Abstract
Purpose: The current study aims the lymphatic delivery of leflunomide loaded nanostructured lipid carriers (LNLC) for the treatment of rheumatoid arthritis, mainly focussed to enhance the lymphatic delivery via chylomicron formation, improved bioavailability and reduced systemic toxicity.Methods: Melt emulsification ultra-sonication method was used to formulate the nanostructured lipid carrier (NLC) containing leflunomide. Four batches were prepared by using various concentration of surfactants (tween 80 and poloxmer 188) and lipid mixtures (stearic acid and oleic acid). All the formulations were studied for various physiochemical propertiesResults: The formulation with increased concentration of lipid and surfactants showed highest entrapment efficiency (93.96 ± 0.47%) and better drug release (90.35%) at the end of 48 hrs. In vivo tests were carried out to determine the antiarthritic potential of the formulation in Sprague-dawley rats for a duration of 30d. The effect was evaluated by measuring the reduction in knee thickness. LNLC showed a marked reduction in inflammation compared to standard drug. Intestinal lymphatic uptake studies of LNLC were performed by intraduodenal administration and compared with leflunomide drug solution. The mesenteric lymph node was analysed by HPLC method and the concentration of drug was estimated. It showed that LNLC having highest uptake (40.34μg/ml) when compared with leflunomide drug solution (10.04μg/ml). Radiographic analysis and histopathological studies showed the formation of healthy cartilage after treatment period.Conclusion: The results suggested that LNLC has the potential to reduce the systemic toxicities associated with conventional therapy along with improved efficacy in the treatment of rheumatoid arthritis.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease, which results in disabilities due to progressive inflammation & destruction of joints.[1]
Leflunomide is a disease modifying anti-rheumatic drug, which is reported to be effective as methotrexate in the treatment of rheumatoid arthritis
Conventional dosage forms of leflunomide are associated with systemic adverse effects and undergo first pass metabolism on oral delivery
Summary
Rheumatoid arthritis (RA) is an autoimmune disease, which results in disabilities due to progressive inflammation & destruction of joints.[1]. DMARDs are a class of anti-rheumatic drugs which not just treats the symptoms associated with the disease but acts on the immune system & modify the disease itself.[3,4] The treatment of RA with currently available DMARDs is based only on empirical observations.[5] Methotrexate, leflunomide, sulfasalazine & hydroxychloroquine are the most commonly prescribed DMARDs.[6] Leflunomide, a pyrimidine synthesis inhibitor, is a leading drug among DMARDs.[7] Leflunomide acts by modifying the inflammatory processes, in RA.[8] The primary challenge in the treatment of RA with leflunomide is its systemic side effects including hepatotoxicity, allergic reactions etc. A site specific delivery of the drug can reduce these systemic side effects. The oral route is having some limitations due to the physicochemical properties of the drugs including low permeability & solubility, instability & rapid metabolism which results in decreased
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