Piribedil loaded thermo-responsive nasal in situ gelling system for enhanced delivery to the brain: formulation optimization, physical characterization, and in vitro and in vivo evaluation.

Methyl cellulose (MC) based nasal in situ gels were developed to enhance the brain delivery of piribedil (PBD), an anti-Parkinson's drug. Different grades of MC and several solutes (NaCl, KCl, Na.Citrate, STPP, PEG-6000, sucrose, etc.) were screened to formulate thermo-responsive nasal in situ gelling systems. Formulations were evaluated for their sol-gel transition temperature and time, rheological behaviour, in vitro drug release, mucociliary clearance (MCC), ex vivo nasal toxicity, and in vivo brain availability studies in Wistar rats. Intranasal (i.n.) administration was carried out using a cannula-microtip setup to deliver PBD at the olfactory region of the nose. The concentration and viscosity grade of MC and also the concentration and type of solute used were found to affect the rheological behaviour of the formulations. Among the solutes tested, NaCl was found to be effective for formulating MC in situ gels. The developed in situ gels significantly delayed the MCC of PBD from the site of administration when compared with conventional suspension (p < 0.05). Further, formulations with higher gel strength showed lower in vitro drug release rate and longer intranasal residence (delayed MCC) (p < 0.05). The absolute brain availability (brain AUC0-t) of PBD increased to 35.92% with i.n. delivery when compared to 4.71% with oral administration. Overall, it can be concluded that intranasal delivery of PBD is advantageous when compared to the currently practiced oral therapy. Graphical abstract.