134 Percutaneous Absorption of Chlormethine Gel in Human Skin: In Vitro Permeation Testing

Abstract

The synthetic DNA-alkylating agent chlormethine (CL, or mechlorethamine) is commercially available as 0.016% CL gel purposely developed and indicated to treat mycosis fungoides cutaneous T-cell lymphoma, with a positive benefit/risk ratio. This study evaluated the permeation of CL from gel formulation via in-vitro permeation testing (IVPT) using ex vivo human skin (dermatomed and epidermal membrane) mounted on flow-through cells. Healthy barrier-competent skin, harvested from elective abdominal surgeries, was either dermatomed to a thickness of 500μm (real skin ∼2000μm) or separated into epidermal membranes. Skin samples were mounted on to flow-through diffusion cells designed to mimic physiological/anatomical skin in situ. CL gel was applied to the surface at 10mg/cm2 and receptor solution samples were automatically collected every 2h postdose for 24h. Liquid chromatography-tandem mass spectrometry was used to quantify mean cumulative CL (ng/cm2), CL flux rates (ng/cm2/h) and residual CL from skin surface (ng). In dermatomed skin (1 donor; 7 replicates) and epidermal membrane (3 donors; 7 replicates), CL in receptor solution rose from 2h postdose to plateau at ∼8–10h. Mean cumulative CL that permeated through dermatomed skin and epidermal membrane were 40ng/cm2 (2.5% of applied dose) and 73ng/cm2 (4.6% of applied dose), respectively after 24h. Mean CL flux through dermatomed skin and epidermal membranes was 5.2ng/cm2/h peaking at ∼4h and 10.8ng/cm2/h peaking at ∼2h, respectively. Mean residual CL from the skin surface of epidermal membranes at 24h was 21ng (1.3% of applied dose). No residual CL was detectable from the dermatomed skin surface. This IVPT demonstrates CL 0.016% gel permeation profiles were similar for dermatomed skin and epidermal membrane. However, CL gel appeared to deliver more CL with a higher CL flux in epidermal membrane than dermatomed skin, suggesting that minimal CL levels pass through epidermal tissue and reach dermal tissue.