Anal fissure nanocarrier of lercanidipine for enhanced transdermal delivery: formulation optimization, ex vivo and in vivo assessment

Abstract

Objective: Pathogenesis of anal fissure (AF) is associated with raised resting anal pressures (RAP) involving contraction of smooth muscle. Therefore, the drug delivery strategy should be customized to reduce this raised RAP. In this investigation, in order to achieve this task, a transdermal nanoemulsion (NE) gel of lercanidipine (LER) was developed and optimized to evaluate its permeation ability and in vivo performance. Further, the same formulation was explored for droplet size analysis, zeta potential measurement and stability studies.

Methods: Pseudo-ternary phase diagram was constructed to determine NE region. The NE was optimized (OPT) by employing three-factor, three-level Box-Behnken design expert software; the independent variables decided were composition of oil, Smix and water and dependent variables, that is, responses were cumulative amount of drug permeated across rat abdominal skin in 24 h (Q₂₄), steady-state flux (J_s) and viscosity. The in vivo efficacy was assessed by measuring anorectal pressure in male Wistar rats.

Results: The OPT NE formulation, composed of Capryol 90 (12.70% w/w), Cremophor EL (18.0% w/w), Transcutol HP (18.0% w/w) and water (60.00%) w/w was found to have permeation flux of 60.27 µg/cm²/h, release of 1699.52 µg/24 h and 491.95 cP viscosity. In addition, a small average droplet size (82.71 ± 9.96 nm) and long-term stability at room temperature (1.666 years) was observed. The in vivo investigation demonstrated direct evidence on significant reduction (27.75%) in anorectal pressure over a period of 4 h.

Conclusion: These preliminary finding suggested that NE-based gel system of LER may provide promising perspective in management of AF.

Keywords::

• anal fissure
• lercanidipine
• nanoemulsion
• optimization
• pharmacodynamics

Acknowledgment

The authors wish to express their appreciation to F Ahmad, HIMSR Jamia Hamdard New Delhi, for providing laboratory for pharmacodynamic study. The authors also acknowledge the support of Gattefosse (Mumbai, India) for providing different excipients and A kumar from Aimil instrument for determining zeta potential in his laboratory.