The role of electroosmotic flow in transdermal iontophoresis.

Iontophoresis enhances transdermal drug delivery by three mechanisms: (a) the ion-electric field interaction provides an additional force which drives ions through the skin; (b) flow of electric current increases permeability of skin; and (c) electroosmosis produces bulk motion of the solvent itself that carries ions or neutral species, with the solvent 'stream'. The relative importance of electroosmotic flow is the subject of this review. Experimental observations and theoretical concepts are reviewed to clarify the nature of electroosmotic flow and to define the conditions under which electroosmotic flow is an important effect in transdermal iontophoresis. Electroosmotic flow is bulk fluid flow which occurs when a voltage difference is imposed across a charged membrane. Electroosmotic flow occurs in a wide variety of membranes, is always in the same direction as flow of counterions and may either assist or hinder drug transport. Since both human skin and hairless mouse skin are negatively charged above about pH 4, counterions are positive ions and electroosmotic flow occurs from anode to cathode. Thus, anodic delivery is assisted by electroosmosis, but cathodic delivery is retarded. Water carried by ions as 'hydration water' does not contribute significantly to electroosmotic flow. Rather electroosmotic flow is caused by an electrical volume force acting on the mobile counterions. The simple 'limiting law' theory commonly given in textbooks and some research articles is a very poor approximation for transdermal systems. However, several extensions of the limiting law are compatible with each other and with the available experimental data. One of these theories, the Manning theory, has been incorporated into a theory for the effect of electroosmotic flow on iontophoresis, the latter theory being in good agreement with experiment. Both theory and experimental data indicate that electroosmotic flow increases in importance as the size of the drug ion increases. The 'ionic' or Nernst-Planck effect is the largest contributor to flux enhancement for small ions. Increased skin permeability or the skin 'damage effect', is a significant factor for both large and small ions, particularly for experiments at high current density. For monovalent ions with Stokes radii larger than about 1 nm, electroosmotic flow is the dominant flow mechanism. Because of electroosmotic flow, transdermal delivery of a large anion (or negatively charged protein) from the anode compartment can be more effective than delivery from the cathode compartment.