Logo: to the web site of Uppsala University

Pulmonary drug delivery has been used for decades to treat local diseases like asthma. When using the pulmonary route to deliver drugs, several important lung features are being used, such as a large surface area available for absorption, high organ vascularization, and a thin blood-alveolar barrier. Pulmonary drug delivery systems on the market are formulations with a rapid release, which leads to a high drug concentration initially and a prompt decline in concentration shortly thereafter. This could cause unfavourable adverse effects or toxicity to the lung tissue at the onset of the release and could also result in decreased efficacy. To overcome these challenges, there is a need to develop controlled release drug delivery systems to improve the therapeutic effectiveness of inhaled drugs. When a drug is inhaled, the drug particles will deposit in the lung, and the drug needs to dissolve in the lung fluids before the drug is available for uptake locally or in the systemic circulation. The absorption inhaled drug thus depends on the dissolution of the drug particles in the lung fluid. As a result, it could be possible to prolong the duration of the drug effect, by prolonging the time it takes for the dissolution of the drug particles. Due to this, in vitro methods analysing the dissolution of the drug particles in the lung are of high relevance for the development of novel pulmonary drug delivery systems. It is therefore of high importance that the dissolution profiles that are measured are well understood. The overall aim of this thesis was to evaluate and characterise an in vitro dissolution method (Transwell system) for assessment of novel pulmonary drug delivery systems, with a focus on future controlled release systems. A developed mechanistic model was used to analyse experimental dissolution data and to predict which process was the rate limiting step in the obtained profiles. The developed mechanistic model provided the same rank order as the Weibull fit, however the model provided additional detailed understanding of the used dissolution process and setup. In addition, two novel controlled release drug delivery systems, mesoporous silica particles and hyaluronic based hydrogels, were successfully analysed using this in vitro dissolution system. Both delivery systems showed a promising aerosolization and control over the release profiles. Finally, the micellar contribution to diffusion of poorly soluble inhaled drugs during in vitro dissolution was defined and validated using the obtained in vitro dissolution profiles. Physiologically based biopharmaceutics modelling tools were successfully established for Bud, BDP and FP using the diffusivity values taking into account the micellar contribution of the surfactant.