WO2020037294A1

WO2020037294A1 - System and method for biphasic transdermal iontophoretic delivery of diclophenac and other therapeutic agents

Info

Publication number: WO2020037294A1
Application number: PCT/US2019/046955
Authority: WO
Inventors: Mir Imran; Mir Hashim; Sanjay Patel; Joel Harris
Original assignee: Incube Labs, Llc
Priority date: 2018-08-17
Filing date: 2019-08-16
Publication date: 2020-02-20

Abstract

Various embodiments provide methods and systems for the iontophoretic transdermal delivery of therapeutic agents including NSAIDs e.g., diclophenac, to a target tissue site (TTS), using at least one electrode assembly that is positioned to be in electrical communication with a patient's skin above the TTS. In embodiments, a dose of agent is passively delivered from an assembly to the TTS during a first period, using a first current having a characteristic e.g., polarity and/or magnitude, that repels the agent out of the assembly. During a second period, a second current having a characteristic to attract the agent is used to retain the agent in the assembly such that delivery of agent into skin is minimized. Embodiments are particularly useful for delivery of agents which cause adverse effects from unwanted passive diffusion.

Description

SYSTEM AND METHOD FOR BIPHASIC TRANSDERMAL IONTOPHORETIC DELIVERY OF DICLOPHENAC AND OTHER THERAPEUTIC AGENTS

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 62/719,547 filed August 17, 2018 which is incorporated herein for all purposes; the aforementioned priority applications being hereby incorporated by reference in their respective entirety.

FIELD OF THE INVENTION

[0002] Embodiments described herein relate to assemblies and methods for transdermal drug delivery. More specifically, embodiments described herein relate to assemblies and methods for the iontophoretic transdermal delivery of drugs and other therapeutic agents including analgesic agents such as

diclophenac or other Nonsteroidal Anti-inflammatory Drugs (NSAIDs).

BACKGROUND

[0003] 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 such as Nonsteroidal Anti-inflammatory Drugs (NSAIDs). 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' 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

[0004] 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 under-dose due to unpredictable pharmaco-kinetics in a given patient. 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 including NSAIDs (non-steroidal anti-inflammatory drugs) such as diclophenac, cause intestinal bleeding particularly when taken on empty stomach. They are also associated with other GI problems as well cramping, etc. For the particular case of diclophenac which is a very effective drug for treating pain (as is explained below), taking this NSAID with food has drawbacks as well. It particular, when it is taken with food or afterwards, the initial absorption of diclophenac is dramatically reduced delayed in the rate compared with the case where they are taken on an empty stomach, and in some cases, the maximum absorption occurs ten or more hours after taking the oral dose, with significant differences in absorption rates depending on the amount and type of food consumed

[0005] Other forms administration have problems as well. For example, for the case of diclophenac, while rectal suppositories provide a more reliable rapid- acting effect, there are many patients who are reluctant to use them.

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 including for NSAIDs.

[0006] 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

[0007] 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, inflammation, 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 NSAIDs such as diclophenac ibuprofen, ketoprofen, indomethacin and piroxicam and opioids such as fentanyl and its derivatives and analogues and. Other embodiments can be configured for use in the delivery of antiemetics such as dolasetron (and other 5-HT3 receptor antagonists), domperidon (and other dopamine antagonists) and promethazinen (and other antihistamines).

[008] Other embodiments provide for systems and methods for localized delivery of NSAIDs by transdermal iontophoresis to targeted sites in the body to treat pain and/or inflammation at those sites. Such targeted sites can include among others the knee, arm, elbow, foot, neck and lower back. Desirably, the amounts delivered to the target site are controlled such that pain and/or inflammation is treated without raising a systemic level of the NSAID above a threshold level. Such embodiments are particularly useful for treating pain or inflammation at a local site, e.g., the knee which may arise from an injury or arthritis without the adverse side effects from systemic delivery of the NSAID particularly for long term administration. Further, they allow for faster relief of systems than that for oral delivery or passive topical application of the NSAID or topical application.

[009] 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, diclophenac for the treatment of pain including localized pain, 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 (e.g., pain management or inflammation reductions) and/or to minimize adverse effects to the patient. Such controlled initiation (either of a delivery period or a 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.

[0010] In one aspect, the invention provides methods for the transdermal iontophoretic delivery of a therapeutic agent (e.g., an NSAID) to a patient and in particular embodiments, to a target tissue site in the patient such as the arm, elbow, leg, knee, neck, back etc. One embodiment of such a method comprises positioning at least one electrode assembly in electrical communication with a patient e.g., with the patient'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 NSAIDs including diclophenac where: i) oral delivery can cause gastric bleeding, nausea, discomfort and other complications and ii) passive delivery may be insufficient. They are also useful for the delivery of opioids as well as NSAIDs such as diclophenac, where over-delivery of the therapeutic agent from passive diffusion may be harmful to the patient. In particular embodiments of the above methods adapted for delivery of diclophenac compounds, the delivered amount of diclophenac compound can be in the range of 1-50 mg, more preferably 1-25 mg for a single delivery period, while the total amount/dose delivered over multiple delivery periods (described below as a delivery cycle) for a given day may be limited to no more than about 150 mg, more preferably to no more than about 100 mg. These delivered dose restrictions can be achieved using embodiments of a controller and software described herein.

[0011] Particular embodiments provide for systems and methods for localized delivery of NSAIDs such as diclophenac by transdermal iontophoresis to targeted sites in the body to treat pain and/or inflammation at those sites. Such targeted sites can include among others the knee, arm, elbow, foot, neck, back and lower back. In particular embodiments, the NSAID dose and/or depth of delivery is selected to treat particular tissue at those sites including for example muscle, tendinous or cartilage tissue which may be inflamed or otherwise injured. Such depth of delivery can range from 1 to 20mm, more preferably from 1 to 10 mm, though other ranges are also contemplated (e.g. 5 to 25). Desirably, the amounts delivered to the target site and/or depth of delivery are controlled such that pain and/or inflammation is treated without raising a systemic level of the NSAID above a threshold level (e.g. a toxic threshold) and/or without causing a substantial adverse systemic effect. Further, in particular embodiments, the dose of delivered NSAID can be titrated for a particular condition at particular tissue site, for example tennis elbow, arthritis of the knee, strained muscles in the lower back, arthritic vertebrae in the neck. Titration can be done at the factory or using embodiments of a software controlled microprocessor other controller described herein which may configured to be accessed by the medical provider, pharmacist or patient. The titration can also be done to taper off the dose of delivered NSAID over a period of time as the condition (e.g., muscle soreness, tendonitis) improves.

[0012] The delivered amounts and depth of delivery of the NSAID can be controlled by selection of one more of the current, voltage, or duty cycle parameter (including delivery period and non-delivery period times and the amount of holding current.). Such adverse systemic effects may include one or more of bleeding at various locations in the body including the stomach (gastric bleeding), brain (intracranial or cerebral bleeding aka hemorrhage), anemia, elevated blood pressure, nausea or other gastric discomfort or adverse effect to the kidney or liver including adverse effect to the function of either organ (e.g., as determined by elevated serum creatinine or urea levels for the kidney, and elevated serum bilirubin or altered enzymes levels for the liver (e.g., alanine transaminase (ALT) and Aspartate transaminase (AST). Such embodiments are particularly useful for treating pain or inflammation at a local site, e.g., the knee which may arise from an injury or arthritis without the adverse side effects from systemic delivery of the NSAID particularly for long term administration.

Further, they allow for faster relief of systems than that for oral delivery or passive topical application of the NSAID or topical application.

[0013] In another aspect, the invention provides embodiments of a patch assembly for the iontophoretic transdermal delivery of a diclophenac compound to a target tissue site of a patient such as the arm, elbow, leg, neck, leg or back. One embodiment of such a patch assembly comprises a patch for iontophoretic transdermal delivery of the diclophenac compound, a current source and a controller for controlling the iontophoretic transdermal delivery of the

diclophenac compound to skin to ultimately to the delivery site. The patch has a tissue contacting side, a non-tissue contacting side, a reservoir containing the diclophenac compound and a first and second electrode with at least one of the electrodes electrically coupled to the reservoir. The current source is coupled to the patch and electrically coupled to the first and second electrodes. Typically, the current source will comprise an alternating current source (herein an AC current source) such as an AC generator, but in alternative embodiments may also comprise a direct current source (herein a DC-current source) which may correspond to an electrochemical storage battery. The controller is configured to deliver a dose of diclophenac compound from the patch into the skin during a first period using a first current (described herein as a delivery current) having a polarity and magnitude to repel the diclophenac compound out of the patch; and retain the diclophenac compound in the patch during a second period using a second current (described herein as a holding current) having a polarity and magnitude to retain the diclophenac compound in the patch such that delivery of the diclophenac compound into the skin during the second period is minimized. The first period comprises a delivery period and the second period comprises a non-delivery period which together comprise a delivery cycle. Typically the controller will correspond to a microprocessor including one or more software modules for controlling various aspects and/or parameters of the iontophoretic drug delivery process including one or more of voltage, current, and frequency of the delivery and/or holding currents and length of the delivery period and non-delivery periods as wells as the total number of delivery cycles.

Alternatively, the controller may correspond to an analogue controller known in the electrical control arts.

[0014] According to one or more embodiments of the patch assembly, at least one of the current source or the controller is disposed or otherwise positioned in a housing coupled to the non-tissue contacting side of the patch. Desirably, (though not necessarily) the housing has sufficient flexibility such that when the housing is engaged with the patch to form the patch assembly and the patch is adhered to a target site on a patient's skin (e.g., the arm, knee or back), the patch assembly has sufficient flexibility to deform with movement of the patient's skin so as to remain sufficiently adhered to the patient's skin over an extended period of time to transdermally deliver the diclophenac compound.

The extended period may be, for example, 1, 2, 3 or 7 days or even longer. Also according to one or more embodiments, the patch and/or patch assembly can be shaped or otherwise adapted to fit over or around a selected target tissue site and stay adhered to the site during movement of the patient's skin at the selected target tissue site. In specific embodiments, the patch and/or patch assembly is adapted to fit over or around the patient's leg, knee, foot, arm, elbow, back, neck or lower back, with adjustments in size and shape of the patch being made for the patient's size as well as their degree and type of activity (e.g., walking, running, engaging in a sport and the like). In these and related embodiments, where the patch is adapted for a given tissue site, the patch may include at least one bending feature configured to enhance flexibility of the patch assembly with movement of the patient's skin such as may occur during walking or other activity (e.g., engaging in exercise or a sport). The bending feature will typically comprise a shaped opening positioned along a perimeter or edge of the patch or within the patch interior. According to various embodiments, the shaped opening may correspond to a circle, a semicircle, a crescent like shape, a u-shaped opening, a rectangle, a rounded rectangle, a v- shaped notch or v-shaped notch with a rounded point. Desirably, though not necessarily, whatever the shape of the bending feature/shaped opening, it has rounded vs pointed edges so as to minimize edge effects where unwanted current concentration and subsequent tissue heating or burning may occur.

[0015] Typically, the diclophenac compound in the reservoir will be in the form of an aqueous solution (herein a diclophenac solution) in which the diclophenac compound (e.g., a diclophenac salt such as sodium diclophenac) is dissolved. According to one or embodiments, the diclophenac compound and/or

diclophenac solution is contained or incorporated into a hydrophilic polymer matrix which will typically comprise a hydrogel such as a polyvinyl alcohol or fully hydrolyzed polyvinyl alcohol and combinations thereof. Also according to one or more embodiments, the hydrogel or other hydrophilic polymer matrix may comprise at least of one of a transport enhancing agent a thickener, solubility enhancer, a buffer or a humectant. In particular embodiments, the transport enhancing agent comprises a terpene such as geraniol or l-menthol. The transport enhancing agent may also correspond an ion-exchange material or such as an ion-exchange fiber bound to which diclophenac ion in the diclophenac compound is ionically bound. In additional or alternative embodiments for enhancing iontophoretic transport of the diclophenac compound into the skin, the solution/and or hydrophilic polymer matrix (also described as a diclophenac solution) containing the diclophenac salt or other diclophenac compound may include substantially no buffer ions and/or no salt ions such as those derived from NaCI, KCI and other salts known in pharmaceutical arts.

[0016] Further details of these and other aspects and embodiments of the invention are described more fully below, with reference to the attached drawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] 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.

[0018] 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.

[0019] Fig. 3a 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.

[0020] Fig. 3b 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.

[0021] Figs. 4a and 4b are side and top views showing an embodiment of a skin patch including an active electrode and lateral electrodes.

[0022] Fig. 5a is a top down view showing an embodiment of an on demand user-activated transdermal delivery system including a patch assembly.

[0023] Figs. 5b, 5c and 5d 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. 5b shows an activation signal for initiating a drug delivery cycle, the signal generated by a patient activated device or other signal generation means; Fig. 5c shows an embodiment of a current waveform initiated by the activation signal the waveform having a delivery current and holding current; Fig. 5d shows an embodiment of a drug delivery profile corresponding to the periods of delivery current and holding current.

[0024] Figs. 6a and 6b 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. 6a shows a top view and Fig. 6b shows a bottom view.

[0025] Fig. 6c is a block diagram of an embodiment of the electronics assembly including a controller, current source and current switching device.

[0026] Fig. 7a is a perspective view showing placement of the embodiment of Figs. 6a and 6b on an example site on the skin of a user.

[0027] Fig. 7b is a lateral view showing an embodiment of a patch assembly having a curved contour positioned at a tissue site having a curved contour.

[0028] Figs. 8a through 8f illustrate various waveforms or current output variations that can be used to promote various characteristics of embodiments of the transdermal iontophoretic delivery system.

[0029] 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.

[0030] Figs. 10a and 10b are plots of delivered therapeutic agent versus time. Fig 10a shows the cumulative input vs. the estimated system response based on an optimum cross-correlation FIR filter response of the measured system response; Fig. 10b plot shows the density input vs. the estimated system response based on an optimum cross-correlation FIR filter response of the measured system response.

[0031] Figs lla-llc illustrate embodiments of a patch assembly configured for placement on a patient's forearm to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's forearm. Fig. 11a shows the placement of the patch assembly on the patient's forearm; Fig. lib shows an embodiment of the forearm patch assembly including at least one bending feature; and Fig 11c shows an embodiment of the forearm patch assembly without any bending features. [0032] Figs. 12a-12c illustrate embodiments of a patch assembly configured for placement on a patient's elbow to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's elbow. Fig. 12a shows the placement of the patch assembly on the patient's elbow; Fig. 12b shows an embodiment of the elbow patch assembly including at least one bending feature; and Fig. 12c shows an embodiment of the elbow patch assembly without any bending features along the patches perimeter.

[0033] Figs. 13a-13c illustrate embodiments of a patch assembly configured for placement on a patient's knee to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's knee. Fig. 13a shows the placement of the patch assembly on the patient's knee; Fig. 13b shows an embodiment of the knee patch assembly including at least one bending feature; and Fig. 13c shows an embodiment of the knee patch assembly without any bending features.

[0034] Figs. 14a-14c illustrate embodiments of a patch assembly configured for placement on a patient's shoulder/upper back to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's shoulder/upper back. Fig 14a shows the placement of the patch assembly on the patient's shoulder/upper back; Fig. 14b shows an embodiment of the shoulder/upper back patch assembly including at least one bending feature; and Fig. 14c shows an embodiment of the shoulder/upper back patch assembly without any bending features.

[0035] Figs. 15a-15c illustrate embodiments of a patch assembly configured for placement on a patient's lower back to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's lower back. Fig 15a shows the placement of the patch assembly on the patient's lower back; Fig. 15b shows an embodiment of the lower back patch assembly including at least one bending feature; and Fig. 15c shows an embodiment of the lower back patch assembly without any bending features.

[0036] Figs. 16a-16c illustrate embodiments of a patch assembly configured for placement on a patient's foot to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's foot. Fig 16a shows the placement of the patch assembly on the patient's foot; Fig. 16b shows an embodiment of the foot patch assembly including at least one bending feature; and Fig. 16c shows an embodiment of the foot patch assembly without any bending features.

DETAILED DESCRIPTION OF THE INVENTION

[0037] Various embodiments of the invention 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, non-steroidal anti-inflammatory drugs (NSAIDs) 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.). Also, many embodiments provide for the delivery of therapeutic agents such as opioids and NSAIDs (e.g. diclophenac) without producing any substantial adverse systemic effect(s). Such systemic effects may include one or more of bleeding (e.g., gastric, intracranial or cerebral), anemia, nausea, constipation or diarrhea, elevated blood pressure; adverse effect on kidney or liver function; or rash, anaphylactic shock or other allergic reaction. As used herein, the term "substantial adverse effects" means those which are out of baseline levels per medical standards or are readily observable in the case of a rash or anaphylactic shock which are readily perceptible by the patient and/or cause them discomfort (e.g., nausea making the patient vomit or want to vomit or anaphylactic shock causing them perceptible edema or making it difficult to breath). For the case of anemia, the substantial adverse effect may also include and/or by defined by a decrease in the patient's hematocrit or red blood cell count below levels considered normal and/or by more than 10 %, preferably by more than 5%. For the case of adverse effect(s) to the kidneys, the substantial adverse effect may include and/or be defined by elevated creatinine or urea levels outside of normal levels; and for the case of the liver, by elevated serum bilirubin or altered enzymes levels (e.g., alanine transaminase (ALT) and Aspartate transaminase (AST) outside of normal levels. Also, as used herein the term, "about" means within ± 10% of a stated property, dimension, or other value and, more preferably, ± 5% of the stated value. Also, as used herein, the term

"substantially" means within ± 10% of a stated property or quality and where appropriate within a numerical value of a stated property or quality, more preferably, ± 5% of the stated property or quality.

[0038] 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 pm) 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.

[0039] 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.

[0040] Referring now to Figs. 2-4b, 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. Target tissue site TS may also correspond to one or more of the patients leg (including the knee), arm (including the elbow) neck, back (including the upper and lower back), particularly for embodiments containing or otherwise configured to deliver an NSAID such as diclophenac or other therapeutic agent 51p for the treatment of pain or inflammation. Active electrode assembly 20 is used to deliver the therapeutic agent 51, 51p 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. For brevity, in some examples, the 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.

[0041] 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 the art. 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.

[0042] 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.

[0043] 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 (AgCI) or other conductive materials known in the art.

[0044] Typically, adhesive portion 25 will surround the perimeter 24p of porous portion 24 as is shown in the embodiment of Figs. 4a and 4b, 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 25a, such as one or more releasable adhesives attached to a substrate layer 25s, 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.).

[0045] 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. 3b. 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.

[0046] 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. 3b.

[0047] 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 24p of porous portion 24 as is shown in the embodiments of Figs. 3a- 3b and 4a-4b. 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.

[0048] 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 may be found in U.S. Patent No. 8,348,922.

[0049] Referring now to Figs 5a-5d, 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 15cp. 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 51p (herein after pain medication 51p) 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.

[0050] Referring now to Fig. 5a an embodiment of an "on demand" transdermal delivery system 5' will now be described. The system may be 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 93p described below. The system 5' includes a patch assembly 15cp 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 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.

[0051] In various embodiments, patch 15 can have a substantial oval shape 15o including, for example, peanut or cassini-shaped ovals 15oc having side portions 15s and a tapered center portion 15c as is shown in the embodiment of Fig 5a. Electrodes 14 including active electrode 20 and return electrode 30, can be positioned in side portions 15s and an electronics module 90 positioned in the center portion 15c. Desirably, electrodes 20 and 30 are positioned on opposite side portions 15s as is shown in the embodiment of Fig 5a; however other configurations are also contemplates such as the placement of electrodes 20 and 30 in each side portion 15s. Electronics module 90 can include a controller 93 which may correspond to controller 530 (shown in Fig. 6a) and a power source 97 which may correspond to power source 570 (shown in Fig. 6b) 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 91s 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.

[0052] Referring now to Figs. 5b-5d, 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 15cp 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. 5b-5d, 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 93p for starting a drug delivery period 340 upon receiving the signal 300. The control program 93p 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).

[0053] 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. 5d (the delivery period and delivery current can be stored in controller 93 and/or determined by program 93p 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 5d. 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's skin.

[0054] 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 over- dosing 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 51p, 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's age and weight, their condition and other therapeutic agents they are receiving (currently, previously or in the future). [0055] Referring now to Figs. 6a, 6b, 6c, 7a-7b and 12a-16c, in various embodiments, a system 500 for iontophoretic transdermal delivery of various pain medication 51p 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 Nos.

8,423,131 and 8,417,330. 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 Serial No. 8,433,401.

[0056] 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.

[0057] 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'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 560c (which can be achieved in some embodiments by putting a crimp or articulated zone 560a 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.

[0058] 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's clothing and can bend and flex sufficiently so that: i) it is not readily detached by pressure or force from the user'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's clothes; and ii) is not readily visible beneath the user'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's arm (including the wrist and elbow), leg (including the knee), 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's skin when the patch assembly 500 is placed on the patient's abdomen, arm (including the forearm and elbow), neck, back (including the upper and lower back), shoulder, leg (including the knee) 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'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'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'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).

[0059] 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 505s) and flexibility of patch 505 such that when the patch assembly 500 is worn openly or beneath the patient'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'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).

[0060] 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 (e.g. 2 to 5 times or larger) 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.

[0061] With specific reference now to Figs lla-16c, according to one or more embodiments, the patch 505 and/or patch assembly 500 can be shaped and/or otherwise adapted to fit over or around a selected target tissue site TS and stay adhered to the site during movement of the patient's skin at the selected target tissue site. In specific embodiments, the patch 505 an/or patch assembly 500 can be is adapted to fit over or around one or more of the patient's leg, knee, foot, arm, elbow, back, neck or lower back, with adjustments in size and shape of the patch 505 being made for the patient's size as well as their degree and type of activity (e.g., walking, running engaging in sport and the like). As described below, various embodiments of such patches adapted for a specific target tissue site TS can include one or more bending features 505b comprising a specifically shaped opening 505o to allow for enhanced flexibility of the patch 505 and patch assembly 500 at the selected target tissue site TS. [0062] Figs lla-llc illustrate embodiments of a patch assembly 500, 500FA configured for placement on a patient's forearm FA to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's forearm for the treatment of a condition in or around the forearm such as tendinitis or carpal tunnel syndrome. Fig. 11a shows the placement of the patch assembly 500FA on the patient's forearm FA. Fig. lib shows an embodiment of the forearm patch assembly 500FB including at least one bending feature 505b. Fig 11c shows an embodiment of the forearm patch assembly 500FA without any bending features.

[0063] Figs. 12a-12c illustrate embodiments of a patch assembly 500, 500E configured for placement on a patient's elbow E to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's elbow to treat a condition of the elbow such as tennis elbow or tendinitis. Fig. 12a shows the placement of the patch assembly 500E on the patient's elbow E. Fig. 12b shows an

embodiment of the elbow patch assembly 505E including at least one bending feature 505b. Fig. 12c shows an embodiment of the elbow patch assembly 500E without any bending features along the patches perimeter 505p.

[0064] Figs. 13a-13c illustrate embodiments of a patch assembly 500, 500K configured for placement on a patient's knee K to deliver an NSAID such as diclophenac or other therapeutic agent to a patient's knee K for treatment of a condition in or around the knee such as a sprain, worn cartilage or arthritis. Fig. 13a shows the placement of the patch assembly 500K on the patient's knee K. Fig. 13b shows an embodiment of the knee patch assembly 500K including at least one bending feature 505b. Fig. 13c shows an embodiment of the knee patch assembly 500K without any bending features.

[0065] Figs. 14a-14c illustrate embodiments of a patch assembly 500, 500S configured for placement on a patient's shoulder/upper back SUB to deliver an NSAID such as diclophenac or other therapeutic agent to a patient's

shoulder/upper back to treat a condition in or around this area such as a sore/torn muscle, tendinitis or rotator cuff injury. Fig 14a shows the placement of the patch assembly 500S on the patient's shoulder/upper back SUB. Fig. 14b shows an embodiment of the shoulder/upper back patch assembly 500S including at least one bending feature 505b. Fig. 14c shows an embodiment of the shoulder/upper back patch assembly 500S without any bending features. [0066] Figs. 15a-15c illustrate embodiments of a patch assembly 500, 500LB configured for placement on a patient's lower back LB to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's lower back to treat a condition in the area of the lower back such as a pulled/strained muscle, tendinitis or spinal stenosis. Fig 15a shows the placement of the patch assembly 500LB on the patient's lower back LB. Fig. 15b shows an embodiment of the lower back patch assembly 500LB including at least one bending feature 505b. Fig. 15c shows an embodiment of the lower back patch assembly 500LB without any bending features.

[0067] Figs. 16a-16c illustrate embodiments of a patch assembly configured for placement on a patient's foot F to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's foot to treat a condition of the foot such as a sprain (ankle, foot or toe), plantar fasciitis or Morton's Neuroma. Fig 16a shows the placement of the patch assembly 500F on the patient's foot F. Fig. 16b shows an embodiment of the foot patch assembly 505F including at least one bending feature 505b, Fig. 16c shows an embodiment of the foot patch assembly 505F without any bending features.

[0068] In the above and related embodiments, where the patch assembly 500 and/or patch 505 is adapted for a given tissue site TS, the patch 505 may include at least one bending feature 505b configured to enhance flexibility of the patch 505 and/or assembly 500 with movement of the patient's skin such as may occur during walking or other activity (e.g., engaging in exercise or a sport). Bending feature 505b may correspond to a shaped opening placed 505o positioned along a perimeter (or edge) 505p of patch 505 or within an interior portion 505i of patch 505. According to various embodiments the bending feature 505b/shaped opening 505b may correspond to a circle, semicircle, a u- shaped opening, a rectangle, a rounded rectangle, a v-shaped notch or v-shaped notch with a rounded point. Desirably though not necessarily, whatever the shape of the opening 505b it has rounded vs pointed edges so as to minimize edge effects where unwanted current concentratio505n and subsequent tissue heating or burning may occur.

[0069] According to some 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's clothes to the housing and/or patch and/or forces of the patch 505 being bent or deformed by the patient's position or movement. 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.

[0070] 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.

[0071] 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.

[0072] 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 505s 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.

[0073] 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 505S.

[0074] 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 505s 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.

[0075] 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.

[0076] System 500 including patch 505 and assembly 550, can be sized and shaped to be placed in any number of locations on the patient'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 500k (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, the Cloud and/or a mobile communication device such as cell phone, to send a message to the patient's pharmacy and/or doctor to do one or more of the following : i) renew the patient'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's pick up at his or her drug store; and/or iii) ship an order for the therapeutic agent patch 505 to the patient's house.

[0077] 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.

[0078] 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.

[0079] Embodiments of waveforms 800 described below are variable between a minimum and maximum value. Some embodiments of waveform 800, such as described with Fig. 8b, 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. [0080] Fig. 8a 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. 5c), 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 Ii. For example, in some implementations, the maximum current delivery (Ii) is assumed to be 80 milliamps for one minute. In such an implementation, the delivery duration is set for 20 seconds at a 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 8b and above in the embodiment of Fig 5b (e.g., in the form of holding current 320). Desirably, the maximum delivered current (Ii) and/or the particular delivery current over the delivery period are selected so that no burning on the skin beneath or around the electrode occurs. In particular embodiments maximum delivered current during the delivery period can be kept below about 80 milliamps, more preferably below about 60 milliamps and still more preferably below about 40 milliamps. Also the delivery current over the delivery period is desirably kept below about 4 milliamps, more preferably below about 2 milliamps, still more preferably below about 1 milliamp. [0081] 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.

[0082] 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 (ti), followed by short(er) rest durations (t₂). The rest durations may correspond to periods of no current, or as shown, reverse current (I₂). 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.

[0083] 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, Ii 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.

[0084] 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 Psio 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 Pen 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 Psio 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's age, skin type and skin location

[0085] 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. The embodiment of Fig. 8F illustrates that the high-frequency oscillations 811 may be generated to be present only during the delivery duration 840, in alternative embodiments, the high frequency oscillations during both the delivery and non delivery durations 840 and 830.

Diclophenac and other NSAID Delivery Applications

[0086] Various embodiments of the invention contemplate the delivery of a diclophenac compound which may include diclophenac and/or its analogues and derivatives for the treatment of one or more medical conditions including pain and/or inflammation. Accordingly, a discussion will now be presented on diclophenac and the use of various embodiments of the invention for its transdermal delivery. Such embodiments can include various systems, patches and electrode assemblies described herein. Diclofenac having the chemical formula of 2-(2,6-dichloro-anilino)-phenyl-acetic acid, is a type of non-steroidal anti-inflammatory drug (NSAID). NSAIDs have the therapeutic effect or reducing pain and inflammation. They produce this therapeutic effect through inhibition of cyclooxygenase (COX), the enzyme that makes prostaglandins (PGs). COX-1 makes PGs that protect the stomach and kidneys. COX-2 produces PGs that cause pain and inflammation. Diclofenac is a non-selective NSAID that inhibits both types of COX enzymesl and is thus able to treat both pain and inflammation.

[0087] The forms of diclophenac compounds which may be delivered by various embodiments of the invention include, without limitation, a free acid of diclofenac, an alkali metal salt such as a sodium or potassium salt, or an organic salt, particularly an amine salt, such as diethylamine. A particular embodiment includes a combination of a diclofenac acid and diclofenac potassium.

Embodiments of the invention also contemplate analogues and derivatives of diclophenac as well which are described in more detail herein.

[0088] Typically, the diclophenac compound delivered by various

embodiments of the invention will comprise an aqueous solution 54 of a water soluble diclofenac salt (e.g., diclofenac sodium (diclofenac potassium and diclofenac diethylammonium) as well as its/their analogues or derivatives. In some embodiments, the aqueous solution 54 may be contained within or otherwise incorporated into a hydrophilic polymer matrix 21m (also referred to as matrix 21m) such as a hydrogel matrix, with other hydrophilic matrix materials considered as well. The hydrogel matrix 21m may be contained in reservoir 21, tissue contacting layer 24 or other portion of an electrode/patch assembly such as assemblies 14 and 15cp and 500 described herein. The hydrogel or other hydrophilic polymer matrix 21m containing or incorporating the diclophenac salt or other form of diclophenac be can suitably be made of any number of materials including a hydrophilic polymeric material, including those for example that are polar in nature so as to enhance the stability of the diclophenac compound or other NSAID or therapeutic agent. Suitable polar polymers for the hydrogel matrix 21m 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 diclophenac compound (e.g., a diclophenac salt). According to one or more embodiments, suitable hydrophilic polymers for hydrophilic polymer matrix 21m may correspond to a polyvinyl alcohol such as a washed and fully hydrolyzed polyvinyl alcohol (PVOH).

[0089] In various embodiments, the hydrophilic matrix 21m may contain a solubility enhancing agent 52se, (herein a solubility enhancer) which functions to enhance the solubility of a diclophenac salt or other form of diclophenac

(including diclophenac analogues) in the hydrophilic matrix allowing for loading of greater dosages of diclophenac into the matrix. Suitable solubility enhancing agents 52se include without limitation polyvinylpyrrolidone polymers,

polyethylene oxide, polyacrylic acid, polyvinyl alcohol, silicone dioxide, silica, celluloses and cellulose derivatives such as hydroxymethyl cellulose,

hydroxypropyl cellulose, gelatins, gums, starches, dextrins and dextrans, sterols, bile acids and other similar agents. In a preferred embodiment, the invention uses a soluble polyvinylpyrrolidone (PVP) as a matrix constituent. Use of such PVP provides the advantage of allowing the hydrophilic matrix 21 to be thin with high concentrations of the diclophenac compound or other active ingredient 50 within the patch 15, 500. Soluble PVP is preferably present composition in an amount ranging from about 5% to about 20% and more preferably from about 10% to about 20% by weight of the total adhesive matrix composition.

[0090] In various embodiments, the hydrophilic matrix may also contain a buffering agent to buffer the pH of the solution within the matrix. Suitable buffers include 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 & 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 6.0. Use of a humectant in the hydrogel formulation is beneficial to inhibit the loss of moisture from the hydrogel or other hydrophilic matric. An example of a suitable humectant is guar gum. Various embodiments of the invention also contemplate the use of thickeners hydrogel formulation or other hydrophilic matric as these confer benefits to the matric. 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 diclophenac (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 % diclophenac salt (or analogue or derivative). The remainder is water and ingredients such as humectants, thickeners, etc. Suitable doses of diclophenac 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.

[0091] Embodiments For Enhancing Iontophoretic Transport Of Diclophenac Compounds (DC) Into The Skin And Tissue.

[0092] Various approaches for enhancing the iontophoretic transport of Diclophenac compounds into the patients skin and underlying tissue will now be discussion. In various embodiments the hydrogel or other hydrophilic polymer matrix 21m containing the diclophenac salt (or form of diclophenac) may also containing various agents, herein transport enhancing agents or transport enhancers 52te, to enhance the iontophoretic transport of a diclophenac compound or diclophenac analogue into the patient's skin and underlying tissue. Such transport enhancers 52te may include various terpenes such as geraniol and l-menthol as well as their functional analogues and derivatives. In other approaches for increasing transport of DC's into the skin, the solution/and or hydrophilic polymer matrix 21m (also described as a diclophenac solution) containing the diclophenac salt or other DC may include substantially no buffer ions and/or salt ions such as those derived from NaCI, KCI or other salt used in the pharmaceutical arts. As used herein, substantially no buffering ions or salt ions means less than 5% weight, molarity or volume, more preferably less than 2% and still more preferably less than 1%. In these and related embodiments, the enhanced transport of the DC is due to reduced completion from the buffer ion and/or salt ion. In still other approaches for increasing the transport of the DC, the iontophoretic sale (e.g., sodium diclophenac can be bound to an ion- exchange material such as ion exchange fibers). According to some

embodiments, the ion exchange materials may be present in the solution containing the DC and/or in the hydrophilic matrix material containing the DC.

In still other approaches the diclophenac salt used for transport may include a counterion (i.e., the ion (cation) having the opposite charge as the ionized form diclophenac) includes a ring structure such as amine structure or other ring structure having hydrophilicity and polarity which contribute to the increased transport.

[0093] In various embodiments, between 1 to 4 doses of diclophenac may be delivered over a 24 hour period in order to achieve a desired pain reduction and/or anti-inflammatory effect at a selected tissue site, with larger number of doses contemplated as well e.g., 5 to 10. As an individual dose can be in the range from 20 to 80 mg, the total dose of diclophenac delivered for a 24 hour period will generally range from 40 to 240 mg, more preferably in a range from 100 to 150 mg. The specific dosage limit per day can adjusted depending on the condition (e.g., disease) to be treated, e.g., pain, inflammation etc. Example daily dosage regimens and ranges for particular conditions include the following: osteoarthritis: 50 mg 2 to 3 times per day (i.e. 24 hours), 150mg maximum; ankylosing spondylitis: 25 mg 4 to 5 times per day, 125 mg maximum;

dysmenorrhea, 50 mg 3 times per day, 150mg maximum; rheumatoid arthritis, 50 mg 3 to 4 times per day or 75 mg 2 to 3 times per day, 225 mg maximum.

[0094] In one or more embodiments of systems and methods of the invention, a dosage of diclophenac or other NSAID can be delivered in

combination with a topical analgesic such as lidocaine, bupivacaine or enhance the analgesic effect. For the case of bupivacaine in combination with the diclophenac, the dosage of diclophenac can be in the range of about 50 to 75 mg per delivery period a dosage of bupvicaine can be in the range from 100 to 175 mg per dose with a maximum of 400 mg per day (i.e., 24 hours).

[0095] Suitable analogues of diclophenac include without limitation : Methyl 2-[(2,6-Dichlorophenyl)amino]benzene Acetate; 2-[(2,6- Dichlorophenyl)amino]benzene-ethan-l-ol; 2-[(2,6-Dichlorophenyl)amino] Benzeneacetamide; 2-[(2,6-Dichlorophenyl)amino]benzoic Acid; l-Chloro-2- [(2,6-dichlorophenyl)amino]benzene-ethane; and -[(2,6- Dichlorophenyl)amino]benzene-ethane. A fuller description of these and other diclophenac analogues may be found in the paper by V Oza, et al, entitled:

Synthesis, Structure, and Activity of Diclofenac Analogues as Transthyretin Amyloid Fibril Formation Inhibitors, J. Med. Chem. 2002, 45, 321-332. Examples

[0096] Various embodiments of the invention are further illustrated with reference to the appended example which details the use of embodiments of a biphasic transdermal iontophoretic 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 Aug; 2011 : 1225-8). 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

[0097] System Description: One embodiment of a system that was tested for delivery of therapeutic agents comprised an active electrode, passive electrode, iontophoresis system and a programmer which are described below.

[0098] Active electrode: This was constructed by using a DuPel Model #198809-001 (Empi, Inc., Clear Lake, SD, 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 1.2g of FeCI2 (Sigma-Aldrich, St. Louis, MO, USA) and 300 mg of Poly-Ethylene Oxide (PEO, Mol wt. 100k) into 4 ml of DI water. The active electrode area was 13.3 cm2.

[0099] 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.

[0100] Iontophoresis system : This system 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 ~650mV steps and a maximum compliance voltage of 80V. The variable current source had a programmable current target with a resolution of ~40 mcA with an upper limit of 5 mA. The microcontroller was able to update these values at a rate of 5Hz 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. l shows a picture of the system along with a simplified block diagram of the internals.

[0101] 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.

[0102] Experimental Setup: Ten in-vitro test chambers were constructed out of a block PTFE and filled with 120ml of Hanks Buffered Salt Solution

(HBSS). Freshly excised abdominal skin from a male Yorkshire pig (35 kg) was sectioned into 10 (100 mm x 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 1 V* " 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.

[0103] 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 3mA. 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 3mA and in hour 6 the system was in an inhibit mode with a current value of -3mA.

[0104] 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.

[0105] 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)-l,

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 50pg/dl.

Results

[0106] 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, hes_t(t) which is shown in block diagram form in Fig. 9.

[0107] The transfer function h_est(t) of the system was estimated based on Fourier transforms of the input and output signals on the system.

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.

[0108] 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 R² value of 0.802, confirming that the predicted model correlated well with the estimated pulsatile drug delivery model as shown in Figs 10a and 10b.

[0109] The measured results show a time lag of around 45 minutes between the start of the therapy cycle and the detection of the FeCI₂ 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

[0110] 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, NSAID dose, as well as various pediatric applications. [0111] 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. Further, for any positive recitation of an element, characteristic, constituent, feature, step or the like embodiments of the invention specifically contemplate the exclusion of that element, value, characteristic, constituent, feature, step or the like. 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.

Claims

WHAT IS CLAIMED IS:

1. A method for the transdermal iontophoretic delivery of a non- steroidal anti-inflammatory drug (NSAID) to a target tissue site in a patient in need thereof, the method comprising :

positioning at least one electrode assembly in electrical communication with the skin of the patient, the at least one electrode assembly including a skin contacting layer and a solution comprising the NSAID, wherein the NSAID passively diffuses into the skin without application of an external force;

delivering a dose of NSAID from the at least one electrode assembly into the skin to the target site during a first period using a first current having a polarity and magnitude to repel the NSAID out of the electrode assembly;

retaining the NSAID in the at least one electrode assembly during a second period using a second current having a polarity and magnitude to retain the NSAID in the electrode assembly such that delivery of the NSAID into the skin during the second period is minimized, wherein the first period comprises a delivery period and the second period comprises a non-delivery period, which together comprise a delivery cycle; and

delivering subsequent doses of NSAID over subsequent delivery cycles and wherein the NSAID is delivered to the target tissue site without causing a substantial adverse systemic effect.

2. The method of claim 1, wherein the target tissue site is the patient's leg, knee, foot, arm, elbow, shoulder, neck, back, upper back or lower back.

3. The method of claim 1, wherein the electrode assembly is adapted to fit over or around the target tissue site.

4. The method of claim 1, wherein the NSAID is delivered to a selected depth to treat the target tissue site.

5. The method of claim 4, wherein the selected depth is in a range of about 1 to 20 mm.

6. The method of claim 4, wherein the NSAID is delivered to the selected depth to treat inflamed muscle tissue at the target tissue site.

7. The method of claim 4, wherein the NSAID is delivered to a selected depth to treat inflamed tendinous tissue at the target tissue site.

8. The method of claim 4, wherein the NSAID is delivered to a selected depth to treat inflamed cartilage at the target tissue site.

9. The method of claim 1, wherein the adverse systemic effect is selected from the group consisting of bleeding, gastric bleeding, intracranial bleeding, cerebral bleeding, an adverse effect on kidney or liver function, elevated blood pressure and nausea.

10. The method of claim 1, wherein the adverse systemic effect is nausea.

11. The method of claim 1, wherein the solution is contained or incorporated into a hydrophilic polymer matrix.

12. The method of claim 11, wherein the hydrophilic polymer matrix comprises a hydrogel, a polyvinyl alcohol or soluble polyvinylpyrrolidone.

13. The method of claim 1, wherein the electrode assembly comprises a first electrode and a NSAID reservoir electrically coupled to the first electrode and fluidically coupled to the skin contacting layer.

14. The method of claim 13, wherein the electrode assembly further comprises a second electrode.

15. The method of claim 14, wherein the second electrode is configured as a return electrode.

16. The method of claim 1, wherein substantially no NSAID is delivered during the non-delivery period.

17. The method of claim 1, wherein an amount of NSAID delivered during the non-delivery period produces substantially no therapeutic effect in the patient.

18. The method of claim 1, wherein the NSAID produces a therapeutic effect of pain reduction or reduced inflammation.

19. The method of claim 1, wherein the NSAID comprises a diclophenac compound comprising diclophenac or a diclophenac analogue.

20. The method of claim 19, wherein the diclophenac solution contains substantially no buffering ions and/or salt ions.

21. The method of claim 19, wherein the diclophenac compound comprises a diclophenac salt.

22. The method of claim 21, wherein the diclophenac salt comprises an alkali metal salt or organic salt.

23. The method of claim 22, wherein diclophenac salt comprises a potassium salt or a sodium salt.

24. The method of claim 22, organic salt comprises an amine salt or diethylamine.

25. The method of claim 22, further comprising enhancing transport of the diclophenac compound into the skin using a transport enhancing agent.

26. The method of claim 25 , wherein the transport enhancing agent comprises a terpene, geraniol and l-menthol.

27. The method of claim 25 , wherein the transport enhancing agent comprises an ion-exchange material or exchange fiber bound to the diclophenac ion in the diclophenac compound.

28. The method of claim 19, wherein the diclophenac compound comprises a diclophenac acid and diclophenac potassium.

29. The method of claim 19, wherein about 20 to about 75 mg of the diclophenac compound is delivered during the delivery period.

30. The method of claim 29 wherein about 50 mg of the diclophenac compound is delivered during the delivery period.

31. The method of claim 19, wherein the delivery period is about 20 minutes.

32. The method of claim 19, wherein a maximum of about 150 mg of the diclophenac compound is delivered over the course of multiple delivery cycles.

33. The method of claim 19, where a dose of diclophenac compound delivered during the delivery period is adjusted to treat a disease or condition.

34. The method of claim 33, wherein the disease or condition is osteoarthritis, rheumatoid arthritis or ankylosing spondylitis.

35. The method of claim 33, wherein the disease or condition is a sprain, bruise or tendonitis

36. The method of claim 1, further comprising delivering an analgesic along with the NSAID during the delivery period.

37. The method of claim 36, wherein the analgesic comprises lidocaine or bupvicaine.

38. The method of claim 37, wherein the topical analgesic comprises bupvicaine.

39. The method of claim 38, wherein about 50 to 75 mg of diclophenac and 100 to 175 mg of bupvicaine is delivered during the delivery period.

40. The method of claim 1, wherein at least one of the first or the second currents has a waveform having a square wave shape.

41. The method of claim 1, wherein at least one of the first or the second currents has a waveform having a trapezoidal shape.

42. The method of claim 1, wherein at least one of the first or the second currents has a waveform comprising a low frequency base waveform and a superimposed high frequency waveform.

43. The method of claim 1, wherein the first and the second currents are charge balanced over the delivery cycle.

44. The method of claim 1, wherein the magnitude of the second current is proportional to a concentration of the NSAID in the solution.

45. The method of claim 1, further comprising :

adjusting a magnitude of the second current relative to a concentration of the NSAID in the solution.

46. The method of claim 1, further comprising :

utilizing the second current to control delivery of the NSAID so as to minimize the adverse systemic effect from the NSAID over at least one delivery cycle.

47. The method of claim 46, wherein the adverse systemic effect is gastric bleeding.

48. The method of claim 47, wherein the NSAID comprises diclophenac or a diclophenac analogue.

49. The method of claim 1, wherein the delivery period is initiated by a patient input.

50. The method of claim 49, wherein the patient input is received from a patient activated device, a push-button device or a wireless device.

51. The method of claim 49, wherein a number of delivered doses of NSAID is limited to a maximum number over a selected period.

52. The method of claim 51, wherein the maximum number of delivery cycles is selected to maintain a plasma concentration of the NSAID below a threshold which results in the adverse systemic event.

53. The method of claim 52, wherein the adverse systemic effect is selected from the group consisting of bleeding, gastric bleeding, intracranial bleeding cerebral bleeding, an adverse effect on kidney or liver function, elevated blood pressure or nausea.

54. The method of claim 49, wherein the patient input will not initiate another delivery period until after a refractory period.

55. The method of claim 54, wherein the refractory period is a period of time from an end of the delivery period to an end of the non-delivery period.

56. The method of claim 1, wherein at least one of the delivery period or the non-delivery period is selected to maintain a plasma concentration of the NSAID below a threshold which results in the adverse systemic event.

57. A method for the biphasic transdermal delivery of a diclophenac compound to a target tissue site in a patient by iontophoresis, the method comprising:

positioning at least one electrode assembly in electrical communication with the skin of the patient, the at least one electrode assembly including a skin contacting layer and a solution comprising a diclophenac compound having an electrical charge, wherein the diclophenac compound passively diffuses into the skin without the application of an external force;

delivering a dose of diclophenac compound from the at least one electrode assembly into the skin during a first drug delivery phase using a first current having at least one characteristic to repel the diclophenac compound out of the electrode assembly;

retaining the diclophenac compound in the at least one electrode assembly during a second phase using a second current having at least one characteristic to retain the diclophenac compound in the electrode assembly such that delivery of the diclophenac compound into the skin during a second phase is minimized, wherein the first phase comprises a delivery period and the second period comprises a non-delivery period, which together comprise a delivery cycle; and

delivering subsequent doses of the diclophenac compound over

subsequent delivery cycles wherein the diclophenac compound is delivered to the target tissue site without causing a substantial adverse systemic effect.

58. The method of claim 57, wherein the target tissue site is the patient's leg, knee, foot, arm, elbow, shoulder, neck, back, upper back or lower back.

59. The method of claim 57, wherein the electrode assembly is adapted to fit over or around the target tissue site.

60. The method of claim 57, wherein the diclophenac compound is delivered to a selected depth to treat the target tissue site.

61. The method of claim 60, wherein the selected depth is in a range of about 1 to 20 mm.

62. The method of claim 60, wherein the diclophenac compound is delivered to the selected depth to treat inflamed muscle tissue at the target tissue site.

63. The method claim 60, wherein the diclophenac compound is delivered to a selected depth to treat inflamed tendinous tissue at the target tissue site.

64. The method claim 60, wherein the diclophenac compound is delivered to a selected depth to treat inflamed cartilage at the target tissue site.

65. The method of claim 57, wherein the adverse systemic effect is bleeding, gastric bleeding, intracranial bleeding or cerebral bleeding.

66. The method of claim 57, wherein the adverse systemic effect is an adverse effect on kidney or liver function.

67. The method of claim 57, wherein the adverse systemic effect is elevated blood pressure.

68. The method of claim 57, wherein the adverse systemic effect is nausea.

69. The method of claim 57, wherein the diclophenac solution is contained or incorporated into a hydrophilic polymer matrix.

70. The method of claim 69, wherein the hydrophilic polymer matrix comprises a hydrogel, a polyvinyl alcohol or soluble polyvinylpyrrolidone.

71. The method of claim 57, wherein the at least one characteristic for repelling the diclophenac compound comprises at least one of a magnitude or polarity of the first current.

72. The method of claim 57, wherein the at least one characteristic for retaining the diclophenac compound comprises at least one of a magnitude or polarity of the second current.

73. The method of claim 57, wherein the diclophenac compound comprises diclophenac or a diclophenac analogue.

74. The method of claim 57, wherein the diclophenac compound comprises a diclophenac salt.

75. The method of claim 73, wherein the diclophenac salt comprises an alkali metal salt or organic salt.

76. The method of claim 75, wherein the diclophenac salt comprises a potassium salt or a sodium salt.

77. The method of claim 57, wherein the diclophenac compound comprises a diclophenac acid and diclophenac potassium.

78. The method of claim 57, wherein the diclophenac solution contains substantially no buffering ions and/or salt ions.

79. The method of claim 57, further comprising enhancing transport of the diclophenac compound into the skin using a transport enhancing agent.

80. The method of claim 79, wherein the transport enhancing agent comprises a terpene, geraniol and l-menthol.

81. The method of claim 79 , wherein the transport enhancing agent comprises an ion-exchange material or exchange fiber bound to the diclophenac ion in the diclophenac compound.

82. A patch assembly for the iontophoretic transdermal delivery of a diclophenac compound to a target tissue site of a patient, the assembly comprising:

a patch for iontophoretic transdermal delivery of the diclophenac compound, the patch having a tissue contacting side, a non-tissue contacting side, a reservoir containing the diclophenac compound and a first and second electrode, at least one of the electrodes electrically coupled to the reservoir; a current source coupled to the patch and electrically coupled to the first and second electrodes; and

a controller coupled to the patch for controlling the iontophoretic transdermal delivery of the diclophenac compound; the controller configured to deliver a dose of diclophenac compound from the patch into the skin during a first period using a first current having a polarity and magnitude to repel the diclophenac compound out of the patch; and retain the diclophenac compound in the patch during a second period using a second current having a polarity and magnitude to retain the diclophenac compound in the patch such that delivery of the diclophenac compound into the skin during the second period is minimized, wherein the first period comprises a delivery period and the second period comprises a non-delivery period which together comprise a delivery cycle.

83. The patch assembly of claim 82, wherein at least one of the current source or the controller is positioned in a housing coupled to the non-tissue contacting side of the patch, the housing having sufficient flexibility such that when the housing is engaged with the patch to form the patch assembly and the patch is adhered to a target site on a patient's skin, the patch assembly has sufficient flexibility to deform with movement of the patient's skin so as to remain sufficiently adhered to the patient's skin over an extended period of time to transdermally deliver the diclophenac compound.

84. The patch assembly of claim 83, wherein the patch is shaped or otherwise adapted to fit over or around a selected target tissue site and stay adhered to the site during movement of the patient's skin at the selected target tissue site.

85. The patch assembly of claim 84, wherein the selected target tissue site is the patient's leg, knee, foot, arm, elbow, shoulder, neck, back, upper back or lower back.

86. The patch assembly of claim 84, wherein the patch includes a bending feature to enhance flexibility of the patch assembly with movement of the patient's skin.

87. The patch assembly of claim 86, wherein the bending feature comprises a shaped opening in the patch.

88. The patch assembly of claim 87, wherein the shaped opening comprises a circle, semicircle, a u-shaped opening, a crescent like shape, a rounded rectangle, a notch or a notch with a rounded point.

89. The patch assembly of claim 87, wherein the shaped opening is positioned on a perimeter of the patch or an interior portion of the patch.

90. The patch assembly of claim 83, wherein the extended period of time is up to about seven days.

91. The patch assembly of claim 83, wherein the housing has a profile shaped and sized to allow the patch assembly to be worn underneath the patient's clothing without substantially detaching from the patient's skin from movement of the patient's clothes or skin.

92. The patch assembly of claim 83, wherein the housing is

conformable to a flexing contour of the patient's skin to allow the patch assembly to remain adhered to the patient's skin over the extended period of time.

93. The patch assembly of claim 82, wherein the controller comprises a microprocessor.

94. The patch assembly of claim 82, further comprising an input device for initiating a delivery cycle, the input device operably coupled to the controller.

95. The patch assembly of claim 94, wherein the input device comprises a patient activated button or switch.

96. The patch assembly of claim 94, wherein the controller includes logic for control of patient initiation of the delivery cycle.

97. The patch assembly of claim 96, wherein the controller includes logic for limiting a maximum number of delivered doses of diclophenac

compound over a selected period.

98. The patch assembly of claim 96, wherein the controller includes logic for controlling a start of another delivery period until after a refractory period.

99. The patch assembly of claim 98, wherein the refractory period is a period of time from an end of the delivery period to an end of the non-delivery period.

100. The patch assembly of claim 82, wherein at least one of the delivery period and non-delivery period are selected to maintain a plasma concentration of the diclophenac compound within a therapeutic index.

101. The patch assembly of claim 82, wherein the diclophenac compound comprises diclophenac or a diclophenac analogue.

102. The patch assembly of claim 82, wherein the diclophenac compound comprises a diclophenac salt.

103. The patch assembly of claim 102, wherein the diclophenac salt comprises an alkali metal salt or organic salt.

104. The patch assembly of 102, wherein diclophenac salt comprises a potassium salt or a sodium salt.

105. The patch assembly of claim 82, wherein the diclophenac compound comprises a diclophenac acid and diclophenac potassium.

106. The patch assembly of claim 82, wherein the patch assembly has a substantially oval shape or cassini oval shape.

107. The patch assembly of claim 82, wherein the current source comprises an electrochemical battery, an alkaline battery, a lithium battery or a lithium-ion battery.

108. The patch assembly of claim 82, wherein the current source is configured to deliver an alternating current.

109. The patch assembly of claim 82, wherein the diclophenac compound is contained or incorporated into a hydrophilic polymer matrix.

110. The patch assembly of claim 109, wherein the hydrophilic polymer matrix comprises a gel, a hydrogel, a polyvinyl alcohol, fully hydrolyzed polyvinyl alcohol or soluble polyvinylpyrrolidone.

111. The patch assembly of claim 109, wherein the hydrophilic polymer matrix comprises at least one of a thickener, solubility enhancer, a buffer or a humectant.

112. The patch assembly of claim 109, where the solubility enhancer comprises at least one of a polyvinylpyrrolidone polymer, polyethylene oxide, polyacrylic acid, polyvinyl alcohol, silicone dioxide, silica, celluloses and cellulose derivatives

113. The patch assembly of claim 83, wherein the diclophenac compound is dissolved in a solution.

114. The patch assembly of claim 113, wherein the diclophenac solution contains substantially no buffering ions and/or salt ions.

115. The patch assembly of claim 113, wherein the diclophenac solution is contained or incorporated into a hydrophilic polymer matrix.

116. The patch assembly of claim 113, wherein the diclophenac

compound or the diclophenac solution contains a transport enhancing agent

117. The patch assembly of claim 116, wherein the transport enhancing agent comprises a terpene, geraniol and l-menthol.

118. The method of claim 116, wherein the transport enhancing agent comprises an ion-exchange material or exchange fiber bound to the diclophenac ion in the diclophenac compound.

119. A method for biphasic transdermal iontophoretic delivery of an NSAID to a patient, the method comprising :

positioning at least one electrode assembly in electrical communication with the skin of the patient, the at least one electrode assembly including a skin contacting layer and a solution comprising a NSAID having an electrical charge, wherein the NSAID passively diffuses into the skin without the application of an external force;

delivering a dose of NSAID from the at least one electrode assembly into the skin during a first drug delivery phase using a first current having at least one characteristic to repel the NSAID out of the electrode assembly;

retaining the NSAID in the at least one electrode assembly during a second phase using a second current having at least one characteristic to retain the NSAID in the electrode assembly such that delivery of the NSAID into the skin during a second phase is minimized, wherein the first phase comprises a delivery period and the second period comprises a non-delivery period, which together comprise a delivery cycle;

delivering subsequent doses of the NSAID over subsequent delivery cycles; and

utilizing the second current to control delivery of the therapeutic agent so as to minimize an adverse effect from the NSAID over at least one delivery cycle.

120. The method of claim 119, wherein the adverse systemic effect is selected from the group consisting of bleeding, gastric bleeding, intracranial bleeding, cerebral bleeding, an adverse effect on kidney or liver function, elevated blood pressure and nausea.

121. The method of claim 119, wherein the NSAID is a diclofenac compound.

122. The method of claim 121, wherein the diclophenac compound comprises at one of a gel, a diclophenac acid or a diclophenac salt.