Drug-in-micelles-in-liposomes (DiMiL) systems as a novel approach to prevent drug leakage from deformable liposomes

Abstract

Deformable liposomes (DL) are successfully exploited to enhance the skin penetration of several compounds. Nevertheless, the "soft" nature of the bilayer favors the drug leakage, mainly in the case of hydrophobic compounds. This work aimed to develop a suitable strategy to stabilize the lipid bilayer, without compromising the deformability properties of DL. The approach relied on the design of a "matryoshka" system, namely a drug in micelles in deformable liposomes (DiMiL) system. The performances (drug leakage, deformability and in vitro skin penetration profile) of DiMiLs were tested using nifedipine and piroxicam as model compounds and compared to those of traditional DL. The micelles were made of Kolliphor HS15 whereas the lipid vesicles were composed of egg-phosphatidylcholine and Tween 80 (T80) at 95:5 or 85:15 w/w ratios. As expected, the drug leakage from DL was high after only one month of storage (almost 50% in the case of nifedipine and in the range of 39-79% in the case of piroxicam loaded DL, depending on T80 content). Optimized DiMiL formulations retained instead the drug content up to two-months storage period. Moreover, the constant of deformability of DiMiLs felt in the acceptance range for deformable vesicles intended for cutaneous application and the skin permeated amount of the delivered drugs was increased of at least 4 times. In conclusion, DiMiL reveals to be a suitable approach to avoid the leakage of hydrophobic compounds and an attractive transdermal drug delivery system for poorly permeable drugs.

Keywords: Elastic vesicles; Ethosomes; Nifedipine; Piroxicam; Transdermal; Transethosomes; Transfersomes.