Crotamiton

Crotamiton is an anti-scabies drug that also suppresses non-scabietic itching in mice, though the underlying mechanism was largely unclear. This study investigated the anti-pruritic mechanism of crotamiton using fluorometric intracellular calcium assays in HEK293T cells expressing H1R/TRPV1 and MRGPRA3/TRPA1, as well as in primary cultured mouse dorsal root ganglion neurons. Crotamiton strongly inhibited histamine-induced calcium influx in H1R/TRPV1-expressing cells in a concentration-dependent manner with an IC50 of 101.2 μM, but did not directly block TRPV1 activation by capsaicin. Crotamiton also inhibited chloroquine-induced calcium influx in MRGPRA3/TRPA1-expressing cells with an IC50 of 326.2 μM, without directly blocking TRPA1 activation by AITC.
Furthermore, crotamiton suppressed both histamine- and chloroquine-induced calcium influx in primary cultures of mouse DRG neurons. In vivo, intraperitoneal injection of crotamiton significantly reduced histamine- and chloroquine-induced scratching behavior in mice. These findings demonstrate that crotamiton exerts anti-pruritic effects against both histamine-dependent and histamine-independent itch pathways by acting upstream of the TRPV1 and TRPA1 ion channels.

Fig. 1 Crotamiton inhibits histamine-induced calcium influx in the cells expressing H1R. (Choi D S.; et al. 2020)

Crotamiton-loaded microemulsion hydrogel containing tea tree oil was developed to improve the solubility and bioavailability of crotamiton. Pseudo-ternary phase diagrams were constructed with tea tree oil as the oil phase and Cremophor EL as the surfactant. The optimized formulation was evaluated for skin penetration, retention and dermatokinetics. Skin histopathology confirmed the nonirritant behavior of the formulation with no changes in normal skin histology. Dermatokinetic experiments revealed that crotamiton had greater penetration and distribution in the epidermis of mice skin compared to the conventional product. The lipid-based microemulsion hydrogel provided a better and safer delivery option for crotamiton in substantial quantities to the epidermis and deeper skin layers.

Fig. 2 Characterization of optimized Crotamiton-loaded microemulsion hydrogel. (Chen L.; et al. 2021)