| Rheumatoid arthritis(RA)is a symmetric,inflammatory autoimmune disease.The disease-modifying antirheumatic drugs(DMARDs)are recommended as the priority drugs for the treatment of RA and nonsteroidal anti-inflammatory drugs(NSAIDs)provide partial relief of pain and stiffness.In long-term care,NSAIDs should be used together with DMARDs.Teriflunomide is an active metabolite of DMARDs leflunomide,and lornoxicam(LOX)is an effective derivative of the oxicam class of NSAIDs,but their long-term oral administration often results in gastrointestinal irritation.Transdermal delivery of TEF and LOX is an ideal alternative to avoid their gastrointestinal irritation.In this study,because of low skin permeability of TEF and LOX,a compound transdermal patch containing TEF and LOX is designed with ion pair technology to control skin permeation of TEF and LOX with a similar speed for a remission of RA symptoms.The penetrations of TEF and LOX across rabbit skin in the presence of equimolar organic amines,triethylamine(TEtA),diethylamine(DEtA),N-(2'-hydroxyethanol)-piperdine(NP),triethanolamine(TEA)and diethanolamine(DEA),were investigated in isopropyl palmitate solutions.It was found that ion pairs in a non-aqueous solution were formed by the hydrogen-bonded interaction by FTIR and 1H-NMR spectroscopy.The formation of ion pairs enhanced the percutaneous absorption of TEF and LOX,and the degree of enhancement highly depended on the physiochemical properties of ion pairs such as partition coefficients,?pAKa and the stability of ion pairs.The corresponding amine salts of TEF and LOX with TEtA,DEtA,NP,TEA and DEA were synthesized in CHCl3.The TEtA salts of TEF and LOX presented the best skin permeation from transdermal patches and Azone had the best enhancement for both of TEF-TEtA and LOX-TEtA.The compound patch formulation containing TEF-TEtA,LOX-TEtA and Azone was optimized by central composite design(CCD)for the maximizing skin permeation of TEF and LOX with a similar steady-state flux and the minimum loading of chemical enhancer.The optimized formulation of compound patches was acquired with DURO-TAK(?)87-4098 as a matrix,5%TEF-TEtA,10%LOX-TEtA and 15%Azone.The local tissue disposition of TEF and LOX was investigated by measuring joint tissue concentrations of TEF and LOX in rabbits with two knee joints after cutaneous application of the optimized formulation to only one joint.The concentrations of TEF and LOX were significantly higher in patch-applied skin,ligament and fat pad,while the synovial fluid concentrations of TEF and LOX were no difference between application site and non-application site and the absorption behaviors of TEF and LOX in synovial fluid were similar with that in plasma.The preliminary pharmacodynamic studies were performed in rat adjuvant-induced arthritis model and mouse writhing test induced by acetic acid for the anti-inflammatory and analgesic effect of the optimized formulation.Following transdermal administration on only left foot,the optimized compound patch presented a same swelling inhibition on the primary inflammation of two feet and there was no significant difference between the swelling alterations of bilateral hind paws in all the groups.In analgesic test,the optimized compound patch had a reliable analgesic effect which was the same with positive control which was better than other groups.In the irritation study,after administrating blank matrix and compound patches for 4h,no erythema or scabs was observed by naked eye.Although transdermal administration applied topically can provide a local enhanced drug delivery for the superficial joint tissues by direct diffusion,the accumulation of TEF and LOX in synovial fluid(the RA targeting site)is originated from redistribution by the systemic blood rather than direct diffusion.Therefore,we keep deep reservations for the opinion that local transdermal application enhanced site-specific delivery of drugs into the joints.In conclusion,the optimized compound patch is an ideal alternative of oral administration of TEF and LOX. |
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