Chlormethine Gel for the Treatment of Mycosis Fungoides Cutaneous T-Cell Lymphoma: In Vitro Release and Permeation Testing.

INTRODUCTION: The DNA-alkylating agent chlormethine (CL, or mechlorethamine) is approved in several countries worldwide as a 0.016% w/w topical CL gel formulation, to treat mycosis fungoides cutaneous T-cell lymphoma, with a positive benefit/risk ratio. METHODS: Release profiles of CL from the gel and a compounded ointment-based 0.016% CL formulation were compared via in vitro release testing (IVRT), utilizing static diffusion cells, a pseudo-infinite dose, and polytetrafluoroethylene membranes, over 5 h. The percutaneous absorption profile of CL gel in ex vivo human skin was also examined, using in vitro permeation testing (IVPT) with flow-through diffusion cells, dermatomed skin (epidermis plus dermis) and epidermal membranes, a finite dose, over 24 h. RESULTS: In IVRT experiments, the mean ± SD CL release rate was significantly higher for the gel versus the ointment (5.70 ± 0.73 versus 2.38 ± 1.03 µg/cm2/√h); the formulations were inequivalent per the US Food and Drug Administration scale-up and postapproval changes for nonsterile semisolid dosage forms (FDA SUPAC-SS) criteria. Mean IVPT cumulative CL (gel) permeating through epidermal membrane was higher than for dermatomed skin (4.6% versus 2.5% of applied dose). Mean residual CL on the epidermal membrane surface was 1.3% of the applied dose. CONCLUSIONS: CL gel (0.016%) and ointment were inequivalent, with an optimized release profile, suggesting minimal passage of CL gel through human epidermal tissue to the dermis.