Medizinische Universität Graz - Research portal
Selected Publication:
Radivojev, S.
Optimization of the current state of the art in vitro systems for improved prediction of the in vivo performance of inhalation products by in silico models
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp.
- Authors Med Uni Graz:
- Advisor:
- Fröhlich Eleonore
- Altmetrics:
- Abstract:
- Although for many centuries inhalation has been used as a common route to deliver active pharmaceutical ingredients (APIs) to patients, formulation development has been focused mainly on trial and error approaches. In the last decades, with the advances in technologies, many efforts have been invested into better understanding processes that occur in the lung. These enabled scientists to improve and create novel formulations but also optimize old ones and develop new in vitro and in silico systems that can be used to predict in vivo performance of inhalation products. Therefore, this work aimed to first assess what are the risks when patients mishandle their dry powder inhalers (DPIs), by thorough in vitro investigation of potential changes in the aerosolization performance and physical solid state due to high storage humidity. Secondly, a detailed investigation of the currently used dissolution methodologies for inhalation products as well as the media that can be used to simulate the lung lining fluid (LLF) was done. Additionally, the impact of mucus on the drug permeability and dissolution was studied. Finally, the application of physiologically based pharmacokinetic modelling (PBPK) as a feedback-feedforward approach was evaluated. It was found that erroneous storage of DPIs can have a detrimental impact on the formulation stability and its subsequent aerosolization performance. This, in turn, resulted in altered in vivo performance, which can have a notable influence on the desired therapeutic effect. Also, it was observed that in the case of highly soluble APIs, media used to mimic LLF can remain simple (for example phosphate buffer saline (PBS)), while in the case of lipophilic APIs it is important to consider the presence of lipids and proteins in the lung when designing in vitro experiments. An important factor that should not be neglected as well is the presence of mucus, that showed to influence drug permeability across the Calu-3 cells as well as dissolution of the double combination product, Symbicort®. The comparison of dissolution methodologies indicated that APIs dissolution performance will notably depend on the setup i.e. whether the dissolution is monitored in the setup with agitating aqueously based micelle suspension or in a flow-through design. Yet, simple methodologies can be used in early phase developments to discriminate between formulations. Lastly, the use of PBPK modelling was recognized as a valuable tool that can be applied to design in vitro methodologies that will better predict the in vivo behaviour of formulations but also as a risk assessment during a life cycle of a product.