Patrícia Henriques1,2, Joana Bicker1,3 Slavomíra Doktorovová2, Ana Fortuna1,3
1Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
2R&D, Drug Product Development, Hovione FarmaCiencia SA, Lisbon, Portugal
3CIBIT/ICNAS, Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
Summary
In nasal drug product development, biorelevant in vitro methodologies are vital in order to select promising compounds or formulations, potentially reducing pre-clinical and clinical trials. Permeability assays are often applied to predict drug absorption and bioavailability. For nasal delivery products, permeation models include ex vivo models using excised nasal mucosa and in vitro cell culture models. However, ex vivo models present high variability and cell culture models are very time consuming. The Parallel Artificial Membrane Permeability Assay (PAMPA) has emerged as a high throughput screening tool to evaluate drug permeability, and it has been applied to several barriers such as the intestine, skin or blood-brain-barrier. Herein, a new PAMPA model was developed and optimized to predict nasal permeability, using a biorelevant donor medium containing mucin. The apparent permeability (Papp) of 15 reference compounds was assessed in six different experimental conditions. The model with 0.5% (w/v) mucin in the donor compartment and 2% (w/v) phosphatidylcholine in the lipid membrane correctly distinguished high and low permeable compounds, with no false positives or negatives. In addition, it exhibited the highest correlation with permeation across human nasal epithelial RPMI 2650 cells (R2 = 0.71). Overall, the optimized PAMPA model was reproducible, predictive and inexpensive, showing to be a promising non-cell based and biorelevant in vitro tool that could be applied in an early screening stages of new nasal drug delivery products.
Key Message
A new nasal-PAMPA model with 0.5% (w/v) mucin on donor compartment and 2% (w/v) phosphatidylcholine in lipid membrane can differentiate high and low permeable compounds for nasal delivery and shows to be a promising predictive and high throughput tool for assessment of intranasal drug permeability for application in early phase screening studies.