Investigation of a series of methotrexate dialkyl esters as potential prodrugs for topical delivery
Abstract
Methotrexate (MTX), an effective systemic antipsoriatic agent, has been previously demonstrated to be ineffective topically, due to its polar nature, leading to poor stratum corneum permeability. A series of lipophilic MTX dialkyl esters were synthesized and characterized as to their physical properties including melting point partition coefficient, aqueous solubility, and aqueous stability. The compounds were also evaluated for their permeability through full-thickness hairless mouse skin, and permeability/bioconversion through tape-stripped hairless mouse skin. The compounds exhibited a parabolic relationship of permeability versus chain length in both systems, with the optimum compound being dimethyl MTX. In both the tape-stripped hairless mouse skin diffusion studies and in dermal and epidermal homogenates, the compounds demonstrated an increase in hydrolysis rate with chain length, without the regeneration of MTX. Dimethyl MTX, and dipropyl MTX produced no statistically significant effect on hairless mouse epidermal DNA synthesis rate versus control, upon topical application. Mathematical models for simulating concentration-distance profiles in full-thickness and tape-stripped hairless mouse systems for MTX dialkyl esters were also developed.
Degree
Ph.D.
Advisors
Mitra, Purdue University.
Subject Area
Pharmaceuticals
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