Percutaneous absorption of physostigmine: optimization of delivery from a binary solvent by thermodynamic control.
A series of binary vehicles was used to deliver physostigmine across dermatomed human skin. The vehicles consisted of isopropyl myristate (IPM) and isopropyl alcohol (IPA) mixed in various volume fractions. The kinetics of penetration is conveniently considered as the sum total of two contributing effects: a "push" process resulting from the excess free energy (delta EG) of the penetrant in the donor vehicle, and a "pull" process resulting from the effect of IPA and IPM on the skin barrier. The inverse ratio of the solubility of the drug in a given vehicle to that in pure IPA was used to estimate the relative delta EG, hence the relative "push" effect. The solubility of physostigmine was highest in pure IPA (delta = 11.5), lowest in pure IPM (delta = 8.5), and intermediate in their various mixtures. But the permeability coefficient (Kp) of physostigmine was highest when delivered from a 1:9 (v/v) solution of IPA:IPM and a calculated delta y = 8.8. A further increase in the volume fraction of IPA caused an opposite decrease in the Kp values of physostigmine. The "steady-state" flux (Jss) of IPA from the same vehicle was lowest at a volume fraction of 1:9 and highest at one of 1:1 IPA:IPM. Thus, the maximal physostigmine penetration enhancing effect of IPA occurs at the lowest flux of IPA found in the present series. This indicates that the "pull" process ascribed to the presence of IPA in the barrier membrane is not important enough to outweigh the decrease in delta EG of physostigmine following an increase in the volume fraction of IPA in the donor vehicle, or that an excess of IPA in the barrier is not conducive to further enhancement of physostigmine diffusivity across the barrier. Optimized percutaneous delivery of physostigmine is possible by thermodynamic control of the penetration process.
Department of Physiology and Pharmacology, Tel Aviv University, Sackler School of Medicine, Israel.
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Pardo
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Shiri
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Cohen
D000433:1-Propanol; D000279:Administration, Cutaneous; D004058:Diffusion; D006801:Humans; D066298:In Vitro Techniques; D009226:Myristates; D010830:Physostigmine / Q000493:pharmacokinetics*; D012869:Skin Absorption; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics
D009226:Myristates; D012997:Solvents; C008205:isopropyl myristate; D000433:1-Propanol; D010830:Physostigmine