(128b) Effect of Molecular Weight of Penetrants on Iontophoretic Transdermal Delivery in Vitro

Transdermal delivery is preferable for some drugs to oral administration or intravenous injection. Macromolecules such as peptide drugs, however, little penetrate through the skin. In this paper, we have studied the effect of the molecular weight of penetrants on the diffusion across the skin, under the influence of the electric field applied. Large molecular drugs hardly penetrated across the intact skin. However, the drugs permeated through the viable skin, without stratum corneum more than 100 times greater than through the intact skin. This finding implies that the stratum corneum is the major diffusional barrier. In addition, the diffusion coefficients of the compounds across viable skin were inversely proportional to the molecular weight to the exponent of 0.38, suggesting a similar trend in the aqueous medium. The flux of Vitamin B₁₂ (M.W.=1.4×10³) increased appreciably during iontophoresis application, and the fluxes were proportional to the current density applied. Permeation of non ionic substance such as VB₁₂ could be increased mainly by convective solvent flow caused by electro-osmosis. The flow rate increases proportionally to the current density applied, and the resulting increase in VB₁₂ permeation occurs. However, FITC-Dextrans with the average molecular weight of 4.4×10³ to 19×10³ increased negligibly during iontophoresis. After the removal of the electric field, FITC-Dextrans continuously penetrated at a higher level. Two hypotheses can be considered from the results of these experiments. First, FITC-Dextrans might be pushed into stratum corneum temporarily by electro repulsion during iontophoresis, and then penetrated slowly from it (reservoir effect). The other hypothesis is that skin barrier function might decrease during iontophoresis (decrease of skin barrier function). To confirm the reservoir effect, the drug gel was removed immediately after iontophoresis. The cumulative amount of FITC-Dextran permeated increased slightly just after the iontophoresis, and then reached a plateau. This finding indicates that FITC-Dextran is not stored enough to increase the cumulative amount permeated continuously. Permeation experiments were conducted after pretreatment with electric field for one hour so as to confirm the decrease in the skin barrier function. After the pretreatment, the cumulative amount of FITC-Dextran permeated was increased, and the trend of permeation profile was similar between iontophoresis and pretreatment experiments. The results may indicate that the penetrants diffusivity in the stratum corneum increases due to the influence of the electric field. Moreover, the decrease of skin barrier function was shown clearly by applying iontophoresis twice: during 1~2 hour and 8~9 hour. The convective solvent flow caused by applying electric field could be considered as a trigger of skin hydration. The flux of VB₁₂ increased during iontophoresis application, and the flux was proportional to the current density applied. The flux of FITC-Dextrans little increased during iontophoresis, while the flux appreciably increased during the post-iontophoresis, probably due to skin hydration.