Drug Diffusion through Cystic Fibrotic Mucus: Steady-State Permeation, Rheologic Properties, and Glycoprotein Morphology

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Abstract
One manifestation of cystic fibrosis (CF) is the presence of a viscid mucus secretion in the lungs. The clearance of this mucus is significantly slower than in "normals" due to uncoordinated beating of the cilia and the increased viscosity of the mucus. In these studies, the permeabilities of p-aminosalicylic acid, isoniazid, and pyrazinamide through unpurified CF respiratory mucus and through purified pig gastric mucus solutions were compared in order to evaluate the relative barrier properties of these mucus solutions. These model compounds, while not often used clinically in CF, are used in other pulmonary diseases and have the potential to be administered by inhalation delivery systems. Permeability studies were carried out in Side-Bi-Side diffusion cells fitted with a custom membrane holder capable of retaining the mucus solutions. Permeabilities through CF mucus solution and its fractions were compared to those measured through buffer and reconstituted purified pig gastric mucus. There were 28--75% decreases in drug permeability when pig gastric mucus was replaced by different CF mucus solutions. This indicates that optimal drug delivery directly to the lungs must take into account the decreased drug transport rate across diseased mucus in addition to drug loss due to binding to the glycoproteins or inefficient delivery via aerosolization. Transmission electron microscopy revealed minor differences in the glycoprotein strand structure between reconstituted pig gastric mucus and CF mucus primarily with regard to glycoprotein chain length and extent of branching. Similar viscoelastic behaviors between the CF gel fraction and synthetic CF mucus were observed. This model CF mucus system can simulate diseased mucus and can be utilized for in vitro studies to optimize drug permeability.