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

Abstract

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/cm 2 /√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. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-022-00813-y.

Mechanism of action of chlormethine gel in mycosis fungoides

“…The amount of CL gel permeating through the skin was measured by sampling the receptor solution that flowed continuously underneath the skin, every 2 h post dose for 24 h. Residual CL gel was also retrieved from the skin surface at the end of the experiment. 50 After 24 h, the mean cumulative amount of CL permeation through skin was greater for the epidermal membrane (73.3 ng/cm 2 ) than for the dermatomed skin (40.4 ng/cm 2 ), representing 4.6% and 2.5% of the applied dose, respectively. The mean peak CL flux values for epidermal membrane and dermatomed skin were 10.8 and 5.2 ng/cm 2 /h, respectively.…”

“…50,51 Additional statistical analysis (t-test assuming unequal variances) confirmed that the CL release rate and cumulative amount of CL released were significantly greater (both p < 0.0001) for CL gel versus CL ointment. 50 The substantially higher CL release rate suggests that drug delivery from the gel is more efficient than from the ointment, and may explain the higher response rates seen with CL gel versus ointment in Study 201. 36 Study 201 was a randomized, observer-blinded, controlled, noninferiority trial, comparing once-daily CL gel with CL ointment for 12 months in 260 patients with stage IA-IIA MF; use of corticosteroids was prohibited.…”

“…Toward elucidating the mechanism of action of CL gel, the release profiles of CL 0.016% from the registered gel formulation and a compounded ointment-based formulation were compared using in vitro release testing. 50 CL gel and CL ointment were applied to a polytetrafluoroethylene (PTFE) membrane, sandwiched between a donor compartment and a receptor solution compartment in a vertical diffusion cell. The receptor solution was sampled regularly for 5 h after application of the CL formulations to the PTFE membrane.…”

“…In vitro permeation testing (IVPT) has been performed to evaluate the percutaneous absorption profile of CL gel in ex vivo human skin. 50 In those experiments, CL gel was applied at a dose of 10 mg/cm 2 to the upper surface of ex vivo skin samples (epidermal membranes or dermatomed skin [epidermis plus dermis]) mounted into the donor compartment of flowthrough diffusion cells. The amount of CL gel permeating through the skin was measured by sampling the receptor solution that flowed continuously underneath the skin, every 2 h post dose for 24 h. Residual CL gel was also retrieved from the skin surface at the end of the experiment.…”

MFM-300(Sc): a chemically stable Sc(iii)-based MOF material for multiple applications

“…However, FA is easily photodegraded, decreasing its shelf life and efficacy. 147 The loading to FA was carried out by impregnation method at pH = 9; thus, the loaded species was the ion ferulate (FER À ). The maximum FER À loading (16.1 wt%) was obtained after five days, corroborated by TGA of the solid and concentration determined by UV-Vis of the loading solution.…”