PAMPA–Excipient Classification Gradient Map

摘要

The effect of excipients on the artificial membrane permeability (Double-Sink PAMPA) properties of eight sparingly soluble drugs was studied. Quantities of excipient were selected to match the concentrations expected in the gastrointestinal fluid under clinically relevant conditions. Over 1,200 measurements were performed. To correct for the effects of the aqueous boundary layer and determine the intrinsic permeability, precisely measured ionization constants were used. The intrinsic permeability of weak acids was enhanced (up to 100 fold) but that of weak bases depressed (up to 270 fold) by the excipients: mefenamic acid > glybenclamide > progesterone > griseofulvin > clotrimazole > astemizole > dipyridamole > butacaine. Excipient enhancement ranked: 3 mM NaTC > 0.24% PEG400 > 0.2 M KCl > 0.24% NMP > 5% PEG400 > 0.24% PG > 1% PEG400 > 0.1M KCl > 1% PG > 1% NMP > 5% PG > 0.24% HP-β-CD > 1% HP-β-CD > 15 mM NaTC. The study clearly indicates that the method is suitable for use in preclinical development to assess the effect of excipients on the permeability of sparingly soluble drug candidates. The method is quick, cost-effective, and reasonably accurate. The self-rank-ordered PAMPA-Mapping may be a helpful visualization tool for delivery screening.