Drug delivery to the nose : formulation, deposition and permeation of poorly soluble drugs

Publication Type:
Thesis
Issue Date:
2017
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The nose, is a promising site to deliver drugs with low oral bioavailability and for treatment of conditions that require a rapid onset of action. It is the first option to treat localized diseases such as rhinitis but also it can be used as site to deliver drug systemically. In the future, the number of product administered through the nose it is expected to increase, as more drugs will require an effective route for drug absorption. Hence, while the current characterization of nasal product focus mainly on the physicochemical properties of spray formulations, the biopharmaceutical evaluation of new nasal drug delivery products and formulations will require robust and reliable pre-clinical in vitro models. The first aim of this study was to develop an apparatus able to perform deposition and permeation of nasal formulation at the same time, mimicking so the in vivo process of drug administration. The second aim was the application of this model to the characterization of commercial products and the development of novel formulations. In particular, to provide a physiologically relevant surface and barrier for the deposition and permeation studies, the cell line RPMI 2650 was chosen in order to establish a model of the nasal mucosa. The model was obtained using the air-liquid interface culturing method, in which the upper surface of the cell is exposed to air after the seeding on cell culture insert. The model developed showed production of mucus, expression of xenobiotic transporters similar to primary nasal cells and barrier properties matching those reported in literature for excised human nasal mucosa. The deposition apparatus was produced via 3D printing starting from an expansion chamber proposed by FDA for the determination the aerodynamic particle size of nasal sprays with cascade impactors. The apparatus developed consists of a plastic chamber able to accommodate cell culture inserts on its internal surface. This allows the deposition of aerosolised particles directly onto the surface of the RPMI 2650 cells previously cultured on inserts. The apparatus was validated against FDA glass expansion chamber using three different commercial products: two suspensions and one powder. The powder has shown faster permeation rate across RPMI 2650 cells nasal mucosa model. In conclusion, this work has developed, validated and tested an in vitro method to assess particles deposition and drug permeation in conditions similar to those occurring in vivo and which will be useful for the characterization and development of future nasal products.
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