Development of an Ex Vivo Model Simulating the Human Urethra: Application to Drug Diffusion

Résumé

The development of topically applied drugs for the human urethra requires experimental models that simulate the urethra's structural characteristics and assess drug diffusion through its various tissue layers. This study aimed to describe a novel ex vivo model that simulates the different layers of the male urethral wall and to evaluate its applicability for investigating drug diffusion using a halofuginone (HF)-containing intraurethral gel as a model formulation, to support the future development of intraurethral therapies. The study used the human ureter as a substitute for the urethra because both tissues share a similar histological structure and the ureter is more readily available. The experimental model consisted of two parts. The first part employed a diffusion cell to investigate the diffusion kinetics of three HF gel formulations over a period of 2 hours. The second part used the formulation selected from the first phase to evaluate the three-dimensional (3D) distribution of HF following ex vivo intraurethral instillation. Three gel formulations with different viscosities were prepared. A high-performance liquid chromatography (HPLC) method was used to determine the concentration of HF diffused into the human ureteral wall. Following ex vivo intraurethral instillation, HF was uniformly distributed throughout the tissue. No HF was detected in the receiver compartment during the 2-hour diffusion period. These findings suggest that topical delivery of HF via an intraurethral gel may be a promising therapeutic approach for treating and preventing urethral stricture recurrence. The development and characterization of this ex vivo urethral model may facilitate the evaluation and development of new intraurethral therapies for urethral diseases.