The Amalgamation of Risk Assessment Using Quality by Design Principles and Prediction of Regression Models in the Development of Dexmedetomidine-loaded Lipospheres for Intra-articular Administration

Background: Dexmedetomidine is a promising candidate for pain relief and is being evaluated as an alternative or adjuvant to other treatment modalities. The intraarticular administration of such drugs is expected to give localised effect and the release of drug from drug delivery systems can be programmed to lengthen the duration of action. Purpose: The aim of the present investigation was to develop dispersion of lipospheres for the Dexmedetomidine for intraarticular administration that releases drug over a period of one week. Materials and Methods: DEX-LPS were formulated using the multiple emulsion technique. The particle size of lipospheres, drug entrapment, and percentage of drug release qualified as critical quality attributes. Risk assessment was done for the material attributes and process parameters based on the quality by design principles. The amount of cholesterol, triglyceride and the speed of homogenization during the primary emulsion formulation were identified as critical variables and therefore studied systematically using a Box-Behnken Design. Mathematical models generated for each critical quality attribute and their relationship with predictors was explored, using RStudio, to get a product that had the largest particle size, highest entrapment and desirable drug release profile. Results: Overlay plots were generated and the formulation at the center point settings had the required desirability. The acceptance range for the in-process and end-product quality attributes was established and tested in the product. The product remained stable at 2-8°C during 6 months of study. Conclusion: Stable DEX-LPS that could sustain drug release for 7 days was developed.