Purpose. To design a double-coated nanoparticulate delivery system of tacrolimus capable of overcoming the P-glycoprotein pump and CYP3A barriers without affecting their physiological activities. Materials and Methods. Tacrolimus loaded oil cores were first nanoencapsulated with two polymethacrylate polymers followed by the microencapsulation of these nanocapsules within hydroxypropylmethylcellulose using a spray drying technique. The Trojan effect of these double-coated nanocapsules was evaluated in Caco-2 monolayer by monitoring the tacrolimus uptake and measuring the transport of tacrolimus across the rat jejunum membrane. Results. The formulation was shown to release nanocapsules rather than dissolved drug under sink conditions. The nanocapsules protected tacrolimus from degradation in the diluted intestinal fluids following 2 h incubation. The Caco-2 and intestinal segment uptake of tacrolimus from the novel delivery system with and without verapamil was significantly higher than the uptake of tacrolimus from the aqueous solution and emulsion. The blank drug delivery system did not inhibit the P-gp pump activity. The nanocapsules internalized rapidly in the enterocytes as confirmed by the histological results. Conclusion. The overall results suggest that the novel nanodelivery system which does not alter the activity of the P-gp is a potential platform for intestinal transport of sensitive lipophilic molecules that are P-gp substrates.
Bibliographical noteFunding Information:
This work was supported in part by a grant from the Chief Scientist Office of the Ministry of Trade and Industry (NOFAR program), Jerusalem, Israel and from Nanolymf Ltd., Rosh Ha’ayin, Israel. Simon Benita is affiliated with the David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem.