Intranasal Delivery of Darunavir-Loaded Mucoadhesive In Situ Gel: Experimental Design, In Vitro Evaluation, and Pharmacokinetic Studies

Abstract

The clinical efficacy of antiretroviral therapy in NeuroAIDS is primarily limited by the low perfusion of the drug to the brain. The objective of the current investigation was to design and develop an in situ mucoadhesive gel loaded with darunavir to assess the feasibility of brain target¬ing through the intranasal route. Preliminary batches (F1-F9) were prepared and evaluated for var¬ious pharmaceutical characteristics. A full factorial design of the experiment was applied to opti¬mize and assess the effect of two influencing variables (Carbopol 934P (X1) and Poloxamer 407 (X2)) on the response effects (gelation temperature (Y1) and % drug release (Y2) at 8 h). The data demon¬strate that both influencing variables affect the response variables significantly (p < 0.05). The opti¬mized formulation (F7) exhibited favorable rheological properties, adequate mucoadhesion, sus¬tained drug release, and greater permeation across the nasal mucosa. An in vitro ciliotoxicity study confirms the nontoxicity of the optimized in situ gel (D7) on the nasal mucosa. An in vivo pharma-cokinetic study in rats was performed to assess drug targeting to the brain following the nasal ap¬plication of the selected in situ gel (D7). Significantly higher (p < 0.0001) Cmax (~4-fold) and AUC0-a (~3.5-fold) values were noticed in the brain after nasal application, as compared to the intravenous route. However, less systemic exposure to darunavir was noticed with nasal therapy, which con¬firms the low absorption of the drug into the central compartment. Overall, the data here demon¬strate that the optimized in situ mucoadhesive nasal gel is effective in targeting darunavir to the brain by the nasal route and could be a viable option for the treatment of NeuroAIDS.