Iontophoresis electroporation

Nowadays, scientists are exploring various physical forces to enhance the transport through the skin to expend the number of drugs being delivery such as electricity, (iontophoresis, electroporation) or ultrasounds. 

Apparent Flux Values of Estradiol and L-Glutamic Acid through Human Epidermis during Three Stages of the Experiment for Three Electrical Protocols Iontophoresis, Electroporation, or Combined Electroporation and Iontophoresis. Enhancement Ratios and Damage Ratios for Both Compounds are also Given 5 < n < 9... 

Stage Iontophoresis Electroporation Combined Iontophoresis Electroporation Combined... 

Recently another electrically assisted drug delivery technology, electroporation, was proposed as an alternative or adjuvant to iontophoresis. Electroporation comprises the use of electric pulses to induce transient changes in the cell membrane architecture that turn it into more permeable barrier. Beside the permeabilization effect on cell membrane, it was postulated that this technique induces electrophoretic effect on charged macromolecules and drives them to move across the destabilized membrane [205]. 

The dead cells on the surface of skin offer a formidable barrier to drugs. The use of permeation enhancers in controlled delivery patches and techniques such as iontophoresis, electroporation, and ultrasound are applied to enhance the permeation of drugs across skin.131... 

Transdermal Electrophoretic (iontophoresis), electroporation, chemical permeation enhancers, prodrugs, ultrasonics ... 

These devices are similar to the microneedle devices produced by microfabrication technology. They include the use of needle-like structures or blades, which disrupt the skin barrier by creating holes and cuts as a result of a defined movement when in contact with the skin. Godshall and Anderson [101] described a method and apparatus for disruption of the epidermis in a reproducible manner. The apparatus consists of a plurality of microprotrusions of a length insufficient for penehation beyond the epidermis. The microprotrusions cut into the outer layers of the skin by movement of the device in a direction parallel to the skin surface. After disruption of the skin, passive (solution, patch, gel, ointment, etc.) or active (iontophoresis, electroporation, etc.) delivery methods can be used. Descriptions of other devices based on a similar mode of action have been described by Godshall [102], Kamen [103], Jang [104] and Lin et al. [105]. 

Currently, various technologies are used to increase the permeability of macromolecules by exploring iontophoresis, electroporation, ultrasound, and micro-poration using electrical current/voltage, radio frequency, and microneedles to open the skin. Although mechanical abrasion and chemical enhancers may increase drag permeation, their effects on the skin s inherent rate-controlling properties are difficult to control and they may irritate the skin [85]. 

Edwards [105] has extended the macrotransport method, originally developed by Brenner [48] and based upon a generalization of Taylor-Aris dispersion theory, to the analysis of electrokinetic transport in spatially periodic porons media. Edwards and Langer [106] applied this methodology to transdermal dmg delivery by iontophoresis and electroporation. 

Denet A, Ucakar B, Preat V. Transdermal delivery of timolol and atenolol using electroporation and iontophoresis in combination a mechanistic approach. Pharm Res 2003 20 1946-1951. 

Fang J, Hung C, Fang Y, Chan T. Transdermal iontophoresis of 5-fluorouracil combined with electroporation and laser treatment. Int J Pharm 2004 270 241-249. 

Transdermal iontophoresis involves the application of an electric field across the skin to facilitate (primarily) ionic transport across the membrane. Iontophoresis, it is important to point out, is differentiated from electroporation [14], another electrical approach to enhance transdermal transport, by the low fields employed. Whereas iontophoresis has achieved commercialization, there is (to our knowledge) no active development in progress of a transdermal delivery system employing electroporation. 

It is therefore desirable to devise strategies both to enhance the penetration of molecules, which can already breach the skin barricade passively to some extent, and also to widen the spectrum of drug molecules that can penetrate the skin at therapeutically beneficial doses. Many tactics have been utilized to help overcome the barrier function. These include chemical means (e.g., chemical penetration enhancers or entrapment of molecules within lipid vesicles) or physical methods (such as ultrasound, microneedles, or electrical methods). Two important electrical methods are iontophoresis and electroporation. 

Current was delivered to the membranes through silver/silver chloride (Ag/AgCl) electrodes for iontophoresis, whereas stainless steel electrodes were employed for electroporation studies. Of the two model compounds, L-glutamic acid carries a net negative charge of 1 at pH 7.4, whereas estradiol is nonionized. Hence, they were delivered under the cathode and anode, respectively. 

The experimental protocol involved three consecutive stages of treatment to the same HEM a first passive permeation stage, which lasted for 3 h, followed by a 2 h electrical treatment period during which electroporation or iontophoresis or both protocols were applied to the skin and finally a second passive stage (2 h) evaluated possible reversibility of skin barrier function following electrical treatment. 

In contrast to low-current iontophoresis, which utilizes an electrical driving force to push permeants into and across the skin, electroporation increases transdermal transport primarily... 

Electroporation has been combined with iontophoresis to enhance the penetration of peptides such as vasopressin, neurotensin, calcitonin, and LHRH, as well as other compounds such as defibrase and dextran sulfate [44-49]. However, failures have also been reported [50,51],... 

During the first passive stage, both permeants penetration slowly built up. Upon application of all three electrical protocols, the apparent fluxes for both molecules were always significantly enhanced in relation to their respective steady-state passive values (P < 0.05). During the second passive period, penetration rates considerably reduced, though the apparent fluxes were always significantly greater after electroporation or combined treatment than with iontophoresis alone (P < 0.05). 

Table 15.2 shows that for estradiol, the ER during electroporation (8.7) was greater than during iontophoresis (2.5, P < 0.05). In contrast, the apparent L-glutamic acid fluxes were... 

FIGURE 15.3 Instantaneous flux profiles of estradiol through human epidermal membrane during a three stage experiment. Electrical procedures were iontophoresis (0.8 mA/cm2), electroporation (5 x 100 Y pulses with a pulse width of 100 ms), or electroporation followed by iontophoresis (n = 5-9). 

Iontophoresis by definition is the process of transport of ions into or through a tissue by the use of an applied potential difference across the tissue [52], Depending on the physicochemical characteristics of a molecular species, electrorepulsion is usually the primary mechanism of transdermal transport for ions, whereas electroosmosis and increased passive diffusion (as a result of the reduced barrier properties) are more prominent for neutral species [53]. In contrast, enhancement in flux for neutral or weakly charged species during electroporation arises predominantly from the reduced barrier properties of the membrane, whereas direct electrorepulsion is usually of secondary importance [25],... 

As the mechanisms of penetration and acceleration during iontophoresis or electroporation are different, the application of a constant direct current after pulsing may raise penetration even further in comparison with either method alone. Table 15.2 shows that for L-glutamic... 

---