Development of In-situ Gel of Bupropion Hydrochloride-loaded Chitosan Nanoparticles using an Inotropic Gelation Method for Smoking Cessation via Nose to Brain: In-vitro and Ex-vivo Characterization and Evaluation

Abstract

Introduction: Tobacco use is the leading preventable cause of various diseases, disabilities, and death. It is estimated that 480000 deaths annually are attributed to cigarette smoking, including secondhand smoke exposure. The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to delivering drugs selectively and effectively to the brain. The blood-brain barrier (BBB) and first-pass metabolism constitute the major obstacle to the uptake of drugs into the brain following systemic administration. Intranasal delivery offers a non-invasive and convenient method to bypass the BBB and avoid first-pass metabolism, which leads to the delivery of therapeutics directly to the brain. Objective: The objective of this study was to develop an In-situ gel of Bupropion Hydrochloride-loaded chitosan nanoparticles using the inotropic gelation method for Smoking Cessation via the nose to the brain to improve the bioavailability of Bupropion Hydrochloride, avoiding first-pass metabolism and bypassing Blood Brain Barrier. Method: Fourier transform infrared spectroscopy (FTIR) was used to determine the identity and purity of the drug. A UV Spectrophotometer was employed in the analytical procedure. Chitosan nanoparticles loaded with bupropion HCl were made using the ionic gelation method, and then the optimized batch was made using simulated in-situ gelation. Utilizing Central composite design, optimization was done by Design Expert-13. Evaluation of polymeric nanoparticles was performed by measuring their particle size, PDI, and entrapment efficiency. Additionally, they were tested for drug release in vitro. The final nanoparticles were subsequently tested for gelation using nasal simulation fluid, and an ex vivo investigation was also conducted. An ion-sensitive polymer gellan gum was used as a gelling agent, which formed an immediate gel and remained for an extended period. The finished formulation was also subjected to several characterizations, including TEM and FTIR. Results: The developed formulation was stable and showed enhanced contact time in the nasal mucosa, minimizing the frequency of administration. In-vitro studies through Franz diffusion cell and Ex-vivo studies on sheep nasal mucosa showed good results. In the Histopathological study, the optimized batch was found to be safe and stable in an accelerated stability study for one month. Conclusion: Bupropion HCl-loaded chitosan nanoparticles In-situ gel proved to be suitable for the administration of Bupropion HCl through the nasal route. The ease of administration coupled with less frequent administration enhanced patient compliance. The formulation was found to be liquid at the formulated condition and formed gel in the presence of ions present in the nasal mucosa. The gel formed in situ showed sustained drug release. The formulations were less viscous before instillation and formed a strong gel after instilling in the nasal cavity.