Permeation of Therapeutic Drugs in Different Formulations across the Airway Epithelium In Vitro.
BACKGROUND
Pulmonary drug delivery is characterized by short onset times of the effects and an increased therapeutic ratio compared to oral drug delivery. This delivery route can be used for local as well as for systemic absorption applying drugs as single substance or as a fixed dose combination. Drugs can be delivered as nebulized aerosols or as dry powders. A screening system able to mimic delivery by the different devices might help to assess the drug effect in the different formulations and to identify potential interference between drugs in fixed dose combinations. The present study evaluates manual devices used in animal studies for their suitability for cellular studies.


METHODS
Calu-3 cells were cultured submersed and in air-liquid interface culture and characterized regarding mucus production and transepithelial electrical resistance. The influence of pore size and material of the transwell membranes and of the duration of air-liquid interface culture was assessed. Compounds were applied in solution and as aerosols generated by MicroSprayer IA-1C Aerosolizer or by DP-4 Dry Powder Insufflator using fluorescein and rhodamine 123 as model compounds. Budesonide and formoterol, singly and in combination, served as examples for drugs relevant in pulmonary delivery.


CONCLUSIONS
Membrane material and duration of air-liquid interface culture had no marked effect on mucus production and tightness of the cell monolayer. Co-application of budesonide and formoterol, applied in solution or as aerosol, increased permeation of formoterol across cells in air-liquid interface culture. Problems with the DP-4 Dry Powder Insufflator included compound-specific delivery rates and influence on the tightness of the cell monolayer. These problems were not encountered with the MicroSprayer IA-1C Aerosolizer. The combination of Calu-3 cells and manual aerosol generation devices appears suitable to identify interactions of drugs in fixed drug combination products on permeation.
Center for Medical Research, Medical University of Graz, Graz, Austria.
Claudia
C
Meindl
Research Center Pharmaceutical Engineering GmbH, Graz, Austria.
Sandra
S
Stranzinger
Research Center Pharmaceutical Engineering GmbH, Graz, Austria.
Neira
N
Dzidic
Research Center Pharmaceutical Engineering GmbH, Graz, Austria.
Sharareh
S
Salar-Behzadi
Research Center Pharmaceutical Engineering GmbH, Graz, Austria.
Stefan
S
Mohr
Department of Pharmaceutical Technology, Institute of Pharmaceutical Sciences, Karl-Franzens-University of Graz, Graz, Austria.
Andreas
A
Zimmer
Center for Medical Research, Medical University of Graz, Graz, Austria.
Eleonore
E
Fröhlich
D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage / Q000493:pharmacokinetics; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019819:Budesonide / Q000008:administration & dosage / Q000493:pharmacokinetics; D000069502:Budesonide, Formoterol Fumarate Drug Combination / Q000008:administration & dosage / Q000493:pharmacokinetics; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation* / Q000379:methods*; D004847:Epithelial Cells / Q000187:drug effects; D004867:Equipment Design; D019793:Fluorescein / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068759:Formoterol Fumarate / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D009330:Nebulizers and Vaporizers; D020112:Rhodamine 123 / Q000008:administration & dosage / Q000493:pharmacokinetics
D000336:Aerosols; D001993:Bronchodilator Agents; D000069502:Budesonide, Formoterol Fumarate Drug Combination; D004338:Drug Combinations; D020112:Rhodamine 123; D019819:Budesonide; D019793:Fluorescein; D000068759:Formoterol Fumarate