TY  - THES
T1  - Pulmonary epithelial cells as model to investigate in vivo drug absorption across the human air-blood barrier
A1  - Bur,Michael
Y1  - 2007/09/13
N2  - The lung is more and more of interest for local as well as for systemic administration of drugs. Nevertheless, the development of modern inhalable medicines is moving forward only slowly. Especially the lack of safety and efficacy data combined with unsatisfactory in vitro models for the investigation of the complex processes on the air-blood barrier decelerates the development of new aerosol medicines.
In the first part of this thesis the transport of peptides with different molecular weight across submersed human alveolar epithelial cells has been investigated. The measured absorption/ secretion rates allow quantifying of permeability and the identification of active or passive transports, but the influence of formulation parameters like size or charge disappears after preparing solutions and adding these in the fluid filled apical compartment of submersed cell culture. However, with the aid of a relatively simple insufflator syringe and air interface cultivated cells, a deposition more close to the in vivo situation was possible. It was found that air interface deposition yielded higher absorption rates and that differences in particle size significantly influenced the absorption rates only after air interface deposition but not after liquid interface deposition. Even if the application with the insufflator syringe offers the opportunity to deposit dry particles on the air interface of cell monolayers the method wasn';t able to simulate in vivo relevant impaction processes. Especially in case of dry powder aerosols composed of large carrier lactose particles and adherent micronized drug crystals, impaction processes during aerosolisation normally accomplish separation of the drug from the carrier. Only the sufficiently small (< 5 µm) drug crystals are deposited in the deeper regions of the lung. As the insufflator fails to separate the drug crystals from the carrier lactose, and as the particle size of the carrier particles significantly influences the dissolution and absorption behaviour, a cell compatible aerosol impingement system was designed. A commercial available MSLI was modified to incorporate cell culture inserts in the relevant stages. Complex powder formulations could be size fractionated and the size fractions which are able to reach in vivo the deep lung were deposited on cell monolayers. Significantly changed absorption behaviour could be detected in dependency of cell culture fluid volume, particle size and deposition mode.
KW  - Zellkultur
KW  - Lunge
KW  - Permeabilität
KW  - Resorption
KW  - Arzneimittel
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2007/1278
ER  -