PT  - JOURNAL ARTICLE
AU  - Hendrik Fischer
AU  - Rudolf Lucas
AU  - Helmut Pietschmann
AU  - Susan Tzotzos
AU  - Bernhard Fischer
TI  - Pharmaceutical development of a liquid formulation for pulmonary application of a peptide
DP  - 2012 Sep 01
TA  - European Respiratory Journal
PG  - P2183
VI  - 40
IP  - Suppl 56
4099  - http://erj.ersjournals.com/content/40/Suppl_56/P2183.short
4100  - http://erj.ersjournals.com/content/40/Suppl_56/P2183.full
SO  - Eur Respir J2012 Sep 01; 40
AB  - ALI/ARDS are acute and severe conditions with mortality up to 50%. Currently, no specific drug-related treatment exists. ALI/ARDS are characterized by pulmonary oedema due to increased permeability of the endothelial/epithelial barrier. Oedema clearance is linked to Na uptake at the apical side of Type I/II alveolar cells through the amiloride-sensitive epithelial sodium channel “ENaC”. AP301, a synthetic peptide derived from the lectin-like domain of TNFα, enhances Na transport through ENaC and thus oedema clearance. As ENaC is located at the inner surface of alveoli, the water soluble AP301 is administered by inhalation of a nebulised aqueous solution. Hence, pharmaceutical development of AP301 as potent new drug for oedema resolution differs from standard orally or parenterally applied medicine and has to follow specific pharmaceutical and medicinal regulations of the Pharmacopoeia and inhalation medicine guidelines. AP301 is nebulised by a mesh-type not a jet or supersonic type nebulizer due to simplicity and effective, but gentle aerosol generation. In order to reach the alveoli the particle size of the aerosol was optimized to <5µm by testing a range of different concentrations of AP301 in combination with various nebulizers. Analyses of biological activity of AP301 in the generated aerosol showed that it was retained during nebulisation. To exactly predict clinically relevant doses of AP301, the amount of aerosol reaching the mouth of subjects was analyzed with a breath simulator. To correlate animal toxicity and safety data to human equivalent dose, scaling between species was done according to the AP301 concentration per lung weight, rather than per body surface area or body weight.