A novel nanocapsule delivery system to overcome intestinal degradation and drug transport limited absorption of P-glycoprotein substrate drugs.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Nassar
Taher
T
Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, P. O. Box 12065, 91120, Jerusalem, Israel.
Rom
Alona
A
Nyska
Abraham
A
Benita
Simon
S
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D020895:Enterocytes / Q000201:enzymology; D006801:Humans; D065347:Hypromellose Derivatives; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007419:Intestinal Secretions / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects / Q000201:enzymology*; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D008863:Microspheres; D053769:Nanocapsules; D009821:Oils / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D016559:Tacrolimus / Q000737:chemistry / Q000378:metabolism*; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D053769:Nanocapsules; D009821:Oils; D011109:Polymethacrylic Acids; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus