Abstract
Formulators face great challenges in adopting systematic approaches for designing self-nanoemulsifying formulations (SNEFs) for different drug categories. In this study, we aimed to build-up an advanced SNEF development framework for weakly basic lipophilic drugs, such as cinnarizine (CN). First, the influence of formulation acidification on CN solubility was investigated. Second, formulation self-emulsification in media with different pH was assessed. Experimentally designed phase diagrams were also utilized for advanced optimization of CN-SNEF. Finally, the optimized formulation was examined using cross polarizing light microscopy for the presence of liquid crystals. CN solubility was significantly enhanced upon external and internal acidification. Among the various fatty acids, oleic acid-based formulations showed superior self-emulsification in all the tested media. Surprisingly, formulation turbidity and droplet size significantly decreased upon equilibration with CN. The design was validated using oleic acid/Imwitor308/Cremophor El (25/25/50), which showed excellent self-nanoemulsification, 43-nm droplet size (for CN-equilibrated formulations), and 88 mg/g CN solubility. In contrast to CN-free formulations, CN-loaded SNEF presented lamellar liquid crystals upon 50% aqueous dilution. These findings confirmed that CN-SNEF efficiency was greatly enhanced upon drug incorporation. The adopted strategy offers fast and accurate development of SNEFs and could be extrapolated for other weakly basic lipophilic drugs.
Highlights
As a result of modern drug discovery practices, there has been a consistent rise in the number of newly discovered chemical entities that are considered poorly water-soluble drugs (PWSDs)
It was crucial to investigate the influence of formulation acidification on CN solubility
The model formulation presented poor homogeneity/dispersibility with all the investigated buffer salts. These results suggest that the poor selfemulsification of the coconut oil fatty acids (COFA) formulation might be related to the fatty acid itself rather than any interaction with the buffer salts
Summary
As a result of modern drug discovery practices, there has been a consistent rise in the number of newly discovered chemical entities that are considered poorly water-soluble drugs (PWSDs). Owing to their poor dissolution, these PWSDs often present low and erratic bioavailabilities. SNEFs are commonly developed using the “trial and error approach” which involves changing one parameter at a time or the conventional “ternary phase diagrams” technique. These two methods require several experiments, resulting in high cost and long development periods (Bahloul, Lassoued, Sfar, 2014).
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