Patent Publication Number: US-10780266-B2

Title: System and method for biphasic transdermal iontophoretic therapeutic agents

Description:
RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 14/755,840, filed Jun. 30, 2015, which is a divisional of U.S. patent application Ser. No. 13/430,662, filed Mar. 26, 2012 (now U.S. Pat. No. 9,095,503), which application claims the benefit of Provisional U.S. Patent Application Ser. No. 61/465,896, entitled “Biphasic Transdermal Iontophoretic System For The Transdermal Delivery Of Therapeutic Agents”, filed Mar. 24, 2011; and Provisional U.S. Patent Application Ser. No. 61/518,486, entitled “Biphasic Transdermal Iontophoretic System For The Transdermal Delivery Of Therapeutic Agents For The Control Of Addictive Cravings”, filed May 6, 2011. Said Ser. No. 14/755,840 is also a continuation-in-part of U.S. patent application Ser. No. 12/537,243, entitled “Iontophoretic System For Transdermal Delivery Of Active Agents For Therapeutic And Medicinal Purposes”, filed Aug. 6, 2009 (now U.S. Pat. No. 8,190,252), which claims the benefit of Provisional U.S. Patent Application No. 61/152,251 entitled “Kit, System and Method for Transdermal Iontophoretic Delivery of Therapeutic Agents”, filed Feb. 12, 2009. All of the above-identified applications are fully incorporated by reference herein for all purposes. 
    
    
     FIELD OF THE INVENTION 
     Embodiments described herein relate to assemblies and methods for transdermal drug delivery. More specifically, embodiments described herein relate to assemblies and methods for iontophoretic transdermal delivery of drugs and other therapeutic agents. 
     BACKGROUND 
     Chronic pain is a debilitating disease affecting millions of Americans. It destroys quality of life, results in significant number of lost work days and costs billions of dollars each year. Current forms of pain management include IV and oral delivery of various opioids and other pain medication. However, both IV and oral forms of drug delivery have a number of limitations. Both, in particular oral forms, can be ineffective for the treatment of chronic breakthrough pain. Breakthrough pain is pain that comes on suddenly for short periods of time and is not alleviated by the patients&#39; normal pain suppression management. It is common in cancer patients who commonly have a background level of pain controlled by medications, but the pain periodically “breaks through” the medication. The characteristics of breakthrough cancer pain vary from person to person 
     Also both oral and IV forms of opioids and other pain medication are susceptible to the development of patient addiction due to excessive self medication. Further, both put the patient at risk of overdose and underdose due to unpredictable pharmaco-kinetics. The former resulting in a number of complications including addiction, depressed respiration, irregular heart rate and even death. The latter includes continued patient exposure to chronic pain. Also, oral delivery can have poor absorption particularly in the presence of other medications or food resulting in a delayed or uneven analgesic/therapeutic effect which in turn causes the patient to take more, thus increasing the chances of addition. Also, a number of oral analgesics, NSAIDS (non-steroidal anti-inflammatory drugs) for example, cause intestinal bleeding and various GI problems, such as cramping, etc. Intravenous limitations include the requirement to mix and store the medication in liquid form as well as the use of sterile techniques in administration. Also, IV administration can include several risk factors including anaphylaxis and cardiovascular complications. Thus, there is a need for improved methods of drug delivery for pain management. 
     Transdermal iontophoresis is a non-invasive method of propelling high concentrations of a drug or other therapeutic agent through the skin of a human or other animal by repulsive electromotive force using a small electrical charge. The electrical charge repels ionized (i.e., charged) forms of the drug or other therapeutic agent. Using such an approach, doses of pain medication can be delivered to the patient using a skin contacting patch containing pain medication that has been dissolved in a solution disposed within the patch. The application of a current causes the dissolved medication to be propelled from the solution through a contacting layer of the patient and into the skin. However, over-administration/overdose remains a problem for such devices due to the fact that the pain medication continues to passively diffuse from the patch reservoir into the patient even when iontophoretic current is off due to concentration gradients between the patch and the skin (under the principles of Fickian diffusion). Also, there is nothing to stop the patient from overdosing themselves by reactivating the device or even leaving the current on continuously to give themselves repetitive or even continuous doses. Improved systems and methods are needed for preventing over-administration of drugs due to passive diffusion as well as excessive administration by the patient. 
     BRIEF SUMMARY 
     Embodiments of the invention provide methods and assemblies for the transdermal delivery of drugs and other therapeutic agents to humans, mammals and other animals. Many embodiments provide a biphasic transdermal iontophoretic system having a delivery current to deliver doses of a therapeutic agent over a delivery period and a holding current to substantially halt or reduce the delivery of agent during a non-delivery period. Such embodiments can be configured to allow for repetitive cycles of delivery and non-delivery of drugs and other therapeutic agents to treat various conditions. Further, various embodiments provide systems and methods allowing for on-demand initiation of a delivery period (e.g., by the patient, caregiver or other person) to allow for treatment of various acute conditions such as pain, nausea (e.g., chemotherapy induced), migraine headache and other conditions. Such systems and methods can be configured for use in the delivery of various analgesic agents including opioids such as fentanyl and its derivatives and analogues. Other embodiments can be configured for use in the delivery of various antiemetics such as dolasetron (and other 5-HT3 receptor antagonists), domperidon (and other dopamine antagonists) and promethazinen (and other antihistamines). 
     Still other embodiments of systems and methods of the invention provide for controlled initiation of a delivery period and/or cycles of delivery and non-delivery by a controller such as a microprocessor or other controller known in the art (e.g., an analogue controller). Such embodiments can be configured for the cyclical delivery of a variety of therapeutic agents including, for example, parathyroid hormones and like compounds for the treatment of osteoporosis and various chemotherapeutic agents for the treatment of cancer. Further, such embodiments are particularly useful for the delivery of therapeutic agents where the time course of delivery of the agent needs to be controlled to produce a desired therapeutic effect and/or to minimize adverse effects to the patient. Such controlled initiation (either of a delivery period or cycle of delivery and non delivery periods) can be incorporated into a delivery regimen which can be programmed into the controller either directly, wirelessly or by means of a memory device operably coupled to the controller. The system can be configured to allow the program to be selected by a doctor, pharmacist, or other medical care provider. The selection can be done directly by the medical care provider via an input device (e.g., touch screen) coupled to the controller or wirelessly using a wireless device such as a cell phone, tablet device or like device. In either case, lockout codes can be employed to prevent anyone but the medical care provider from entering or changing a particular delivery regimen. 
     One embodiment provides a method for the transdermal delivery of a therapeutic agent to a patient comprising positioning at least one electrode assembly in electrical communication with a patient e.g., with the patient&#39;s skin. The electrode assembly includes a skin contacting layer and a solution having a dissolved therapeutic agent having an electrical charge, wherein the dissolved agent passively diffuses into the skin without the application of an external force. A first dose of agent is delivered from the electrode assembly into the skin during a first period using a first current having a polarity and magnitude or other characteristic to repel the agent out of the assembly. During a second period, a second current having a polarity and magnitude or other characteristic to attract the agent is used to retain the agent in the assembly such that delivery of the agent into the skin during the period is minimized. Embodiments of this method are particularly useful for the delivery of various therapeutic agents, such as opioids where over-delivery of the therapeutic agent from passive diffusion may be harmful to the patient. 
     Further details of these and other embodiments and aspects of the invention are described more fully below, with reference to the attached drawing figures. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a cross sectional view showing the three main layers of the skin, the epidermis, the dermis and subcutaneous tissue as well as the passageways into the skin. 
         FIG. 2  is a lateral view of an embodiment of a system for the transdermal iontophoretic delivery of various therapeutic agents using delivery and lateral electrodes. 
         FIG. 3 a    is a schematic side view showing placement of an embodiment of a transdermal iontophoretic patch device on the surface of the skin, wherein the device comprises an active electrode assembly and a return electrode assembly. 
         FIG. 3 b    is a schematic side view showing placement of an embodiment of transdermal iontophoretic patch device on the surface of the skin, wherein the device comprises two active electrode assemblies. 
         FIGS. 4 a  and 4 b    are side and top views showing an embodiment of a skin patch including an active electrode and lateral electrodes. 
         FIG. 5 a    is a top down view showing an embodiment of an on demand user-activated transdermal delivery system including a patch assembly. 
         FIGS. 5 b , 5 c  and 5 d    are time sequence graphs illustrating an embodiment of a patient controlled or other “on-demand” biphasic transdermal iontophoretic delivery system having a delivery current and a holding current so as to cycle between delivery periods and non delivery periods of a drug or other therapeutic agent.  FIG. 5 b    shows an activation signal for initiating a drug delivery cycle, the signal generated by a patient activated device or other signal generation means;  FIG. 5 c    shows an embodiment of a current waveform initiated by the activation signal the waveform having a delivery current and holding current;  FIG. 5 d    shows an embodiment of a drug delivery profile corresponding to the periods of delivery current and holding current. 
         FIGS. 6 a  and 6 b    are perspective views showing an embodiment of a system/patch assembly for iontophoretic transdermal delivery of a therapeutic agent including a patch and an electronics assembly,  FIG. 6 a    shows a top view,  FIG. 6 b    shows a bottom view.  FIG. 6 c    is a block diagram of an embodiment of the electronics assembly including a controller, current source and current switching device. 
         FIG. 7 a    is a perspective view showing placement of the embodiment of  FIGS. 6 a  and 6 b    on an example site on the skin of a user. 
         FIG. 7 b    is a lateral view showing an embodiment of a patch assembly having a curved contour positioned at a tissue site having a curved contour. 
         FIGS. 8 a  through 8 f    illustrate various waveforms or current output variations that can be used to promote various characteristics of embodiments of the transdermal iontophoretic delivery system. 
         FIG. 9  is a block diagram of a transfer function used to model an embodiment of the transdermal iontophoretic delivery system used in the example. 
         FIGS. 10 a  and 10 b    are plots of delivered therapeutic agent versus time.  FIG. 10 a    shows the cumulative input vs. the estimated system response based on an optimum cross-correlation FIR filter response of the measured system response;  FIG. 10 b    plot shows the density input vs. the estimated system response based on an optimum cross-correlation FIR filter response of the measured system response. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Various embodiments described herein provide a device, system and method for the transdermal iontophoretic delivery of various drugs and other therapeutic agents. Many embodiments provide devices, systems and methods for the biphasic transdermal iontophoretic delivery of various therapeutic agents such as opioids and antiemetics. As used herein, the term transdermal delivery refers to the delivery of a compound, such as a drug or other therapeutic agent, through one or more layers of the skin (e.g., epidermis, dermis, etc.). Referring now to  FIG. 1 , the layers of the skin include the epidermis EP, dermis D and subdermis SD. The upper most layer of the epidermis includes the stratum corneum SC, a dead layer of skin (having a thickness of about 10 to 40 μm) and the viable epidermis EP. Transdermal delivery can proceed by one of the three passage ways into the skin, via 1, the sweat pores SP, 2, the hair follicles HF or via permeation 3 through the epidermis EP (starting at the stratum corneum) and the dermis. 
     Iontophoresis is a non-invasive method of propelling high concentrations of a charged substance, known as the active agent, transdermally by repulsive electromotive force using a small electrical charge. The active agent can include a drug or other therapeutic agent. The charge is applied by an electrical power source to an active electrode assembly placed on the skin which contains a similarly charged active agent and a solvent in which it is dissolved. Current flows from the electrode assembly through the skin and then returns by means of a return or counter electrode assembly also placed on the skin. A positively charged electrode assembly, termed the anode will repel a positively charged active agent, or anion, into the skin, while a negatively charged electrode assembly, termed the cathode, will repel a negatively charged active agent, known as a cation, into the skin. 
     Referring now to  FIGS. 2-4   b , an embodiment of a system  5  for the transdermal iontophoretic delivery of a therapeutic agent  51  to a tissue site TS (such as the arm A) also referred to as a delivery site TS, on the skin S of patient, comprises at least two electrode assemblies  14  including an active electrode assembly  20  and a return electrode assembly  30  and a power supply  100 . Active electrode assembly  20  is used to deliver the therapeutic agent through skin S via current delivered to the skin from power supply  100 . Return electrode assembly  30  provides a return path for current (e.g., current  60 ) to power supply  100 . Collectively, the active and return electrode assemblies  20  and  30  comprise a transdermal iontophoretic delivery device  10  also described herein as patch device  10 . In embodiments using an alternating current, both electrode assemblies  14  can be configured as active and return electrode assemblies  20  and  30  depending on the direction of current flow. In some cases for sake of brevity, electrode assembly  14 , active electrode assembly  20  and/or return electrode assembly  30  will sometimes be referred to as electrode  14 , active electrode  20  and return electrode  30  respectively. 
     In many embodiments, the electrode assemblies  14  (e.g., active and return assemblies  20  and  30 ) comprise or are otherwise disposed on one or more patches  15  configured to be applied to the skin surface. Patches  15  are desirably conformable to a contour CR of a skin surface S and can be fabricated from layers of elastomeric or other flexible polymer material. In some embodiments, two or more electrodes assemblies  14  including active and return electrode assemblies  20  and  30  can be placed on a single patch  15 . In other embodiments, system  5  can include separate patches  15  for electrode assemblies  14 , for example, a first patch  15 ′ for the active electrode assembly  20  and a second patch  15 ″ for the return electrode assembly  30 . In other embodiments, three or more patches  15  can be used so as to have either multiple active electrode assemblies  20  or return electrode assemblies  30  or both. For example, in one embodiment system  5  can comprise three patches  15 ; including two patches containing active electrode assemblies  20  and a third patch  15  containing a return electrode assembly  30 . Other combinations of multiple patches and electrode assemblies are also contemplated, e.g., four patches, two for active electrode assemblies  20  and two for return electrode assemblies  30 . 
     In many embodiments, active electrode assembly  20  can comprise a reservoir  21  for the therapeutic agent, a tissue contacting porous portion  24  in fluidic communication with the reservoir, an adhesive portion  25  for adhering the assembly to the skin, and an electrical connector  26  for coupling the electrode assembly  20  to an electrical power supply  100  as is shown in the embodiment of  FIG. 2 . Reservoir  21  can be sized for the particular dose of therapeutic agent to be delivered. In various embodiments, the power supply  100  can include various features to facilitate use by medical personnel both in a hospital setting and in the field. For example, the power supply can include or be configured to be coupled to a bar code reader (not shown) for reading bar codes positioned on one or more of electrode assemblies  14 , patches  15  or power supply  100 . 
     Tissue contacting portion  24  is also electrically conductive (herein conductive) so as to function as an active electrode  20  and/or return electrode  30 . This can be achieved by fabricating tissue contacting portion  24  from conductive porous materials (e.g., conductive carbon or other conductive fibers) and/or by having it become wetted with a conductive solution  54  (the conductivity being due to therapeutic agent  51  or various electrolytes added to the solution). Connector  26  can extend into or otherwise make electrical contact with tissue contacting portion  24  so to be electrically coupled to portion  24 . In some embodiments, connector  26  can be coupled to a conductive element  28  positioned within the electrode assembly  14  and coupled to conductive porous portion  24 . One or more of conductive element  28 , conductive layer  34  (described below) as well as lateral electrodes  40  (also described below) can comprise various conductive materials including stainless steel, carbon, silver chloride (AgCl) or other conductive materials known in the art. 
     Typically, adhesive portion  25  will surround the perimeter  24   p  of porous portion  24  as is shown in the embodiment of  FIGS. 4 a  and 4 b   , though other arrangements are also contemplated. In various embodiments, porous portion  24  can comprise a porous layer  24  that in turn comprises various porous materials including polymers foams, membranes or weaves of polymer fibers known in the art including polyesters, PETs and like materials. Adhesive portion  25  may be attached to porous layer  24  and include various releasable adhesives known in the art. The adhesive portion  25  can comprise an adhesive layer  25   a , such as one or more releasable adhesives attached to a substrate layer  25   s , which can comprise various hydrogels, polyurethanes, silicones or like polymeric materials. The size and configuration of adhesive portion  25  can be adapted for the particular skin location (e.g., arm vs. leg, amount of hair, etc.) and type of skin (e.g., pediatric vs. geriatric etc., amount of hair, etc.). 
     Typically, the therapeutic agent  51  will be dissolved in a therapeutic agent solution  54 , also described as therapeutic agent composition  54  which is used to fill reservoir  21 . In addition to therapeutic agent  51 , solution  54  can include one or more pharmaceutical excipients  52  such as preservatives (e.g., citric acid). The viscosity of the solution  54  can be adjusted to have the solution readily wick from reservoir  21  into porous layer  24 . Solution  54  can be preloaded into the reservoir  21  at the factory or can be added by medical personnel prior to use through means of a port  22 , such as a self-sealing port (allowing injection of liquid through the port) which is coupled to reservoir  21  via means of a channel  27  as is shown in the embodiment of  FIG. 3 b   . Suitable therapeutic agents  51  can include, without limitation, ferric pyrophosphate or other iron containing compound for the treatment of iron deficient anemia, insulin or various glucagon like peptides for treatment of diabetes or other blood sugar regulation disorder, fentanyl or other opioid compound for pain management and various chemotherapeutic agents for the treatment of cancer. 
     The return electrode assembly  30  comprises a tissue contacting conductive layer  34 , an adhesive layer  35  and a connector  26  for coupling the electrode assembly to the electrical power source. In many embodiments, the return electrode assembly  30  can have substantially the same elemental configuration as active electrode assembly  20  (e.g., a reservoir  21 , conductive tissue contacting layer  24 ) so as to function as an active electrode assembly as is shown in the embodiment of  FIG. 3   b.    
     In many embodiments, patch  15  also includes one or more pair of electrodes known as lateral electrodes  40 . Lateral electrodes  40  are desirably placed on either side of porous portion  24  at a selectable distance from the perimeter  24   p  of porous portion  24  as is shown in the embodiments of  FIGS. 3 a -3 b  and 4 a -4 b   . Lateral electrodes  40  can comprise various conductive materials including metals, graphite, silver chloride and other like materials. In various embodiments, all or a portion of lateral electrode  40  can include an insulative coating so as to be a capacitively coupled electrode that delivers current to the skin via capacitive coupling. Lateral electrodes  40  are also desirably electrically isolated from electrodes  20  and  30  and will typically include their own wave form generator circuits. 
     The lateral electrodes  40  are desirably arranged with respect to porous portion  24  such that they result in a conductive pathway  104  which goes through the skin S underlying portion  24  and is substantially parallel to the skin. Embodiments of patch  15  that employ lateral electrodes  40  with delivery electrodes  20 , allow for the flow of two currents, a first current  60  and a second current  70 . First current,  60  flows between electrodes  20  and  30  and serves to provide an electromotive force which acts to drive the therapeutic agent  51  into and across the layers of the skin S. The second current  70 , known as sieving current  70 , provides an electromotive force that acts on the therapeutic agent  51  in a direction parallel to the skin S so as to cause oscillation of therapeutic agent  51  in a direction parallel to skin S. This oscillation acts to sieve the therapeutic agent through pathways of lesser or least diffusional resistance in the skin. For embodiments where second patch  15 ″ contains lateral electrodes  40  and is used to deliver therapeutic agent, a third current  70 ′ can be delivered from lateral electrodes on the second patch  15 ″ to also create an electromotive driving force to oscillate the therapeutic agent substantially parallel to the skin surface underneath the second patch  15 ″. Further description on the arrangement and use of lateral electrodes  40  including their use in generating a sieving current is found in U.S. patent application Ser. No. 12/658,637, filed Feb. 10, 2010 which is incorporated by reference herein in its entirety. 
     Referring now to  FIGS. 5 a -5 d   , various embodiments of the invention for use in on demand transdermal delivery of a therapeutic agent will now be described. Such embodiments include systems  5 ′ and methods for on demand delivery of therapeutic agents  51 . As used herein, the term “on demand”; refers to the ability of the patient or other person (e.g., a medical care provider) to initiate the delivery of therapeutic agent. This includes the initiation of a therapeutic agent delivery period and/or cycle of therapeutic agent delivery periods described below. The initiation of any of these can be a signal/input from a patient activation device such as a push button device and/or a signal received from a wireless device such as cell phone or other RF-enabled device. Such “on demand” embodiments provide for one or more of the following: i) the ability for the patient, other user or a controller/machine to initiate the delivery of therapeutic agent  51  to the patient; and ii) the ability to stop or otherwise limit the passive diffusion of therapeutic agent  51  during periods of time when an iontophoretic current is not supplied to patch assembly  15   cp . In many embodiments, on demand transdermal delivery can be implemented by use of a biphasic transdermal iontophoretic delivery system  5 ″ (biphasic transdermal iontophoretic delivery is defined and further described below). Such embodiments are particularly useful for the delivery of therapeutic agents  51   p  (herein after pain medication  51   p ) for the treatment of pain (e.g., pain reduction), such as an opioid-based pain medication (e.g., fentanyl and its analogues). However, it should be appreciated that embodiments of such a system  5 ″ can be used for the delivery of any therapeutic agent  51  described herein or known in the art for the treatment of any number of conditions. 
     Referring now to  FIG. 5 a    an embodiment of an “on demand” transdermal delivery system  5 ′ will now be described. The system may configured for on demand delivery of therapeutic agent  51  by the patient and/or a medical care provider. System  5 ′ may also be configured as a biphasic transdermal iontophoretic delivery system  5 ″ described herein, for example, through the use of a control program  93   p  described below. The system  5 ′ includes a patch assembly  15   cp  including a patch  15 , electrodes  14 , therapeutic agent reservoir  21  and electronic module or section  90  including a user activated device  91  (also referred to as activation device  91 ) for allowing the patient or other user to initiate delivery of therapeutic agent  51 . Electrodes  14  and will typically include a delivery or active electrode  20  and a return electrode  30  as described herein. Active electrode  20  is configured to be in fluidic communication with a therapeutic agent reservoir  21  for storing a supply of therapeutic agent  51 . As described herein, in many embodiments, therapeutic agent  51  will be dissolved in a solution  54  (contained in reservoir  21 ) so as to be in ionic form. According to one or more embodiments, solution  54  containing therapeutic agent  51  can be loaded into reservoir  21  at the factory and/or at the pharmacy by a pharmacist before pickup by the patient. According to other embodiments, therapeutic agent  51  is stored in reservoir  21  in solid form and liquid comprising solution  54  is added to the reservoir by the user or medical care provider immediately prior to use. 
     In various embodiments, patch  15  can have a substantial oval shape  15   o  including, for example, peanut or cassini-shaped ovals  15   oc  having side portions  15   s  and a tapered center portion  15   c  as is shown in the embodiment of  FIG. 5 a   . Electrodes  14  including active electrode  20  and return electrode  30  can be positioned in side portions  15   s  and an electronics module  90  positioned in the center portion  15   c . Desirably, electrodes  20  and  30  are positioned on opposite side portions  15   s  as is shown in the embodiment of  FIG. 5 a   ; however other configurations are also contemplates such as the placement of electrodes  20  and  30  in each side portion  15   s . Electronics module  90  can include a controller  93  which may correspond to controller  530  (shown in  FIG. 6 a   ) and a power source  97  which may correspond to power source  570  (shown in  FIG. 6 b   ) and can include an electrochemical storage battery and circuitry for converting a DC (direct current) signal from the battery(s) into an AC (alternating current) signal. The electronics module  90  includes a user activation device  91  such as a push-button or switch for initiating a drug delivery cycle to deliver a dose of an opioid or other therapeutic agent  51  (e.g., an antiemetics). Other electromechanical activation devices  91  known in the art are also contemplated. Typically, activation device  91  is coupled to controller  93  (or other controller) so that signals  91   s  generated by device  91  provide an input to the controller for initiating a function such as initiation of a delivery period and/or delivery cycle of therapeutic agent  51 . However, in additional or alternative embodiments, activation device  91  may comprise an externally connected device such as a push-button device that is electrically connected to module  90  (e.g., by a wire) and positioned and configured for easy access by the patient (e.g., a device that is attached to the patient belt or may lie by the patients bed side). In still other embodiments, activation device  91  may comprise a wireless device, such as a cell phone, pda or RF-enabled communication device that can be carried, worn or placed in close proximity to the patient. For such wireless embodiments of device  91 , device  91  and/or controller  93  may include various passwords or other codes to prevent accidental and/or other unauthorized use. 
     Referring now to  FIGS. 5 b -5 d   , embodiments of a method for “on demand” drug delivery using a biphasic transdermal iontophoretic delivery system  5 ″ will now be described. Embodiments of this method are applicable with various embodiments of the patch and electrode assemblies described herein such as patch assembly  15   cp  and  500 . “Biphasic transdermal iontophoretic delivery” refers to the use of a transdermal iontophoretic delivery system having a first and second phase of drug delivery. In some embodiments, the first and second phase of drug delivery may correspond to a delivery period and a non-delivery period. The delivery period in turn may correspond to a period of active transport of the therapeutic agent (e.g., using a drive current) and the non-delivery period to a period of active inhibition of such transport (e.g., using a holding current). As shown in  FIGS. 5 b -5 d   , before the initiation of a delivery cycle (e.g., by the patient, or other user) no or minimal agent is delivered as the agent is held within reservoir  21  by a holding current  320  described below. When the patient presses activation device  91  this generates a signal  300  which is fed into the controller  93 . The controller  93  can include a control program or other logic  93   p  for starting a drug delivery period  340  upon receiving the signal  300 . The control program  93   p  then initiates the beginning of a drug delivery period  340  by the flow of a first current known as a drug delivery current  310  (also referred to herein as a drive current  310 ) which has a polarity and magnitude or other characteristic configured to repel therapeutic agent  51  from the reservoir  21  and into the skin (the polarity being the same in sign (i.e., positive or negative) to the charge to that of the ionic form of therapeutic agent  51 ). The other characteristics of current  310  can include, without limitation one or more of the voltage, frequency/period or shape of the waveform of current  310  (these characteristics can also be used for adjustment of holding current  320  to perform its function). 
     Controller  93  keeps the delivery current  310  on for the delivery period  340  to deliver a selected dose of the therapeutic agent  51  into the skin as shown by the delivery curve  350  in  FIG. 5 d    (the delivery period and delivery current can be stored in controller  93  and/or determined by program  93   p  for example using the transfer function and other modeling methods described in the appended example). At the end of the delivery period  340 , the controller stops the delivery current  310  and starts a non-delivery period  330  (also known as refractory period  330 ) by generating a holding current  320 . Holding current  320  has a polarity and magnitude or other characteristic configured to retain agent  51  within reservoir  21  by the force of electrostatic attraction (e.g., the polarity of the holding current  320  has the opposite sign as the charge of the ionic form of the therapeutic agent) so as to prevent or minimize passive diffusion of the therapeutic agent from the patch into the skin. Such minimal diffusion is shown in the non-delivery curve  360  in  FIG. 5 d   . Such passive diffusion would otherwise occur without the presence of attractive force from the holding current  320 . In particular embodiments, one or more characteristics of holding current  320  can be adjusted relative to the concentration of the therapeutic agent  51  within solution  54  and/or other property of solution  54  so as to assure that the holding current is sufficient to retain agent  51  within reservoir  21 . For example, the magnitude of the current  320  can be proportionally or otherwise adjusted (e.g., geometrically) relative to the concentration of therapeutic agent  51  within solution  54 . The adjustment can be done at the factory, by the medical caregiver or via software within controller  93 . The adjustments can also be done dynamically over the course of a delivery cycle to account for changes in the changes of the concentration of agent  51  within solution  54 . In particular embodiments, a sensor may be employed to measure the concentration of agent  51  within solution  54  within output of the sensor being fed as an input to controller  93 . In related embodiments similar adjustments can be in the characteristics of current  310  relative to the concentration of agent  51  in solution  54  or other property of solution  54  so as to assure that sufficient agent  51  is delivered out of reservoir  21  and into the patient&#39;s skin. 
     Also, during non-delivery period  330 , the controller locks out or otherwise prevents the start of another delivery period so as to prevent the patient (or other person) from repetitively dosing themselves and thus overdosing themselves. After the lockout period, the controller then allows the start of another delivery cycle. The controller can also be programmed or otherwise configured to only allow a maximum number of administered doses of agent  51  over a selected period of time, for example, 12, 24 hours etc. In particular embodiments for the delivery of opioid-based therapeutic agents  51   p , such as fentanyl and its analogues, the maximum number of doses can correspond to 24, 40, 48, 60, 80, 98 or 100 doses. Desirably, the maximum number of doses is configured to keep the concentration (e.g., plasma concentration) of therapeutic agent within a therapeutic index (known in the art) and prevent the dose from exceeding a maximum tolerated dose such as that which would cause or begin to cause respiratory depression, low blood pressure, slowed heart rate and/or other adverse physiologic affects. Similarly, the maximum number of delivered doses and/or lockout period can be selected to keep the rate of delivery of therapeutic agent  51  to the patient below that which would cause such adverse affects. The maximum number of dose and lockout period can be determined based on one or more parameters including without limitation, the therapeutic agent, the patient&#39;s age and weight, their condition and other therapeutic agents they are receiving (currently, previously or in the future). 
     Referring now to  FIGS. 6 a , 6 b , 6 c , 7 a  and 7 b   , in various embodiments, a system  500  for iontophoretic transdermal delivery of various pain medication  51   p  and/or other therapeutic agents can comprise a skin conformable patch  505  and an electronics assembly  550 . System  500  (also described herein as patch assembly  500 ) can be configured as an “on demand” transdermal delivery system  5 ′ and/or biphasic transdermal iontophoretic delivery system  5 ″ as described herein. Patch  505  includes first and second electrode assemblies  510  and  512  which can correspond to one or more embodiments of electrode assemblies described herein. The materials used to fabricate the electrode portions of the assemblies can include various corrosion resistant materials such as graphite further described in U.S. patent application Ser. Nos. 12/824,146 and 12/824,147 (both filed Jun. 10, 2010) which are fully incorporated by reference herein for all purposes. Also, one or both of electrode assemblies  510  and  512  can include a pair  520  of tissue contacting ring shaped electrodes  521  and  522  concentrically spaced or otherwise arranged to reduce edge effects as is further described in U.S. patent application Ser. No. 12/832,011 (filed Jul. 7, 2010) which is fully incorporated by reference herein for all purposes. 
     Electronics assembly  550  typically includes a housing  560  which engages patch  505  so as to form patch assembly  500 . Housing  560  includes a bottom and top surface  561  and  562  respectively, with the bottom surface  561  typically being the area of contact for engaging patch  505 , though other arrangements are also contemplated. In particular embodiments, the housing  560  can be configured to be detachably coupled to patch  505  via one or more detachment elements  600 . 
     Housing  560  can have a variety of shapes. In many embodiments, it can include a shaped contour  563  such as a curved shaped contour  564  (which can be for one or both of bottom surface  561  and top surface  562 ) that is configured to correspond to the contour C of the skin surface SS at the target tissue site TS where patch assembly  500  is placed such as the contour of the patient&#39;s arm, leg or abdomen (e.g., on the front or side of the stomach including below the waist line so as to not be visible). Contours  563  and  564  may: i) correspond to a standard contour for a particular target site TS; ii) may come in different sizes and shapes for different target tissue sites and sizes of patients; or iii) may be custom shaped for the particular patient and target tissue site. Also, the housing  560  can be conformable so as to at least partially conform to the contour C of the skin surface SS at the target tissue site TS where the patch  505  and housing  560  are placed (both when the patient is still and when they are moving resulting in bending movement and other deformation of the skin such that the skin surface contour is a flexing contour). Accordingly, in various embodiments, all or a portion of housing  560  can comprise various flexible polymers known in the art such as various elastomeric polymers, e.g., silicone and polyurethane. Other flexible polymers are also contemplated. The flexibility/conformability of the housing can also be configured to vary over the length of the housing to meet the needs of the particular target tissue site TS. For example, the housing  560  can be configured to have the greatest amount of flexibility at its center portions  560   c  (which can be achieved in some embodiments by putting a crimp or articulated zone  560   a  near the center of the housing). Also, the flexibility profile of the housing  560  can be matched or otherwise correlated to the shape and flexibility profile of the patch  505 . For example, in particular embodiments, the flexibility/conformability of the housing can be configured for embodiments of the patch  505  having ring shaped electrodes  521  and  522 . In these and related embodiments, housing  560  may have a structure which include areas  566  of greater flexibility (e.g., less stiffness) which may approximately align with ring shaped electrodes  521  and  522  (or others) such that the overall flexibility of the assembly  500  is not decreased over these areas. Areas  566  can have a shape which corresponds to the shape of electrodes  521  and  522  (or other shaped electrodes), though the size of the areas can be different from the size of the electrodes. Areas  566  can be achieved by decreasing the thickness of the housing in these areas and/or the use of more flexible materials. Other structures for housing  560  including shaped areas  566  are also contemplated, such as structures which have oval shapes areas  566  or even recessed areas  566 . 
     Also in various embodiments, housing  560  cannot only be conformable, but also have a profile  565  shaped and sized such that the entire patch assembly  500  can be worn beneath the user&#39;s clothing and can bend and flex sufficiently so that: i) it is not readily detached by pressure or force from the user&#39;s clothing (due to movement of the clothes and/or skin), allowing the patch assembly  500  to stay on for extended periods when adhered to a tissue site underneath the user&#39;s clothes; and ii) is not readily visible beneath the user&#39;s clothes. In various embodiments, the profile  565  of the housing can have a contour  564  (of one or both of top and bottom surfaces  562  and  561 ) which corresponds to the contour C of the surface of the patient&#39;s arm, leg, abdomen or other target tissue site TS. Further, embodiments of the housing  560  can be sized, shaped and otherwise fabricated to bend and flex sufficiently to account for movement of the patient&#39;s skin when the patch assembly  500  is placed on the patient&#39;s abdomen, arm, leg and other target tissue sites. In this way, even when the patch assembly  500  is placed under clothes (or not), the assembly can remain sufficiently adhered/attached to the patient&#39;s skin for an extended period of time so as to allow a desired dose of the drug or other therapeutic agent  51  to be delivered. In various embodiments, the time period can be up to 24 hours, up to three days, up to a week with even longer periods contemplated. Specific combinations of a patch  505  and housing  560  can be configured for specific desired attachment periods using one or more factors described herein (e.g., flexibility surface area, etc.). For embodiments of the patch including elemental iron, such configurations can allow the patch to remain sufficiently adhered to the patient&#39;s skin for a sufficient time to deliver a therapeutic dose of elemental iron for the treatment of iron deficient anemia (e.g., 1 to 100 mg with specific embodiments of 20, 30 and 50 mg) at rates which facilitate uptake and utilization by the patient&#39;s iron metabolism. Similar configurations and methods can be employed for delivery of other drugs and therapeutic agents described herein (e.g. opioids such as fentanyl and its analogues and derivatives). 
     Further, one or more of the size and shape (e.g., shape of the housing bottom surface  561  such as oval, circular, dogbone etc.) and flexibility of the housing  560  can be selected relative to one or more of the size and shape (e.g., shape of patch surface  505   s ) and flexibility of patch  505  such that when the patch assembly  500  is worn openly or beneath the patient&#39;s clothes, the applied amount of force from the housing  560  to the skin surface SS beneath the patch (due to movement of the patient&#39;s skin) or the clothing to the skin surface beneath the patch  505  (due to movement of the clothing or skin) is fairly uniform (e.g., there is a substantially uniform force distribution with minimal areas of force concentration). In use, these and related embodiments serve to minimize the amount of thermal, electrical or other injury to the skin from high current densities and/or hot spots from such force concentrations. Additionally for embodiments using delivery of therapeutic agent(s)  51  from embodiments of patch  505  having two more or electrode assemblies (e.g., assemblies  510  and  512 ) such configurations minimizing force concentrations (from skin movement etc) also serve to minimize any effect on the delivery of therapeutic agent from the first electrode relative to the second electrode (or others). In particular embodiments, this can serve to minimize any effect on the delivery rate or total delivered amount of therapeutic agent from the first electrode assembly  510  relative to the second electrode assembly  512  (or other electrode assemblies). 
     In particular embodiments, such results can be achieved by matching the flexibility of the housing  560  to the patch  505  (either approximately equivalent or a selected amount higher or lower, e.g., 5 to 50%) as well as configuring the surface area of the patch  505  to be large enough relative to the surface area of the housing  560  so as produce a snow-shoe like effect so as to evenly distribute any applied force to the housing from clothing or other applied force (such as that due to movement of the skin) over the entire surface area of the patch  505 . Surface area ratios in the range of 1:1.5 to 1:10 (housing surface area to patch surface area) are contemplated, with specific embodiments of 1:2, 1:3, 1:5. 
     In still other embodiments, the housing  560  or patch  505  may include a pressures sensor  567 , such as a solid state strain gauge which senses the amount of force applied by the user&#39;s clothes to the housing and/or patch. Input from the pressure sensor can then be used to modulate (either increase or decrease) current delivered to the patch relative to the applied force. The current can be modulated down to prevent the development of hot spots on the patch from excessive pressure or modulated up to account for any increase in the electrical impedance of the skin due to the applied pressure. 
     Assembly  550  will typically include a power source  570  (also referred to herein as current source  570 ) and a controller  530  (e.g., a microprocessor or like device) for controlling one or more aspects of the iontophoretic delivery of the agent to the skin. Controller  530  can also include an integrated or separate power controller  535  for controlling the delivery of current to the skin. One or both of the controllers  530  and  535  can be coupled to an H-bridge or other current switching/limiting device  540  for limiting or otherwise controlling the delivery of current to the skin. The housing will also typically include a cavity  580  for current source  570 , such as a cylindrical shaped cavity which may be sized for standard size batteries such as AA or AAA batteries. Other shapes for cavity  580  are also contemplated. 
     In various embodiments, current source  570  can comprise one or more electrochemical batteries including an alkaline, lithium, lithium-ion and like chemistries. For ease of discussion, current source  570  will be referred to herein as battery  570  but other current sources are equally applicable. Battery  570  can also comprise a rechargeable battery known in the art. The battery  570  can have a selected capacity to deliver sufficient current/voltage to the skin for transdermal delivery of the therapeutic agent for periods ranging from 2 to 24 hours or even longer. Power source  570  may also correspond to alternating current power source. Accordingly, in embodiments including an electrochemical battery(s), power source  570  may include circuitry for converting a DC signal from the battery(s) into an AC signal. Other power/current sources  570  are also contemplated, such as various storage capacitors and piezo-electric based energy harvesting devices. 
     The patch  505  will typically include one or more conductive areas  506  for electrical coupling to conductive elements  591  on the electronics assembly  550 . The conductive areas  506  can be coupled to conductive traces  590  placed on the patch surface  505   s  or within the patch  505 . The conductive elements on the electronics assembly  550  can be coupled to one or both of controller  530  and current source  570 . 
     Detachment elements  600  can be spring loaded and can be configured to be engaged by the fingers of a user. In particular embodiments, detachment elements  600  may include or be mechanically coupled to one or more anchoring elements  601  such as a hook for anchoring into patch  505 . The anchoring elements  601  may also comprise adhesive areas placed on the housing bottom surface  561  which engage the patch surface  505 S. 
     In use, detachment elements  600  allow the user to attach and detach an electronics assembly  550  to a selected patch  505 . This allows the electronics assembly  550  to be reused for multiple patches. In an exemplary embodiment of using system  500 , the user can obtain a particular patch  505 , scan information about the patch using a bar code reader (or other indicia reading means) described below and then attach the patch  505  to the assembly  550 . When the user is done using the patch (e.g., such as when the desired amount of drug has been delivered) the user then detaches assembly  550  from the patch  505  discarding patch  505 . In particular embodiments, assembly  550  can include programming which provides a signal such as beep or other alarm indicating to the user when to remove the patch  505 . As an alternative, the patch surface  505   s  can include an indicator portion  507  which changes color or otherwise provides visible indicia  508  to the user when the required amount of agent has been delivered to the skin. In one embodiment, the indicia  508  can comprise a symbol or marking  509  that becomes visible when the amount of therapeutic agent  51  has been delivered. Visibility of the marking can be due to depletion of therapeutic agent  51  within patch  505  and/or a chemical or electrochemical reaction within or on the patch. 
     In particular embodiments, the electronics assembly  550  can also include a bar code reader for reading a bar code printed on patch  505  for ascertaining various information about the patch  505  including for example, the type and amount of therapeutic agent  51  contained in the patch, a desired delivery regimen, lot numbers (of the patch  505  and the therapeutic agent  51 ) shelf life, expiration date and related information. In an additional or alternative embodiment, patch  505  may contain a memory device (e.g. an EEPROM and the like)  506  which contains similar information and is readable by electronics assembly  550  (e.g., by controller  530 ). Assembly  550  may also contain a memory device  556  for storing information (described above) which may be coupled to microcontroller  530 . The information contained in memory device  556  (e.g., type, dose and lot number of therapeutic agent  51 ) can be entered at the factory and/or by the doctor or pharmacist. Also information entry can be done directly or over a network such as the internet or cellular phone network or other like network. Other indicia reading means, for reading/detecting other indicia of information about patch  505  are also contemplated. Such indicia reading means can include, without limitation, use of various RFID chips known in the art. 
     System  500  including patch  505  and assembly  550 , can be sized and shaped to be placed in any number of locations on the patient&#39;s skin including the arm, leg or abdomen, back or other location. The particular material properties of the patch  505  and housing  560  (e.g., thickness, modulus of elasticity, bendability, etc.) can also be so selected to allow placement at the desired location. For example, more flexible material properties can be selected for placement of the system  500  over skin areas with greater amounts of bending by the user, such as the stomach. Also, patch  505  and assembly  550  can be packaged together, for example, as a kit  500   k  (which can include instructions for use) wherein the assembly  550  is matched to patch  505  in terms of size, current source, programming mechanical properties etc. Further, a given assembly  550  can be calibrated for such a group of patches  505  or patches  505  from a particular lot number. In such embodiments, multiple patches  505  can be included with a particular assembly  550 . In use, this allows the patient to obtain a complete supply of patches to meet the delivery requirements for a particular therapeutic agent  51  over a period of days, weeks, or months. Further, the assembly  550  can be programmed such that when the patient is near the end of his or supply of patches  505 , that the assembly will give the patient a message to purchase more patches. In related embodiments, the assembly  550  can be configured to interface with the Internet and/or a mobile communication device such as cell phone, to send a message to the patient&#39;s pharmacy and/or doctor to do one or more of the following: i) renew the patient&#39;s prescription for a particular therapeutic agent patch  505 ; ii) have an order for a supply of the therapeutic agent patch  505  ready for the patient&#39;s pick up at his or her drug store; and/or iii) ship an order for the therapeutic agent patch  505  to the patient&#39;s house. 
     Referring now to  FIGS. 8A through 8F , a discussion will be presented of various waveforms  800  or current output variations (over time) and their characteristics which can be used to promote delivery or retention of one or more therapeutic agents  51 . Embodiments of these waveforms can be used for embodiments of the invention having a single or two or more active electrodes  20 . Numerous embodiments described herein provide for waveforms  800  that vary between a given polarity and zero, wherein at that polarity, the current (e.g., current  310 ) causes the therapeutic agent  51  to be repelled into the skin. In other embodiments, the waveforms  800  alternate between positive and negative polarity such waveforms are referred to herein as waveforms  801 . 
     For embodiments having a waveform  801  alternating between a positive and negative polarity, the waveform  801  can be a charged balanced wave form  802  configured such that the current delivered to each electrode assembly (e.g., assemblies  20  and  30 ) in use is a charged balanced AC current. A charged balance AC current means over a given duration, the amount of current delivered to the skin at each polarity is substantially equivalent. As used herein substantially equivalent means that two values are within 80% of one another, and more preferably within 90% or 99% over the period of one or more waveforms. By orienting the waveform to alternate in a charged-balance fashion, electrical toxicity or other damage to the skin can be reduced or minimized. In other embodiments, an alternating current waveform is used that is oriented towards being balanced in charge, but some asymmetry may exist. 
     Embodiments of waveforms  800  described below are variable between a minimum and maximum value. Some embodiments of waveform  800 , such as described with  FIG. 8 b   , may alternate in charge value (i.e. include reverse polarity) such waveforms are referred to herein as alternating charge waveforms  801 . In such embodiments, the current delivery may be balanced in charge so that waveform  801  is a charged balanced waveform  802  as described above. 
       FIG. 8 a    illustrates a waveform  800  that includes an extended or long drug delivery period or duration  840  (which may correspond to delivery period  340  shown in  FIG. 5 c   ), according to an embodiment. In some embodiments, the skin may be assumed to handle only a maximum amount of current in a given duration (maximum current delivery) (e.g. 80 milliamps per minute). For a given amperage, the duration of the output of an alternating power source (e.g., power source  100  described above) may be set so as to not exceed the maximum current delivery. The delivery duration  840  may be set to some portion or fraction (e.g. 50% for n=2) of the overall period of the current output I 1 . For example, in some implementations, the maximum current delivery (I 1 ) is assumed to be 80 milliamps for one minute. In such an implementation, the delivery duration is set for 20 seconds on 4 milliamp output. Rather than switch to negative polarity, the output of the power source  100  may alternate to no amperage output (rather than switch polarity). While the waveform  800  depicted in  FIG. 8A  is rectangular, various embodiments of waveforms  800  may have alternative shapes (e.g. sinusoidal, trapezoidal), with the current delivery corresponding to the area under the curve. In the example shown by  FIG. 8A , an alternating power source  100  initiates a delivery duration  840  on one electrode (e.g., active electrode  20 ), with delivery durations being set by a current that has a polarity that matches that of the charge of the therapeutic agent. The current may alternate to zero output, in which the drug delivery is substantially ceased. Thus, the non-delivery duration  830  may coincide with no current output, rather than reverse current. In other embodiments, non-delivery duration  830  is achieved through the use of a current which has a polarity which is opposite to the charge of active agent  51  as described below in the embodiment of  FIG. 8 b    and above in the embodiment of  FIG. 5 b    (e.g., in the form of holding current  320 ). 
       FIG. 8B  illustrates another embodiment in which the alternating power signal outputs a symmetrical wave  803  such as symmetrical square wave  804 .  FIG. 8B  (and other waveforms illustrated herein) illustrates use of charge balanced waveforms  802  to deliver charge balanced alternating currents. For example, symmetrical waveforms in polarity may be considered as charged balanced. Depending on the application, the period P of the cycle of waveform  802  may be long (e.g. 20 minutes) or short ( 1/60 seconds). The delivery duration  840  may correspond to half of the period P of the waveform  802 . In the implementation shown, a reverse current is used in the non-delivery duration  830 , to actively prevent agent delivery to the skin. 
       FIG. 8C  illustrates another embodiment of the invention in which the alternating power signal outputs an asymmetrical wave  805  such as an asymmetrical square wave  806 , in that the delivery duration  840  is different than the non-delivery duration  830 . More specifically, the asymmetrical square wave  805  may include longer delivery durations (t 1 ), followed by short(er) rest durations (t 2 ). The rest durations may correspond to periods of no current, or as shown, reverse current (I 2 ). In one application, the rest duration enables the skin layer to recuperate from the drug delivery in the prior duration (e.g., to dissipate any heat, concentration of ions, or other by products resulting from the delivery of current). As an alternative or variation, the rest period may follow a period where no current is applied to the skin layer, so as to enable the skin layer to recuperate from application of current. 
       FIG. 8D  illustrates another embodiment in which the alternating power signal has a trapezoidal waveform  807 , so as to include ramp-up and/or ramp-down periods  808  and  809 . As depicted, I 1  is the maximum current output generated from an alternating power source (e.g. power source  100 ). The ramp-up period  808  extends for a duration t r , that is selected for reasons that include enabling the user to physically accustom to the application of current and/or delivery of therapeutic agent  51 . The ramp-up period  808  may be long, to enable the ramp-up duration to be effective. In an embodiment, a ramp-down period  809  may optionally be implemented. 
       FIG. 8E  and  FIG. 8F  illustrate alternative waveform variations including compound waveforms  813  in which high-frequency oscillations  811  are superimposed on a low frequency base waveform  810 . The base waveform  810  may have a period P 810  that lasts seconds or minutes, corresponding to output current to the electrode assemblies ranging from a maximum (e.g., 4 mA) to no current and/or reverse current. The high-frequency oscillations reflect small variations in the current value at instances in the period. The period P 811  of the high-frequency oscillations  811  may be one or more magnitudes shorter than that of the base waveform. As an example, the base waveform  800  may have a period P 810  ranging from seconds to minutes, and the high-frequency oscillations of the waveform may have a period that ranges between milliseconds and seconds. The effect of the high-frequency oscillations  811  is to reduce the effects of the capacitive charge in the skin layer in receiving the therapeutic agent  51 . The high frequency oscillations  811  may also be used to facilitate transport of the therapeutic agent through the skin including the stratum corneum by causing oscillations in the movement of the therapeutic agent as it travels through the skin so as to find pathways of least resistance through the skin. In such embodiments, the high frequency oscillations may be adjusted to enhance this effect through use of modeling (e.g., pharmacokinetic modeling) and/or the patient&#39;s age, skin type and skin location 
     The base waveform  810  may be selected for considerations such as described in prior embodiments. For example, in  FIG. 8E , the waveform  813  includes a ramp-up time period  808 . In  FIG. 8F , the waveform  800  has a delivery duration  840  that is switched to a non-delivery duration  830 . An embodiment of  FIG. 8F  illustrates that the high-frequency oscillations  811  may be generated to be present only during the delivery duration  840 . 
     Fentanyl Applications 
     A discussion will now be presented on fentanyl and the use of various embodiments of the invention for its transdermal delivery. Such embodiments can include various systems, patch and electrode assemblies described herein. The forms of fentanyl which may be delivered by various embodiments of the invention include, without limitation, fentanyl and its analogues and derivatives as well as salts of fentanyl such as fentanyl hydrochloride, fentanyl citrate and fentanyl pamoate. Fentanyl (also known as fentanil) is a potent synthetic narcotic analgesic with a rapid onset and short duration of action. It is a strong agonist at the μ-opioid receptors. It is manufactured under the trade names of SUBLIMAZE, ACTIQ, DUROGESIC, DURAGESIC, FENTORA, ONSOLIS INSTANYL, ABSTRAL and others. Historically, it has been used to treat chronic breakthrough pain and is commonly used before procedures as an anesthetic in combination with a benzodiazepine. Fentanyl is approximately 100 times more potent than morphine with 100 micrograms of fentanyl approximately equivalent to 10 mg of morphine and 75 mg of pethidine (meperidine) in analgesic activity. Typically, the fentanyl delivered by various embodiments of the invention (including its analogues or derivatives) will comprise an aqueous solution of a water soluble fentanyl salt. In some embodiments, the aqueous solution is contained within a hydrophilic polymer matrix such as a hydrogel matrix. The hydrogel matrix may be contained in reservoir  21 , tissue contacting layer  24  or other portion of an electrode/patch assembly such as assemblies  14  and  15   cp  described herein. The fentanyl (or analogue or derivative) salt-containing hydrogel can suitably be made of any number of materials including a hydrophilic polymeric material, such as one that is polar in nature so as to enhance the drug stability. Suitable polar polymers for the hydrogel matrix comprise a variety of synthetic and naturally occurring polymeric materials. In one embodiment, the hydrogel formulation comprises a suitable hydrophilic polymer, a buffer, a humectant, a thickener, water and a water soluble fentanyl or analogue or derivative salt. The suitable hydrophilic polymer may comprise a hydrophilic polymer matrix which in one or more embodiments may correspond to polyvinyl alcohol such as a washed and fully hydrolyzed polyvinyl alcohol (PVOH). A suitable buffer includes an ion exchange resin which is a copolymer of methacrylic acid and divinylbenzene in both an acid and salt form. One example of such a buffer is a mixture of Polacrilin (the copolymer of methacrylic acid and divinyl benzene available from Rohm &amp; Haas, Philadelphia, Pa.) and the potassium salt thereof. A mixture of the acid and potassium salt forms of Polacrilin functions as a polymeric buffer to adjust the pH of the hydrogel to about pH 6. Use of a humectant in the hydrogel formulation is beneficial to inhibit the loss of moisture from the hydrogel. An example of a suitable humectant is guar gum. Thickeners are also beneficial in a hydrogel formulation. For example, a polyvinyl alcohol thickener such as hydroxypropyl methylcellulose aids in modifying the rheology of a hot polymer solution as it is dispensed into a mold or cavity. The hydroxypropyl methylcellulose increases in viscosity on cooling and significantly reduces the propensity of a cooled polymer solution to overfill the mold or cavity. In one embodiment, the fentanyl (or analogue or derivative) salt-containing hydrogel formulation comprises about 10 to 15 wt % polyvinyl alcohol, 0.1 to 0.4 wt % resin buffer, and about 1 to 2 wt % fentanyl (or analogue or derivative) salt. The remainder is water and ingredients such as humectants, thickeners, etc. Suitable doses of fentanyl for administration over a delivery period include, for example, 20 to 60 micrograms, or 35 to 45 micrograms, or 40 micrograms. A delivery period typically is up to, for example, 20 minutes. Generally 10 to 100 doses of fentanyl are delivered over a 24 hour period in order to achieve the desired analgesic effect; for example, 40, 60 or 80 doses of fentanyl can be delivered over a 24 hour period. Consequently, the total dose of fentanyl delivered for a 24 hour period will generally range from 0.2 to 6.0 milligrams, or 0.35 to 4.5 milligrams, or 0.4 to 4.0 milligrams, or 3.0 milligrams. 
     Suitable analogues of fentanyl include, without limitation, the following: alfentanil (trade name ALFENTA), an ultra-short-acting (five to ten minutes) analgesic; sufentanil (trade name SUFENTA), a potent analgesic for use in specific surgeries and surgery in heavily opioid-tolerant/opioid-dependent patients; remifentanil (trade name ULTIVA), currently the shortest-acting opioid, has the benefit of rapid offset, even after prolonged infusions; carfentanil (trade name WILDNIL) an analogue of fentanyl with an analgesic potency 10,000 times that of morphine and is used in veterinary practice to immobilize certain large animals such as elephants; and lofentanil an analogue of fentanyl with a potency slightly greater than carfentanil. Doses of fentanyl analogues are selected taking into consideration their individual potency and pharmacokinetics. For example, for a typical delivery period of up to 20 minutes, suitable doses of sufentanyl include, for example, 2.3 to 7 micrograms, or 4 to 5.5 micrograms, or 4.7 micrograms. In various embodiments, 10 to 100 doses of sufentanyl are delivered over a 24 hour period in order to achieve the desired analgesic effect; for example, 24, 30, 40, 60 or 80 doses of sufentanyl can be delivered over a 24 hour period. Consequently, the total dose of sufentanyl delivered for a 24 hour period can range from 23 to 700 micrograms, or 40 to 550 micrograms, or 47 to 470 micrograms. 
     EXAMPLES 
     Various embodiments of the invention are further illustrated with reference to the appended example which details the use of embodiments of a biphasic transdermal iontophoreritic delivery system. Portions of the example are also described in a paper entitled: Biphasic Transdermal Iontophoretic Drug Delivery Platform (McLaughlin, G. W, et al Conf. Proc. IEEE Eng. Med. Biol. Soc. 2011 August; 2011:1225-8) which is incorporated by reference herein for all purposes. It should be appreciated that this example is presented for purposes of illustration and the invention is not to be limited to the information or the details therein. For example, while the example presented describes the delivery of ferrous chloride, it should be understood that various embodiments of the invention can be used for the delivery of any number of compounds using this approach including, for example, various opioids and other analgesics (e.g., fentanyl), anitemetics, (e.g., Dimenhydrinate) and other therapeutic agents. 
     Methodology 
     System Description: 
     One embodiment of a system that was tested for delivery of therapeutic agent comprised an active electrode, passive electrode, iontophoresis system and a programmer which are described below. 
     Active Electrode: 
     This was constructed by using a DuPel Model #198809-001 (Empi, Inc., Clear Lake, S. Dak., USA) electrode with the buffering agent removed and replaced with a teabag filled with two sheets of 3M gauze with 4.0 ml of solution. The solution was prepared by dissolving 1.2 g of FeCl2 (Sigma-Aldrich, St. Louis, Mo., USA) and 300 mg of Poly-Ethylene Oxide (PEO, Mol wt. 100 k) into 4 ml of DI water. The active electrode area was 13.3 cm2. 
     Passive Electrode: 
     This was constructed using a DuPel Model #198809-001 electrode with the buffering agent removed and replaced with a teabag filled with two sheets of 3M gauze and 300 mg of Polyethylene Oxide (PEO) with 4 ml of DI water added. The active electrode area was 13.3 cm2. 
     Iontophoresis System: 
     This comprised a custom made unit that was controlled by a MSP430F428 (Texas Instruments, Dallas, Tx, USA) microcontroller. This microcontroller coordinated the activities between the switch states of an H-bridge circuit in conjunction with a variable current source. The H-bridge had a programmable voltage rail with a resolution of ˜650 mV steps and a maximum compliance voltage of 80V. The variable current source had a programmable current target with a resolution of ˜40 μxA with an upper limit of 5 mA. The microcontroller was able to update these values at a rate of 5 Hz along with measure and store their values with a time stamp for data archival purposes. Two AA batteries were used to power the system. These batteries were capable of providing up to 40 hours of operation under a standard therapy profile.  FIG. 1  shows a picture of the system along with a simplified block diagram of the internals. 
     Programmer: 
     This comprised a personal computer that was able to be interfaced to the iontophoresis system via a USB cable. The application code used to program the device was written in TCL/TK. This program was able to set the therapy pulse duration and current value along with the inhibit pulse duration and current value. It was also capable of specifying the total therapy duration. In addition, the programmer was also able to retrieve the data stored in the unit for analysis. 
     Experimental Setup: 
     Ten in-vitro test chambers were constructed out of a block PTFE and filled with 120 ml of Hanks Buffered Salt Solution (HBSS). Freshly excised abdominal skin from a male Yorkshire pig (35 kg) was sectioned into 10 (100 mm×175 mm) pieces. Yorkshire pig skin was used as it has been shown to closely mimic the properties of human skin. The subcutaneous fat beneath the dermis layer of the skin was removed so that only the stratum corneum, epidermis, basal layer and dermis layers remained. The skin was then shaved and inspected for blemishes or scratches that might alter transport. Each test chamber had a piece of skin placed on top. Particular care was taken to not damage the integrity of the skin. The skin was affixed to the test chamber via 1¼″ clips. The active and passive electrodes were then placed on the pig skin and attached to the iontophoresis system. All skin irregularities were avoided during this process. 
     The iontophoresis system was configured to provide a 6 hour therapy session. The first hour of the therapy session consisted of the system in an inhibit mode with a current value of −3 mA. The second hour of the therapy session was a drive mode with a current value of 3 mA. In hour 3 and 4 the system was in the inhibit mode with a current value of −3 mA. In hour 5 the system was in a drive mode with a current value of 3 mA and in hour 6 the system was in an inhibit mode with a current value of −3 mA. 
     The experimental chambers were placed on magnetic stirrer-hotplates to maintain the HBSS solution between 29° C. to 34° C., which kept the surface of the pig skin between 28° C. to 33° C. Samples of 1 ml were drawn every 15 minutes from the reservoir, using a 25 gauge needle. An equivalent volume of HBBS solution was replenished to maintain the level in the test chamber. During the data analysis, appropriate correction factors were used to compensate for this fluid replacement. 
     Upon completion of the therapy, the skin samples were visually examined for irritation and or staining. The samples were then photographed. The concentration of iron was quantified, after the required dilutions, by using a standard colorimetric assay. The samples were added to an acidic buffered reagent containing hydroxylamine, thiourea and Ferene (5,5′ (3-(2-pyridyl)-1,2,4-triazine-5,6 diyl)-bis-2-furansulfonic acid, disodium salt). The acidic pH of the buffered reagent was used to release the ferric iron, which is then reduced to ferrous form by the hydroxylamine. This ferrous iron then reacted with the Ferene producing a colored complex. The absorption of this ferrous-Ferene complex was then read at 595 nm using a spectrophotometer (Multiscan EX; Thermo Electron Corporation, Vantaa, Finland). The absorption spectrum provided a proportional relationship to that of the iron concentration within the sample. This assay method provides a lower limit of quantification of 50 μg/dl. 
     Results 
     The average of the ten samples was taken for each 15 minute sample period to obtain a mean cumulative density data set. This data set was then used as the measured output of the system to be identified, y(t). The input to the system was the known integral of the active portion of the therapy session, x(t). These sets of data were than used to identify the system transfer function, h est (t) which is shown in block diagram form in  FIG. 9 . 
     The transfer function h est (t) of the system was estimated based on Fourier transforms of the input and output signals on the system. 
               H   ⁡     (   ω   )       =             X   ⁡     (   ω   )       _     ·     Y   ⁡     (   ω   )                  X   ⁡     (   ω   )            2       =         R   ^     xy         R   ^     xx               
An inverse Fourier transform was then taken of the resulting transfer function. This data set was then cropped, limiting the memory of the system transfer function to a period of 10 samples or 2.5 hours. The known input data was then convolved with this transfer function to obtain the estimated cumulative system density response. This data was then analyzed to determine how well the predicted output matched the measured output. This resulted in an R2 value of 0.912, confirming a good correlation between the model and the data.
 
     Next, the derivative of the measured cumulative density data was taken. In order to obtain an accurate estimate of the derivative of the data a first order least means squares fit was performed for each 4 samples of the data moving in a single sample step. The slope of this fit was then used as the representative value for the derivative of the data. This data was then analyzed using the same method as that of the cumulative density function data. This resulted in an R 2  value of 0.802, confirming that the predicted model correlated well with the estimated pulsatile drug delivery model as shown in  FIGS. 10 a    and  10   b.    
     The measured results show a time lag of around 45 minutes between the start of the therapy cycle and the detection of the FeCl 2  in the saline solution. This time lag is expected in the in-vitro studies due to the transport time required to traverse all the layers of the skin and reach the saline bath. In an in-vivo study this lag would be expected to be substantially smaller due to an active micro-capillary system just under the basal layer, alleviating the need for the material to pass through the dermis layer. 
     CONCLUSION 
     The foregoing description of various embodiments of the invention has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise forms disclosed. Many modifications, variations and refinements will be apparent to practitioners skilled in the art. For example, the iontophoretic patch can be modified in size, shape and dose of therapeutic agent for different medical conditions, different tissue sites as well as for various pediatric applications. Additionally, the patch assemblies, methods and control algorithms can also be modified for skin type, therapeutic agent dose, as well as various pediatric applications. 
     Elements, characteristics, or acts from one embodiment can be readily recombined or substituted with one or more elements, characteristics or acts from other embodiments to form numerous additional embodiments within the scope of the invention. Moreover, elements that are shown or described as being combined with other elements, can, in various embodiments, exist as standalone elements. Hence, the scope of the present invention is not limited to the specifics of the described embodiments, but is instead limited solely by the appended claims.