(M1530-03-19) Impact of Food on the Release and Bioaccessibility of an Oral BCS Class IV Compound formulated from Different Conventional and Enabling Formulations using the Dynamic Gastrointestinal Model Tiny-TIMsg

Purpose: The study aims to determine the percentage of an oral BCS Class IV compound (Compound A) available for intestinal absorption (Bioaccessibility) using an advanced dynamic gastrointestinal model tiny-TIMsg. The study also aims to understand the impact of concomitant administration of food on bioaccessibility of the drug substance, a free base with pH dependent solubility when formulated as conventional dosage forms such as Drug-in-Capsule (DIC) and tablet versus an enabling Amorphous Solid Dispersion (ASD).

Methods: The DIC capsule formulations were prepared by filling crystalline API into size 0 capsules and tablet formulations were manufactured by blending crystalline API with conventional tableting excipients followed by roller compaction and tableting. Enabling formulations were prepared using spray drying as 1:1 mixture of API and polymer filled into size 00 capsules at a comparable dose. The tiny-TIMsg system is a dynamic, computer-controlled, two-compartmental in vitro model equipped with an advanced gastric compartment which allows a realistic simulation of the rate and composition of gastric secretions as well as the process of gastric emptying into a single intestinal compartment. Fasted and fed state conditions were simulated by implementing physiologically relevant pH profiles and fluid secretions. A clinically relevant dose of the compound was administered to the stomach compartment with high fat meal (HFM) in fed conditions or water in fasted experiments. To determine the fraction available for absorption, i.e., bioaccessible, tiny-TIMsg performed automatic sampling by filtrating the intestinal content through a filter at predefined time intervals. Filtrate samples were analyzed for their concentration of Compound A using UPLC-UV.

Results: The bioaccessibility (% of dose) from the small intestinal compartment, was slightly lower under fasted state compared to the fed state for all three formulations indicating a minimal positive food effect. After 5 hours of testing in the tiny-TIMsg under fasted state conditions, the bioaccessibility measured in the filtrate fractions was comparable between DIC and tablet, with 86.1 ± 2.2 % and 85.7 ± 0.6 % of the initial dose, respectively, whereas this was considerably lower for SDD capsule with 52.3 ± 2.8 %. Similarly, after 6 hours of testing under fed state conditions, the bioaccessibility measured in the filtrate fractions was comparable between DIC and tablet, with 94.5 ± 0.2 % and 94.7 ± 0.8 %, respectively, and significantly lower for SDD capsule with 60.8 ± 8.3 %. DIC and tablets showed comparable maximum bioaccessibility (BA_max) in the fasted state with 16.5 ± 1.5 % and 15.8 ± 0.1 % of dose, respectively, whereas tablets had the highest BA_max in the fed state with 25.9 ± 0.1 %. SDD capsules had the lowest BA_max in both the fasted and fed state, with 8.8 ± 0.5 % and 9.6 ± 2.1 %, respectively. The time to BA_max (t_max) was comparable for all three formulations and was registered between 120 and 150 minutes from the start of the experiment in the fasted state and between 150 and 180 minutes from the start of the experiment for all tested formulations in the fed state. Moreover, the t_max in the fasted TIM studies (120-150 minutes) closely matched the observed t_max in PK studies conducted in pre-clinical species for DIC and tablet formulations in fasted state (Data not shown).

Conclusion: The findings of this study revealed the absence of a significant food effect on Compound A bioaccessibility, as this was comparable in the fasted and fed state after the full time period of an experiment for all the three formulations. The newly developed SDD formulation showed the lowest total bioaccessibility as compared to the DIC and tablet formulations which could be due to the poor wettability of the ASDs in intestinal media compared to crystalline API and could be overcome by formulating the ASDs using extragranular disintegrant and dissolution aids. However, since the DIC and tablet formulations showed similar behavior and immediate release profile under fasted state simulated conditions, further optimization of ASDs was unwarranted. The advanced dynamic tiny-TIMsg was able to discriminate differences between the formulations and can be employed as a predictive tool for fast formulation testing and iteration, prior to the performance in human clinical trials.

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Cumulative bioaccessible Compound A using the DIC formulation over time as measured in the small intestinal filtrate under fasted and fed state conditions in the tiny-TIMsg (% of dose, average ± stdevp, n = 2).

Cumulative bioaccessible Compound A using the tablet formulation over time as measured in the small intestinal filtrate under fasted and fed state conditions in the tiny-TIMsg (% of dose, average ± stdevp, n = 2).

Cumulative bioaccessible Compound A using the SDD capsule formulation over time as measured in the small intestinal filtrate under fasted and fed state conditions in the tiny-TIMsg (% of dose, average ± stdevp, n = 2).