Methotrexate (MTX)
is the first line agent for therapy against
rheumatoid arthritis (RA); however, orally its efficacy is hampered
by poor solubility, less permeability, short plasma half-life, and
reduced bioavailability. Meanwhile, parenteral formulations are associated
with severe adverse effects. In an attempt to improve the efficacy
of MTX, we synthesized polycaprolactone-polyethylene glycol-polycaprolactone
(PCL-PEG-PCL) triblock copolymer by a ring-opening copolymerization
reaction and used it as a carrier for the fabrication of MTX-loaded
nanomicelles. Surfactant-free, self-assembled nanomicelles were prepared
by nanoprecipitation technique and optimized through central composite
design. The optimized nanomicelles exhibited a size distribution of
31 nm and an encapsulation efficiency of 91%. In vitro, the nanomicelles exhibited hemocompatibility, sustained release,
and significantly high uptake in lipopolysaccharide activated macrophages.
To facilitate application on the skin, optimized nanomicelles were
loaded into a Carbopol 934-based hydrogel with eucalyptus oil as a
penetration enhancer. Eucalyptus oil significantly improved the permeation
of nanomicelles through the skin (p < 0.001).
When the hydrogel was applied on the RA mice model, nanomicelles exhibited
preferentially highest accumulation in the inflamed joints than other
organs. As compared with the free MTX, MTX nanomicelles significantly
improved the pharmacokinetic (4.34-fold greater half-life, 3.68-fold
higher AUC0–t
, and 3.15-fold higher
mean residence time) and pharmacodynamic profile ascertained through
low inflammatory cytokines expression, improved oxidation protection,
recovered behavioral responses, and radiological analysis. MTX nanomicelles-based
hydrogel also significantly reduced the hepatotoxicity and did not
activate the immune system. These results suggest that the MTX-loaded
nanomicelles-based transdermal hydrogel can prove to be a promising
agent against RA.