Applications of a Biorelevant In Vitro Dissolution Method Using USP Apparatus 4 in Early Phase Formulation Development.

摘要

Dissolution plays various roles throughout drug development, including assessment of the lot-to-lot quality of a drug product, guidance for development of new formulations, and assurance of continuing product quality and performance throughout a drug's lifecycle. To that end, one of the most important and useful applications of dissolution testing is to predict the in vivo performance of solid oral dosage forms.;However, there are several limitations of the traditional dissolution method that often emphasizes its quality control role with the primary objective to achieve 100% drug release, particularly during first in human trials. Some of these limitations include inadequate dissolution of poorly soluble drugs as well as the use of simple aqueous buffer solutions and hydrodynamics, which do not represent the in vivo environment.;The USP apparatus 4 in the open system configuration has more laminar hydrodynamics than other USP apparatuses. Together with the use of biorelevant dissolution media, this in vitro dissolution system may better mimic the in vivo environment, which may provide information that is clinically-relevant throughout clinical development. Using this system, an in vitro dissolution method was developed in a systematic way using the BCS class II compound, ibuprofen as the model compound.;This in vitro dissolution method was then applied to additional BCS class II compounds spanning a broad range of commercial and development compounds within this BCS class. Specifically, the work presented in this thesis suggests there are several potential applications for the in vitro biorelevant dissolution method developed. These applications include rank ordering of formulations, evaluation of pH modifiers, evaluation of food effect, evaluation of dose assessment, and lot-to-lot consistency.