A delivery system to avoid self-aggregation and to improve in vitro and in vivo skin delivery of a phthalocyanine derivative used in the photodynamic therapy

摘要

The hydrophilic character and aggregation phenomena exhibited by the photosensitizer zinc phthalocyanine tetrasulfonate (ZnPcSO_4) make it difficult for this compound to penetrate the skin, and reduce the compound's photodynamic efficacy. A microemulsion (ME) was developed to increase the skin penetration of ZnPcSO_4 while avoiding its aggregation. Ternary phase diagrams composed of surfactants (Span? 80/Tween? 80), canola oil and a propylene glycol (PG)/water mixture (3:1) were constructed as a basis for choosing an adequate ME preparation. Rheological, electrical conductivity, dynamic light scattering and zeta potential studies were carried out to characterize the ME formulations. Monomerization of ZnPcSO_4 in the ME was determined photometrically and fluorometrically. In vitro skin penetration and retention of the compound in the skin were measured using porcine ear skin mounted on a diffusion cell apparatus. The in vivo accumulation 6 h after ZnPcSO_4 application was determined fluorometrically in hairless mice skin. Confocal laser scanning microscopy was used to visualize ZnPcSO _4 distribution in the skin. A ME composed of canola oil:surfactant:PG-water at 38:47:15 (w/w/w) was chosen for ZnPcSO_4. This was oil-in-water with internal phase diameter of 15.7 ± 0.15 nm. Spectroscopic techniques confirmed that the ME was able to keep ZnPcSO _4 in its monomeric form. In the in vitro penetration of ZnPcSO _4 in the stratum corneum (SC) and in epidermis (without stratum corneum) with dermis ([E + D]) was 33.0- and 28.0-fold higher, respectively compared to the control solution of the drug. In vivo studies, confirmed that when the ME was used as carrier, ZnPcSO_4 concentrations in the SC and [E + D] were about 1.6- and 5.6-fold higher, respectively, than controls. Visualization of ZnPcSO_4 skin penetration by confocal laser scanning microscopy confirmed that the ME increased both penetration and biodistribution of this photosensitizer in the skin.