Arginine Hydrochloride Reduce Rectal Mucosal Irritation of Sodium Aescinate: Molecular Docking, Physical Properties, Anti-Hemorrhoidal Activity, Safety and Topical Gel Formulations Investigation

Background/Objectives: Sodium aescinate (SA) is commonly used topically due to its anti-inflammatory, anti-edematous, and anti-swelling properties. However, the clinical application of SA is limited by strong irritation, and cannot be used on the damaged skin and mucous membrane. This study aimed to investigate whether arginine hydrochloride (Arg·HCl) could reduce the rectal mucosal irritation of SA through the formation of a gel. Methods: Molecular docking was first used to explore potential interactions between SA and Arg·HCl. Gels for rectal administration were then formulated by combining SA with various ratios of Arg·HCl (from 1:0 to 1:10). In vitro tests, including pH, centrifuge stability, viscosity, and spreadability analysis, were conducted. The optimal gel formulation was determined based on rectal mucosal irritation tests and anti-inflammatory experiments. Additionally, the anti-hemorrhoidal characteristics and safety of the optimal gel in terms of acute toxicity and dermal sensitivity were evaluated. Results: The optimal SA to Arg·HCl ratio of 1:6 (F5-SA gel) was identified, significantly reducing rectal mucosal irritation while enhancing anti-inflammatory activity. The F5-SA gel demonstrated high efficacy against hemorrhoids, notably promoting anal ulcer healing. When administered rectally to rabbits at a dose of 132 mg·kg−1·d−1 (198 times the recommended therapeutic dose), no other obvious side effects were observed except a significant reduction in food intake on the day of administration. In addition, the gel did not induce dermal sensitivity. Conclusions: The F5-SA gel is a promising formulation that can reduce irritation and toxic side effects, and enhance the therapeutic effect to some extent, ultimately achieving a safer and more effective rectal delivery system for SA.