title: Effective transdermal delivery of methotrexate through nanostructured lipid carriers in an experimentally induced arthritis model.
abstract: Rheumatoid arthritis (RA), an autoimmune and inflammatory pathology, is resulted due to the disruption of immune-homeostasis and failure of host immune-surveillance mechanism leading to cartilage degradation and bone erosion. Orally and parenterally administered methotrexate (MTX) have had adverse systemic complications in RA therapeutics. Therefore, transdermal application of MTX is recommended for the treatment of RA [1]. Present study is designed to develop MTX loaded nanostructured lipid carriers and chemical enhancer co-incorporated hydrogel (gel-(MTX-NLCs+CE)) for an efficient transdermal delivery of MTX in a Freund's adjuvants induced experimental animal model of RA. A gel-(MTX-NLCs+CE) was formulated and evaluated for its biocompatibility in hyper keratinocytes (HaCaT) and human monocytic cells (U937). Further, systemic and local inflammation was assessed by the estimation of pro-inflammatory cytokines & joint-destructive enzymes (TNF-α, IL-6, MMP-1 & IL-1β,; iNOS & COX-2) in the serum and synovial fluid, respectively in an experimentally induced RA animal model. Prepared formulations were also evaluated with respect to arthritis index, arthritis score and histopathology of paw and ankle bones. The biocompatibility study of formulation on U937 and HaCaT is suggestive of safe and greater therapeutic efficacy of the developed formulations. Our results show that transcutaneous ability of MTX loaded nanostructured lipid carries (NLCs) and chemical enhancer (CE) co-incorporated hydrogel significantly (p<0.001) decreases the inflammation in RA animal model. In conclusion, developed NLCs-based gel formulation loaded with MTX opens new avenues for developing novel therapeutic modality for RA patients with the acceptably minimum adverse effects.
authors.affiliation: Drug Delivery Research Group, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh 160014, India.
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Garg
authors.affiliation: Drug Delivery Research Group, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh 160014, India; UGC-Centre of Excellence in Applications of Nanomaterials, Nanoparticles & Nanocomposites (Biomedical Sciences), Panjab University, Chandigarh 160 014, India.
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Periodontics, College of Dental Medicine Georgia Regents University, 1120, 15th Street, Augusta, GA 30912, USA; Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad 382 481 Gujarat, India.
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Tyagi
authors.affiliation: Drug Delivery Research Group, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh 160014, India.
authors.forename: Gajanand
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Drug Delivery Research Group, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh 160014, India. Electronic address: drkatare@yahoo.com.
authors.forename: Om Prakash
authors.initials: OP
authors.lastname: Katare
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008055:Lipids / Q000737:chemistry*; D008727:Methotrexate / Q000008:administration & dosage* / Q000494:pharmacology; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016207:Cytokines; D008055:Lipids; D008727:Methotrexate
keywords: Chemical enhancer; Gelucire(®) 50/13; Methotrexate; Phospolipon S 100; Rheumatoid arthritis; Transcutol(®)P; Transdermal delivery