Purpose: To develop and characterise simulated gastrointestinal fluids for Ulcerative Colitis (UC) patients as a cost- and labour-effective in vitro tool for the assessment of drug solubilisation and dissolution in UC patients to identify drugs at risk of altered drug absorption in this patient population.
Methods: For the development of UC biorelevant media, the media simulating the gastrointestinal (GI) fluids in healthy subjects (FaSSGF, FaSSIF-V2, FaSSCoF, FeSSIF-V2, FeSSCoF) were used as reference. A literature search was performed to identify the main differences in the composition of GI fluids of UC patients compared to healthy subjects (all GI compartments: lecithin concentration; fasted state colonic media: bile salt concentration, pH, osmolality, soluble proteins; fed state colonic media: pH). The observed differences were included as factors with two levels in a Design of Experiment (DoE) approach for each prandial state (fasted, fed) and GI compartment (stomach, intestine, colon) to account for the observed interindividual variability in UC patients and resulted in 28 simulating UC GI media with centre points for gastric and intestinal media (Figure 1). For gastric and intestinal media, the bile salt/lecithin ratio was included as factor in the DoE to keep the same colloidal aggregates (mixed micelles) in some media. Differences in the osmolality were compensated by adjusting the concentration of sodium chloride when osmolality was not included as factor in the DoE. Media characterisation included the measurement of surface tension, osmolality, dynamic viscosity and buffer capacity. Statistical analysis was performed with XLSTAT® (Addinsoft) using one-way analysis of variance with post-hoc Tukey’s test to identify differences between properties of UC media and the corresponding healthy media at a significance level of p < 0.05.
Results: Surface tension in fasted state gastric media was significantly higher (+24%, p < 0.05) in the UC medium with low lecithin and low bile salt concentrations (UC-FaSSGF 1) compared to the healthy medium. In fasted state intestinal media, a significantly higher surface tension compared to the healthy medium was observed for the UC media with low lecithin concentrations (UC-FaSSIF 2 +4%, UC-FaSSIF 1 +15%, p < 0.05). In fasted state simulated colonic media, the surface tension in three UC media with low pH (UC-FaSSCoF 3 -11%, UC-FaSSCoF 7 -26% and UC-FaSSCoF 5 -31%, p < 0.05) was significantly lower compared to the healthy medium and the surface tension of UC-FaSSCoF 6 was increased by 7% (p < 0.05). In the fed state, the surface tension of UC media was significantly decreased compared to the healthy medium (-7 to -12%, p < 0.05). The surface tension of FeSSCoF was significantly higher compared to six of the UC media (UC-FeSSCoF 1, 2, 3, 4, 5, 7; p < 0.05). Differences in osmolality were observed in fasted state colonic media when osmolality was included as factor in the experimental design. In terms of dynamic viscosity, all healthy and UC media showed pseudoplastic behaviour and the viscosity at an applied shear stress of 0.15 Pa was in the range of 3.23 to 3.50 mPas in UC biorelevant media. The buffer capacity was not significantly different in healthy fasted and fed state intestinal media compared to UC media. In fasted state colonic media, the healthy medium had a significantly lower buffer capacity compared to all UC media whereas the opposite was found in the fed state (p < 0.05).
Conclusion: Differences in the properties of simulated gastrointestinal fluids of UC patients compared to biorelevant media developed based on healthy subjects were observed. This indicates that pathophysiological changes in UC patients compared to healthy subjects may alter surface tension, osmolality, viscosity and buffer capacity of gastrointestinal fluids of UC patients and thus, drug solubilisation and dissolution may be affected in this patients’ population.
Acknowledgements
This work has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 674909 (PEARRL).
Angela Effinger
– PhD student, University of Bath, Bath, EnglandAngela Effinger
– PhD student, University of Bath, Bath, EnglandCaitriona O'Driscoll
– Professor of Pharmaceutics, University College CorkMark McAllister
– Drug Delivery Group Leader, Pfizer Ltd.Nikoletta Fotaki
– Reader in (Bio)Pharmaceutics, University of Bath, EnglandNikoletta Fotaki
– Reader in (Bio)Pharmaceutics, University of Bath, EnglandAngela Effinger
– PhD student, University of Bath, Bath, England251 Views