Supervisors info:
Χριστοφόρου-Συμιλλίδου Μοίρα (επιβλέπουσα), Αναπληρώτρια Καθηγήτρια, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Ρέππας Χρήστος, Καθηγητής, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Βαλσαμή Γεωργία, Αναπληρώτρια Καθηγήτρια, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
Purpose: (i) To implement and evaluate the usefulness of a scaled down version of BioGIT, named μBioGIT. (ii) To use the BioGIT system for predicting the luminal performance of amorphous solid dispersions of two lipophilic drugs (Compound A and Compound B). (iii) To implement a new non-continuous in vitro methodology (“20-30 min one-step”) for the ex vivo and in vitro evaluation of products of lipophilic drugs in upper gastrointestinal lumen using human intestinal aspirates (HIFfasted) and FaSSIF Level II in the duodenal compartment respectively. (iv) To evaluate the particle size distribution of Compound B in the duodenal compartment during experiments with BioGIT and “20-30 min one-step” methodologies.
Methods: The evaluation of the μBioGIT methodology was achieved by comparing total and dissolved amount per volume in the duodenal compartment of three model compounds (ranitidine solution, ketoconazole solution and pioglitazone tablets) with corresponding data collected with BioGIT. Two different dose levels (high and low) were examined with the BioGIT system for the two solid dispersions and the differences between the two doses were evaluated. For the “20-30 min one-step” methodology the time interval of 20-30 minutes was chosen for the experiments. The total amount per volume, the concentration and the solid fraction, estimated using pioglitazone tablets, Compound A and Compound B in gastric compartment and FaSSIF or HIFfasted in the duodenal compartment, were evaluated. Finally, the particle size distribution of Compound B in the duodenal compartment was estimated with successive filtrations through filters with different pore sizes (1μm, 0,45 μm and 0,1 μm). The percentage of particles in each size range was estimated (>1 μm, 1-0,45 μm, 0,45-0,1 μm και <0,1 μm). Data collected using FaSSIF Level II and HIFfasted, as well as the BioGIT and “20-30 min one-step” methodologies were evaluated.
Results: The mean relative difference (%MRD) for total and dissolved amount per volume for each compound was estimated for the comparison between BioGIT - μBioGIT. In all cases, the %MRD was <10%, apart from the total amount of ketoconazole per volume at the sample of 5 minutes (15,33 %) and both total and dissolved amounts of pioglitazone per volume at the same sampling time point (25,95 % και 22,00 % respectively). The drug amount profiles in duodenal compartment of all three compounds between the two methodologies were also found to be similar when indices f1,area, ξ1 and ξ2 were calculated. The BioGIT experiments for both solid dispersion compounds showed that the low doses were totally dissolved during the experiment. Regarding the high doses, pronounced supersaturation was observed in the case of Compound A, whereas a relatively constant value of supersaturated concentration, about 1,5 times greater than the solubility, was observed for Compound B. In the majority of cases examined no statistically significant differences in drug amount per volume were observed when FaSSIF or HIFfasted was used in the duodenal compartment. The evaluation of the particle size distribution of Compound B, showed that during a BioGIT experiment the size of the particles changes (mainly < 0,45 μm at sampling time points of 5 and 45 minutes, > 0,45 μm during 15-35 minutes). Regarding the two methodologies, in BioGIT higher particle sizes were observed compared to the “20-30 min one-step” methodology. Differences in particle size distribution were observed between FaSSIF or HIFfasted in the duodenal compartment of “20-30 min one-step” set-up. The trend of these differences was not the same for the two doses of Compound B.
Conclusions: The μBioGIT methodology was found as effective as BioGIT for the evaluation of intraluminal performance of lipophilic compounds. High doses of both solid dispersions were found to supersaturate the contents of duodenal compartment throughout the experiment. Drug amounts per volume in FaSSIF and in HIFfasted were not statistically different, indicating that FaSSIF is quite effective as simulated intraluminal media. Overall, there are no substantial differences in particle size distribution of Compound B between FaSSIF and HIFfasted. Differences in particle size distribution between FaSSIF and HIFfasted may be related to factors that differentiate the composition of the two media and their effect may vary with the dose of the drug.
Keywords:
BioGIT, μBioGIT, 20-30 min one-step, human intestinal aspirates, dissolution study, precipitation, gastrointestinal transfer, solid dispersions, lipophilic drugs.
