(766c) Core-Shell Nanocomposites for Fast Release of Hydrophobic Active Pharmaceutical Ingredients: Impact of Carrier Size

The bioavailability of a large percentage (estimated to be between 40% and 70%) of newly discovered active pharmaceutical ingredients (APIs) is limited by their poor water solubilityâ??hydrophobicity and slow dissolution rate. Over the last decade, major research efforts have been focused on the development of API nanocrystals in suspension form and subsequently converting it into dry core-shell nanocomposite microparticles (NCMPs) to overcome the aforementioned challenges. Preparing NCMPs via fluidized bed (FB) coating of the API nanosuspensions onto inert excipient particles has been used in the manufacturing of nanoformulation based solid dosages. Recent work shows that if the suspensions are properly stabilized, core-shell NCMPs having a water-soluble core can enhance the dissolution rate of poorly water soluble APIs signficantly^1,2. However, the impact of the carrier particle size has not been investigated. In this study, formation of core-shell nanocomposites of Fenofibrate and Itraconazole, model poorly water soluble APIs, via FB coating of their well-stabilized high drug loaded nanosuspensions is investigated. Specifically, the extent of dissolution enhancement, when fine carrier particles (sub-50 mm) as opposed to the traditional large carrier particles (>300 µm) are used, is examined. This allows testing the hypothesis that greatly increased carrier surface area and corresponding thinner shell at the same API loading for finer carriers can significantly increase the dissolution rate. Fine sub-50 µm lactose (GranuLac^® 200) carrier particles were made fluidizable via dry coating with nano-silica, enabling decreased cohesion, fluidization and nanosuspension coating. For both APIs, 30% loaded suspensions were wet-stirred media milled along with a polymer and a surfactant as stabilizers. The stabilizer amounts were screened to achieve stable suspensions with small particle size. The suspensions were FB coated onto hydrophilic nano-silica (M5P) dry coated sub-50 micron lactose (GranuLac^® 200) carrier particles or larger carrier particles of median size >300 µm (PrismaLac^®40). The resulting finer composite powders (sub-100 mm) based on GranuLac^®200 were freely flowing, had high bulk density, and exhibited much faster, immediate release of the poorly water-soluble drugs, in particular for Itraconazole. This is attributed to a much higher specific surface area of the carrier leading to corresponding thinner coating layer for fine carriers as opposed to those for large carrier particles.

Keywords: Active Pharmaceutical Ingredients/drugs, Poorly Water Soluble, Wet-Stirred Media Milling, Fluidized Bed Coating, Fine and large Carrier Particles, Fast Release/Dissolving Nanocomposite Powders

References:

1. C. Knieke, M. Azad, D. To, E. Bilgili, R. Dave, Sub-100 micron Fast Dissolving Nanocomposite Drug Powders, Powder Technol. 271 (2015) 49â??60.
2. A. Bhakay, M. Azad, E. Bilgili, R. Dave, Redispersible Fast Dissolving Nanocomposite Microparticles of Poorly Water-Soluble Drugs, Int. J. Pharm. Sci. 461(2014) 367â??379.