Dorota Justyna Sarwinska

• Orally administered medications are susceptible to different conditions, which can change the pharmacokinetics (PK), and directly influence the bioavailability of a drug. Because older adults are susceptible to drug adverse effects, changes in drug PK may be harmful to them, therefore, it is favourable to know how they take their medications in real life. The presented thesis combines theoretical and practical aspects of dosing conditions. First, by means of a questionnaire study, the real-life dosing conditions in older adults were investigated to identify the possible problems that can affect the safety and efficiency of orally administered medications from a biopharmaceutical perspective. The developed questionnaire was applied in Germany and Poland. Both study populations were similar regarding drug intake. Typical dosing conditions reported by older populations in Germany and Poland that were the most important for drug absorption were as follows: I. Drug intake was on average, with ~100 mL of fluid (in Germany, most often ~200 mL, in Poland ~50 mL). II. Non-carbonated water, tea, coffee, and carbonated water were commonly used for drug administration. III. Medications were mostly taken directly after meals; in Germany, also 30 minutes before breakfast. IV. Bread-based meals dominated breakfast and dinner. V. Solid dosage forms were preferred for their ease of use and swallowing. Second, the data about the most common fluids co-administered with medications by older adults were used to investigate the influence of real-life fluids on the disintegration of gelatine and HPMC capsules in vitro and in vivo. For in vitro studies, the USP 2 apparatus and the biorelevant GastroDuo model were used. In a clinical study with 12 young, healthy volunteers and 6 study arms, the salivary tracer technique was used. In the clinical study, the gastric emptying of administered fluids was also investigated. In vitro data demonstrated that co-administered fluids strongly affected capsules' behaviour. For gelatine capsules, temperature had the greatest influence. HPMC capsules were more consistent, however, black tea delayed their opening time and drug release in the USP 2 apparatus. In vivo, gelatine capsules were also highly affected by the temperature, with the fastest opening in warm water and significantly slower in cold water. However, warm black tea significantly delayed the opening time of gelatine capsules in comparison to warm water. HPMC capsules behaved consistently in all fluids, showing no effect of temperature or black tea ingredients. Overall, HPMC capsules were more robust under fasting conditions. Results also highlighted differences between in vitro models. USP 2 apparatus captured mainly temperature effects, while GastroDuo better reflected in vivo conditions by simulating gastric emptying, pH, volumes of media, secretion and pressure events and predicted well the behaviour of HPMC capsules in vivo. No significant differences in gastric emptying of tested fluids were observed, which demonstrates that the indirectly detected capsule behaviour is the result of their properties and the influence of the co-administered fluid, not a matter of differences in gastric emptying. Older adults in Poland and Germany interviewed within the presented thesis mostly administered their medications with non-carbonated water. However, the usage of black tea was also worth noting, since it was especially prevalent among the Polish population and in further studies it was demonstrated that it significantly delayed the opening time of gelatine capsules in vivo. The collected data gave an overview of capsules' behaviour in real-life fluids and demonstrated that dosing conditions are important. Investigating how patients take their medications is a way to ensure a more patient-centric approach in drug development.