Development and Bio-Predictive Evaluation of Biopharmaceutical Properties of Sustained-Release Tablets with a Novel GPR40 Agonist for a First-in-Human Clinical Trial

Abstract

Sustained-release (SR) formulations may appear advantageous in first-in-human (FIH) study of innovative medicines. The newly developed SR matrix tablets require prolonged maintenance of API concentration in plasma and should be reliably assessed for the risk of uncontrolled release of the drug. In the present study, we describe the development of a robust SR matrix tablet with a novel G-protein-coupled receptor 40 (GPR40) agonist for first-in-human studies and introduce a general workflow for the successful development of SR formulations for innovative APIs. The hydrophilic matrix tablets containing the labeled API dose of 5, 30, or 120 mg were evaluated with several methods: standard USP II dissolution, bio-predictive dissolution tests, and the texture and matrix formation analysis. The standard dissolution tests allowed preselection of the prototypes with the targeted dissolution rate, while the subsequent studies in physiologically relevant conditions revealed unwanted and potentially harmful effects, such as dose dumping under an increased mechanical agitation. The developed formulations were exceptionally robust toward the mechanical and physicochemical conditions of the bio-predictive tests and assured a comparable drug delivery rate regardless of the prandial state and dose labeled. In conclusion, the introduced development strategy, when implemented into the development cycle of SR formulations with innovative APIs, may allow not only to reduce the risk of formulation-related failure of phase I clinical trial but also effectively and timely provide safe and reliable medicines for patients in the trial and their further therapy.

Keywords: GPR40 agonist; biorelevant dissolution testing; first in human clinical trials; simulation of gastrointestinal passage; stress test device; sustained-release tablets.

Figure 1

The analysis workflow.

Figure 2

The dissolution profiles obtained in the USP II paddle apparatus in phosphate buffer pH = 6.8. Profiles for prototypes (Panels A and B) are presented as means from n = 3 replicates, while final formulations of hardness 185–225 N (Panel C) are presented as means from n = 6 replicates, and standard deviations as error bars.

Figure 3

Mean deformation profiles obtained for the final formulations of hardness 185–225 N (n = 3) with standard deviations presented as shaded areas.

Figure 4

Comparison of dissolution profiles obtained in biorelevant media in the StressTest device under simulated standard fasted and fed conditions. (A,B) Dissolution profiles of the prototypes. (C,D) Dissolution profiles of the final formulations of different hardnesses, containing 5, 30, and 120 mg of the API. The data are presented as means of the cumulative amount of the drug released in percent (n = 6 for final, J and K batches, n = 3 for batches H and I under simulated fasted conditions, n = 2 for batches H and I under simulated fed conditions) with standard deviations presented as shaded areas.

Figure 5

Comparison of dissolution profiles of the final formulations (hardness 185–225 N) containing 5, 30, and 120 mg API, obtained in biorelevant media in the StressTest device under simulated modified fasted and fed conditions. The data are presented as means of the cumulative amount of the drug released in percent (n = 6, n = 4 for the “Increased agitation” protocol under simulated fed conditions) with standard deviations presented as shaded areas.