QBD Approach for the Development of Capsaicin-Loaded Glycyrrhetinic Acid Conjugated Stearic Acid Grafted Chitosan Polymeric Micelles for Active Hepatic Targeting

Abstract

Objective: Capsaicin (CAP) is a naturally occurring alkaloid forecasted in the treatment of Alcoholic Hepatitis (AH), but least studied due to its hydrophobicity, low bioavailability, and less target-specific release. Hence, the present study aimed to synthesize glycyrrhetinic acid conjugated stearic acid grafted chitosan (GA-CS-g-SA) and prepare CAP-loaded GA-CS-g-SA micelles. Methods: Quality by design (QbD) approach in coordination with "Box-Behnken Designs (BBD)" was used to optimize the process parameters. GA-CS-g-SA was synthesized and characterized for its physic-chemical. Results: The "Proton Nuclear Magnetic Resonance (1H NMR)" spectrum depicted a strong signal at d=1.0 ppm and endorsed to-CH2 group of SA and d=3.5-3.65 ppm depicting GA, which confirms the formation of GA-CS-g-SA. Critical micellar concentration (CMC) was found to be 13.45±1.72 µg/ml and amino groups substitute degree (SD %) was 10.12%±1.09%, indicating successful linkage of GA and SA on CS. The prominent peaks of CAP (0.9 and 1.31 ppm) in 1H NMR spectra disappeared, indicating drug loading in the micellar core. Micelle's normal particle range was 167.54 nm, and encapsulation efficiency was 67.85%. The CAP-GA-CS-g-SA was found to be biocompatible following the hemolysis test. In vitro release pattern showed 78.68±3.12% in 24h, indicating the slower release of CAP from micelle, whereas 99.48±2.56% was released from non-micellar formulations in 6 h. CAP release from drug-loaded micelles showed a biphasic model with an early burst release in four hours, following a slower and sustained release pattern till 24h. Conclusion: CAP-GA-CS-g-SA micelle is a hopeful advancement to progress bioavailability and controlled release of highly hydrophobic CAP. Further in vivo studies would be evident for targeting hepatocytes and treating AH using CAP-GA-CS-g-SA.