN-ISG increased the PBD (AUC)(brain) by about 4-folds and reduced the (C-max)(plasma) by 2.3-folds when compared to plain intranasal suspension of PBD (PBD-Susp). Further, PBD-Susp showed limited direct nose to brain uptake with direct transport percentage (DTP) values less than 0, while the optimized PBD-SLN-ISG showed DTP value of 27% indicating efficient direct nose to brain uptake.

Automated summary

In this study, solid lipid nanoparticles (PBD-SLNs) were developed as a drug delivery system for the anti-Parkinson's drug, Piribedil (PBD), to improve its absorption efficiency and stability. By optimizing the particle size and morphology, the PBD-SLNs showed significantly increased drug uptake and stability. Loading the SLNs into thermoresponsive Methyl Cellulose in situ gel (PBD-SLN-ISG) led to improved drug delivery to the brain in rats, resulting in a four-fold increase in the area under the curve (AUC) and a 2.3-fold decrease in maximum plasma concentration (C-max) compared to plain intranasal suspension of PBD.