In vitro release, ex vivo penetration, and in vivo dermatokinetics of ketoconazole-loaded solid lipid nanoparticles for topical delivery

The study focused to evaluate and investigate optimized (using QbD) and novel ketoconazole (KTZ)-loaded solid lipid nanoparticles (KTZ-SLNs; 2% w/v KTZ) for enhanced permeation across skin. KTZ-SLNs were evaluated for size, distribution, zeta potential (ZP), percent entrapment efficiency (%EE), drug release, morphology (HRTEM and FESEM), thermal behaviour (DSC), spectroscopic (FTIR), and solid-state/diffraction characterization (X-ray diffraction, XRD). Moreover, ex vivo permeation and drug deposition into rat skin were conducted using Franz diffusion cell. The same was confirmed using human dermatome skin and fluorescence, confocal Raman, and vibrational ATR-FTIR microscopic methods. An in vivo dermatokinetics study was performed in rats to assess the extent of KTZ permeation into the skin. Stability including accelerated and photostability studies were conducted at different temperatures (2-8, 30, and 40 degrees C) for 12 months. The spherical, optimized KTZ-SLN formulation (KOF1) showed particle size of 293 nm and high EE of 88.5%. Results of FTIR, DSC, and XRD confirmed formation of KTZ-SLNs and their amorphous nature due to presence of KTZ in a dissolved state in the lipid matrix. In vitro release was slow and sustained whereas ex vivo permeation parameters were significantly high in KTZ-SLNs as compared to free drug suspension (KTZ-SUS) and marketed product (Nizral (R); 2% KTZ w/v). Drug retention was 10- and five-fold higher than KTZ-SUS and marketed product, respectively. In vivo dermatokinetics parameters improved significantly with SLN formulation (410-900% enhanced). Confocal Raman spectroscopy experiment showed that KTZ-SLNs could penetrate beyond the human stratum corneum into viable epidermis. Fluorescent microscopy also indicated improved penetration of KTZ-SLNs. KTZ-SLNs were photostable and showed long-term stability over 12 months under set conditions.

Automated summary

This study evaluated the enhanced permeation across the skin of optimized ketoconazole-loaded solid lipid nanoparticles. The nanoparticles showed improved size, distribution, and entrapment efficiency. In vitro and in vivo experiments demonstrated enhanced permeation and retention of the drug compared to free drug suspension and a marketed product. Confocal Raman spectroscopy confirmed the penetration of the nanoparticles into viable epidermis. The nanoparticles also showed long-term stability and photostability.