Evaluation of pilocarpine in situ forming buccal gels as potential formulations for the management of xerostomia

Buccally administrated pilocarpine (PIL) can be a unique formulation approach for the management of xerostomia. In this way the severity of systemically induced side effects can be effectively controlled, while maintaining a high level of therapeutic efficacy. The aim of the present study was to evaluate the sol-gel and mucoadhesive properties of an in situ thermoresponsive hydrogel designed for PIL's buccal administration. For this purpose, poloxamer 407 (P407) and 188 (P188) were used as in situ gel forming agents, while xanthan gum (XG) was added as a mucoadhesion enhancer. Implementation of a Box-Behnken experimental design, combined with multi-linear regression (MLR) fitting, unraveled the role of formulation factors on several critical product attributes (such as gel transition temperature, gelation time, solution viscosity and gel viscosity). Artificial neural networks (ANNs) showed excellent generalizing ability, with verification experiments showing good agreement between the ANN- predicted and the experimentally-obtained results. The optimum sol-gel formulations were sprayable at room/storage temperature, while forming a strong gel at temperatures prevailing in the buccal cavity. In vitro dissolution profiles of all optimum formulations exhibited a sustained release pattern (releasing almost 80% of the total dose in 360 min) characterized by an initial rapid release followed by a steady state plateau. The evaluation of drug release kinetics, by applying different release kinetic models, suggested that the drug release from the in situ gels predominantly follows Fick's law and is primarily diffusion-controlled. The in vitro studies were complemented with ex vivo studies, performed on a freshly excised porcine buccal mucosa, showing good mucoadhesion properties with approximately 27% of the total drug permeating the buccal porcine mucosa, while no damage to the epithelium was observed based on the histological evaluation.