PURPOSE: Low-dose @entity1499 ( @entity1500 ) is approved for the treatment of recalcitrant @entity309 ( @entity309 ). The objective of this study was to determine the effect of vehicles and penetration enhancers on the percutaneous absorption of @entity1500 and its analog @entity18872 (EDAM), and develop transdermal (TD) delivery systems of the drugs for the treatment of @entity309 . METHODS: From previously published pharmacokinetic parameters with low-dose @entity1500 therapy, and considering a 50 cm2 diffusional area, the target steady state in vitro TD flux for @entity1500 was calculated to be 35 micrograms/cm2/hr. Modified Franz diffusion chambers and hairless @entity19 skin were used for in vitro skin permeation studies. Hairless @entity19 were used for in vivo studies. Delivered amounts of @entity1500 and EDAM were determined by assaying the receiver phase fluid (or blood) with validated reversed phase HPLC methods. RESULTS: Intrinsic partition coefficient of @entity1500 was low (log P = -1.2). Target @entity1500 fluxes of > or = 35 micrograms/cm2/hr were achievable only with 1-15% (v/v) @entity14787 in @entity2771 (PG). Flux of EDAM (85 micrograms/cm2/hr) was higher than @entity1500 from an @entity5723 ( @entity9348 )-5% (v/v) @entity14787 system. Clinically significant steady state in vivo blood concentration of @entity1500 and EDAM was achieved using delivery systems containing > or = 2.5% @entity14787 in PG. Area under the drug concentration-time curves (AUC0-24 hr) for @entity1500 were 2379 and 3534 ng*hr/ml from PG-2.5% @entity14787 and PG-7.5% @entity14787 systems respectively. AUC0-24 hr of EDAM was 6893 ng*hr/ml using a PG-2.5% @entity14787 system. CONCLUSIONS: Results of this study show the feasibility of using a transdermal delivery system of @entity1500 and EDAM for the treatment of @entity309 .

Effect of vehicles and penetration enhancers on the in vitro and in vivo percutaneous absorption of @entity1499 and @entity18872 through hairless XXXX skin.

@entity14787 :: ('MESH:C035229', 'Chemical') :: ['Azone'] @entity2771 :: ('MESH:D019946', 'Chemical') :: ['propylene glycol'] @entity19 :: ('10090', 'Species') :: ['mice', 'mouse'] @entity9348 :: ('CHEBI:17824', 'Chemical') :: ['IPA'] @entity1500 :: ('CHEBI:44185', 'Chemical') :: ['MTX'] @entity1499 :: ('MESH:D008727', 'Chemical') :: ['methotrexate'] @entity5723 :: ('MESH:D019840', 'Chemical') :: ['isopropyl alcohol'] @entity309 :: ('MESH:D001172', 'Disease') :: ['rheumatoid arthritis', 'RA'] @entity18872 :: ('MESH:C040210', 'Chemical') :: ['edatrexate']
@entity19 :: (10090,Species) :: ['mouse']
