Monoterpenes-containing PEGylated transfersomes for enhancing joint cavity drug delivery evidenced by CLSM and double-sited microdialysis

The synovial tissues are natural sites of drug delivery for the treatment of rheumatoid arthritis. Our previous study showed that mixed monoterpenes edge-activated PEGylated transfersomes (MMPTs) could significantly enhance the percutaneous absorption of sinomenine (SIN), an anti-inflammation drug. The aim of this study was to investigate the potential of MMPTs for delivery of SIN to the synovial tissues in joint cavities. To this end, conventional liposomes (LPSs) were used as a reference. Transmission electron microscope, constant pressure extrusion method, and differential scanning calorimetry (DSC) were used for physicochemical characterization of the formulations. Confocal laser scanning microscopy (CLSM) and double-sited microdialysis coupled with LC-MS/MS were exploited to study the distribution of MMPTs in different skin layers and pharmacokinetics of SIN in the blood and the joint cavities. The results showed that mixed monoterpenes could significantly enhance the elasticity of MMPTs, evidenced by a decrease in the main transition temperature (Tm) and transition enthalpy (△H). CLSM analyses demonstrated that MMPTs were distributed in deep layers of the skin, indicating that MMPTs might transport SIN through the skin. In contrast, LPSs were confined in the stratum corneum, which deterred SIN from penetrating through the skin. The results from double-sited microdialysis pharmacokinetics showed that in the joint cavities the steady state concentration (Css) and AUC0→t of SIN from MMPTs were 2.1-fold and 2.5-fold of those from LPSs, respectively. In contrast, in the blood the Css and AUC0→t of SIN from MMPTs were about 1/3 of those from LPSs. This study suggested that MMPTs could enhance the delivery of SIN to the joint cavities. A combination of CLSM and double-sited microdialysis could give an insight into the mechanism of transdermal and local drug delivery. [Display omitted] •MMPTs-B can penetrate the skin barrier and bring much drug to the deep layers of skin.•MMPTs-B can not only realize enhanced joint cavity drug delivery, but also reduce the systemic exposure to the drug.•MMPTs not only have desired transdermal permeation feature, but also can provide local enhanced delivery profile.