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.

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 (188.1nm), degree of entrapment (86.77±3.33%), permeation flux (5.47±0.48µg/cm2/h) and skin retention (17.72±0.68µg/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±1.69pg/mL) and serum (132.43±2.70pg/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.

Alginate coated chitosan microparticles mediated oral delivery of diphtheria toxoid. Part A. Systematic optimization, development and characterization.

The current study was embarked upon to develop "optimized" alginate coated chitosan microparticles (ACMs) loaded with Diphtheria toxoid (DTx) employing formulation by design approach. The developed system was characterized for particle size, zeta potential, surface morphology, acidic degradation protection studies, in process stability studies, storage stability studies and in-vivo uptake studies. Microparticles with minimum of average size of 5 µm (PDI, 0.184) were chosen after optimizing the composition and process conditions. The optimized chitosan microparticles were subjected to alginate coating for better protection of loaded antigen till it reached to uptake site i.e. M cells in the Peyer's patches (PPs) and transport of higher amount antigen to the PPs. The zeta-potential values for uncoated chitosan microparticles and ACMs were found to be +29 ± 3.3 mV and -32.6 ± 4.2 mV, respectively. This change of zeta potential, for uncoated to coated, can be explained by the fact that the coating of alginate on chitosan microparticles led to negative side of the zeta potential by virtue of its predominance on the surface. The developed ACMs were able to transport the antigen effectively to the M cell as revealed by confocal laser scanning microscopy. Further, DTx-loaded ACMs demonstrated significant immune responses at serum IgG as well as mucosal sIgA level.