Effect of common excipients on Caco-2 transport of low-permeability drugs.

The Biopharmaceutics Classification System (BCS) allows waivers of in vivo bioequivalence for rapidly dissolving immediate-release (IR) formulations of drugs with high solubility and high permeability. One potential issue in possibly extending BCS biowaivers to low-permeability drugs is the potential for excipients to modulate the intestinal permeability of the drug. The objective of this work was to evaluate the effect of nine individual excipients on the Caco-2 permeability of seven low-permeable compounds that differ in their physiochemical properties. Generally, most excipients had no influence on drug permeability. With the exception of sodium lauryl sulfate, no excipient affected Caco-2 monolayer integrity. Sodium lauryl sulfate moderately increased the permeability of almost all the drugs. Tween 80 significantly increased the apical-to-basolateral direction permeability of furosemide, cimetidine, and hydrochlorothiazide, presumably by inhibiting their active efflux, without affecting mannitol permeability. Additionally, docusate sodium moderately increased cimetidine permeability. Other excipients did not have significant effect on the permeability of these three drugs. Further work is needed to interpret the in vivo consequences of these observations from cell culture.

Transport of poly amidoamine dendrimers across Madin-Darby canine kidney cells.

The objective of this study was to determine the permeability of a series of poly amidoamine (PAMAM) dendrimers of generations 0-4 (G0-G4) across MDCK (Madin-Darby Canine Kidney) cell line. PAMAM dendrimers with incremental increase in size and molecular weight were labeled by fluorescein isothiocyanate (FITC) and the least polydisperse fractions were collected by size exclusion chromatography. MDCK cells were grown on Transwell filters for four days. The conjugates were detected by HPLC equipped with fluorescence detector. The permeability of the dendrimers across MDCK cells was determined in the apical to basolateral direction. The rank-order permeability of the PAMAM dendrimers was G4 >> G1 approximately G0 > G3 > G2. The permeability of mannitol in the presence of G4 increased by nine-fold. Results suggest that the transepithelial transport of PAMAM dendrimers is effected by both the polymer size, and the modulation of the cell membrane by the cationic dendrimers.