delivery
and improved analgesic activity of caryophyllene oxide. In addition, this work explores new potential
mechanisms of analgesic activity of the active compound including alpha-amino-3-hydroxy-5-methyl-4-
isooxazole-propionic acid (AMPA) and Cyclooxygenase 2 (COX-2).
Methods: The transethosomal system containing various caryophyllene concentrations was prepared. The optimum
formulation was characterized for the presence of nanovesicles by atomic force microscopy (AFM) and
dynamic light scattering (DLS). FTIR was conducted to examine the interaction between the nanovesicle components.
The ability of the representative system to enhance the delivery of caryophyllene oxide into and through
the skin compared with a coarse emulsion, was examined using porcine ear skin, Franz diffusion cells, and HPLC
analysis. The in vivo analgesic efficacy of caryophyllene oxide administrated from the nanovesicular carrier was
assessed using the acetic acid-induced pain mouse model compared to a conventional topical formulation. In the
second part of the study, the mechanism of analgesic activity of caryophyllene oxide was investigated using
AMPA and COX-2 receptors activity in vitro assays.
Results: Characterization studies revealed the presence of spherical nanovesicles with an average size of 450.7 ±
55.03 nm. The transethosomal system demonstrated superior skin penetration compared to a conventional
emulsion, as demonstrated by the in vitro skin penetration study, with a caryophyllene oxide permeated amount
of 40.3 ± 0.881 μg/cm2 via the transethosomal system compared to the emulsion which delivered only 29.5 ±
10.5 μg/cm2. Moreover, a significantly greater amount of caryophyllene oxide was extracted from the skin
following the application of the transethosomal formulation (251.8 ± 76.03 μg/cm2) compared to that extracted
from the skin following the ointment application (13.5 ± 0.6 μg/cm2). The in vivo experiment demonstrated that
the transethosomal formulation significantly reduced writhing episodes, achieving an 80.5 % Maximum Possible
Effect (%MPE) compared to 24.7 % for the conventional topical formulation. In vitro mechanistic studies
indicated that caryophyllene oxide exhibited a potent COX-2 selectivity and significantly modulated AMPA receptor
subunit activity, highlighting a potential mechanism for pain therapy via the two investigated
mechanisms.
Conclusions: These findings underscore the effectiveness of the caryophyllene oxide transethosomal system in
enhancing topical drug delivery and achieving adequate therapeutic efficacy, making it a promising candidate
for further clinical development. The study’s outcomes shed light on the possible mechanism of analgesia of
caryophyllene oxide via COX and AMPAR modulation.

العنوان

International Journal of Pharmacuetics

الناشر

Elsevier

بلد الناشر

هولندا

Indexing

Thomson Reuters

معامل التأثير

5,3

نوع المنشور

Both (Printed and Online)

المجلد

670

السنة

2025

الصفحات

125111