This study presents the development and evaluation of a transethosomal formulation to
enhance the topical delivery and analgesic efficacy of caryophyllene oxide. Nanovesicles
containing various concentrations of the active compound were prepared and optimized, with
the final formulation characterized by atomic force microscopy and dynamic light scattering,
confirming spherical vesicles averaging 450.7 nm in size. In vitro skin permeation studies
using porcine ear skin and Franz diffusion cells revealed that the transethosomal system
significantly outperformed a conventional emulsion in both skin penetration and retention of
caryophyllene oxide. In vivo testing using a mouse pain model showed markedly higher
analgesic activity for the transethosomal formulation, achieving an 80.5% Maximum Possible
Effect compared to 24.7% for the conventional formulation. Furthermore, mechanistic in
vitro assays demonstrated that caryophyllene oxide selectively inhibited COX-2 and
modulated AMPA receptor subunit activity, suggesting dual mechanisms for its analgesic
effect. These findings highlight the potential of the transethosomal delivery system for
effective topical pain management and support further exploration of caryophyllene oxide as
a therapeutic agent targeting both COX-2 and AMPA receptor pathways.
