Evaluation of the effects of selected disintegrants on drug membrane permeation

Abstract

Virtually all solid dosage forms contain a disintegrating agent to help facilitate breakup, dissolution and absorption. Traditionally, excipients were thought to be pharmacologically inert, but recently, an increasing number of studies have shown that they may play a part in either increasing or decreasing drug membrane permeation. This study focused on investigating the effects of selected disintegrants on intestinal epithelial drug permeation. Five different disintegrants were selected and tested together with a model compound which is a known P-glycoprotein (P-gp) substrate, namely Rhodamine 123 (R123). Bi-directional transport studies were conducted across excised pig jejunum tissue using a Sweetana-Grass diffusion apparatus. Samples of 180 μl were taken at 20 min intervals over a 2 h period and analyzed for R123 by means of a validated fluorescence spectroscopic method using a Spectramax Paradigm® plate reader. All transport studies were conducted in triplicate at four different concentrations of each selected disintegrant. The percentage transport, apparent permeability coefficient (Papp) values as well as efflux ratio (ER) values were calculated from the transport data. Trans-epithelial electrical resistance (TEER) was measured every 20 min using a Warner Instruments® EC-825A epithelial voltage clamp and changes were calculated to ensure membrane integrity was maintained and/or to register any effects on tight junctions by the disintegrants. Croscarmellose sodium (Ac-di-sol®) mediated pronounced increases in R123 transport in the absorptive (i.e. apical-to-basolateral) direction and decreased R123 transport in the secretory (i.e. basolateral-to-apical) direction when compared to the control group (R123 alone). This proved that Ac-di-sol® is capable of inhibiting P-gp-mediated efflux in a concentration dependent manner. Microcrystalline cellulose (Avicel® PH-200) caused less R123 transport at higher concentrations in both directions when compared to the control but also seemingly inhibited P-gp at lower concentrations. However, results were inconclusive, due multi-molecular complexes that may have formed and led to inconsistent R123 transport at higher concentrations. Sodium starch glycolate (Explotab®) exhibited an inhibitory effect on R123 transport at all concentrations and in both directions when compared to R123 alone, possibly indicating inhibition of transport by an increase in the diffusion distance. Crospovidone (Kollidon® CL-M) exhibited a concentration dependent inhibition of efflux, but to a lesser extent than Ac-di-sol®. Sodium alginate had no direct effect on P-gp, but did concentration dependently increase TEER in both transport directions. Increased TEER values indicate a closing of tight junctions, resulting in an apparent increase in efflux as paracellular transport is inhibited. The results of this study confirmed that some excipients, such as certain disintegrants, influence drug absorption by means of efflux inhibition or other mechanisms, which may result in changes in the bioavailability of certain drugs.