Dissolution into surfactant and emulsion systems: Implications to the formulation of bio-relevant dissolution media for water -insoluble drugs.

Abstract

Dissolution rate limited absorption is a concern for the oral delivery of poorly water soluble drugs. An <italic>in vitro</italic> methodology capable of evaluating drug release under bio-relevant test conditions may contribute significantly to product development. A key component of an <italic>in vitro </italic> dissolution method is the dissolution media. Media comprising pharmaceutical surfactants (dodecyltrimethylammonium bromide (DTAB), sodium lauryl sulfate (SLS) or Tween 20), a series of oil-in-water emulsions (e.g., representing the fed state) and gastrointestinal fluids obtained from the fasted dog were used to study the solubilization and dissolution rate (rotating disk) of griseofulvin, a model water-insoluble compound for the purposes of bio-relevant dissolution media development. The surfactant media achieved a broad range of griseofulvin solubilization and dissolution rate enhancement. For example, the equilibrium distribution coefficient, an indicator of drug solubilization capacity, exhibited an approximate 7-fold increase from the lowest to the highest value (357 L mole<super>-1 </super> for Tween 20, 802 L mole<super>-1</super> for DTAB and 2393 L moles for SLS). The dissolution rate results paralleled those of the solubility studies in that the greatest dissolution enhancement was observed in SLS followed by DTAB and the Tween 20 media. However, the magnitude of the dissolution rate enhancement achieved in the surfactant media was limited by the slower diffusional transport of the drug-loaded micelle species. The results also indicated that a surfactant media can be formulated to match the drug solubilization and dissolution in the dog intestinal fluids. In the emulsion systems, the emulsified oil phase contributed to the overall extent of griseofulvin dissolution due to its greater drug solubilization capacity than the aqueous micelle phase. However, the emulsified oil had a smaller effect on the dissolution rate due to its slower diffusional transport as compared to the free solute or the micelle species (approximately 100 and 10 times slower, respectively). The results suggest that for a poorly water soluble drug, a simple surfactant media may be sufficient to match the in vivo solubilization and dissolution rate. An emulsion media may be considered to provide a greater extent of drug release (e.g., low solubility drug given at a high dose).