Oral proliposomal delivery of cromolyn and tiludronate: Formulation and in vitro characterization in Caco-2 cells and isolated rat gut

Cromolyn and tiludronate represent a wide class of hydrophilic drugs characterized by poor membrane partitioning and hence low and variable oral bioavailability. In an attempt to improve their oral absorption, it was hypothesized that an increase in the lipophilic nature of these drugs by encapsulation into lipid vesicles would make them conducive to uptake by the intestinal membrane. Phospholipid, cholesterol and surfactant based mixed micelle systems were formulated as beads for proliposomal delivery and their ability to enhance transport was evaluated using Caco-2 cells and the everted rat intestinal sac model.; Cromolyn loaded non-pareil beads were spray-coated with DSPC, cholesterol and a surfactant (Tween 80 or sodium cholate) mixed in varying proportions. The calculation of permeability coefficients (cm/s) indicate that transport of cromolyn across Caco-2 cell monolayers was maximum at a lipid-to-surfactant ratio of 3.2 (5.2 × 10−6 for cromolyn, 20.9 × 10−6 for DSPC:cholesterol:sodium cholate, 38.5 × 10−6 for DSPC:cholesterol:Tween 80). In order to evaluate the effect of lipid composition on drug transport, formulations of tiludronate using three phospholipids (DPPC/DSPC/DMPC) were prepared. Transport studies in the Caco-2 cell model exhibited a 12-fold increase in tiludronate transport with DMPC/cholesterol/Tween 80 formulation and an 8-fold increase with DMPC/cholesterol/sodium cholate formulation. The increase in cromolyn and tiludronate transport was found to be significantly higher with the proliposomal formulation compared to that observed with the addition of n-lauryl-β-D-maltopyranoside (LM), a known permeation-enhancer.; In the everted rat intestinal sac model, enhanced drug transport was accompanied by substantial tissue accumulation, indicating transport via the transcellular route. A comparison of drug clearance values in the Caco-2 cell and intestinal sac model from the proliposomal formulations yielded a strong linear correlation (R2 = 0.9262 for cromolyn; R2 = 0.982 for tiludronate), suggesting that drug delivery from the proliposomal formulations is robust to variability related to model properties. Unlike LM, the proliposomal formulations were free from membrane toxicity. In conclusion, proliposomal drug delivery systems may offer a safe and effective strategy to enhance transcellular transport and, hence, improve the absorption of hydrophilic drugs.