Development of biomimetic phospholipid vesicle-based permeation assays (PVPA) as screening tool in drug development

Abstract

Although several routes of administration can be utilized to bring a drug to the desired site of action, oral administration is still the most important and prevalent route of administration, due to its cost efficiency, convenience and patient compliance. A prerequisite for successful oral therapy is the ability of a drug to cross the gastrointestinal barrier. Over the past two decades, the number of new biological active chemical entities has increased due to the modern discovery programs, often based on combinatorial chemistry and high-throughput screening. Consequently, appropriate and reliable high-throughput in vitro models to assess the permeability of new drug candidates and drug formulations are required to increase the success rate and to reduce the time and cost for development. The phospholipid vesicle-based permeation assay (PVPA) is an in vitro permeability model consisting of a tight layer of liposomes immobilized on a filter that successfully has been used to test novel active substances and formulations. The first part of this thesis was to employ the PVPA for the first time as a screening tool to assess and improve the permeability of acyclovir (ACV), a poorly permeable model drug, by designing mucoadhesive liposomal formulations. The incorporation of ACV into liposomes resulted in a significant increase in the in vitro permeability of ACV, and mucoadhesive coating further enhanced the permeability for some of the formulations. The next part of this thesis was to develop a more robust, biomimetic PVPA with a lipid composition mimicking that of the intestinal barrier. The permeability values obtained showed that the positively charged basic compounds showed increased permeability through the negatively charged biomimetic PVPA compared to the original PVPA. The results from the model drugs also correlated well with in vivo on fractions absorbed in humans. Further, the charge in lipid composition resulted in a tremendously increase in barrier robustness in the presence of tensides compared with the original PVPA as well as improved storage stability for up to 6 months at -70oC. The biorelevance of the model was further improved by using biorelevant media. The biomimetic barrier was found to be compatible with fasted state and fed state simulated intestinal fluids (FaSSIF and FeSSIF). Four model drugs exhibited changes in permeability in the presence of the different simulated intestinal fluids in agreement with previous reports. Collectively, these findings moved the biomimetic PVPA an important step forward toward use as a better in vitro permeability model in drug development.