Patent Publication Number: US-9402904-B2

Title: Method for transdermal iontophoretic delivery of chelated agents

Description:
RELATIONSHIP TO OTHER APPLICATIONS 
     This application claims the benefit of priority to U.S. Provisional Application Ser. No. 61/214,642 filed Apr. 25, 2009, entitled “Method for Transdermal Iontophoretic Delivery of Chelated Agents” which is fully incorporated by reference herein. This application also claims the benefit of priority to U.S. patent application Ser. No. 12/459,186, filed Jun. 25, 2009, entitled “Patches And Methods For The Transdermal Delivery Of A Therapeutically Effective Amount Of Iron”, which claims the benefit of priority to U.S. Provisional Application Ser. No. 61/075,720 filed Jun. 25, 2008, entitled “Patches And Methods For The Transdermal Delivery Of A Therapeutically Effective Amount Of Iron” which are fully incorporated by reference herein. This application also claims the benefit of priority to U.S. patent application Ser. No. 12/459,183, filed Jun. 25, 2009, entitled “Patches And Methods For The Transdermal Delivery Of A Therapeutically Effective Amount Of Iron”, which claims the benefit of priority to U.S. Provisional Application Ser. No. 61/075,720 filed Jun. 25, 2008, entitled “Patches And Methods For The Transdermal Delivery Of A Therapeutically Effective Amount Of Iron” which are fully incorporated by reference herein. 
    
    
     FIELD OF THE INVENTION 
     Embodiments described herein relate to transdermal delivery of various therapeutic agents. More specifically, embodiments described herein relate to transdermal iontophoretic delivery of various chelated complexes. Still more specifically, embodiments described herein relate to transdermal iontophoretic delivery of various iron chelated complexes. 
     BACKGROUND 
     Nutrient deficiency is a world wide heath problem. Iron deficiency in particular is the most common form of nutritional deficiency in the world, affecting over 3 billion people in the Third World alone. It is associated with a number of diseases and conditions and is blamed for 100,000 maternal deaths during childbirth each year as well as 134,000 deaths among children. It is also co-morbid with a number of parasitic infections and is a key underlying factor in impaired mental development in children. 
     Iron deficiency anemia is one of the more serious conditions caused by iron deficiency. It is an advanced stage of iron deficiency and occurs when the dietary intake or absorption of iron is insufficient, and hemoglobin, which contains iron, cannot be formed. 
     Children and pre-menopausal women are the two groups most prone to developing this disease. The principal cause of iron deficiency anemia in premenopausal women is blood lost during menses. Causes in children include malnutrition during pregnancy, malnutrition, premature birth, GI bleeding, and parasitic infection. 
     The typical form of treatment for iron deficient anemia includes oral or intravenous delivery with various ferrous compounds. However, both of these treatments have a number of limitations. Oral iron preparations in particular have many disadvantages. First and foremost, they cause gastrointestinal side effects including nausea, bloating, constipation, and diarrhea. This leads to discontinuation of iron supplementation in approximately 40-66% of the patients taking such supplements. Furthermore, the absorption of iron is variable and affected by the oral ingestion of other compounds. For example, oral ingestion of food products reduces iron absorption by approximately 50%, which is problematic since many patients take iron with food in order to reduce the gastrointestinal side effects. 
     Second, many drugs are known to reduce iron absorption. For example, oral ingestion of antacids and other drugs that reduce stomach pH is known to decrease iron absorption. In turn, oral ingestion of iron also reduces the absorption of many drugs, including antibiotics. Additionally, many conditions associated with iron deficiency anemia respond poorly to oral iron supplementation because iron cannot be properly absorbed through the cells of the gastrointestinal system. This is especially true of certain inflammatory conditions of the bowel, such as Crohn&#39;s disease. Additionally, diseases associated with functional iron deficiency, such as the anemia of renal failure, are also associated with limited absorption of orally administered iron. This is also true of many other so-called “inflammatory conditions” associated with functional iron deficiency, such as those associated with rheumatoid arthritis and other autoimmune diseases, as well as anemia secondary to cancer or cancer chemotherapy treatment. This is especially true in patients with these conditions who are treated with erythropoietin, who have considerably increased demands for iron. 
     Intravenous administration also has a number of limitations. These include pain and infection at the injection site, the requirement to be connected to an IV drip for a prolonged period of administration (to reduce the risk of anaphylaxis), and the requirement to mix, store and administer the medication in liquid form using sterile technique. The latter can be particularly problematic in third world countries where adequate refrigeration and sterile needles are not readily available, limiting shelf life and exposing the patient to infection. 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 the treatment of iron deficiency including anemia and other related medical conditions which can extend shelf life and are more easily used in settings lacking refrigeration or sterile medical supplies. 
     BRIEF SUMMARY 
     Embodiments described herein provide a device, system and method for the transdermal iontophoretic delivery of drugs and other therapeutic agents. Many embodiments provide a device, system and method for the transdermal iontophoretic delivery of chelated drugs and therapeutic agents. Particular embodiments provide a device, system and method for the delivery of chelated iron compounds for the treatment of iron deficiency including the treatment of iron deficiency anemia (herein after “anemia”) and related conditions. Such embodiments are particularly useful for treatment of anemia by transdermally delivering controlled doses of iron in a form well tolerated by the patient while producing minimal tattooing, marking or other chromogenic effects on the skin due to oxidative reaction of the iron with the skin. 
     One embodiment provides a method for the iontophoretic transdermal delivery of a chelated iron complex for the treatment of anemia comprising the following approach. A patch comprising an active electrode and a chelated iron complex is applied to the skin; a second patch containing an electrode serving as a return electrode is also applied. In many embodiments, (including those using alternating current to deliver the chelated complex), the second patch may include the chelated complex and the second electrode may thus function as an active electrode as well. 
     The chelated complex can comprise an iron ion (e.g., ferrous Fe2 + ; or ferric Fe3 + ) that is electrostatically bound to a chelating agent such as pyrophosphate. An electrical current is then delivered to the skin from the active electrode with current flow penetrating through the layers of the skin into the subdermal layers before it flows back to the return electrode. The current serves to transport the chelated complex across the skin via electromotive force, with the iron ion being substantially chromogenically unreactive with the skin during transport so that there is little or no tattooing or marking of the skin due to the formation of insoluble oxidative products created by reactive iron ions (Fe2+ or Fe3+). These reactive iron ions can form colored precipitates in the skin which result in a tattoo. The iron complex is then dissociated in subdermal tissue by phagocytosis or related intracellular processes to release the iron where it is quickly bound by transferrin. The complex may also be absorbed into the blood stream transported in its chromogenically unreactive form to the spleen where the complex is disassociated by phagocytosis or other cellular processes. 
     Another embodiment provides a transdermal iontophoretic delivery device comprising an active electrode assembly conformable to a contour of a skin surface, and a return electrode assembly conformable to a contour of a skin surface. In many embodiments, the electrode assemblies comprise skin conformable patches. Accordingly, in these and related embodiments the transdermal iontophoretic delivery device comprises a transdermal iontophoretic delivery patch device, herein after a “patch device”. The active electrode assembly includes a reservoir for the therapeutic agent, a tissue contacting porous layer in fluidic communication with the reservoir, and a connector for coupling the active electrode assembly to an electrical power source such as a battery powered source. 
     In some embodiments the patch may also include a self sealing port. The self sealing port comprises a silicone or other elastomeric material and allows the electrode assembly to be filled using an external container of therapeutic agent solution such as a squeezable bottle. 
     The return electrode assembly comprises a tissue contacting conductive layer and a connector for coupling the electrode assembly to the electrical power source. In many embodiments the return electrode assembly can also comprise an active electrode assembly and can thus include a reservoir, a self sealing port and a porous tissue contacting layer. 
     In another aspect, the invention provides a kit for iontophoretic transdermal drug/therapeutic agent delivery which includes an embodiment of the iontophoretic transdermal device and a mixing container. The mixing container has a premeasured dose of therapeutic agent in solid form. Typically, the therapeutic agent will be part of a therapeutic agent composition which can include one or more pharmaceutical excipients such as preservatives. The therapeutic agent composition is configured to be stored for an extended period in solid form and dissolved in liquid to produce a therapeutic agent solution having sufficient concentration to treat a medical condition of a patient, such as anemia, using transdermal iontophoretic delivery of the therapeutic agent solution. In many embodiments, the therapeutic agent comprises a therapeutically effective amount of iron in the form of one or more chelated iron compounds including, ferric pyrophosphate, for the treatment of anemia. 
     The mixing container also includes an applicator having a tip for penetrating the self sealing port of the active electrode assembly, and a port for adding liquid to dissolve the therapeutic agent. This port can also comprise a self sealing port made from an elastomeric material to allow for injection of mixing fluids using a syringe or tissue penetrating end of an IV kit. 
     The mixing container has a shape, volume and radial elastic quality to allow a user to mix the therapeutic agent in the added liquid to prepare the therapeutic agent solution and then deliver the solution to the active electrode by inserting the applicator tip through the self sealing port of the electrode assembly and squeezing the mixing container. In various embodiments the mixing container can comprise a squeezable bottle fabricated from one or more resilient polymers such as HDPE, or polypropylene. 
     Further details of these and other embodiments and aspects of the invention are described more fully below, with reference to the attached drawing figures. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic view of an embodiment of a system for the transdermal iontophoretic delivery of various therapeutic agents. 
         FIG. 2 a    is a schematic side view showing placement of an embodiment of a transdermal iontophoretic patch device on the surface of the skin, wherein the device comprises an active electrode assembly and a return electrode assembly. 
         FIG. 2 b    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 two active electrode assemblies. 
         FIG. 2 c    is a schematic side view showing delivery of a chelated therapeutic complex from a transdermal iontophoretic patch device placed on the skin. 
         FIGS. 3 a  and 3 b    are side and top views showing an embodiment of an active electrode assembly. 
         FIG. 4  is a schematic side view showing an embodiment of a kit and system for the transdermal iontophoretic delivery of a therapeutic agent. 
         FIGS. 5 a  and 5 b    are perspective views showing embodiments of packaging for the transdermal iontophoretic delivery kit.  FIG. 5 a    shows the entire packaging and the packaged kit including instructions for use, while  FIG. 5 b    shows the use of flaps on the packaging for opening the packaging. 
         FIG. 6  is a side view illustrating an embodiment of a mixing container having a premeasured dose of therapeutic agent. 
         FIGS. 7 a -7 c    are schematic side views illustrating use of the mixing container;  FIG. 7 a    shows methods for filling the mixing container by an IV bag or syringe;  FIG. 7 b    shows the mixed therapeutic agent solution;  FIG. 7 c    shows use of the mixing container to fill the active electrode assembly. 
         FIG. 8 a    is a schematic view illustrating an embodiment of a solar powered power supply. 
         FIGS. 8 b , 8 c , 8 d    are top, cross sectional and perspective views illustrating embodiments of a wearable power supply. 
         FIG. 9  is a block diagram illustrating the configuration of various components of an embodiment of the power supply. 
         FIGS. 10 a  and 10 b    are plots showing embodiments of an electrical signal waveform having DC and AC components that is used for providing the electromotive force for transdermal iontophoretic delivery of a therapeutic agent.  FIG. 10 a    shows the separate DC and AC components, while  FIG. 10 b    shows them combined. 
         FIG. 11  is a plot showing an embodiment of an AC signal waveform used for providing the electromotive force for transdermal iontophoretic delivery of a therapeutic agent. 
         FIG. 12  is a plot illustrating the amount of ferrous chloride delivered across porcine skin using DC and AC waveform. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Many embodiments described herein provide a system and method for transdermal iontophoretic delivery of various therapeutic agents including chelated complexes. As used herein, a chelated complex comprises a therapeutic moiety such as an iron ion that is electrostatically bound by an inactive moiety such as pyrophosphate. Also as used herein, the term transdermal delivery refers to the delivery of a compound, such as a drug or other therapeutic or biological agent, through one or more layers of the skin (e.g., epidermis, dermis, etc). The layers of the skin include the epidermis, E, dermis, D and subdermis, SD. The upper most layer of the epidermis includes the stratum corneum, SC. 
     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 or biological compound. 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, or cation, into the skin. 
     Referring now to  FIGS. 1-7 , one embodiment of a system  5  for the transdermal iontophoretic delivery of a therapeutic agent to a tissue site TS (such as the arm A) on the skin S of patient comprises at least two electrode assemblies  15  including an active electrode assembly  20  and a return electrode assembly  30 ; and a power supply  100  as is shown in the embodiment of  FIG. 1 . Collectively, the active and return electrodes  20  and  30  are comprise a transdermal iontophoretic delivery device  10  also described herein as patch device  10  or patch  10 . 
     The active and return electrode assemblies are conformable to a contour C of a skin surface S as is shown in the embodiments of  FIGS. 2 a  and 2 b   . In many embodiments, the electrode assemblies comprise skin conformable patches  15   p  fabricated from layers of elastomeric or other flexible polymer material. The active electrode  20  assembly includes a reservoir  21  for the therapeutic agent, a tissue contacting porous layer  24  in fluidic communication with the reservoir, an adhesive layer  25  for adhering the assembly to the skin and an electrical connector  26  for coupling the electrode assembly  20  to an electrical power source  100  such as a battery and/or solar powered source. 
     In some embodiments, the active electrode can include a self sealing port  22  fluidically coupled to the reservoir for filling the reservoir with therapeutic agent. The self sealing port  22  comprises a silicone or other elastomeric material and allows the electrode assembly to be filled with therapeutic solution  54  using a mixing container  40  described herein and/or a syringe and to do so using sterile technique. In some embodiments the port can include a channel  27  fluidically coupling the port  22  to the reservoir  21 . The porous conductive layer  24  can comprise polymer fibers such as PET fibers or a polymer foam known in the art. The porosity of the porous conductive layer  24  can be selected depending upon the particular therapeutic agent, and current voltage regimen. High porosities can be selected for higher molecular weight therapeutic agents and/or therapeutic agent solutions  54  having greater viscosity. The adhesive layer  25  will typically be positioned on the perimeter  25   p  of the electrode assembly and comprise various releasable adhesives known in the biomedical electrode arts. 
     The return electrode assembly  30  comprises a tissue contacting conductive layer  31 , an adhesive layer  35  and a connector  36  for coupling the electrode assembly to the electrical power source. In many embodiments, the return electrode assembly  30  can also comprise an active electrode assembly  20  as is shown in the embodiment of  FIG. 2 b    and can thus include a reservoir  21 , a self sealing port  22 , channel  27  and a porous tissue contacting layer  24 . 
     In various embodiments, the electrode assemblies  20  and  30  together with a mixing container  40 , which includes solid form therapeutic agent  51  can comprise a kit  60  for the transdermal iontophoretic delivery of a therapeutic agent  51 , as is shown in the embodiment of  FIG. 4 . In various embodiments, system  5  can include kit  60  and power supply  100  as is also shown in  FIG. 4 . Kit  60  can be packaged in sterile packaging  70  as shown in the embodiments of  FIGS. 5 a  and 5 b   . In these embodiments, kit  60  can also include instructions for use  65  of the kit detailing the specific therapeutic agent dose, mixing instructions and power/current delivery regimen to be used. Packaging  70  can include various identifying indicia  75  such as indicia identifying the type, dose and expiration date of agent  51  as well as the patch size of electrodes  20  and  30 . The packaging can also be constructed from vapor impermeable/resistant materials to so as to protect kit  60  from oxidation and water vapor and thus extend the shelf life of kit  60  including therapeutic agent  51 . Additionally the packaging  70  can include peelable flaps  74  to facilitate opening of the packaging using sterile technique. 
     The mixing container  40  has a premeasured dose of therapeutic agent  51  in solid form as is shown in the embodiment of  FIG. 6 . Typically the therapeutic agent will be part of a therapeutic agent composition  50  which can include one or more pharmaceutical  52  excipients such as preservatives. The therapeutic agent composition  50  is configured to be stored for an extended period in solid form and dissolved in liquid to produce a therapeutic agent solution  54  having sufficient concentration to treat a medical condition of a patient such as anemia using transdermal iontophoretic delivery of the therapeutic agent solution  54 . 
     Referring now to  FIGS. 6, 7   a ,  7   b  and  7   c , the mixing container  40  includes an applicator  41  having a tip  42  for penetrating the self sealing port  22  of the active electrode assembly, and a port  43  for adding liquid  53  such as saline or distilled water to dissolve the therapeutic agent composition so as to form therapeutic agent solution  54 . Applicator  41  can also include a removable sheath  46 . Port  43  can also comprise a self sealing port made from an elastomeric material to allow for injection of mixing fluids using a syringe or tissue penetrating end of an IV bag as is shown in the embodiment of  FIG. 7 a   . The mixing container can also include various measurement indicia  47  to assist in filling the container with a selected amount of liquid  53 . 
     The mixing container  40  has a shape, volume and radial elastic quality to allow a user to mix the therapeutic agent  51  in the added liquid  53  to prepare the therapeutic agent solution  54  and then deliver the solution to the active electrode assembly  20  by inserting the applicator tip  42  through the self sealing port  22  of the electrode assembly and squeezing the mixing container  40  into a squeezed state  40   s  as is shown in the embodiments of  FIGS. 7 a -7 c   . Accordingly, the mixing container  40  comprises a squeezable bottle  40   s  fabricated from one or more resilient polymers, such as HDPE or polypropylene. Also, applicator  41  and tip  42  have sufficient column strength and sharpness to be able to puncture port  22  by holding the body of the container  48  and jabbing the port  22 . 
     In an embodiment of a method for using kit  60  and container  40 , after the user opens packaging  70 , he fills container  40  in filling step  81  by either inserting the tip  42  into a sterile IV bag of liquid  53  or through use of a syringe as is shown in  FIG. 7 a   . Then he shakes the container in a mixing step  82  to mix the therapeutic composition  50  to form therapeutic solution  54  as is shown in  FIG. 7 b   . Finally, he adds the mixed solution  54  to the electrode assembly  20  by inserting tip  42  through sealable port  22  and squeezing the container in an electrode assembly filling step  83  as is shown in  FIG. 7   c.    
     As discussed herein, in many embodiments, therapeutic agent  51  is part of a therapeutic composition  50  that comprises the solidly formed therapeutic agent  51  and one or more pharmaceutical excipients  52 . Suitable excipients  52  can include preservatives and buffers to maintain a selected pH of the solution  54 . One or more of these excipients  52  along with therapeutic agent  51  can be solidified using methods such as crystallization and lyophilization. In various embodiments, therapeutic agent composition  50  and agent  51  can also be in a concentrated liquid form that is diluted in mixing container  40 . Whether in solid or liquid form, therapeutic agent composition and agent  50  and  51  are diluted using a solvent  53  also known as carrier  53  to form a therapeutic agent solution  54  that is loaded into the active electrode assemblies  20  using mixing container  40  or by other means. Suitable solvents  53  can comprise distilled water and various aqueous solutions including saline or buffered saline. 
     In various embodiments, the therapeutic agent  51  can include without limitation: iron compounds, antibiotics (e.g., penicillin, ampicillin, erythromycin, ciprofloxacin, vancomycin, etc.), antibodies, proteins, polypeptides, insulin and other glucose regulating compounds, various anti-diarrheal drugs (e.g., Loperamide oxide) various chemotherapeutic agents (e.g., doxorubicin), various vaccines (e.g., diphtheria, cholera, tetanus, flu, measles and polio vaccines; vaccines can also include be in the form of deactivated pathogens as well as antibodies), and various hormones having birth control properties (e.g., estrogen and progesterone as well as combinations thereof). The therapeutic agents can also include various pro-drugs which are metabolized into their active form once released into the body. Suitable pro-drugs can include anti-viral nucleoside analogs, lipid-lowering statins, antibody-directed/gene-directed enzyme prodrugs for chemotherapy, etoposide phosphate, valganciclovir and fosamprenavir. Again, these therapeutic agents can be lyophilized, including vaccines, antibodies, proteins and peptides. 
     In specific embodiments, the therapeutic agent  51  and agent composition  50  can comprise one or more ferrous salts for the treatment of anemia such as ferric chloride or ferrous chloride; other salts are also contemplated. The composition can also comprise one or more preservatives such as ascorbic acid to preserve the charge/ionic state of the ferrous salt (having a +2 charge state) to prevent it from converting to a ferric salt (having a +3 charge state). For embodiments using ferrous chloride, the therapeutic solution  54  can be mixed to have a concentration in the range from 200 to 1000 mg/ml with specific embodiments of 300, 400, 500 and 750 mg/ml. 
     The amount or dose of the respective therapeutic agent  51  and/or therapeutic composition  50  to be included in the mixing container  40  can be determined based on the condition to be treated (e.g., anemia, diabetes, etc.) and patient weight, age, etc. Also, dosages can be based on known therapeutically effective doses for a particular condition that are delivered orally, intravenously or by other delivery means (e.g., intranasally, inhalation, etc.) with adjustment for different absorption/uptake of the known method (e.g., in the case of orally delivered iron compounds). For example, in the case of orally delivered iron compounds (e.g., ferrous sulfate) for the treatment of anemia, typically 50 mg of elemental iron are delivered, of which only 10 to 25 mg are actually absorbed into the blood stream. Accordingly, the dose of elemental iron in the mixing container can be in the range of 10 to 25 mg or 10 to 50 mg with specific embodiments of 10, 15, 20, 25, 30, 40 and 50 mg. Additionally, in particular embodiments, dose response curves can be developed for the transdermal iontophoretic delivery of particular therapeutic agents using known pharmacological methods. These methods can include measurement of various biomarkers of iron status in the body including one or both of serum iron concentrations as well as % transferrin iron saturation (herein transferrin iron saturation). Again, adjustment can be made for the weight and age of the patient as well as their particular condition, e.g., gestational anemia. 
     In particular embodiments, the dose of a chelated iron complex  55  in the mixing container  40  and/or patch  10  can be adjusted or titrated based on measurement of one or more biomarkers of iron status such as serum iron concentration or transferrin iron saturation. Other such biomarkers can include serum/plasma concentrations of one or more of ferritin, transferrin, C-reactive protein, hemoglobin (e.g., hematocrit) and bilirubin. One or both of the rate of delivery of chelated iron complex  55  into the skin can also be titrated based on measurement of one or more biomarkers of iron status. Such titration of delivery rates can be achieved by adjustment of the electrical delivery parameters discussed herein, e.g., current, voltage, waveform, delivery time, etc. In particular embodiments, titration of delivery rates of the therapeutic complex can be achieved by modulation of the current used for iontophoretic delivery. The modulation can be in frequency, amplitude or both. 
     In certain embodiments, therapeutic composition  50  can comprise a chelated complex  55  which comprises a therapeutic agent or moiety  56  that is electrostatically bound to a chelating agent or moiety  57 . In many cases, the therapeutic moiety  56  has a positive charge such as for an iron moiety for treating anemia, and the chelating moiety has a negative charge. The chelated complex  55  can be delivered to the skin S and underlying subdermal tissue SD using various iontophoretic transdermal methods described herein. This can include applying to the skin a patch  10  containing the chelated complex dissolved in solution and then delivering a current to drive the complex into the skin and underlying tissue SD as is shown in  FIG. 2 c   . Once transported across the skin S and into underlying sub dermal tissue SD, the therapeutic moiety  56  remains bound by the unreactive moiety  57  until acted on by one or more cellular mechanisms (e.g., phagocytosis). 
     The above process allows the chelated complex  55  to be chromogenically unreactive with the skin during transport across the skin. Specifically, the complex produces little or no chromogenic marking in the skin including the epidermal and subdermal layers. In the case of iron, such markings, known as tattoos, result from the formation of insoluble oxidative products (specifically, insoluble iron oxide salts) created by reactive iron ions (e.g., Fe 2+  or Fe 3+ ). These salts then precipitate in the epidermal or dermal layers to form colored precipitates causing the tattoo. Use of chelated iron complex minimizes or eliminates the production of these salts and thus eliminates the development of tattoos or other related discolorations causing cosmetic changes to the skin. As is discussed below, use of chelated iron complexes also reduces the amount of cosmetic change due to burning, irritation or other injury to the skin resulting from current delivery. 
     Suitable chelated iron complexes  55  which are chromogenically unreactive include ferric pyrophosphate, and related iron salts. In these and related embodiments, the ferric or other iron ion is sufficiently electrostatically bound by the pyrophosphate or other inactive moiety so that the ferric ion is not available to form insoluble salts within the skin. Thus the iron ion is substantially chromogencically unreactive with the skin. Other suitable chelated iron complexes can include ferrous or ferric complexes comprising edetate, ethylenediamineedetate and/or ethylenediaminesuccinate. In addition to the selection of the chelated complex  55 , chromogenic marking during skin transport can be also reduced by selection of one or more of the electrical parameters (e.g., current, voltage, waveform, etc.) of iontophoretic delivery. 
     In the case of ferric pyrophosphate or like molecules, dissociation occurs by various cellular processes such as phagocytosis, where the chelated complex  55  is engulfed by macrophages  58  or other cells  58  and the molecule is broken down in the cell cytoplasm  59  of the macrophage  58  into its therapeutic agent components by various enzymes within the macrophage or other phagocyte. Phagocytosis can occur subdermally proximate to tissue site TS or in the spleen or other locations. For ferric pyrophosphate, the elemental iron (in the form of ferric ions) released by phagocytosis may then be bound by transferrin where it is then transferred by the plasma to be used throughout the body in various metabolic processes including synthesis of various biological compounds such as heme synthesis, and red blood cell formation in the bone marrow as well as storage in the liver where it is taken up by hepatocytes. The ferric ion may also be taken up and bound intracellularly by a ferritin molecule, which is the main intracellular iron storage protein. This can either occur directly within the macrophage or indirectly when the iron is carried and released by transferrin to a location where it is then taken and bound within the location by ferritin. For patients suffering from iron deficient anemia, the iron released by phagocytosis or other metabolic process can be used to enhance the amount of heme synthesis in the liver or the bone marrow. This in turn, can enhance the amount of hemoglobin in the blood. 
     In addition to reducing or eliminating the formation of tattoos and other related markings, various embodiments using chelated iron complexes can also be configured to minimize burning, erythema (e.g., redness) or other injury irritation of the skin resulting from the delivery of current to the skin for transdermal iontophoresis. This is due to several factors. First, minimizing the formation of precipitates prevents an increase in the skin&#39;s electrical impedance from such precipitates and in turn, the amount of ohmic heating of the skin. Further, when the ions stay in solution they increase the conductivity of the skin, thereby lowering impedance. Finally, because there is little or no precipitate, more of iontophoretically delivered iron is delivered to the subdermal tissue layers in a form which can be used by the body. Thus, the total time period of current delivery, and so the ampere hours, of delivered current is decreased, resulting in less damage to the skin. As discussed herein, it is desirable to keep the amount of total delivered current below a certain level for example below 100 mA-minutes, and still more preferably below 80 mA-minutes. 
     Various embodiments of the invention contemplate use of chelated complexes including chelated iron complexes on a wide variety of iontophoretic transdermal delivery platforms. These include embodiments employing DC current, AC current, single patch delivery, dual patch delivery, and multiple current embodiments including those employing one or more currents for producing oscillatory motion of the therapeutic agent as described in U.S. Provisional Patent Application Ser. No. 61/214,642, the contents of which are incorporated herein by reference (such embodiments involve the use of multiple AC currents delivered by separate pairs of electrodes which creates two electromotive forces acting on the iron or other active agent in its ionic form. The first force acts on the ions perpendicular to the skin surface, and driving them into the skin. The second force oscillates the ions horizontal to the surface of the skin producing a “sieving” action of the iron ions or other agent ions so as to funnel them through the stratum corneum, a process that is described as “oscillophoresis”). The electrical parameters (e.g., current, voltage, waveform, delivery time, etc.) as well as other parameters (e.g., patch size, agent solution concentration, etc.) can be adjusted for each platform to achieve a desired dosage of the selected therapeutic agent. Further, in various AC iontophoretic current embodiments, the current can be modulated (e.g., frequency, and/or amplitude modulation) to achieve one or more of the following: i) titrate the total delivered dose of therapeutic agent, ii) titrate (e.g., enhance) the rate of delivery of therapeutic agent (e.g., by increasing the current); iii) minimize the perceived pain of the patient (typically by keeping the amplitude below a specific level); and iv) minimize the amount of thermal injury and associated discoloration to the skin (e.g., by keeping the amplitude below a set level and/or the ampere-hours below a total amount). Modulation can be achieved using one or more embodiments of controller  150 . 
     Use of chelated complexes is also contemplated for embodiments employing purely passive diffusion of therapeutic agent as well and combinations of passive and active diffusion (e.g., passive and iontophoretic transdermal delivery). 
     In various embodiments employing chelated iron complexes, such as iron pyrophosphate, the electrical parameters and delivery regimen can be configured to deliver therapeutically effective amounts of iron for treatment of iron deficiency anemia and related conditions. In various embodiments, the therapeutically effect amount of iron delivered using an iron chelated complex can be in the range from about 1 to about 300 mg, with specific embodiments of about 1 to about 100 mg, about 1 to about 50 mg, about 1 to about 25 mg and about 3 to about 10 mg. For embodiments employing ferric pyrophosphate, the amount of ferric pyrophosphate required to achieve these delivered doses is roughly three times the desired delivered dose, owing to the fact that iron makes up roughly one third of the molecular weight of ferric pyrophosphate. The concentrations of ferric pyrophosphate to achieve these dosages can be in the range of about 10 to 50 mg/ml with specific embodiments of 20, 30 and 40 mg/ml. So for example, for a patch holding about 1 ml of solution, the concentration of ferric pyrophosphate required to deliver 10 mg of iron would be about 30 mg/ml. Different concentrations can be used for different sized patches. Concentrations can also be adjusted using dose response curve methodology. 
     Referring now to  FIGS. 8-9 , embodiments of power supply  100  will now be described. Various embodiments of the invention contemplate portable power supplies  100  that can be carried by hand and even worn by the user. In various embodiments, power supply  100  can be battery powered or may be powered by an external electrical power source (ac or dc). It may also be solar powered as is described herein. 
     An embodiment of a portable supply  100  shown in  FIG. 8 a   , can include a display  101 , for displaying electrical waveforms  102  and data  103 , one or more control buttons/switches  104  for control and selection of various functions, touchpad/keys  105  for inputting data and one or more pairs of electrical connectors  106  for connecting to patch devices  10 . The power supply can be battery powered or may also be powered by an external power AC or other power source. Also, in some embodiments the supply  100  can include a solar cell  120  as a direct power source and also to charge embodiments of supply  100  having rechargeable batteries discussed here. Solar cell  120  can be any number of photovoltaic cells and systems known in the art and has sufficient area and power generation characteristics to supply power to power supply  100  both for charging and direct power. In various embodiments, cells  120  can be configured to generate about 50 to 1000 watts of power with specific embodiments of 100, 200 and 500 watts. In specific embodiments, solar cell  120  can comprise silicon based cells including monocrystalline, polycrystalline and amorphous silicon. Additionally, cell  120  can be detachably coupled to supply  100  by means of cable  107  coupled to a power connector  108 . Cable  107  can have sufficient length (e.g., 30 feet or longer) to allow the cell to be remotely placed in a window or roof or other location receiving direct or increased sunlight when supply  100  is being used in a location not receiving direct light. 
     In some embodiments, power supply  100  can be configured to have multiple output channels  110  so as to supply electrical/power signal  115  to multiple patch devices  10  and in turn allow for the transdermal iontophoretic delivery to multiple sites on a single patient or multiple patients. In preferred embodiments, the power supply can have up to eight channels  110 , with additional numbers contemplated. Each channel  110  can be independently controlled through use of a controller  150  described herein, or other control means. 
     In many embodiments, power supply  100  can be a portable power supply  100  configured to be carried or even worn by the user, for example, on the arm of the user. In particular embodiments, the power supply  100  can be incorporated into a wearable system  5   w  (which includes patches  10 ) that is worn on the arm or leg or other location of a user. An embodiment of a wearable power supply  100  and system  5   w  is shown in  FIGS. 8 b , 8 c  and 8 d   . Wearable system  5   w  including power supply  100  can be configured to be to worn on the arm/leg of the user being attached to arm with an arm/leg band like device  6  or a similar device. It may also be configured to be attached to patch device  10  as described below. As another alternative, it may be worn on the user&#39;s belt and connected with connective wiring. For arm and leg wearable embodiments, wearable power supply  100  can have a curved or related form factor to facilitate wear on the arm or leg. It may even comprise conformable materials to conform to the shape of the arm or leg. Similar to portable supply  100 , wearable supply  100  can also include a display  101 , and one or more buttons or switches  104  as well as other features of embodiments of portable supply  100 . It may also include a bar code reader  109  for reading bar codes on the packaging for kit  40 , device  10  or container  30  as well as various other bar codes. It can also include one or more electrical connectors or fittings  106  for either directly engaging with connectors  26  of patches  10  or via cabling (not shown). The wearable power supply  100  can also be configured to attach arm band device  6  via VELCO or other attachment means (e.g., a snap or like fitting). Band device  6  can also be an integral component of power supply  100  allowing the user to easily slip or wrap band  6  around their arm or leg. As another alternative, embodiments of a wearable power supply  100  can be configured to directly attach to embodiments of patch  10  which include adhesive layers for attaching to the user&#39;s skin. Again, in such embodiments, power supply  100  can be attached to patch  10  via VELCRO or other attachments means. 
     Typically a wearable power supply will include a battery  140 , though, power storage and/or generation means are also contemplated such as an energy harvesting device and/or a solar cell. Such alternative devices can be used alone or in conjunction with battery  140 . Battery  140  can be lightweight and have a form factor to be readily integrated into the power supply. Suitable batteries can include alkaline, lead acid, nickel metal hydride, lithium, lithium ion cell, and like chemistries. The battery size can include double AA varieties known in the art. Other standard sizes are also contemplated. 
     In some preferred embodiments, power supply  100  can be configured to be solar powered and/or to have a battery rechargeable by solar power or other recharging means including a hand operated generator (such embodiments may also be configured for connection to an external power source). Accordingly, in these embodiments, power supply  100  will typically include a solar cell  120 , recharging circuitry  130 , a battery  140  and a controller  150  as is shown in the embodiment of  FIG. 9 . Suitable rechargeable batteries include lead acid, nickel metal hydride, lithium, lithium ion cell and like chemistries. The controller  150  will typically include a microprocessor  151  for controlling one or more functions of the power supply, memory resources for storing one or more software algorithms and data used by the microprocessor, a dc-dc converter for increasing voltage from the battery, a dc-ac converter for supplying AC power to one or more devices  10  and a multiplexor or power rail for supplying separate power/electrical signals  115  to each channel  110 . The microprocessor can include one or more algorithms for controlling various functions of the power supply  100 , for example the power regimen to device  10  for a particular therapeutic agent and particular patient. 
     Through use of controller  150 , various embodiments of power supply  100  can be configured to perform multiple functions. These include i) generating and supplying voltage and current to one or more devices  10 , ii) generating a specific power/electrical signal  115  for each device  10 ; iii) implementing power/signal regimens (e.g., current, voltage and frequency and waveforms over a duty cycle) for particular patients and therapeutic agents); iv) monitoring the voltage, current, impedance and current dose on each channel; v) regulating including modulating the signal (e.g., voltage, current and frequency) for each channel based on the monitored voltage, current, etc; and vi) perform various power management functions including detecting battery charge, charging the batteries and switching between battery and solar power when needed. 
     Various embodiments of power supply  100  can also be configured to supply selectable voltages and currents to one or more patch devices  10 . In various embodiments, voltages can be in the range 1-14 volts with specific embodiments of 5, 6, 7, 8, 9, 10, 11, 12 or 13 volts. In specific embodiments the power supply can also be configured to have different voltage operating modes, for example, a low, medium and high voltage operating mode which can correspond to exemplary ranges of 1-6, 6-12, and 12-14 volts, with other ranges also contemplated. 
     Currents can be in the range of 0.1 to 0.8 ma, with specific embodiments of 0.1, 0.2, 0.3 and 0.4 ma, with other values contemplated. The controller can also include algorithms for limiting the total current dose (in amperes hours) delivered to the patient. In specific embodiments, the total current dose can be limited to below 100, 80, 60 or 40 mA-minutes. In various embodiments, the controller can shut off current when the maximum dose is reached or switch the polarity of the voltage so that therapeutic agent is now delivered from the other electrode assembly/patch (for dual patch embodiments). The controller can also be configured to decrease the current, e.g., from 0.3 ma to 0.1 ma, as the maximum current dose is approached. In this way the desired amount of therapeutic agent can be delivered without exceeding a current dose threshold. 
     In various embodiments, controller  130  can be configured to generate signals  115  having specific characteristics as well as a particular duty cycle of signals  115  depending upon one or more factors such as the therapeutic agent, patient and medical condition to be treated. The signal  115  can be DC, AC or a combination of both. For DC embodiments, signal  115  can have a range of 1 to 100 volts. In both DC and AC embodiments, signal  115  can be current controlled by controller  150  so that current is fixed and the voltage will vary. In these and related embodiments, the current can be controlled in the range from about 10 μa to 4 ma. Whether DC or AC, signal  115  can be modulated to perform one or more of the following functions including: i) minimization of pain perception by the patient (e.g., by amplitude modulation), ii) titration of the rate of delivery of the therapeutic agent; and iii) titration of the total amount of therapeutic agent delivered. 
     Referring now to  FIGS. 10 a , 10 b    and  11 , in specific embodiments, signal  115  can comprise a combined signal  115   c  having a DC signal  116  component and an overlying AC signal component  117 . AC component  117  can be configured to perform several functions including breaking down the capacitive charge buildup in skin tissue that can occur during application of a transdermal current or voltage as is shown in the embodiments of  FIGS. 10 a  and 10 b   . It can also be configured to oscillate the chelated complex  55  in one or more directions with respect to the skin to enhance transport of the complex through the skin. The amplitude of signal  117  can be in the range of 1 to 100% of the DC signal with specific embodiments of 10, 20 and 50%. AC component  117  can be shaped to as to comprise a sine, square or saw-tooth wave, with a frequency in range between about 1 to 100 hz, about 1 to 50 hz, about 1 to 25 hz, and about 1 to 10 hz. Also, in these and other embodiments, signal  115  can have a trapezoidal  115   t  or other related shape wherein the voltage is slowly ramped up during ramp-up portion  118  and ramped down during a ramp-down portion  119 . The slope of portions  118  and  119  are configured to decrease any pain felt by the patient as a result of a sudden increase or decrease in transdermally applied voltage. 
     Also in many embodiments, signal  115  can substantially comprise an AC signal  115   ac  where the voltage is reversed in polarity at a set frequency as shown in the embodiment of  FIG. 11 . The frequency of the AC signal can be in the range from about 1 to 100 hz, about 1 to 50 hz, about 1 to 25 hz, and about 1 to 10 hz. The waveform of signal  115  can comprise a trapezoidal  115   t  or other like shape where voltage is ramped up and ramped down. Other waveforms are also contemplated including sine wave, etc. In use, such AC signal embodiments can significantly increase the amount of delivered therapeutic agent  51  by one or more means including preventing and/or breaking up the buildup of capacitive charge in the skin as well as the buildup of ionic layers in the skin, both of which can impede the transport of the therapeutic agent  51  into the skin that is driven by applied transdermal voltage. It can also do so by oscillating the therapeutic complex  55  in one or more directions with respect to the skin to find pathways of least resistance through the skin, such as through gaps in the stratum corneum. In one example shown in  FIG. 12 , nearly a 10 fold increase was obtained in the transport of ferrous chloride through porcine skin for the use of an AC vs. a DC signal. 
     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 reader (not shown) for reading bar codes on the packaging for kit  40 , device  10  or container  30  as well as various other bar codes. Additionally the power supply can include a clamp for attaching it the supply to an IV pole or other support stand or device. 
     Also in various embodiments, supply  100  including its electronic components can be configured to have enhanced durability and reliability so as to withstand various temperature and humidity extremes to allow its use in a variety of ambient conditions and environments, including tropical and desert environments. This can be achieved through the use of mil spec electronic components known in the art as well as the use of various protective polymer coverings and coatings internally and externally to confer resistance to moisture, sand and dust. Additionally, the power supply may constructed to have a high degree of fault tolerance and thus be constructed from fault tolerant components and/or have backup components such as a backup battery and a controller. Additional, backup components are also contemplated. Further one or more of the electronic components of the power supply can be configured to be modular to allow for rapid and easy replacement without having to replace the whole unit. This can be facilitated by the use of diagnostic software incorporated into controller  150  to identify faulty modules and components or when components are showing indications of failure or need for replacement. For example battery management software can indicate when the supply&#39;s battery, such as a lead acid battery, is approaching the end of its cycle life. This can be achieved by analyzing the voltage waveform of the battery under a load. 
     CONCLUSION 
     The foregoing description of various embodiments of the invention has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise forms disclosed. Many modifications, variations and refinements will be apparent to practitioners skilled in the art. For example, the iontophoretic patch can be modified in size, shape and dose of therapeutic agent for different medical conditions, different tissue sites as well as for various pediatric applications. Also, embodiments of the invention have broad application for the treatment of a number of diseases and conditions which may benefit from transdermal delivery of a therapeutic agent and to do so in manner which reduces or prevents the likelihood of irritation or discoloration of the skin. 
     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 stand-alone elements. Hence, the scope of the present invention is not limited to the specifics of the described embodiments, but is instead limited solely by the appended claims.