Abstract:
A wearable iontophoresis device for the prolonged delivery of a positively charged pharmaceutical species from a salt formulation is disclosed that includes a readily oxidizable metal-based sacrificial anode in the form of a generally planar layer having a connecting area that has a width that is sufficient to insure complete consumption of the oxidizable metal wherein the anode is configured to have a minimum operating life of at least 6 hours under skin-safe conditions, and a drug delivery gel pad in electrical contact with said anode for accommodating a gel containing a positively charged pharmaceutical species in salt form formulated for transdermal delivery.

Description:
CROSS-REFERENCED TO RELATED APPLICATIONS 
     This application is a non-provisional application of Application No. 61/093,464, filed Sep. 2, 2008 and claims priority from that application which is also deemed incorporated by reference in its entirety in this application. 
    
    
     BACKGROUND OF THE INVENTION 
     I. Field of the Invention 
     The present invention relates generally to a system for transdermal delivery of therapeutic agents using skin-worn iontophoresis devices to introduce such substances into the body. More specifically, this invention provides a method for safe prolonged delivery of drugs that are formulated as hydrochloride salts, particularly including those which are normally skin irritants, such as donepezil HCl, using a skin-worn patch including a sacrificial active metal based electrode system. 
     II. Related Art 
     The process of iontophoresis has found commercial use in the delivery of many ionically charged therapeutic agent compounds. In this delivery method, ions bearing a charge are driven across the skin at the site of an electrode of like charge. The application time and level of current flow (usually reported in units of milli-amp minutes) directly correlates to the amount of drug delivered, and the efficiency of drug delivery can be measured by the proportion of current carried by drug molecules, relative to the current carried by competing non-medication ions having the same charge as the medication. 
     Self-contained, wearable iontophoretic systems have been developed in which the electrical circuitry and power supply have been integrated into a single, skin-worn patch that includes a pair of electrodes in electrical communication with a subject&#39;s skin. An important consideration for reliability and function of iontophoretic devices rests in the choice and design of the electrodes used. Electrode materials can be “inert”, remaining unchanged during the passage of current. Examples include platinum, gold, and carbon. Inert electrode materials, however, are associated with the possibility of pH changes at the electrode sites as a result of electrochemical oxidation of water at the anode and reduction of water at the cathode. These reactions occur with current flow and produce acidic changes at the anode and alkaline changes at the cathode which can cause moderate or even severe skin irritation or burns with a skin-worn patch. 
     The pH changes associated with inert electrode materials can be eliminated by the use of a “sacrificial” electrode materials which are materials that are consumed by an electrochemical reaction during the passage of current. For example, silver chloride in cathodes is reduced to silver during the passage of current. Conversely, sacrificial anodes are oxidized and include materials such as silver, zinc, or other readily oxidizable metals (metals that oxidize in preference to water). 
     In iontophoresis devices, the sacrificial material content must be at least sufficient to deliver the intended amount of drug and to last for the intended delivery period. To accomplish this, it is desirable that the electrode be designed to continue to function until the sacrificial material of the electrode is completely depleted avoiding any premature break in electrical connection to the electrode during a prolonged delivery period. 
     Another important factor for consideration with iontophoresis for prolonged delivery periods relates to skin irritation. Compounds that are themselves irritants to skin have heretofore not been suitable for delivery using iontophoretic devices, as these devices require skin contact with these compounds. This is particularly significant in applications designed to deliver such compounds into the skin for prolonged periods (periods of at least 6 hours and up to 7 days or more, for example). 
     SUMMARY OF THE INVENTION 
     By means of the present development, successful prolonged skin-safe and effective transdermal delivery of a variety of therapeutic substances, including analgesics, anti-emetics and including therapeutic substances which are themselves moderate to severe skin irritants, can now be accomplished using iontophoresis. Certain compounds in a compatible salt form can be formulated into water-based hydrogels at a concentration generally of about 10% or less and can be successfully and safely delivered transdermally using iontophoresis devices. The iontophoresis devices include a sacrificial electrode of a readily oxidizable metal in a skin-worn patch operable at very low current densities, generally less than 100 μA/cm 2 . Patches in accordance with the invention can deliver such compounds into the skin for periods of at least 6 hours and up to 7 days or more in a generally stable pH environment. 
     Embodiments provide iontophoretic patch devices that are safely wearable for a prolonged period and dedicated to the delivery of a positively charged compound that may be formulated as a hydrochloride salt contained in a water-based (aqueous) hydrogel. Example patches include a sacrificial anode containing an amount of readily oxidizable metal such as silver which is designed to be consumed over a prolonged period. These patches further include a source of electric current which can be controlled at a low output, skin-safe level. 
     A particular exemplary embodiment provides a single-use wearable iontophoretic patch dedicated to the delivery of donepezil HCl, a pharmaceutical well known as a skin irritant. In the patch, an amount of the drug is incorporated in an aqueous hydrogel carried by an absorbent delivery gel pad. The patch includes a silver-containing anode and a silver chloride cathode and is further configured to deliver the drug using a current density&lt;100 μA/cm 2  for a period of up to 7 days. 
     An important aspect of the invention has to do with electrode and connecting conductor construction. Accordingly, electrodes, particularly anodes have been devised in which the sacrificial material is entirely consumed during the prolonged operation of the iontophoresis devices. It has been found that in order to assure complete consumption of the sacrificial electrode material and eliminate premature electrode failure caused by a premature severing of the connector segment, a sacrificial anode configured as a continuous layer needs a connecting conductor segment or neck segment generally ≧5% of the corresponding maximum width dimension of the anode and, preferably, the connecting conductor segment is ≧10% of the corresponding maximum width. The anode further should contain sufficient sacrificial silver or other readily oxidizable metal to deliver the required amount of therapeutic agent over the required time span before it is consumed. The metal may be a layer applied as by a silk screening process, or the like, and the thickness of the metal layer may vary, but is generally from about 0.0002 inch (5 microns) to about 0.002 inch (50 microns). 
     In certain embodiments, the anode layer is applied on top of a gel-absorbing drug delivery pad designed to contain a hydrogel formulated with the positively charged hydrochloride salt to be administered. The anode area is adapted to receive the gel-absorbing drug delivery pad containing hydrochloride salt to be administered. The anode area needs to encompass the area contacted by the agent for all of the agent to be administered. Preferably, the gel pad surface to which the silver is applied is irregular or rough or otherwise configured to increase the effective electrode area and create a relatively high surface area that is greater than the surface area of a corresponding smooth surfaced electrode of equal dimensional area. This construction also reduces contact resistance between electrode and gel. 
     As indicated, it has been found that using the electrode system of the present invention iontophoresis can be performed in a manner which is skin-safe and effective even for the delivery of known skin-irritating agents including donepezil HCl. As indicated, it has also been found that clinically effective doses of this agent can be administered for up to seven days without adverse skin symptoms in the great majority of cases. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the drawings wherein like characters denote like parts throughout the same: 
         FIGS. 1A and 1B  depict schematic representations of a typical prior art sacrificial silver anode configuration, prone to premature failure, a failure mode being illustrated in  FIG. 1B ; 
         FIG. 2  is a schematic representation of an anode design in accordance with the present invention utilizing a extended interconnect zone; 
         FIG. 3  is a representation of an alternate anode design in accordance with the present invention utilizing multiple electrical connections; 
         FIGS. 4A and 4B  are representations of other anode designs utilizing rectangular and circular shapes; 
         FIGS. 5A and 5B  are schematic cross sectional depictions of a metal anode layer showing conventional and preferred topography; 
         FIG. 6A  depicts an exploded view of an iontophoretic patch construction suitable for use with the invention; 
         FIG. 6B  depicts a schematic representation of an example circuit suitable for the patch of  FIG. 6   a;    
         FIG. 7  depicts a graphical representation of current levels of several groups of hairless rats during a 24-hour iontophoresis experiment; 
         FIG. 8  depicts the relation between agent deliveries and current levels compared with passive administration for donepezil HCl; and 
         FIG. 9  depicts a bolus profile for donepezil administered by IV. 
     
    
    
     DETAILED DESCRIPTION 
     The invention pertains to a method for treating a subject transdermally with a variety of therapeutic substances, particularly drugs that are normally skin irritants, that can safely be administered in the form of a salt using a skin-worn iontophoresis patch. By means of the present invention, for example, it has been found that an effective amount of donepezil can be transdermally administered to a subject over a prolonged period without substantially irritating the subject&#39;s skin. Donepezil is known to be a skin irritating agent. The Material Safety Data Sheet (MSDS) for this compound warns that it is harmful if held in contact with skin. 
     The invention pertains, in an aspect, to an integrated iontophoretic transdermal patch for the prolonged delivery of a positively charged drug in a salt, preferably a hydrochloride salt, form. The patch is particularly useful for long term delivery of agents exemplified by donepezil and other agents that are normally skin irritants. Further, the electrode to be used in the iontophoretic patch comprises an amount of sacrificial metal, preferably silver, and preferentially is generally planar in form and applied, for example, by a screen-printing process. 
     Sacrificial anodes containing silver have been found to be particularly useful for delivery of therapeutic agents or drugs that are present as hydrochloride (HCl) salts. As silver is oxidized, silver ions (Ag+) produced combine with chloride ions (Cl−) of the drug to form insoluble silver chloride (AgCl). The reaction does not interfere with further silver metal oxidation and also reduces generation of competing ions (ions similarly charged to the drug), the existence which can reduce the efficiency of drug delivery. 
     DEFINITIONS 
     1. The term “electrode” or “anode”, as used herein, is defined as the portion of the readily oxidizable metal such as silver in the iontophoretic patch that is in contact with a positively charged drug solution. 
     2. As used herein, the terms “neck area” or “neck connecting segment” of the electrode or anode is the narrowest region of the electrode in contact with the drug solution. Typically, the neck area is at an edge of the drug reservoir closest to the power source and provides electrical contact to the power source in the circuit. 
     3. The term “prolonged delivery” is defined as a sustained delivery of medication from the iontophoresis patch for a period of at least 6 hours, and as long as 7 days or more. 
     4. The terms “skin-safe” and “does not substantially irritate a subject&#39;s skin” as used herein are meant to include patches, the operation of which result in a skin erythema score of 2.50 or less, preferably 2.00 or less, or, or most preferably, 1.00 or less about two hours after patch removal. In this scoring system, 0=no erythema, 1=very slight erythema (barely perceptible), 2=well defined erythema, 3=moderate to severe erythema, 4=sever erythema to slight eschar formation. 
     Electrodes 
     In relation to this invention, we have also discovered that certain designs or constructions of sacrificial anodes provide superior protection against premature failure, i.e., failure of the electrode due to a premature breach in electrical connection to the electrode before depletion of the sacrificial metal material in the electrode area. Accordingly, it has been found that if the neck area of the planar electrode is of a width generally 5% or more of the maximum electrode width, in either the x or y direction, or as much as fully enveloping the electrode, the conductor arc is sufficient so that the electrode will be reliable in operation for the full prolonged delivery period calculated for depletion of sacrificial metal. 
     To minimize waste of sacrificial metal such as silver and also to minimize contact resistance of the electrode to the drug reservoir an optimized surface has been found. The optimum surface has been discovered to be a rough surface contour, where the difference between high and low points of the electrode surface is 25% or more of the total electrode surface. By using a rough surface contour, the effective contact surface area between sacrificial metal and the drug can be increased by 50% or more as compared to the area based on the corresponding flat surface. This rough surface contour electrode may also be viewed as a high-surface area electrode, where the actual surface area of the electrode exceeds the surface area of a corresponding virtual electrode that is defined by the same length and width dimensions of the high surface area electrode. 
       FIGS. 1A-5B  illustrate representative prior art and present concept sacrificial anode designs.  FIG. 1A  depicts a schematic representation of a typical prior art sacrificial silver anode configuration generally at  20  which includes a main electrode  22  situated in a contact area for a drug pad at  24 . The main electrode  22  is shown with a width on the vertical or y axis of (c-d) and a neck area defined as (a-b) which represents the narrowest part of an electrical connection  26  which connects the electrode  22  with a corresponding power source. The neck area (a-b) also represents the narrowest width on the y or vertical axis. With prior anodes, it has been found that typically the width (a-b)&lt;5% of the width (c-d). As shown in the schematic drawing of  FIG. 1B , the narrowness or lack of sufficient connective area with regard to the connection  26  often results in a premature break in the electrical connection prior to the consumption of the main or sacrificial electrode material. Such a break is shown at  28 . 
       FIG. 2 , on the other hand, illustrates a schematic representation of an anode design in accordance with the present invention, generally at  30 , which includes a main electrode  32  situated in a contact area for a drug pad in phantom at  34  and which has a large area electrical connection to a power source or neck area at  36 . This figure illustrates an electrode configuration in which (a-b)&gt;10% of (c-d). 
       FIG. 3  shows an alternate embodiment of the sacrificial electrode of the invention generally at  40  which includes a main electrode  42  situated in a contact area for a drug pad at  44  and which is provided with multiple electrical connections to a power source shown as a pair of connections at  46  and  48 . This embodiment has a combined neck area width (a-b) which is also &gt;10% of the maximum width of the main electrode of the electrode shown at (c-d). 
     In the embodiments illustrated in  FIGS. 2 and 3 , the contact area of the drug pad exceeds the area of the main electrode. As such, in these embodiments, none of the main electrode extends outside of the contact area for the drug pad, and therefore the “neck area” is defined solely by the one or more electrical connections that extend from the main electrode beyond the contact area for the drug. 
     A further embodiment is shown in  FIG. 4A  at  50  in which the main electrode is shown as a circular device at  52  which exceeds the width or extends outside of the drug pad area shown in phantom at  54 . As such, in contrast to the embodiments shown in  FIGS. 2 and 3 , the main electrode extends outside of the contact area for the drug pad and an example of embodiments where at least a portion of the main electrode extends beyond the area defined by the drug pad. In the embodiment shown in  FIG. 4A , because a portion of the main electrode extends beyond the area defined by the drug pad, the neck area encompasses the electrode. An electrical connection is shown at  56 . As such, the neck area in the embodiment illustrated in  FIG. 4A  includes both the electrical connection and that portion of the main electrode that extends beyond the area defined by the drug pad. 
       FIG. 4B  depicts a main electrode in a rectangular shape  60  that also exceeds the drug pad area shown in phantom at  62  with electrical connection  64 . As with  FIG. 4A , the neck area in the embodiment illustrated in  FIG. 4B  includes both the electrical connection and that portion of the main electrode that extends beyond the area defined by the drug pad. 
     With respect to the embodiments of  FIGS. 4A and 4B , these are examples of device configurations in which the main electrode has an area that exceeds the contact area of the drug pad, where in some instances the area of the main electrode may exceed the area of the drug pad by 5% or more, such as 10% or more, including 15% or more. Depending on a given desired configuration, the main electrode may extend beyond all sides of the drug pad or only some of the sides of the drug pad. 
       FIG. 5A  is a schematic of a sacrificial anode electrode layer  70  laid down as a smooth surface  72  or a substrate layer  74  which produces an electrode area equal to the area of the smooth surface. 
       FIG. 5B  illustrates a sacrificial anode layer  80  having a rough surface at  82  which may correspond to the rough surface afforded by a drug pad in which the electrode may be laid down such that the minimum thickness of material covering the drug pad is 50% or less of the maximum thickness. In any event, however, it is apparent that utilizing a rough surface will significantly increase the effective surface area of the electrode and create a relatively high area of reactive material that is greater than the area occupied by the electrode as determined by length and width dimensions. This enables placement of a larger amount of consumable electrode material in a smaller area and also enlarges the contact area between the drug pad containing the drug and the electrode thereby reducing the contact resistance between a formulated drug material and the electrode. Such a construction may increase the contact area by 50 to 100% based on the electrode footprint. The embodiment illustrated in  FIG. 5B  provides an example of a high surface area electrode. 
     It should be noted that in certain embodiments of the invention, a neck area as described above may be present but a high surface area electrode may not be present. In yet other embodiments, a neck area as described above may not be present but a high surface area electrode may be present. In still other embodiments, both a neck area as described above and a high surface area electrode may be present. 
     Skin-Worn Patches 
     The patches of the invention are preferably self-contained with respect to delivery of a substance of interest as a hydrochloride salt formulated in an aqueous hydrogel form suitable for transdermal administration. The patches deliver the compounds using iontophoresis and, more preferably, are complete integrated or combined devices which need only be removed from packaging and applied to the skin of a patient or subject or which require only simple assembly prior to being applied to the skin. Application of the patch to the skin completes the electrical iontophoresis circuit and the device begins transdermal administration of the therapeutic compound immediately. Preferably, the duration of time necessary to reach a clinically effective level is no more than about 6 hours and that level can be maintained for 7 days or more. 
     One embodiment of a patch suitable for delivery of donepezil HCl or other drug substance in accordance with the invention is shown generally at  100  in the exploded view of  FIG. 6A  and includes an impervious, non-conducting flexible backing layer  102  which is the upper or top layer in an applied patch and which may be attached to a peelable release layer  104 . Backing layer  102  has a peripheral adhesive pattern of medical grade adhesive material applied to the inner or lower surface beneath the release layer (shown outlined at  106 ). The adhesive should be one suitable for a relatively long term adhesion to the skin of a patient or subject in a manner which also seals the periphery of the patch and prevents leakage of any materials beyond the adhesive border. Such materials are readily available articles of commerce. 
     The patch further includes an electrical circuit assembly  110  which includes a power source which may be in the form of a pair of series connected lithium cells  112 , a screen-printed silver anode  114 , silver-silver chloride screen-printed cathode electrode  116 . As shown in the schematic diagram of  FIG. 6B , the circuit may also contain a series connected transistor and a resistor shown at  120  to provide output current level control. The circuit shown is completed by application to the skin and represents an example of a configuration that can be used to operate an iontophoresis patch and provide current level control. Such circuits are generally known and many applicable variations will occur to those skilled in the art. In some instances, the circuit is configured to provide the delivery currents described above. 
     A layer of double-sided medical grade tape  122  is included to provide internal adhesion of components of the device in an assembled state including adhesion between the peelable backing layer  102  and the electrical circuit assembly  110 , absorbent pads  124  and  126  and the electrodes  114  and  116  and a shaped medical grade foamed tape member  128  which defines recesses designed to contain absorbent pads  124  and  126 . 
     One of the absorbent gel-containing pads  124 ,  126  is associated with and in electrical communication with each electrode. One gel pad is used for containing or retaining the therapeutic compound of interest to be administered and a corresponding conductive material is contained in the other gel pad to enable the circuit to be completed at the time the patch is applied to the skin. 
     It should be noted that whether the pad containing material to be administered is associated with the anode or the cathode depends on the charge of the material itself. Accordingly, the hydrochloride or other salt materials administered in accordance with the examples of the present invention are positively charged and so are administered from the pad  124  associated with the anode  114  and the cathode pad  126  is imbibed with unmedicated conductive gel material. As indicated, recesses in the patch for receiving and containing the absorbent gel pads are provided as by a shaped foam barrier  128 , as shown in the figure. 
     The anode and cathode pad structures are preferably of a non-woven material to maintain the continuity of drug-containing hydrogel material in the structure and may include a plurality of layers, possibly up to three layers, of material. Examples of materials that may be suitable for the absorbent non-woven matrix include cotton, polypropylene, polyethylene, and polyester. Most preferably, the absorbent material is polypropylene. One example of an embodiment includes a thick needle-punched polypropylene layer, a thin, permeable polyethylene net layer, and a thin, occlusive peripheral polypropylene layer as at  124   a  and  126   a  in  FIG. 6A . The layers may be heat fused together without requiring adhesives. All three layers are cut to have the same outside perimeter shape. The occlusive layer  124   a ,  126   a  is cut to the shape of a perimeter ring that remains intact and occlusive. Inside the ring, the occlusive layer  124   a ,  126   a  is cut out completely or perforated so that the inside region becomes permeable. The permeable region is shaped to coincide with the shape of the anode  114  and cathode  116  electrodes, by allowing the gel to migrate through this layer and contact the full area of the electrodes when the device is assembled for use. 
     Importantly, the occlusive rings  124   a  and  126   a  provide a barrier for gel migration so the outside surface remains relatively dry during storage if the pads are separately stored and may be designed for adhesive attachment of the pad  124 ,  126  to a corresponding electrode recess using adhesive material in the rings during activation of the device. 
     The gels are preferably formulated with a viscosity range preferably between 8,000-120,000 centipoise, but this is not limited so long as the gel retains shape to be successfully assembled in the patch. The gels useful in the system may be formulated by dissolving an appropriate amount of formulated drug in a cross-linked or cross-linkable gelling agent such as HPMC (hydroxpropylmethylcellulose) such that a conductive gel of appropriate viscosity is created. Other gelling agents, such as PVP (polyvinylpyrrolidone), PEO (polyethyleneoxide), or PVA (polyvinylalcohol) can also be used. Successful gels have been formulated from a HPMC powder at 2% w/w contained in an absorbent scrim. 
     As packaged, the integrated iontophoresis patch of the invention is designed to contain the therapeutic material to be administered, preferably in the form of a hydrogel absorbed into the absorbent composite pads  124  and contained within the patch as manufactured. Thus, the only operation left to the user may be to open the packaging and apply the patch to an affected area sought to be treated. In this way, subjects can successfully treat themselves by simply positioning the patch on the skin using the adhesive at the desired position. 
     As indicated, the hydrogel absorbent pads may also be separately stored in common packaging and simply applied to the patch when the package is opened. 
     One preferred embodiment used as an example herein is dedicated to the administration of donepezil HCl. Donepezil HCl, a cholinestrase inhibitor is indicated for the treatment of mild to moderate Alzheimer&#39;s, the seventh-leading cause of death in the United States. Patient compliance with a highly frequent dosage regimen is a limiting factor in cognitive dysfunction. Clinical usefulness of oral dosage forms is also limited by the gastrointestinal side effects caused by activation of the peripheral cholinergic system. As indicated, Donepezil HCl has also been identified as a definite skin irritant considered harmful if in contact with skin by Sequoia Research in its Material Safety Data Sheet (MSDS). 
     In accordance with the present development, iontophoresis has been successfully used as a technique to achieve the desired therapeutic levels using low cost, disposable, easy to use “active” patches utilizing a low level DC current to propel like charged ions of soluble salts non-invasively across the skin. Donepezil (MW=415.96, pKa=8.9), in its HCl salt form, is positively charged at a pH of 6.0 and therefore would be a desirable candidate for anodal iontophoretic delivery if the negative indication related to skin irritation could be overcome. 
     While certain embodiments of the invention have been described above in connection with the delivery of Donepezil HCL, as summarized above, the invention is suitable for delivery of a wide variety of active agents. For example, other agents finding use in the treatment of Alzheimer&#39;s disease may be delivered via devices of the invention, such as but not limited to: rivastigmine, galantamine, tacrine, amiridine, minaprine, huperzine and huprine. 
     Another type of active agent of interest that may be present in devices of the invention is an anti-emetic. Specific anti-emetic agents of interest include, but are not limited to: alosetron, azasetron, bemesetron, cilansetron, dolasetron, granisetron, indisetron, itasetron, ondansetron, palonosetron, ramosetron, tropisetron, and zatosetron. 
     Also of interest are analgesics. Analgesics of interest include, but are not limited to: fentanyl, sufentanil, carfentanhl, lofentanil, alfentanil, hydromorphone, oxycodone, propoxyphene, pentazocine, methadone, tilidine, butorphanol, buprenorphine, levorphanol, codeine, oxymorphone, meperidine, and dihydrocodeinone. 
     Of course, other types of agents may also be administered using devices of the invention, and the invention is not limited to delivery of the above specific active agents in its broadest sense. 
     Experiments were conducted to demonstrate that the sacrificial electrodes designed in accordance with the present invention are reliable and skin-safe for prolonged delivery periods, using donepezil HCl as a model compound. In a first experiment, Example I, current measurements and blood analysis were conducted to verify that the drug was delivered in continuous fashion over the entire application period. In a second experiment, Example II, an evaluation was conducted to determine whether the prolonged delivery device built in accordance with this invention has minimal irritation potential. In a third experiment, Example III, an experiment was conducted to determine whether a prolonged delivery device built in accordance with this invention has minimal skin sensitization potential. 
     Example I 
     A wearable electronic drug delivery device was used to demonstrate feasibility of iontophoretic delivery and effect of current on the therapeutic dose of Donepezil HCl delivered in hairless rats, using sacrificial electrodes designed in accordance with this invention. 
     Experimental Methods 
     Patches consisting of an Ag anode and Ag/AgCl cathode with 7 volts of power were used. A series transistor was used in each patch to set the current to a desired level. Anode and cathode absorbent pads were imbibed overnight with the drug and saline formulation respectively, and used the next day. The current levels set and the expected dose/day (established from previous in vitro measurements of efficiency) are as follows: 
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE I 
               
             
             
               
                   
               
               
                 Experimental design showing the treatment 
               
               
                 groups with the targeted dose 
               
             
          
           
               
                   
                   
                   
                 Target 
               
               
                   
                 Treatment 
                   
                 dose 
               
               
                 Group 
                 (current 
                 No. of 
                 level 
               
               
                 No. 
                 level) 
                 animals 
                 (mg/day) 
               
               
                   
               
               
                 1 
                 IV 
                 3 
                 — 
               
               
                 2 
                 Passive 
                 4 
                 0 
               
               
                   
                 (0 mA) 
                   
                   
               
               
                 3 
                 0.13 mA 
                 4 
                 2.5 
               
               
                 4 
                 0.26 mA 
                 4 
                 5.0 
               
               
                 5 
                 0.39 mA 
                 4 
                 7.5 
               
               
                   
               
             
          
         
       
     
     Current was monitored throughout the application period to ensure proper connections. Patches were placed on each animal for 24 hours and blood samples collected till 72 hrs at predetermined time points. Drug was extracted from the plasma samples by protein precipitation and analyzed by RP-HPLC using fluorescence detection at an excitation of 325 nm and emission of 390 nm. Pharmacokinetic analysis was done using WinNonlin. 
     Results and Discussion 
     A constant current level was maintained in all the groups indicating the reliability of the electrodes ( FIG. 7 ). 
     A significant increase in the amount of donepezil delivered across hairless rat skin was seen with increasing current levels in comparison with the passive delivery as seen in  FIG. 8 . 
     Clearance values from IV bolus dosing ( FIG. 9 , Table II) were used to calculate the dose delivered per day (Table III). 
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE II 
               
             
             
               
                   
               
               
                 IV bolus pharmacokinetic parameters (n = 3) 
               
             
          
           
               
                   
                 Parameter 
                 Units 
                 Value 
               
               
                   
               
             
          
           
               
                   
                 Elimination 
                 (1/hr) 
                 0.19 
               
               
                   
                 rate const. 
                   
                   
               
               
                   
                 (λ z ) 
                   
                   
               
               
                   
                 Volume of 
                 (ml/kg) 
                 12766.66 
               
               
                   
                 distribution 
                   
                   
               
               
                   
                 (V z ) 
                   
                   
               
               
                   
                 Clearance 
                 (ml/hr/kg) 
                 2285.733 
               
               
                   
                 AUC 0-α   
                 (hr*ug/ml) 
                 1.076667 
               
               
                   
               
             
          
         
       
     
                                                         TABLE III                   Dose delivered for different groups                    Dose   Desired               delivered ± SD   level           Group   (mg/day)   (mg/day)                        2   0   0           (passive)                   3 (0.13 mA)   2.55 ± 0.75   2.5           4 (0.26 mA)   5.83 ± 0.37   5.0           5 (0.39 mA)   8.75 ± 2.83   7.5                    
Conclusion
 
     Donepezil HCl was successfully delivered iontophoretically over a prolonged period without interruption or evidence of premature failure. Transdermal iontophoretic delivery also achieved the desired therapeutic levels of 2.5, 5.0 and 7.5 mg per day. 
     Example II 
     Primary Skin Irritation Test Results 
     PURPOSE: This test was designed to determine the dermal irritation potential of the test iontophoretic patch on the shaved skin of the rabbit, as required by certain regulations for medical device biocompatibility. 
     TEST SAMPLE PREPARATION: The test articles were prepared by instilling 0.5 mL of gel onto each electrode pad of the iontophoretic device. The gel was spread uniformly on the pad and allowed to absorb for approximately 24 hours. 
     EXPERIMENTAL METHODS SUMMARY: Prior to application, the gel pads were placed on the patches labeled drug and the saline gel pads were placed on the patches labeled saline. In addition, negative control patches were prepared by placing dry pads onto adhesive patches. The prepared patches were applied to the shaved dorsal skin of three (3) adult albino rabbits, two (2) test articles (“drug” and “saline”) and one (1) negative control patch on each side of the paravertebral skin. The trunk of each animal was wrapped with an elastic bandage secured with hypoallergenic tape for a minimum 6 hour exposure. Observations for skin irritation were conducted at 60±6 minutes after unwrapping, and at 24±2, 48±2, and 72±2 hours. The tissue reactions were rated for gross evidence of erythema and edema. 
     The sum of the erythema and edema scores for the test article and control sites were calculated for only the 24, 48 and 72 hour observation periods for each rabbit. The total scores were divided by 6 (2 observation sites×3 observation periods) to determine the Primary Irritation Score observation average. The Primary Irritation Score for the test sites of each rabbit were then totaled and subtracted from the total of the control Primary Irritation Score. This value was divided by the total number of animals to yield the Primary Irritation Index. A negligible, slight, moderate or severe response of the test article was categorized based on the Primary Irritation Index (PII) Table IV. 
     
       
         
               
             
               
               
             
           
               
                 TABLE IV 
               
             
             
               
                   
               
               
                 PRIMARY IRRITATION RESPONSE 
               
               
                 CATEGORIES IN THE RABBIT 
               
             
          
           
               
                 RESPONSE CATEGORY 
                 COMPARATIVE MEAN SCORE (PII) 
               
               
                   
               
               
                 Negligible 
                   0 to 0.4 
               
               
                 Slight 
                 0.5 to 1.9 
               
               
                 Moderate 
                   2 to 4.9 
               
               
                 Severe 
                 5 to 8 
               
               
                   
               
               
                 Note - The Primary Irritation Index (PII) is determined by adding the Primary Irritation Score for each animal and dividing the total score by the number of animals. 
               
             
          
         
       
     
     RESULTS: See Table V. Primary Irritation Index (PII)=0 
     CONCLUSION: The test article is considered a non-irritant. 
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
             
               
               
               
             
           
               
                 TABLE V 
               
               
                   
               
               
                 TEST AND CONTROL TOTALS 
               
               
                 CALCULATION OF THE PRIMARY IRRITATION SCORE FOR EACH RABBIT 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 60 MINUTES 
                 24 HOUR 
                 48 HOUR 
                 72 HOUR 
                 SUM OF 
                 OBSERVATION 
               
             
          
           
               
                   
                 LEFT 
                 RIGHT 
                 LEFT 
                 RIGHT 
                 LEFT 
                 RIGHT 
                 LEFT 
                 RIGHT 
                 OBSERVATIONS 
                 AVERAGE 
               
               
                   
               
               
                 RABBIT 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 #3951 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0/6 
               
               
                 TEST 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (Drug 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Scores) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0/6 
               
               
                 TEST 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (Saline) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Scores 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total 
                 0 
                 0 
                 1 
                 0 
                 0 
                 0 
                 0 
                 0 
                 1 
                 1/6 
               
               
                 CONTROL 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Scores 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
             
          
           
               
                 Primary Irritation Score 
                 0* 
               
               
                 Test Observation Average (−) Control Observation Average 
                   
               
             
          
           
               
                 RABBIT 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 #3952 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0/6 
               
               
                 TEST 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (Drug 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Scores) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0/6 
               
               
                 TEST 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (Saline) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Scores 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0/6 
               
               
                 CONTROL 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Scores 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
             
          
           
               
                 Primary Irritation Score 
                 0* 
               
               
                 Test Observation Average (−) Control Observation Average 
                   
               
             
          
           
               
                 RABBIT 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 #3953 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0/6 
               
               
                 TEST 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (Drug 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Scores) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0/6 
               
               
                 TEST 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (Saline) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Scores 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Total 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0/6 
               
               
                 CONTROL 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Scores 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
             
          
           
               
                 Primary Irritation Score 
                 0* 
               
               
                 Test Observation Average (−) Control Observation Average 
               
               
                   
               
             
          
           
               
                 RABBIT # 
                 PRIMARY IRRITATION SCORES 
                 IRRITATION RESPONSE CATEGORY 
               
               
                   
               
               
                 3951 
                 0 
                 0 to 0.4 - - - 
               
               
                 3952 
                 0 
                 Negligible 
               
               
                 3953 
                 0 
                   
               
               
                 Total 
                 0 
                   
               
               
                 Primary Irritation Index (PII) Total/3 
                 0 
               
               
                   
               
               
                 *Negative value is reported as zero. 
               
             
          
         
       
     
     TECHNICAL REFERENCES 
     
         
         16 CFR, Part 1500.41, Method of Testing Primary Irritant Substances, 1-1 97. 
         ISO 10993-10: 2002 Standard, “Biological Evaluation of Medical Devices, Part 10-Tests for Irritation and Sensitization” pp. 6-10, 21. 
         Marzulli, F. N., Maibach, H. I., Dermatotoxicology 4th Edition, pp. 201-208, Hemisphere Publishing Corp. New York, N.Y., 1991. 
         U.S. EPA—Office of Prevention, Pesticides and Toxic Substances (OPPTS), Health Effects Test Guidelines, OPPTS 870.1200 Acute Dermal Toxicity. 
       
    
     Example III 
     Repeated Patch Dermal Sensitization Test 
     Buehler Method Modified for Medical Devices 
     PURPOSE: This test was designed to evaluate the allergenic potential or sensitizing capacity of the iontophoretic test article. This test was used as a procedure for the screening of contact allergens in guinea pigs and extrapolating the results to humans, but does not establish the actual risk of sensitization in humans. 
     TEST SAMPLE PREPARATION: The test article consisted of an iontophoretic device having electrodes of this invention, with white adsorbant pads having clear drug and saline gels. 
     EXPERIMENTAL METHODS SUMMARY: Ten test guinea pigs were patched with the test article and five guinea pigs were patched with a control blank. The bandages and patches were removed after six (6) hours of exposure. After a 24 hour rest period, each site was observed on each animal for erythema and edema. This procedure was repeated once per week for three weeks for a total of three applications. Following a two week rest period, the animals were topically patched with the appropriate test article on the nine test animals and the control blank on the control animals. The patches were removed after 6 hours of exposure. The dermal patch sites were observed for erythema and edema 24 and 48 hours after patch removal. Each animal was assessed for a sensitization response based upon the dermal scores. The test results were based upon incidence and severity of the sensitization reaction. 
     Results for the study are summarized in Tables VI-IX. 
     CONCLUSION: The test article is considered a non-sensitizer. 
     
       
         
               
             
               
               
               
             
           
               
                 TABLE VI 
               
             
             
               
                   
               
               
                 DERMAL CHALLENGE SUMMARY 
               
             
          
           
               
                 MEASURED CRITERIA 
                 24 HOURS 
                 48 HOURS 
               
               
                   
               
               
                 Test Group Challenge Score Totals 
                 0 
                 0 
               
               
                 Severity (Total/10) 
                 0/10 
                 0/10 
               
               
                 Incidence % 
                 0% 
                 0% 
               
               
                 Control Group Challenge Score Totals 
                 0 
                 0 
               
               
                 Severity (Total/5) 
                 0/5  
                 0/5  
               
               
                 Incidence % 
                 0% 
                 0% 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
               
               
             
               
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE VII 
               
               
                   
               
               
                 INDUCTION DERMAL OBSERVATIONS 24 HOURS AFTER 
               
               
                 UNWRAPPING 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 PATCH 1 
                 PATCH 2 
                 PATCH 3 
               
             
          
           
               
                   
                 TEST GROUP 
               
             
          
           
               
                 ANIMAL # 
                 NS 
                 Drug a   
                 NS 
                 Drug a   
                 NS 
                 Drug a   
               
               
                   
               
               
                 39801 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39802 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39803 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39804 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39805 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39806 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39807 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39808 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39809 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39810 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
             
          
           
               
                   
                 NEGATIVE CONTROL GROUP 
               
             
          
           
               
                   
                 NS 
                 Drug b   
                 NS 
                 Drug b   
                 NS 
                 Drug b   
               
               
                   
               
               
                 39811 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39812 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39813 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39814 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 39815 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                   a = Drug patch with Sponsor supplied test article 
               
               
                   b = Drug patch with Normal Saline only (Sponsor supplied) 
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
             
               
               
               
               
               
               
             
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE VIII 
               
               
                   
               
               
                 CHALLENGE DERMAL OBSERVATIONS 
               
               
                 (24 HOURS POST UNWRAPPING) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 24 HOURS 
                   
                 48 HOURS 
                   
               
             
          
           
               
                   
                 Test Group Patches 
                   
               
             
          
           
               
                   
                 ANIMAL # 
                 NS 
                 Drug a   
                 NS 
                 Drug a   
               
               
                   
               
               
                   
                 39801 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39802 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39803 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39804 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39805 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39806 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39807 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39808* 
                 — 
                 — 
                 — 
                 — 
               
               
                   
                 39809 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39810 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 TOTAL OF SCORES 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 SEVERITY 
                 0/10 
                 0/10 
                 0/10 
                 0/10 
               
               
                   
                 (TOTAL/10) 
                   
                   
                   
                   
               
               
                   
                 INCIDENCE % 
                 0% 
                 0% 
                 0% 
                 0% 
               
               
                   
               
             
          
           
               
                   
                 NEGATIVE CONTROL GROUP 
                   
               
             
          
           
               
                   
                 ANIMAL # 
                 NS 
                 Drug b   
                 NS 
                 Drug b   
               
               
                   
               
               
                   
                 39811 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39812 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39813 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39814 
                 0 
                 0 
                 0 
                 0 
               
               
                   
                 39815 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 *Animal found dead on day 19, considered to be unrelated to the test article 
               
               
                   a = Drug patch with Sponsor supplied test 
               
               
                   b = Drug patch with Normal Saline only (Sponsor supplied) 
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                 TABLE IX 
               
             
             
               
                   
               
               
                 POSITIVE CONTROLS (RUN Mar. 28, 2007) 
               
             
          
           
               
                 ANIMAL # 
                 24 HOURS SCORE 
                 48 HOURS SCORE 
               
               
                   
               
             
          
           
               
                 TEST GROUP 
               
             
          
           
               
                 35464 
                 2 
                 1 
               
               
                 35465 
                 1 
                 1 
               
               
                 35466 
                 2 
                 1 
               
               
                 35467 
                 2 
                 2 
               
               
                 35468 
                 2 
                 2 
               
               
                 35469 
                 2 
                 2 
               
               
                 35470 
                 2 
                 2 
               
               
                 35471 
                 1 
                 1 
               
               
                 35472 
                 2 
                 1 
               
               
                 35473 
                 2 
                 2 
               
               
                 TOTAL OF SCORES 
                 18  
                 15  
               
               
                 SEVERITY 
                 18/10 
                 15/10 
               
               
                 (TOTAL/10) 
                   
                   
               
               
                 INCIDENCE % 
                 100% 
                 100% 
               
             
          
           
               
                 NEGATIVE CONTROL GROUP 
               
             
          
           
               
                 35474 
                 0 
                 0 
               
               
                 35475 
                 0 
                 0 
               
               
                 35476 
                 0 
                 0 
               
               
                 35477 
                 0 
                 0 
               
               
                 35478 
                 0 
                 0 
               
               
                 TOTAL OF SCORES 
                 0 
                 0 
               
               
                 SEVERITY 
                 0/5 
                 0/5 
               
               
                 (TOTAL/5) 
                   
                   
               
               
                 Incidence % 
                  0% 
                  0% 
               
               
                   
               
             
          
         
       
     
     TECHNICAL REFERENCES 
     
         
         Dermatotoxicology, Marzulli, F. N. and Maibach, H. I., editors, 4th edition, 1991, pp 381-3385, Hemisphere Publishing Corporation, New York. 
         ISO 10993-10: 1995 Standard, “Biological Evaluation of Medical Devices, Part 10-Tests for Irritation and Sensitization” pp. 13-15. 
         Principles and Methods of Toxicology, Wallace Hayes, A., editor, 3rd edition, 1994. Dermatotoxicology Chapter 21, pp. 777, Ravin Press, New York. 
         Ritz H. L. and Buehler E. V. (1980). Procedure for Conducting the Guinea Pig Assay. Current Concepts in Dermatology, Drill V. A. and Lazar P. (eds), Academic Press, New York, N.Y., pp 25-40. 
         U.S. EPA—Office of Prevention, Pesticides and Toxic Substances (OPPTS), Health Effects Test Guidelines, OPPTS 870.2600 Skin Sensitization