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Effect of Vehicles and Penetration Enhancers on the In Vitro and In Vivo Percutaneous Absorption of Methotrexate and Edatrexate Through Hairless Mouse Skin

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Abstract

Purpose. Low-dose methotrexate (MTX) is approved for the treatment of recalcitrant rheumatoid arthritis (RA). The objective of this study was to determine the effect of vehicles and penetration enhancers on the percutaneous absorption of MTX and its analog edatrexate (EDAM), and develop transdermal (TD) delivery systems of the drugs for the treatment of RA.

Methods. From previously published pharmacokinetic parameters with low-dose MTX therapy, and considering a 50 cm2 diffusional area, the target steady state in vitroTD flux for MTX was calculated to be 35 μg/cm2/hr. Modified Franz diffusion chambers and hairless mouse skin were used for in vitro skin permeation studies. Hairless mice were used for in vivo studies. Delivered amounts of MTX and EDAM were determined by assaying the receiver phase fluid (or blood) with validated reversed phase HPLC methods.

Results. Intrinsic partition coefficient of MTX was low (log P = −1.2). Target MTX fluxes of ≥ 35 μg/cm2/hr were achievable only with 1−15% (v/v) Azone® in propylene glycol (PG). Flux of EDAM (85 μg/cm2/hr) was higher than MTX from an isopropyl alcohol (IPA)—5% (v/v) Azone® system. Clinically significant steady state in vivo blood concentration of MTX and EDAM was achieved using delivery systems containing ≥ 2.5% Azone® in PG. Area under the drug concentration-time curves (AUC0−24hr) for MTX were 2379 and 3534 ng*hr/ml from PG—2.5% Azone® and PG—7.5% Azone® systems respectively. AUC0-24hr of EDAM was 6893 ng*hr/ml using a PG—2.5% Azone® system.

Conclusions. Results of this study show the feasibility of using a transdermal delivery system of MTX and EDAM for the treatment of rheumatoid arthritis.

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Authors and Affiliations

  1. College of Pharmacy Rm. 2059, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109

    Dhruba J. Chatterjee

  2. School of Pharmacy, Rm 200C, University of Southern California, 1985 Zonal Avenue, Los Angeles, California, 90033

    Wen Y. Li & Robert T. Koda

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  1. Dhruba J. Chatterjee
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  2. Wen Y. Li
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Correspondence to Dhruba J. Chatterjee.

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Chatterjee, D.J., Li, W.Y. & Koda, R.T. Effect of Vehicles and Penetration Enhancers on the In Vitro and In Vivo Percutaneous Absorption of Methotrexate and Edatrexate Through Hairless Mouse Skin. Pharm Res 14, 1058–1065 (1997). https://doi.org/10.1023/A:1012109513643

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