Supramolecular nano-engineered lipidic carriers based on diflunisal-phospholipid complex for transdermal delivery: QbD based optimization, characterization and preclinical investigations for management of rheumatoid arthritis

- The solubility of DIF was improved by development of 1:1 DIF-PL stoichiometric complex.
- The DIF-PL complex was incorporated into supramolecular nano-engineered lipid carriers (SNLCs) for transdermal delivery.
- The QbD based methodology was used to optimize the formulation composition.
- The preclinical efficacy was assessed by ear edema, CFA induced rheumatoid arthritis, formalin induced hyperalgesia model.

Diflunisal (DIF) is used for treatment of rheumatoid arthritis, osteoarthritis etc. DIF-phospholipid complex (DIF-PL complex) was prepared by solvent-evaporation method and characterized by molecular docking studies, SEM, FTIR, DSC, PXRD studies. Further, the DIF-PL complex was incorporated into supramolecular nano-engineered lipidic carriers (SNLCs) for transdermal delivery. The optimization exercise was done using Face centered cubic design (FCCD) after screening of variables by L8 Taguchi orthogonal array design. The optimized SNLC formulation depicted average particle size (188.1 nm), degree of entrapment (86.77 ± 3.33%), permeation flux (5.47 ± 0.48 μg/cm2/h) and skin retention (17.72 ± 0.68 μg/cm2). The dermatokinetic studies revealed the higher concentration of DIF in dermis. The Confocal laser scanning microscopy (CSLM) studies revealed penetration of SNLCs into the deeper layers of skin. The results of mice ear edema depicted significant inhibition of ear edema (76.37 ± 12.52%; p < 0.05). In CFA induced rheumatoid arthritis model, the inhibition of paw edema was significantly higher (73.85 ± 14.5%). The levels of TNF-α were reduced in synovial fluid (146.74 ± 1.69 pg/mL) and serum (132.43 ± 2.70 pg/mL). Furthermore, the licking and biting time was reduced in formalin induced hyperalgesia model. Hence, it can be concluded that dual formulation strategy based SNLCs were promising in treatment of pain and inflammation associated with rheumatoid arthritis.

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