Investigating the Potential of High Permeation Vesicle-Based Methotrexate Gel for Localized Therapy in Rheumatoid...

Methotrexate (MTX) is a clinically approved, potent disease-modifying antirheumatic drug used to manage rheumatoid arthritis. However, its systemic administration is associated with severe toxicity and bioavailability challenges. Localized MTX therapy holds significant potential by enabling site-specific action while diminishing the risk of systemic toxicity.

In this study, we investigated the therapeutic potential of systematically designed methotrexate-loaded high permeation vesicles (MTX-HPVs) in rheumatoid arthritis. HPVs comprise biocompatible phospholipids and a synergistic combination of permeation enhancers optimized using a quality-by-design approach. The thin-film hydration technique was used to formulate MTX-HPVs. Furthermore, MTX-HPVs were integrated into the Carbopol® 934P NF gelling matrix for ease of application and prolonged retention.

The optimized MTX-HPVs exhibited optimal quality attributes with a sustained-release pattern for up to 48 h. Morphological assessment revealed a spherical shape of MTX-HPVs. The prepared MTX-HPVs loaded gel displayed enhanced flux (~ 6.9-fold) and permeation (~ 3.5-fold) compared to the free MTX gel. Furthermore, increased cellular internalization and reduced IC₅₀ (0.57 ± 0.03 µg/mL) of the formulation in macrophage cells indicated the improved therapeutic potential of HPV-based therapy. In vivo studies revealed that MTX-HPVs gel significantly reduced inflammation and exhibited superior safety compared to free MTX gel. Radiographic imaging corroborated the enhanced efficacy and joint-restorative action of this formulation.

The MTX-HPVs gel substantially enhanced the therapeutic efficacy of MTX, demonstrating HPVs as a promising carrier system for localized methotrexate therapy.