Studies On Transdermal Electroporational And Iontohoretic Delivery Of Defibrase

Iontophoretic and electroporational delivery of peptides is well known as a topic of the forward position and high technique in pharmacuetical technology. In this paper, the techniques of electroporation and iontophoresis were used in vitro to deliver Defibrase through excised full-thickness rat skin (RSM) or human epidermis membrane (HEM). The enhanced permeation data were compared ~vith that of the passive diffusion and data obtained from subcutaneous injection of Defibrase. The results indicated that combined use of electroporation and anodal iontophoresis or anodal iontophoresis alone at pH6.4 permeation medium could effectively enhance the skin permeation of Defibrase. The apparent permeability coefficient of Defibrase was 1.6?. 8x lO4cm.fr1 and 1.2?.4x lO4cm.fr? respectively. From the standpoint of clinical development, subcutaneous injection of Defibrase was considered to be a more practical and effective route owing to its high bioavailability and prolonged high plasma level of Defibrase which was 32.7 ? 7.5x 103u/ml even at 12h. Mechanisms of enhanced transdermal drug delivery caused by electroporation and iontophoresis were thoroughly investigated. Electroporation was carried out by using an exponential decay pulse generator (Genepulser) for a period of 0.5 hr, followed by a period of 5.5 hr passive diffusion or iontophoresis. The transport of Defibrase across RSM or HEM was enhanced by electroporation compared to that of passive diffusion. No difference of Defibrase permeability was found when the skin was pulsed with the electrode polarity reversed. The result indicated that neither electrophoresis nor electroosmosis contributed significantly to transport, since both phenomena depend on electric field orientation. The transdermal flux of calcein caused by electroporation was compared with that of by iontophoresis. A 1000-fold higher flux caused by pulsed high- voltage suggested that the creation of aqueous pores occurred in the intercellular lipid bilayers of the stratum corneum by a mechanism involving transient structural changes. In pH6.4 permeation medium, electroporation followed by anodal iontophoretic delivery of Defibrase was more effective than by cathodal iontophoresis or by electroporation alone (P<0.05). The apparent permeability coefficient of Defibrase caused by electroporation prior to anodal iontophoresis was 1.6?. 8 x lO4an.h1, which was a 12-fold-higher than that caused by electroporation alone (1.3 ?0.7 x lO5cmJY? . Anodal and cathodal -3 - iontophoretic transdermal delivery of Defibrase were also investigated and compared. The more effect of anodal iontophoresis for the permeation of Defibrase(1.2監.4x lO4cm.h1) compared to that of cathodal iontophoresis(4.3 ?1.4 x 105cm.h1 ) indicated that electroosmotic flow effect might take important role in iontophoretic transdermal delivery of Deflbrase. The effect of pulsed high voltages and some permeation promoters were also investigated. Although the voltages applied to the HEM in three protocols were different from each other (300V, 500V and 1000V), there were no significant differences for the permeation of Defibrase among the three protocols (P>0.05). No enhancing effect of azone was found for the skin permeation of Defibrase during electroporation or iontophoresis. Heparin sodium could enhance skin permeation of Defibrase during electroporation. Anhydrous ethanol pretreatment of rat skin could enhance the iontophoretic permeation of Deflbrase.