Common use of Basic Concepts Clause in Contracts

Basic Concepts. Transdermal iontophoresis is one of the promising alternative techniques for non- invasive continuous delivery of dopamine agonists. By applying a small electrical current (≤ 500 μA.cm-2) across the skin it is possible to enhance the transdermal delivery of small ionized therapeutic agents as illustrated in Figure 4. Besides a continuous administration and increased bioavailability, a particular advantage of iontophoresis is the possibility to adjust the delivery rate to the demand of the therapy. Especially in symptomatic treatment of Pd this can be very important, since individual titration is often required when administering dopaminergic agents. Three transport mechanisms are involved in transdermal iontophoretic delivery: 1) passive diffusion, resulting from a concentration gradient between the patch and the systemic circulation 2) the electromigration which is the result from the current flow from the anode (+ electrode) to the cathode (- electrode) across the skin and 3) electroosmosis, which can be attributed to the current induced solvent flow across the skin in the counter direction of the skin charge [92]. For small charged molecules the contribution of the passive flow is often negligible, making electromigration and electroosmosis the principle transport mechanisms with a dominating transport due to electromigration. With increasing molecular size, however, the contribution of the electroosmosis increases and may be really important for large peptides and proteins [92]. In addition for uncharged molecules electroosmosis is considered to be the only transporting mechanism involved in transdermal iontophoresis. Therefore marker molecules, such as mannitol and acetaminophen, are used to quantify the electroosmotic contribution during iontophoretic transport of various molecules. In the last few years acetaminophen has gained more interest over 14C-mannitol, because of its practical advantages [93-97]. Current application across the skin will drive the molecules through the pathway of least electrical resistance. In case of iontophoresis of the three suggested penetration routes (transcellular, intercellular and transappendageal), transport is reported to occur primarily via the intercellular and transappendageal route (Figure 2). The major contribution is via the appendages in the skin, including hair follicles and sweat glands [98]. In addition ions can also migrate via the damaged structures in the skin [90]. These penetration pathways can exist in parallel [65], as was suggested for the percutaneous penetration of methothrexate [99]. The relative contribution of the different pathways is presumably dependent on the physicochemical properties of the permeant. For instance ▇▇▇▇▇▇ et al. showed that fentanyl, a relatively lipophilic molecule, was distributed across the whole human stratum corneum (HSC), while the more hydrophilic thyrotropin releasing hormone was mainly localized in the pores after iontophoresis [100]. Confocal laser scanning microscopy studies with calcein, a anodal compartment + electrode current source - electrode cathodal compartment stratum corneum viable epidermis + charged ions dermis blood vessels Figure 4: Iontophoresis set-up in vivo with the transport of positively charged ions across the skin during current application charged hydrophilic dye and nile red, a neutral lipophilic dye, confirmed that the more lipophilic compound is transported via the lipid-filled intercellular regions of the stratum corneum, while iontophoresis enhanced the transcutaneous transport of calcein mainly in the follicular structures [101]. Up to today 2 iontophoretic delivery systems made it to the market. In 2007 EMEA approved IONSYS®, manufactured by ALZA corporation, a credit card system delivering fentanyl.HCl for analgesia [102]. However because of safety issues ▇▇▇▇▇▇▇-Cilag withdrew IONSYS® voluntary from the market and as a consequence the EMEA suspended its registration [103]. Currently the only commercialized iontophoresis system on the market is Lidosite® from Vyteris, delivering the anesthetic lidocaine.HCl. Lidosite® can be applied for local analgesia prior to blood sampling, venipunctures or small dermatological procedures [104]. Instead of delivery of molecules, it is also possible with iontophoresis to extract molecules from the skin. Therefore so-called ‘reverse iontophoresis’ has been explored in the last two decades to monitor subdermal levels of several molecules like lithium [105], phenytoin [106], valproate [107], lactate [108], urea [109], amino acids [110] and glucose [111]. The GlucoWatch® Biographer (▇▇▇▇▇▇▇ & ▇▇▇▇▇▇▇, New Brunswick, NJ) was approved in 2002 by the FDA to monitor the glycaemia for up to 12h [111]. These results show the potential of reverse iontophoresis to monitor different molecules subdermally. By monitoring a relevant biomarker it may even be possible to design a feedback system that can control the delivery of the therapeutic drug.