Impact of shelf-life on the pharmaceutical equivalence assessment of a hydrocortisone semisolid W/O emulsion: Evaluation of rheological, structural, and release properties

[EN] Developing generic topical medicines is particularly challenging because of pharmaceutical equivalence criteria at microstructure level. The EMA guideline on bioequivalence of topical products introduced flexibility, acknowledging the high variability inherent to topical formulations. This study evaluated the evolution of rheological parameters (yield stress, viscous modulus in LVR, elastic modulus in LVR, zero shear viscosity and viscosity at 100 s-1), droplet size, and hydrocortisone release in 5 batches of a commercial semisolid W/O hydrocortisone buteprate cream over the 3-year shelf-life. Despite high intrinsically variability, rheological parameters remained stable over time. In contrast, droplet size and release parameters fluctuated over time, although without a distinct temporal pattern. All rheological parameters met equivalence as per the EMA guideline requirements, while droplet size and release parameters only did so in some comparisons. Principal Component Analysis revealed that rheological parameters were strongly interrelated but minimally correlated with release behavior, suggesting that rheological parameters could be redundant and have limited influence on drug release. Overall, the findings indicate that EMA's equivalence criteria with extended limits better reflect the natural variability of dispersed systems, although limits may need to be further broadened for some topical products. The results warrant further research to clarify the role of rheology in topical bioequivalence assessment.