Small scale processing of nanoscopic formulations for preclinical development of poorly soluble compounds
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Abstract
Several processing techniques for the bioavailability enhancement of poorly soluble drugs are described in this work. Three model substances (fenofibrate, griseofulvin, ketoconazole) are evaluated for technical feasibility in nanosuspension, nanoemulsion/microemulsion (fenofibrate only) and cyclodextrin formulations. Different preparational and analytical aspects of the technologies were investigated. Small angle neutron scattering (SANS) was utilized to explore the emulsifying mechanism of a microemulsion preconcentrate. Results suggest development of spherical structures in the first 200s of the process with further size increase of the emulsion droplets later on. Only minor changes in chemical composition of the droplets are suggested. Nanoemulsion formulations were manufactured via novel sucrose ester tensides and compared to established surfactants for parenteral use (Solutol® HS15, Cremophor® RH40, Lipoid® E80, Lipoid® S75). Results demonstrate the suitability of hydrophilic lauryl and myristyl esters regarding particle size and stability. In comparison to other tensides sucrose esters allow for production of smaller particle sizes and stabilize the resulting emulsions during freeze-drying and redispersion. Wet milling in different ball mills was evaluated for manufacturing of nanosuspensions. Besides processing time the bead fill level, rotational speed and size of milling beads were identified as relevant parameters. Differences in comminution efficiency were detected dependent on API chemistry and the stabilizers used. The data underline the relevance of selection of stabilizers and optimization of stabilizer concentration for every individual API to achieve optimal comminution efficiency and dispersion stability. Optimized drug delivery systems were investigated in-vitro in Caco-2 transwell systems. Higher permeation of nanoscalic formulations could be measured in comparison to non-processed API. Nano- and microscale formulations of fenofibrate were tested in an in-vivo study in rats. After peroral administration the nanosuspensions and nanoemulsions lead to higher bioavailability of fenofibrate in accordance to increased permeation in the in-vitro tests. A microemulsion failed to demonstrate increased bioavailability in comparison to pure API. The work demonstrates the applicability of nanosuspension technology as platform for different poorly soluble compounds. Wetmilling proved to be a suitable technique for processing even in the low milligram scale for different API chemistries which qualifies the technique as ideal tool for preclinical and clinical development. Building on a published scheme a decision tree for selection of formulation technologies is proposed that accounts for the technical applicabilities of the different formulation approaches.