Voriconazole Loaded Lipidic Nanoparticles for Ophthalmic Delivery: Development Using QbD Combined with Risk-based Approach

Abstract

Background: Voriconazole (VRZ) is widely used for fungal keratitis topically. It is spar-ingly water soluble and has limited permeability which can lead to poor bioavailability. Nanostruc-tured Lipid Carriers (NLCs) are selected as a carrier for voriconazole as they increase solubility while the lipidic character of the formulation facilitates permeation.. Objectives: Objectives: • To develop a new method of preparation of lipidic nanoparticles • To apply Quality by design and risk-based approach to find variables • To optimize variables and find the design space • To evaluate and characterize the optimized formulation Methods: The present study is an attempt to address the challenges in the formulation of NLCs us-ing a high-speed homogenizer. Quality by Design approach was used to find the material attributes and process parameters playing a significant role in the formulation development. Quality Target product profile was prepared, and failure mode and effect analysis was performed for a better un-derstanding of the risks, ways to alleviate risks, and finally, to propose a control strategy. The for-mulation was optimized by using 3-levels 3-factors central composite design, and design space was obtained by using graphical optimization. The morphology of the particles was studied by using Transmission Electron Microscope. In vitro drug release study was performed using Franz diffusion cell. Results: The amount of solid lipid, solid lipid to total lipid ratio, and concentration of surfactant were found to be high risk variables and their effects on the product quality were examined using Central composite design considering particle size, particle size distribution and %entrapment efficiency as dependent variables. Optimized NLC had a particle size of 72.58 nm with PDI 0.137 and %entrapment efficiency of 78.79%. The in vitro drug release study showed sustained drug release over the period of 24 hrs and followed the Higuchi model with a fickian diffusion mecha-nism. Conclusion: The present study successfully explored QbD along with Risk-based approach for the development of voriconazole containing lipidic nanoparticles.