10th International Aerosol Conference September 2 - September 7, 2018 America's Center Convention Complex St. Louis, Missouri, USA
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Biokinetics of Aerosolized Liposomal Ciclosporin a in Human Lung Cells in Vitro Using an Air-Liquid Cell Exposure System (Alice)
OTMAR SCHMID, Corinne Jud, Yuki Umehara, Dominik Mueller, Albert Bucholski, Friedrich Gruber, Oliver Denk, Roman Egle, Alke Petri-Fink, Barbara Rothen-Rutishauser, Helmholtz Zentrum Munchen, Comprehensive Pneumology Center
Abstract Number: 1490 Working Group: Aerosols in Medicine
Abstract Background Inhalation of drugs in aerosolized form is a promising route for non-invasive targeted drug delivery to the lung. Nanocarrier systems such as liposomes have been explored for inhalation therapy opening new avenues including stabilization of non-soluble drugs (e.g. Ciclosporin A (CsA)) and controlled release. Optimized aerosol delivery technologies are required for implementing aerosols into the early preclinical phases of drug testing (instead of pipetting of substances).
Methods The previously introduced ALICE (Air-Liquid Interface Cell Exposure) system equipped with an investigational eFlow® Technology vibrating membrane nebulizer has been used for an in vitro study of the biokinetic behavior of nano-sized liposomes loaded with the immunosuppressive drug CsA (L-CsA) at the lung epithelial barrier. Human lung epithelial cells (alveolar A549 and bronchial 16HBE14o- epithelial cells) were exposed to aerosolized L-CsA at the air-liquid interface (ALI) and the temporal profile of the L-CsA dose in the apical, basal and cell compartment were monitored up to 24h.
Results Aerosolization of different volumes of L-CsA solution with the ALICE resulted in dose-controlled, efficient (ca. 7% of invested substance reached the cells), spatially uniform (<8% SD for different inserts) and reproducible L-CsA (<12% SD) delivery. The measurements were performed under non-toxic conditions as determined by cell viability in pro-inflammatory cellular response at 24h post-exposure. The biokinetics analysis revealed that both cell types formed a tight but imperfect barrier for L-CsA resulting in initially high transbarrier L-CsA transport rates, which ceased after about 4h. This burst-like L-CsA transport profile, which is typically also observed in patients, cannot be observed with standard non-aerosolized (submerged) biokinetics assays. Moreover, a 150-fold higher L-CsA concentration was established in the apical (air-exposed side of the cells) and cell compartment compared to the basal compartment (“blood” exposure side of cells). Most importantly for pulmonary drug targeting, a high cellular L-CsA dose level (20-25% of the delivered dose) was obtained rapidly (<1h) and maintained for at least 24h suggesting rapidly established and uniform drug levels in the lung epithelium.
Conclusions The ALICE exposure system combined with lung epithelial cells cultured at the ALI offers a reliable and relevant in vitro platform technology to study the effects of inhalable substances such as L-CsA under biomimetic conditions.