MX2008004223A - Transdermal drug delivery systems, devices, andmethods employing opioid agonist and/or opioid antagonist - Google Patents

Abstract

Systems, devices, and methods for transdermal delivery of one or more therapeutic active agents to a biological interface. An iontophoretic drug delivery system is provided for transdermal delivery of one or more therapeutic active agents to a biological interface of a subject. The iontophoretic drug delivery system includes at least one active agent reservoir. The at least one active agent reservoir may include a pharmaceutical composition including at least one opioid agonist and/or opioid antagonist.

Description

SYSTEMS, DEVICES AND METHODS OF TRANSDERMAL SUPPLY OF DRUGS THAT USE AN OPIOID AGONISM AND / OR AN OPIOID ANTAGONIST BACKGROUND OF THE INVENTION Field of the Invention This disclosure generally relates to the field of iontophoresis and, more particularly, to systems, devices and transdermal drug delivery methods employing an opioid agonist and / or an opioid antagonist.

Description of the Related Art Iontophoresis employs an electromotive force and / or current to transfer an active agent (e.g., a charged substance, ionized compound, ionic drug, therapeutic agent, bioactive agent and the like) to a biological interface (e.g. skin, mucous membrane and the like) when applying an electrical potential to an electrode near an iontophoretic chamber containing an active agent with similar charge and / or its vehicle. Iontophoresis devices typically include an active electrode assembly and a counter electrode assembly, each coupled to poles or opposite terminals of a power source, for example a chemical battery or an external power source. Each electrode assembly typically includes a respective electrode element for applying an electromotive force and / or current. These electrode elements frequently comprise a sacrificial element or compound, for example silver or silver chloride. The active agent can be either cationic or anionic and the power source can be configured to apply the appropriate voltage polarity based on the polarity of the active agent. Iontophoresis can be used advantageously to improve or control the delivery rate of the active agent. The active agent may be stored in a reservoir such as a cavity. See, for example, U.S. Patent No. 5,395,310. Alternatively, the active agent may be stored in a reservoir such as a porous structure or a gel. An ion exchange membrane can be placed to serve as a selective polarity barrier between the active agent reservoir and the biological interface. The membrane, typically only permeable with respect to a particular type of ion (e.g., a charged active agent), prevents reflux of the ions with opposite charge from the skin or mucous membrane. Commercial acceptance of the devices Iontophoresis is dependent on a variety of factors, such as manufacturing cost, shelf life, storage stability, efficacy and / or accuracy of active agent supply, biological capacity and / or disposal problems. In addition, an iontophoresis device that is capable of delivering an active agent and that is effective in the induction of analgesia and anesthesia in a subject is likewise desirable. The present disclosure is directed to overcoming one or more of the limitations set forth above and provides additional related advantages.

SUMMARY OF THE INVENTION In one aspect, the present disclosure is directed to an autonomous iontophoretic drug delivery system. The system includes at least one active agent reservoir, an active electrode assembly that includes at least one active electrode element, a power source and a biocompatible backup. In some embodiments, the system is configured to provide the transdermal delivery of one or more therapeutic active agents to a biological interface of a subject and include analgesia or anesthesia in the subject for a limited period of time. At least one active agent deposit includes a composition Pharmaceutical to induce analgesia or anesthesia in the subject. The pharmaceutical composition for inducing analgesia or anesthesia in the subject may include at least one analgesic or anesthetic active agent in combination with at least one opioid antagonist. At least one active electrode element is operable to provide an electromotive force to drive the pharmaceutical composition (comprising at least one analgesic or anesthetic active agent in combination with at least one opioid antagonist) to induce analgesia or anesthesia in the subject of at least one deposit of active agent, to the biological interface of the subject. The power source is electrically coupled to the active electrode assembly and is operable to supply an electromotive force to the active electrode assembly. The biocompatible backing is configured to house at least one active agent reservoir and the active electrode assembly. In another aspect, the present disclosure is directed to a method for the systemic treatment of at least one condition associated with pain, neuropathic pain, acute pain, chronic pain or pain from cancer. The method includes contacting a location in a biological interface with a delivery device iontophoretic drug that includes an active electrode assembly having at least one active agent reservoir. At least one depot of active agent includes a pharmaceutical composition that includes at least a therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist. The method further includes applying a sufficient amount of current to the active electrode assembly for transdermally administering a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist. In another aspect, the present disclosure is directed to a method for treating opioid dependence and / or for producing a substantially opioid-free state in a subject in need thereof. The method includes contacting a location at a biological interface of the subject with an iontophoretic drug delivery that is operable to iontophoretically deliver a pharmaceutical composition comprising a therapeutically effective amount of at least one opioid antagonist. The method also includes delivering a therapeutically effective amount transdermally of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid antagonist. In another aspect, the present disclosure is directed to a method for inducing anesthesia, analgesia or anti-hyperalgesia in a subject. The method includes placing an active electrode and a counter electrode of an iontophoretic delivery device at a biological interface of the subject. In some embodiments, the iontophoretic drug delivery device is operable to iontophoretically deliver a pharmaceutical composition comprising an effective amount of at least one opioid agonist and at least one opioid antagonist. The method further includes iontophoretically delivering a synergistic, anesthesia inducing, analgesic inducing or anti-hyperalgesic inducing amount of a pharmaceutical composition comprising at least one opioid agonist and at least one opioid antagonist. In yet another aspect, the present disclosure is directed to a method for treating narcotic / respiratory depression induced by an opioid agonist in a subject in need thereof. The method includes contacting a location on a biological interface of the subject with an iontophoretic drug delivery device. which is operable to iontophoretically deliver a pharmaceutical composition comprising a therapeutically effective amount of at least one opioid antagonist. The method further includes administering via transdermal route a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid antagonist.

BRIEF DESCRIPTION OF THE DIFFERENT VIEWS OF THE DRAWINGS In the drawings, the identical reference numbers identify similar elements or actions. The relative sizes and positions of elements in the drawings are not necessarily drawn to scale. For example, the shapes of various elements and angles are not drawn to scale and some of these elements are enlarged and placed arbitrarily to improve the readability of the drawing. Furthermore, it is not proposed that the particular shapes of the drawn elements carry any information with respect to the actual shape of the particular elements and have only been selected for ease of recognition in the drawings. Figure 1A is a front, top view of a transdermal drug delivery system according to an illustrated embodiment.

Figure IB is a top plan view of a transdermal drug delivery system according to an illustrated embodiment. Figure 2A is a schematic diagram of the iontophoresis device of Figures 1A and IB comprising active electrode and counter electrode assemblies according to an illustrated embodiment. Figure 2B is a schematic diagram of the iontophoresis device of Figure 2A placed at a biological interface, with an optional exterior release liner, removed to expose the active agent, according to another illustrated embodiment. Figure 2C is a schematic diagram of the iontophoresis device comprising active electrode and counter electrode assemblies and a plurality of microneedles according to an illustrated embodiment. Figure 3A is a front perspective view of a plurality of microneedles in the form of an array according to an illustrated embodiment. Figure 3B is a front perspective view of a plurality of microneedles in the form of one or more arrays according to another illustrated embodiment. Figure 4 is a flow diagram of a method for the systemic treatment of at least one condition associated with pain, neuropathic pain, acute pain, chronic pain or cancer pain according to an illustrated modality. Figure 5 is a flow diagram of a method for inducing anesthesia, analgesia or anti-hyperalgesia in a subject according to an illustrated modality. Figure 6 is a flowchart of a method for treating opioid dependence and / or for producing a substantially opioid-free state in a subject in need thereof according to an illustrated embodiment. Figure 7 is a flow diagram of a method for treating narcotic / respiratory depression induced by an opioid agonist in a subject in need thereof according to an illustrated embodiment. Figure 8 is a diagram of Time (minutes) vs. Transported Drug ^ g) for the supply of hydromorphone through human skin according to an illustrated modality. Figure 9 is a mass spectrum diagram for serum hydromorphone according to an illustrated embodiment. Figure 10 is a diagram of Time (minutes) vs. Hydromorphone (ng (ml) showing the levels of hydromorphone in test animals after iontophoretic delivery according to an illustrated modality.

DETAILED DESCRIPTION OF THE INVENTION In the following description, certain specific details are included to provide a complete understanding of the various embodiments disclosed. However, a person skilled in the relevant art will recognize that the modalities can be practiced without one or more of these specific details, or with other methods, components, materials, and so on. In other cases, well-known structures that are associated with iontophoresis devices that include but are not limited to voltage and / or current regulators have not been shown or described in detail to avoid descriptions of the dark modalities unnecessarily. Unless the context requires otherwise, throughout the specification and the claims that follow, the word "comprise" and variations thereof such as "comprises" and "comprising" should be considered in an inclusive inclusive sense, ie as "that includes, but is not limited to". The reference for all this specification to "this modality" or "a modality" means that a particular peculiarity, structure or characteristic, which is described in connection with the modality, is included in at least one modality. In this way, the appearance of the phrases "in this modality" or "in a modality "or" in another modality "in various parts throughout this specification is not so that they all necessarily refer to the same modality.In addition, the peculiarities, structures or particular characteristics can be combined in any suitable manner in one or more modalities. It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", "the" and "the" include plural referents unless the content clearly dictates otherwise. For example, the reference to an iontophoresis device that includes "an electrode element" includes an individual electrode element or two or more electrode elements, and it should also be noted that the term "or" is generally used in the sense that includes "and / or" unless the content clearly dictates otherwise As used in this document, the term "membrane" means a limit, layer, barrier or material, which may Either not be permeable. The term "membrane" may also refer to an interface. Unless otherwise specified, the membranes may take the form of a solid, liquid or gel and may or may not have a different pattern, a non-crosslinked structure or a crosslinked structure.

As used herein, the term "ion selective membrane" means a membrane that is substantially ion selective, allowing the passage of certain ions while blocking the passage of other ions. An ion selective membrane, for example, it can take the form of a selective charge membrane or it can take the form of a semipermeable membrane. As used herein, the term "selective charge membrane" means a membrane that substantially allows the passage of and / or substantially blocks the ions based primarily on the polarity or charge carried by the ion. Load-selective membranes are typically referred to as ion exchange membranes and these terms are used interchangeably herein and in the claims. The charge or ion exchange selective membranes can take the form of a cation exchange membrane, an anion exchange membrane and / or a bipolar membrane. A cation exchange membrane substantially allows the passage of cations and substantially blocks the anions. Examples of commercially available cation exchange membranes include those available under the NEOSEPTA, CM-1, CM-2, CMX, CMS and CMB designators from Tokuyama Co., Ltd. Conversely, a membrane of Anion exchange substantially allows the passage of anions and substantially blocks the cations. Examples of commercially available anion exchange membranes include those available under the NEOSEPTA, AM-1, AM-3, AMX, AHA, ACH and ACS designators also from Tokuyama Co. , Ltd. As used herein and in the claims, the term "bipolar membrane" means a membrane that is selective for two different charges or polarities. Unless otherwise specified, a bipolar membrane can take the form of a unitary membrane structure, a multiple membrane structure or a sheet material. The unitary membrane structure may include a first portion that includes cationic-ion exchange materials or groups and a second portion opposite the first portion, which includes anionic-ion exchange materials or groups. The multiple membrane structure (for example two film structure) may include a membrane of. cationic exchange laminated or otherwise coupled to an anion exchange membrane. The cationic and anionic exchange membranes initially begin as distinct structures and may or may not retain their individuality in the resulting bipolar membrane structure.

As used herein and in the claims, the term "semipermeable membrane" means a membrane that is substantially selective based on a size or molecular weight of the ion. In this manner, a semipermeable membrane substantially allows the passage of ions of a first molecular weight or size, while substantially blocking the passage of ions of a second molecular weight or size, greater than the first molecular weight or size. In some embodiments, a semipermeable membrane may allow some molecules to pass at a first rate and some other molecules at a second rate different from the first. In still further embodiments, the "semipermeable membrane" can take the form of a selectively permeable membrane that allows only certain selective molecules to pass therethrough. As used herein and in the claims, the term "porous membrane" means a membrane that is not substantially selective with respect to the ions in question. For example, a porous membrane is one that is not substantially selective on the basis of polarity and is not substantially selective based on the molecular weight or size of an exposed element or compound. As used in this document and in the claims, the term "gel matrix" means a type of deposit, which takes the form of a three-dimensional network, a colloidal suspension of a liquid in a solid, a semi-solid, a cross-linked gel, a non-crosslinked gel, a similar state to a jelly and the like. In some embodiments, the gel matrix may result from a three-dimensional network of matted macromolecules (e.g., cylindrical micelles). In some embodiments, a gel matrix can include hydrogels, organogels, and the like. Hydrogels refer to a three-dimensional network of, for example, hydrophilic polymers cross-linked in the form of a gel and substantially water-based. Hydrogels can have a net positive or negative charge or can be neutral. As used herein and in the claims, the term "deposit" means any form or mechanism for retaining an element, compound, pharmaceutical composition, active agent and the like in a liquid state, solid state, gaseous state, mixed state and / or transient state. For example, unless otherwise specified, a reservoir may include one or more cavities formed by a structure and may include one or more ion exchange membranes, semipermeable membranes, porous membranes and / or gels if capable of retaining at least less temporarily an element or compound. Typically, a reservoir serves to retain a biologically active agent prior to the discharge of this agent by an electromotive force and / or current at the biological interface. A reservoir can also hold an electrolyte solution. As used herein and in the claims, the term "active agent" refers to a compound, molecule or treatment that produces a biological response from any host, animal, vertebrate or invertebrate, including for example fish, mammals, amphibians, reptiles, birds and humans. Examples of active agents include therapeutic agents, pharmaceutical agents, pharmaceuticals (e.g. a drug, a therapeutic compound, pharmaceutical salts and the like), non-pharmaceutical products (e.g., a cosmetic substance and the like), a vaccine, an immunological agent , an anesthetic or local or general painkiller, an antigen or a protein or peptide such as insulin, a chemotherapeutic agent, an antitumor agent. In some embodiments, the term "active agent" further refers to the active agent, as well as its pharmacologically active salts, pharmaceutically acceptable salts, prodrugs, metabolites, analogs and the like. In some additional embodiment, the active agent includes at least one therapeutic drug ionic, cationic, ionisable and / or neutral and / or acceptable, pharmaceutical salts thereof. In still other embodiments, the active agent may include one or more "cationic active agents" which have positive charges and / or which are capable of forming positive charges in aqueous media. For example, many biologically active agents have functional groups that can be easily converted to a positive ion or can be dissociated into a positively charged ion and a counterion in an aqueous medium. Other active agents can be polarized or polarizable, ie they exhibit a polarity in one portion relative to another portion. For example, an active agent having an amino group can typically take the form of an ammonium salt in the solid state and dissociate into a free ammonium ion (NH4 +) in an aqueous medium of appropriate pH. The term "active agent" can also refer to electrically neutral agents, molecules or compounds that can be delivered via an electroosmotic flow. Electrically neutral agents are typically transported by the flow of, for example, a solvent during electrophoresis. Therefore, the selection of suitable active agents is within the knowledge of a person skilled in the relevant art.

In some embodiments, one or more active agents may be selected from analgesics, anesthetics, anesthetic vaccines, antibiotics, adjuvants, immunological adjuvants, immunogens, tolerogens, allergens, Toll-like receptor agonists, Toll-like receptor antagonists, immuno-adjuvants, immuno -modulators, immuno-response agents, immuno-stimulators, specific immuno-stimulators, non-specific immuno-stimulators and immuno-suppressors or combinations thereof. Non-limiting examples of these active agents include lidocaine, articaine and others of the class -caine; morphine, hydromorphone, fentanyl, oxycodone, hydrocodone, buprenorphine, methadone and similar opioid agonists; sumatriptan succinate, zolmitriptan, naratriptan HC1, rizatriptan benzoate, almotriptan malate, frovatriptan succinate and other agonists of 5-hydroxytryptamine 1 receptor subtypes; resiquimod, imiquidmod and similar TLR 7 and 8 agonists and antagonists; domperidone, granisetron hydrochloride, ondansetron and antiemetic drugs of that type; zolpidem tartrate and similar sleep-inducing agents; L-dopa and other anti-Parkinson's medications; aripiprazole, olanzapine, quetiapine, risperidone, clozapine and ziprasidone, as well as other medications neuroleptics; drugs for diabetes such as exenatide; as well as peptides and proteins for the treatment of obesity and other conditions. Additional non-limiting examples of anesthetic or calming active agents include ambucaine, amethocaine, isobutyl p-aminobenzoate, amolanone, amoxecaine, amylocaine, eligcaine, azacaine, bencaine, benoxinate, benzocaine, N, N-dimethylalanylbenzocaine, N, N-dimethylglycylbenzocaine, glycylbenzocaine, beta-adrenoceptor antagonists, betoxicaine, bumecaine, bupivicaine, levobupivicaine, butacaine, butamben, butanilicaine, butetamine, butoxicaine, metabutoxicaine, carbizocaine, carticaine, centbucridine, cepacaine, ketacaine, chloroprocaine, cocaethylene, cocaine, pseudococaine, cyclomethicaine, dibucaine, dimetisoquina, dimethocaine, diperodon, dyclonine, ecognine, ecogonidine, ethyl aminobenzoate, etidocaine, euprocin, fenalcomin, fomocaine, heptacaine, hexacaine, hexocaine, hexylcaine, ketocaine, leucinocaine, levoxadrol,. lignocaine, lotucain, marcaine, mepivacaine, metacaine, methyl chloride, myrtacaine, naepain, octacaine, orthocaine, oxetazain, parentoxicain, pentacaine, phenazine, phenol, piperocaine, pyridocaine, polidocanol, polycaine, prilocaine, pramoxine, procaine (Novocaine ™), hydroxyprocaine , propanocaine, proparacaine, propipocaine, propoxicaine, pirocaine, quatacaine, rhinocaine, risocaine, rhodocaine, ropivacaine, salicylic alcohol, tetracaine, hydroxytetracaine, tolicaine, trapecaine, tricaine, trimecaine, tropacocaine, zolamine, a pharmaceutically acceptable salt thereof and mixtures thereof. As used herein and in the claims, the term "subject" generally refers to any host, animal, vertebrate or invertebrate and includes fish, mammals, amphibians, reptiles, birds and particularly humans. As used herein and in the claims, the term "agonist" refers to a compound that can be combined with a receptor (e.g., an opioid receptor, a Toll-like receptor, and the like) to produce a cellular response. An agonist can be a ligand that binds directly to the receptor. Alternatively, an agonist can be combined with a receptor indirectly by forming a complex with another molecule that binds directly to the receptor or otherwise result in the modification of a compound so that it is directly linked to the receptor. As used herein and in the claims, the term "antagonist" refers to a compound that can be combined with a receptor (e.g., an opioid receptor, a Toll-like receptor, and similar) to inhibit a cellular response. An antagonist can be a ligand that binds directly to the receptor. Alternatively, an antagonist can be combined with a receptor indirectly by forming a complex with another molecule that binds directly to the receptor or otherwise results in the modification of a compound so that it binds directly to the receptor. As used herein and in the claims, the term "effective amount" or "therapeutically effective amount" includes an amount that is effective in dosages and for periods of time necessary to achieve the desired result. The effective amount of a composition containing a pharmaceutical agent can vary according to factors such as the disease state, age, gender and weight of the subject. As used herein and in the claims, the term "analgesic" refers to an agent that decreases, alleviates, reduces, mitigates or extinguishes a neural sensation in an area of a subject's body. In some modalities, the neural sensation refers to the pain, in other aspects the neural sensation refers to the discomfort, itching, burning, irritation, tingling, "creeping", tension, temperature fluctuations (such as fever), inflammation, pain or other neural sensations. As used herein and in the claims, the term "anesthetic" refers to an agent that causes a reversible loss of sensation in an area of a subject's body. In some embodiments, the anesthetic is considered a "local anesthetic" because it produces a loss of sensation only in a particular area of a subject's body. As a person skilled in the relevant art would recognize, some agents can act as an analgesic and also as an anesthetic, depending on the circumstances and other variables that include but are not limited to the dosage, delivery method, medical condition or treatment and a genetic structure of an individual subject. Additionally, agents that are typically used for other purposes may possess local anesthetic or membrane stabilization properties under certain circumstances or under particular conditions. As used herein and in the claims, the term "immunogen" refers to any agent that produces an immune response. Examples of an immunogen include, but are not limited to, natural or synthetic peptides (including modified), proteins, lipids, oligonucleotides (AR, DNA, etc.), chemicals or other agents. As used herein and in the claims, the term "allergen" refers to any agent that produces an allergic response. Some examples of allergens include but are not limited to chemicals and plants, drugs (such as antibiotics, serums), foods (such as milk, wheat, eggs, etc.), bacteria, viruses, other parasites, inhalants (dust, pollen) , perfume, smoke) and / or physical agents (heat, light, friction, radiation). As used herein, an allergen can be an immunogen. As used herein and in the claims, the term "adjuvant" and any derivative thereof refers to an agent that modifies the effect of another agent while having some direct effect, if any, when administered alone. For example, an adjuvant can increase the potency or efficacy of a pharmaceutical product or an adjuvant can alter or affect an immune response. As used herein and in the claims, the term "opioid" generally refers to any agent that binds to and / or interacts with opioid receptors. Among the classes of Opioids Examples include endogenous opioid peptides, opium alkaloids (eg, morphine, codeine and the like), semi-synthetic opioids (eg, heroin, oxycodone and the like), synthetic opioids (e.g., buprenorphinemeperidine, fentanyl, morphinan, benzomorphan derivatives and the like), as well as opioids having structures unrelated to the opium alkaloids (e.g., pethidine, methadone and the like). As used herein and in the claims, the terms "carrier", "carrier", "pharmaceutical carrier", "pharmaceutical carrier", "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" can be used interchangeably and they refer to pharmaceutically acceptable solid or liquid, dilution or encapsulation, filler or transport agents, which are usually employed in the pharmaceutical industry to make pharmaceutical compositions. Examples of vehicles include any liquid, gel, balm, cream, solvent, diluent, fluid ointment base, vesicle, liposomes, nisomes, etasomes, transisersomes, virosomes, non-ionic surfactant vesicles, phospholipid surfactant vesicles, micelle and the like, which be suitable for use in contact with a subject. In some modalities, the pharmaceutical vehicle it may refer to a composition that includes and / or supplies a pharmacologically active agent, but which is generally considered to be pharmacologically inactive in another way. In some other embodiments, the pharmaceutical carrier may have some therapeutic effect when applied to a site such as a mucous membrane or the skin, by providing, for example, protection at the site of application of conditions such as injury, additional injury or exposure to The elements. Accordingly, in some embodiments, the pharmaceutical carrier can be used for protection without a pharmacological agent in the formulation. The titles provided in this document are for convenience only and do not interpret the scope or meaning of the modalities. Figures 1A and IB show an exemplary iontophoretic drug delivery system 6 for delivering one or more active agents to a subject. The system 6 includes an iontophoresis device 8 that includes active electrode and counter electrode assemblies 12, 14, respectively, and a power source 16. The active electrode and counter electrode assemblies 12, 14 can be electrically coupled to the power source 16 for delivering an active agent contained in the active electrode assembly 12, via the iontophoresis, to a biological interface 18 (for example, a portion of skin or mucous membrane). The iontophoresis device 8 may optionally include a biocompatible backing 19. In some embodiments, the biocompatible backing 19 coats the iontophoresis devices 8. In some other embodiments, the biocompatible backing 19 physically couples the iontophoresis device 8 to the biological interface 18 of the device. subject. In some embodiments, system 6 is configured to provide a transdermal delivery of one or more therapeutic active agents to a biological interface of a subject and induce analgesia or anesthesia in the subject for a limited period of time. As shown in Figures 2A and 2B, the active electrode assembly 12 may further comprise, from an inner side 20 to an outer side 22 of the active electrode assembly 12: an active electrode element 24, an electrolyte reservoir 26 which stores an electrolyte 28, an interior ion selective membrane 30, one or more interior active agent reservoirs 34, which store one or more active agents 36, an optional external ion selective membrane 38 that optionally captures additional active agents 40 and an agent additional, optional active 42 carried by an outer surface 44 of the external ion selective membrane 38. The assembly of Active electrode 12 may further comprise an optional exterior release coating 46. In some embodiments, one or more of the active agent reservoirs 34 may be loaded with a vehicle and / or pharmaceutical composition to transport, deliver, encapsulate and / or transport one or more than active agents 36, 40, 42. In some embodiments, at least one deposit of active agent 34 includes a pharmaceutical composition for inducing analgesia or anesthesia in the subject. The pharmaceutical composition for inducing analgesia or anesthesia in the subject may include at least one analgesic or anesthetic active agent in combination with at least one opioid antagonist. In some embodiments, the pharmaceutical composition includes at least one or more therapeutically effective active agents 36, 40, 42 selected from one or more opioid agonists. In some embodiments, the pharmaceutical composition includes at least one or more therapeutically effective active agents 36, 40, 42 selected from one or more opioid antagonists. In still some additional embodiments, the pharmaceutical composition includes a therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist. At least one opioid agonist can be selected from endogenous opioid peptides, alkaloids from opium, semi-synthetic opioids and fully synthetic opioids or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, at least one opioid agonist is selected from (5a, 7a, 8β- (-) - N -methyl- N- [7- (1-pyrrolidinyl) -1-oxaespiro (4, 5) dec-8 -yl] -benzene-acetamide (U69,593)), [D-Ala2, N-Me-Phe4, Gly5-ol] encephalitis (DAMGO), delta- ([D-Pen2, D-Pen5] -encephalin (DPDPE )), buprenorphine, code na, dextromoramide, dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, meperidine, methadone, morphine, nicomorphine, opium, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, and tilidine, or analogs or derivatives, or salts or pharmaceutically acceptable solvates thereof. At least one opioid antagonist can be selected from [(-) - (IR, 5R, 9R) -5, 9-diethyl-2- (3-furyl-methyl) -2'-hydroxy-6,7-benzomorphan] (MR2266), acid [allyl] 2-tir-alpha-amino-isobutyric (Aib) -Aib-Phe-Leu-OH (ICI-174864), 4- (3-hydroxyphenyl) -34-dimethyl-alpha-phenyl-1-piperidinpropanol (LY117413), 6p ~ naltrexol, 7-benzylidene-naltrexone (BNTX), b-funaltrexamine (b-FNA) , cyclazocine, ciclorfan, dezocine, diprenorphine, levorphanol, meptazinol, methiodide, methylnaltrexone, nalida, nalmefene, nalmexone, nalorphine, nalorphine dinicotinate, naloxonazine, naloxone, naltrexone, naltriben (NTB), naltrindole (NTI), isothiocyanate naltrindole (NTII), N-cyclopropylmethyl-4, 14-dimethoxy-morphinan-6-one (cyprodime), nor-binaltorphimine (nor-BNI), oxllorfano, nalbuphine and trans-3, 4-dimethyl-4-fenilpiperidas or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, at least one opioid antagonist is selected from hydromorphone or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof; and at least one opioid antagonist is selected from naloxone, naltrexone, nalmefene, naloxonazine, NTI, nor-BNI, LY25506, LY9935, LY255582 and LY117413, or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, at least one opioid antagonist is selected from hydromorphone or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof; and at least one opioid antagonist is selected from naloxone, naltrexone, 6β-naltrexol, nalmefene and naloxonazine or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, at least one opioid antagonist is selected from palladium, Palladone SRMR, Dilaudid ™, and hydromorphone hydrochloride; and at least one opioid antagonist is selected from Narcan ™, Trexan ™, Revex, Nubian, nalaxone hydrochloride, naltrexone hydrochloride, nalmefene hydrochloride and nulbufine hydrochloride. In some embodiments, at least one opioid agonist and at least one opioid antagonist are present in effective, anti-hyperalgesic, synergistic amounts. The pharmaceutical composition may further comprise at least one active agent selected from vaccines, antibiotics, adjuvants, immunological adjuvants, immunogens, tolerogens, allergens, agonists Toll-like receptors and receptor antagonists Toll, immuno-adjuvants, immuno-modulators, agents type of immuno-response, immuno-stimulators, specific immuno-stimulators, non-specific immuno-stimulators and immunosuppressants or combinations thereof. In some embodiments, the pharmaceutical composition can include a therapeutically effective amount of at least one opioid agonist, at least one opioid antagonist and at least one active agent selected from an anti-histamine drug, a vasoconstrictor drug (e.g. epinephrine, adrenaline, norepinephrine and the like), a steroid and the like. The pharmaceutical composition may be useful for the systemic treatment of at least one condition associated with pain, neuropathic pain, acute pain, chronic pain or cancer pain. In some modalities, at least the condition associated with pain, neuropathic pain, acute pain, chronic pain or pain from cancer includes cancer; chemotherapy; alcoholism; amputation; a back, leg or hip problem; diabetes; a problem of facial nerves; an HIV infection or AIDS; multiple sclerosis; spinal surgery; narcotic / respiratory depression induced by opiates; or detoxification of opioid dependence. The onset of acute pain caused, for example, by an injury to a tissue typically results from the stimulation of special nerve endings called nociceptors. Nociceptors respond to a variety of stimuli that include burns, cuts, infection, chemical changes, pressure and many other sensations that are interpreted as pain by a biological subject. By eliminating the cause of this nociceptive pain and allowing the healing process to begin, the sensitivity and pain associated with the injury or other stimuli typically dissipate. Although a neuropathic pain is certainly real, the cause can be difficult to determine. Neuropathic pain is often described as throbbing, lancinating, burning or burning. How I know used in this document and in the appended claims, this pain is termed "neuropathic pain". Conditions with which neuropathic pain can be commonly associated include, but are not limited to, herpes (herpes zoster virus infection, post-herpetic pain); Cancer; chemotherapy; alcoholism; amputation (for example, phantom limb syndrome); problems in the back, legs and hips (sciatica); diabetes; problems of facial nerves (trigeminal neuralgia); HIV infection or AIDS; multiple sclerosis; and spinal surgery. Chronic pain can also occur without any known injury or illness. For example, subjects may experience pain without an obvious injury or other stimulus. In some other cases, subjects may experience chronic pain that persists for prolonged periods that include months, years or even decades. This pain results predominantly from damage within the peripheral or central nervous system. Although the cause of neuropathic pain may be unknown or uncontrollable, in a disclosed modality, a treatment may include chronic continuous administration of drugs or other active agents that improve pain, such as analgesic active agents, anesthetic active agents and / or soothing These drugs or other active agents can be passively administered by means of applying one or more devices 8 to a biological interface 18 (e.g., skin or mucous membrane) in or near areas where a subject is experiencing neuropathic pain. Once the device 8 is in contact with the biological interface 18, one or more of the agents are available from the device 8 on or within the biological interface 18 to exert its effect in pain relief. Alternatively, one or more agents can be advantageously actively administered by a device 8 through a biological interface 18 and tissue within the systemic circulation. Accordingly, the agent can exert its therapeutic effect locally and more broadly. In one embodiment, for example, one or more active agents are administered through an area portion of a biological interface from which they can enter the bloodstream and can be transported systemically within a capillary bed or other vasculature of an area that experience pain (for example, neuropathic pain and the like). In certain embodiments, the device for the active administration of an anesthetic or calming agent is an iontophoretic device, as described in detail herein. As used in this document and in the appended claims, the "systemic circulation" is typically refers to the movement of blood through the portion of a cardiovascular system and / or circulatory system that transports oxygenated blood from the heart to the body and oxygen depleted blood from the body back to the heart. Within this portion of the cardiovascular system, blood can flow through blood vessels that include, but are not necessarily limited to, arteries, arterioles, capillaries, venules, and veins. The systemic circulation, as used in this document and in the claims, may also refer to the movement of fluids through a lymphatic system, which collects tissue lymph and returns it to the cardiovascular circulatory system. Lymph typically originates from blood plasma that escapes from the cardiovascular system into spaces within the tissue. "Systemic delivery," as used herein and in the claims, refers to the movement of compounds, such as active agents, from one location to another via the systemic circulation. With reference to Figures 2A and 2B, the active electrode assembly 12 of the iontophoretic delivery device 8 may further comprise an optional inner seal coating (not shown) between two layers of the active electrode assembly 12, eg, between the membrane selective ion interior 30 and the inner active agent reservoir 34. The inner sealing liner, if present, would be removed prior to the application of the iontophoretic device to the biological surface 18. Each of the above elements or structures will be described in detail below. In some embodiments, system 6 takes the form of an autonomous iontophoretic drug delivery system. The system 6 includes at least one active agent reservoir 34, an active electrode assembly 12 that includes at least one active electrode element 24 and a power source 16. At least one active agent reservoir 34 includes a composition Pharmaceutical to induce analgesia or anesthesia in the subject. The pharmaceutical composition for inducing analgesia or anesthesia in the subject may include at least one analgesic or anesthetic active agent in combination with at least one opioid antagonist. The active electrode element 24 is electrically coupled to a first pole 16a of the power source 16 and is placed in the active electrode assembly 12 to apply an electromotive force to transport the active agent 36, 40, 42 via other various components of the active electrode assembly 12. Under ordinary conditions of use, the magnitude of the Applied electromotive force is generally that required to deliver one or more of the active agents according to an effective therapeutic dosage protocol. In some embodiments, the magnitude is selected such that it covers or exceeds the operational electrochemical potential of ordinary use of the iontophoresis delivery device 8. At least one active electrode element 24 is operable to provide an electromotive force to drive the composition Pharmaceutical (comprising at least one analgesic or anesthetic active agent in combination with at least one opioid antagonist) to induce analgesia or anesthesia in the subject of at least one deposit of active agent 34, at the biological interface 18 of the subject. The active electrode element 24 can take a variety of forms. In one embodiment, the active electrode element 24 can advantageously take the form of a carbon-based active electrode element. This may comprise, for example, multiple layers for example a polymer matrix comprising carbon and a conductive sheet comprising carbon fiber or carbon fiber paper, such as that described in commonly pending Japanese Patent Application 2004/317317, presented on October 29, 2004. Carbon-based electrodes are inert electrodes since they do not undergo or 7 they participate by themselves in electrochemical reactions. In this way, an inert electrode distributes the current through the oxidation or reduction of a chemical species capable of accepting or donating an electron to the potential applied to the system (for example, generating ions either by reduction or oxidation of water). Additional examples of inert electrodes include stainless steel, gold, platinum, capacitive carbon or graphite. Alternatively, an active electrode of sacrificial conductive material, such as a chemical compound or alloy, can also be used. A sacrificial electrode does not cause water electrolysis, but it would be oxidized or reduced by itself. Typically, a metal / metal salt can be used for an anode. In this case, the metal would oxidize the metal ions, which would then precipitate as an insoluble salt. An example of this anode includes an Ag / AgCl electrode. The reverse reaction takes place at the cathode in which the metal ion is reduced and the corresponding anion is released from the surface of the electrode. The electrolyte reservoir 26 can take a variety of forms including any structure capable of retaining the electrolyte 28 and in some embodiments can still be the electrolyte 28 itself, for example, where the electrolyte 28 is in a gel, semisolid or solid For example, the electrolyte reservoir 26 may take the form of a sachet or other receptacle, a membrane with pores, cavities or interstices, particularly where the electrolyte 28 is a liquid. In one embodiment, the electrolyte 28 comprises ionizable or ionizable components in an aqueous medium, which can act to conduct a current toward or away from the active electrode element. Suitable electrolytes include, for example, aqueous solutions of salts. Preferably, electrolyte 28 includes salts of physiological ions, such as sodium, potassium, chloride and phosphate. In some embodiments, one or more of the electrolyte reservoirs 24 includes an electrolyte 28 comprising at least one biologically compatible antioxidant selected from ascorbate, fumarate, lactate and malate or salts thereof. Once an electric potential is applied, when an inert electrode element is in use, the water is electrolyzed in the assemblies of both active electrode and counter electrode. In certain embodiments, such as when the active electrode assembly is an anode, the water is oxidized. As a result, oxygen is removed from the water while protons (H +) are produced. In one embodiment, the electrolyte 28 may further comprise an antioxidant. In some modalities, the antioxidant is select from antioxidants that have a lower potential than that of, for example, water. In these modalities, the selected antioxidant is consumed before hydrolysis of the water occurs. In some additional embodiments, an oxidized form of the antioxidant is used at the cathode and a reduced form of the antioxidant is used at the anode. Examples of biologically compatible antioxidants include, but are not limited to, ascorbic acid (vitamin C), tocopherol (vitamin E) or sodium citrate. As noted above, the electrolyte 28 may take the form of an aqueous solution housed within a reservoir 26 or in the form of a dispersion in a hydrogel or hydrophilic polymer capable of retaining a substantial amount of water. For example, a suitable electrolyte may take the form of a 0.5 M disodium fumarate solution: 0.5 M polyacrylic acid: 0.15 M antioxidant. The interior ion selective membrane 30 is generally placed to separate the electrolyte 28 and the active agent reservoir inside 34, if this membrane is included inside the device. The inner ion selective membrane 30 can take the form of a charge selective membrane. For example, when the active agent 36, 40, 42 comprises a cationic active agent, the The interior ion selective membrane 30 can take the form of an anion exchange membrane, selective to substantially allow the passage of anions and substantially block the cations. The indoor ion selective membrane 30 can advantageously prevent the transfer of undesirable elements or compounds between the electrolyte 28 and the inner active agent reservoir 34. For example, the indoor ion selective membrane 30 can prevent or inhibit the transfer of sodium ions. (Na +) of the electrolyte 28, increased thereby the transfer speed and / or biological compatibility of the iontophoresis device 8. The inner active agent reservoir 34 is generally placed between the inner ion selective membrane 30 and the ion selective membrane external 38. The inner active agent reservoir 34 may take a variety of forms including any structure capable of temporarily retaining the active agent 36. For example, the inner active agent reservoir 34 may take the form of a sachet or other receptacle , a membrane with pores, cavities or interstices, particularly where the active agent 36 is a liquid. The inner active agent reservoir 34 may further comprise a gel matrix. Optionally, an ion selective membrane external 38 is generally positioned opposite through the active electrode assembly 12 of the active electrode element 24. The outer membrane 38, as in the embodiment illustrated in Figures 2A and 2B, may take the form of an ion exchange membrane having pores 48 (only one convened in Figures 2A and 2B for the purpose of illustration clarity) of the selective membrane of ions 38 include a material or ion exchange groups 50 (only three summoned in Figures 2A and 2B for the purpose of illustration clarity). Under the influence of an electromotive force or current, the ion exchange material or groups allow the passage of selectively substantial ions of the same polarity as the active agent 36, 40, 42 while substantially blocking the polarity ions opposite. In this way, the external ion exchange membrane 38 is charge selective. Where the active agent 36, 40, 42 is a cation (e.g., lidocaine), the outer ion selective membrane 38 can take the form of a cation exchange membrane, thereby allowing the passage of the cationic active agent while blocks the reflux of the anions present in the biological interface, such as the skin. The external ion selective membrane 38 can optionally capture the active agent 40. Without being limited by a theory, ion exchange groups or material 50 temporarily retain ions of the same polarity as the polarity of the active agent in the absence of an electromotive force or current and substantially release those ions when they are replaced by substitution ions of polarity or charge similar under the influence of an electromotive force or current. Alternatively, the outer ion selective membrane 38 may take the form of a semipermeable or microporous membrane which is selective for size. In some embodiments, this semi-permeable membrane can advantageously capture the active agent 40, for example by employing a removably releasable outer release coating to retain the active agent 40 until the outer release coating 72 is removed prior to use. The outer ion selective membrane 38 may optionally be pre-charged with the additional active agent 40, such as ionized or ionisable drugs or therapeutic agents and / or polarized or polarizable drugs or therapeutic agents. Where the outer ion selective membrane 38 is an ion exchange membrane, a substantial amount of active agent 40 can be bound to the ion exchange groups 50 in the pores, cavities or interstices 48 of the external ion selective membrane 38. The active agent 42 that fails to bind to the ion exchange groups of the material 50 can adhere to the outer surface 44 of the external ion selective membrane 38 as the additional active agent 42. Alternatively or additionally, the additional active agent 42 can be positively deposited in and / or adhered to at least a portion of the outer surface 44 of the external ion selective membrane 38, for example, by means of spraying, waterlogging, coating, electrostatic way, vapor deposition and / or otherwise. In some embodiments, the additional active agent 42 may sufficiently cover the outer surface 44 and / or may be of sufficient thickness to form a distinct layer 52. In other embodiments, the additional active agent 42 may not be sufficient with respect to volume, thickness or coverage to constitute a layer in a conventional sense of this term. The active agent 42 can be deposited in a variety of highly concentrated forms such as, for example, a solid form, an almost saturated solution form or a gel form. If it is in a solid form, a source of hydration can be provided, either integrated into the active electrode assembly 12 or applied from the outer side of it just before use. In some embodiments, the active agent 36, the additional active agent 40 and / or the additional active agent 42 may be identical or similar compositions or elements. In other embodiments, the active agent 36, the additional active agent 40 and / or the additional active agent 42 may be compositions or elements different from each other. In this way, a first type of active agent can be stored in the inner active agent reservoir 34, while a second type of active agent can be captured in the external ion selective membrane 38. In this embodiment, either the first type or the second type of active agent can be deposited on the outer surface 44 of the external ion selective membrane 38 as the additional active agent 42. Alternatively, a mixture of the first type and the second type of active agent can be deposited in the outer surface 44 of the external ion selective membrane 38 as the additional active agent 42. As a further alternative, a third type of active agent composition or element can be deposited on the outer surface 44 of the external ion selective membrane 38 as the additional active agent 42. In another embodiment, a first type of active agent can be stored in the active agent reservoir interior 34 as the active agent 36 and can be captured in the outer ion selective membrane 38 as the additional active agent 40, while a second type of active agent can be deposited on the outer surface 44 of the external ion selective membrane 38 as the additional active agent 42. Typically, in embodiments where one or more other active agents are employed, the active agents 36, 40, 42 will all be of common polarity to prevent active agents 36, 40, 42 from competing with each other. Other combinations are possible. The outer release coating can generally be placed above or covering the additional active agent 42 carried by the outer surface 44 of the external ion selective membrane 38. The outer release coating can protect the additional active agent 42 and / or the external ion selective membrane 38 during storage, before the application of an electromotive force or current. The outer release coating may be a selectively releasable coating made of impervious material, such as release liners commonly associated with pressure sensitive adhesives. A coupling means with the interface (not shown) can be used between the electrode assembly and the biological interface 18. The coupling means with the interface may take the form of, for example, an adhesive and / or a gel. The gel can take the form of a moisturizing gel. The selection of suitable bioadhesive gels is within the knowledge of a person skilled in the relevant art. In the embodiment illustrated in Figures 2A and 2B, the counter electrode assembly 14 comprises, from an inner side 64 to an outer side 66 of the counter electrode assembly 14: a counter electrode element 68, an electrolyte reservoir 70 that stores an electrolyte 72. , an indoor ion selective membrane 74, an optional buffer reservoir 76 that stores a cushioning material 78, an optional external ion selective membrane 80, and an optional exterior release coating (not shown). The counter electrode element 68 is electrically coupled to a second pole 16b of the power source 16, the second pole 16b has a polarity opposite the first pole 16a. In one embodiment, the counter electrode element 68 is an inert electrode. For example, the counter electrode element 68 may take the form of a carbon-based electrode element described above. The electrolyte reservoir 70 can take a a variety of shapes including any structure capable of retaining the electrolyte 72 and in some embodiments may even be the electrolyte 72 itself, for example, where the electrolyte 72 is in a gel, semi-solid or solid form. For example, the electrolyte reservoir 70 can take the form of a sachet or other receptacle or a membrane with pores, cavities or interstices, particularly where the electrolyte 72 is a liquid. The electrolyte 72 is generally positioned between the counter electrode element 68 and the external ion selective membrane 80, near the counter electrode element 68. As described above, the electrolyte 72 can provide ions or can donate charges to prevent or inhibit the formation of bubbles of gas (eg, hydrogen or oxygen depending on the polarity of the electrode) in the counter electrode element 68 and can prevent or inhibit the formation of acids or bases or neutralize them, which can improve the efficiency and / or reduce the irritation potential of the biological interface 18. The inner ion selective membrane 74 is placed between and / or to separate the electrolyte 72 from the absorbing material 78. The inner ion selective membrane 74 may take the form of a selective membrane of charges , such as the ion exchange membrane illustrated that substantially allows the passage of ions of a first polarity or charge while substantially blocking the passage of ions or charge of a second opposite polarity. The indoor ion selective membrane 74 will typically allow the passage of polarity ions or charge opposite to those passed through the outer ion selective membrane 80 while substantially blocking the polarity or similar charge ions. Alternatively, the inner ion selective membrane 74 may take the form of a semipermeable or microporous membrane that is selective on the basis of size. The indoor ion selective membrane 74 can prevent the transfer of undesirable elements or compounds into the buffer material 78. For example, the indoor ion selective membrane 74 can prevent or inhibit the transfer of hydroxy (0H-) or chloride (C1) ions. -) of the electrolyte 72 into the interior of the damper material 78. The optional damper reservoir 76 is generally positioned between the electrolyte reservoir and the external ion selective membrane 80. The damper reservoir 76 can take a variety of forms capable of temporarily holding the damper material 78. For example, the damper reservoir 76 may take the form of a cavity, a porous membrane or a gel. The material buffer 78 can supply ions for transfer through the outer ion selective membrane 42 to the biological interface 18. Consequently, the buffer material 78 can comprise, for example, a salt (eg, NaCl). The outer ion selective membrane 80 of the counter electrode assembly 14 can take a variety of forms. For example, the external ion selective membrane 80 may take the form of a charge-selective ion exchange membrane. Typically, the outer ion selective membrane 80 of the counter electrode assembly 14 is selective for ions with a charge or polarity opposite to that of the external ion selective membrane 38 of the active electrode assembly 12. Therefore, the selective membrane of External ions 80 is an anion exchange membrane, which substantially allows the passage of anions and blocks the cations, thereby preventing the reflux of the cations from the biological interface. Examples of suitable ion exchange membranes include the membranes previously described. Alternatively, the outer ion selective membrane 80 can take the form of a semipermeable membrane that allows the passage and / or substantially blocks ions based on the size or molecular weight of the ion. The outer release coating (not shown) can be placed generally above or covering an outer surface 84 of the outer ion selective membrane 80. The outer release coating can protect the outer ion selective membrane 80 during storage, before the application of an electromotive force or current. The exterior release coating may be a selectively peelable coating made of impervious material, such as the release liner commonly associated with pressure sensitive adhesives. In some embodiments, the outer release coating may coincide with the outer release coating (not shown) of the active electrode assembly 12. The iontophoresis device 8 may further comprise an inert molding material 86 adjacent to the exposed sides of the other various structures forming the active electrode and counter electrode assemblies 12, 14. The molding material 86 can advantageously provide environmental protection to the various structures of the active electrode and counter electrode assemblies 12, 14. The wrapping of the active electrode assemblies and counter electrode 12, 14 is a material of housing 90. As best seen in Figure 2B, the active electrode and counter electrode assemblies 12, 14 are placed in the biological interface 18. The placement in the biological interface 18 can close the circuit, allowing an electromotive force to be applied and / or a current flows from a pole 16a of the power supply 16 to the other pole 16b, via the active electrode assembly, the biological interface 18 and the counter electrode assembly 14. In use, the external ion selective membrane of the active electrode 38 can be placed directly in contact with the biological interface 18. Alternatively, a coupling means can be employed with the interface (not shown) between the outer ion selective membrane of the active electrode 22 and the biological interface 18. The means of coupling with the interface may take the form of, for example, an adhesive and / or a gel. The gel can take the form of, for example, a moisturizing gel or a hydrogel. If used, the coupling means with the interface must be permeable by the active agent 36, 40, 42. In some embodiments, the power source 16 is selected to provide sufficient voltage, current and / or duration to ensure the supply of one or more of the active agents 36, 40, 42 of the reservoir 34 and through a biological interface (for example, a membrane) to grant the desired physiological effect. The power supply 16 can take the form of one or more chemical battery cells, super- or ultra-capacitors, fuel cells, secondary cells, thin-film secondary cells, button-shaped cells, lithium ion cells, zinc-air cells, nickel-metal hydride cells and the like. The power supply 16 can provide, for example, a voltage of 12.8 V of direct current, with a tolerance of 0.8 V of direct current and a current of 0.3 mA. The power supply 16 can be selectively electrically coupled to the active electrode and counter electrode assemblies 12, 14 via a control circuit, for example, via carbon fiber tapes. The iontophoresis device 8 may include discrete and / or integrated circuit elements for controlling the voltage, current and / or power supplied to the electrode assemblies 12, 14. For example, the iontophoresis device 8 may include a diode to provide a constant current to the electrode elements 24, 68. As suggested above, one or more of the active agents 36, 40, 42 can take the form of one or more ionic, cationic, ionisable and / or neutral drugs or other therapeutic agents . Consequently, the poles or terminals of the power supply 16 and the selectivity of the outer ion selective membranes 38, 80 and the inner ion selective membranes 30, 74 is selected accordingly. During iontophoresis, the electromotive force through the electrode assemblies, as described, leads to an emigration of charged active agent molecules, as well as ions and other charged components, through the biological interface into the biological tissue . This migration can lead to an accumulation of active agents, ions and / or other charged components within the biological tissue beyond the interface. During iontophoresis, in addition to the migration of charged molecules in response to repulsion forces, there is also an electroosmotic flow of solvent (eg, water) through the electrodes and the biological interface into the tissue. In certain embodiments, the electroosmotic flow of solvent improves the migration of both charged and uncharged molecules. Improved migration via the electroosmotic flow of solvent can occur particularly with an increased size of the molecule. In certain embodiments, the active agent may be a molecule of higher molecular weight. In certain aspects, the molecule can be a polar polyelectrolyte.

In other aspects, the molecule can be lipophilic. In certain embodiments, these molecules may be charged, may have a low net charge, or may not be charged under the conditions within the active electrode. In certain aspects, these active agents can migrate poorly under the iontophoretic repulsive forces, in contrast to the migration of small, highly charged active agents under the influence of these forces. These active agents of higher molecular weight can thus be transported through the biological interface into the underlying tissues principally via an electroosmotic flow of solvent. In certain embodiments, high molecular weight polyelectrolyte active agents may be proteins, polypeptides or nucleic acids. In other embodiments, the active agent can be mixed with another agent to form a complex capable of being transported through the biological interface via one of the motor methods described above. In some embodiments, the transdermal drug delivery system 6 includes an iontophoretic drug delivery device 8 for providing the transdermal delivery of one or more therapeutic active agents 36, 40, 42 to a biological interface 18. The delivery device 8 includes the assembly of active electrode 12 including at least one active agent reservoir and at least one active electrode element that is operable to provide an electromotive force to drive an active agent from at least one active agent reservoir. The delivery device 8 may include a counter electrode assembly 14 that includes at least one counter electrode element 68 and a power supply 16 electrically coupled to at least the active electrode and counter electrode elements 20, 68. In some embodiments, the Iontophoretic drug delivery 8 may further include one or more active agents 36, 40, 42 loaded in at least one active agent reservoir 34. As shown in Figure 2C, the delivery device 8 may further include a substrate 10 which includes a plurality of microneedles 17 in fluid communication with the active electrode assembly 12 and placed between the active electrode assembly 12 and the biological interface 18. The substrate 10 can be placed between the active electrode assembly 12 and the biological interface 18. In some embodiments, in at least one active electrode element 20 is operable to provide an electromotive force for imp ulsar an active agent 36, 40, 42 of at least one deposit of active agent 34, through the plurality of microneedles 17 and to the interface biological 18. As shown in Figures 3A and 3B, the substrate 10 includes a first side 102 and a second side 104 opposite the first side 102. The first side 102 of the substrate 10 includes a plurality of microneedles 17 projecting outwardly from the first side 102. The microneedles 17 can be provided individually or can be formed as part of one or more arrangements. In some embodiments, the microneedles 17 are formed integrally from the substrate 10. The microneedles 17 can take a solid and permeable form, a solid and semipermeable form and / or a solid, impermeable form. In some other embodiments, solid impermeable microneedles may further comprise notches along their outer surfaces to assist in the transdermal delivery of one or more active agents. In some other embodiments, the microneedles 17 may take the form of hollow microneedles. In some embodiments, the hollow microneedles may be filled with ion exchange material, ion selective materials, permeable materials, semipermeable materials, solid materials and the like. The microneedles 17 are used, for example, to deliver a variety of pharmacological compositions, molecules, compounds, active agents and the like to a living body via a biological interface, such as the skin or a mucous membrane. In certain embodiments, pharmaceutical compositions, molecules, compounds, active agents and the like can be delivered into or through the biological interface. For example, in the delivery of pharmaceutical compositions, molecules, compounds, active agents and the like via the skin, the length of the microagu at 17, either individually or in arrays 100a, 100b, and / or insertion depth is they can be used to control either the administration of pharmaceutical compositions, molecules, compounds, active agents and the like only in the epidermis, through the epidermis to the dermis or subcutaneously. In certain embodiments, the microneedle 17 may be useful for delivering high molecular weight active agents, such as those comprising proteins, peptides and / or nucleic acids and corresponding compositions thereof. In certain embodiments, for example, wherein the fluid is an ionic solution, the microneedles 17 can provide electrical continuity between the power supply 16 and the tips of the microneedles 17. In some embodiments, the microneedles 17, either individually or in arrays 100a, 100b, can be used to distribute, supply and / or take fluid samples through hollow openings, through the materials Permeable or semipermeable solids or through external notches. The microneedles 17 may also be used to distribute, deliver and / or take samples of pharmaceutical compositions, molecules, compounds, active agents and the like by means of iontophoretic methods, as disclosed herein. Accordingly, in certain embodiments, for example, a plurality of microneedles 17 in an array 100a, 100b may advantageously be formed in a contact surface with the external biological interface of a transdermal drug delivery system 6. In some embodiments, the Pharmaceutical compositions, molecules, compounds, active agents and the like distributed and taken as samples by this system 6 can comprise, for example, active agents of high molecular weight, such as proteins, peptides and / or nucleic acids. In some embodiments, a plurality of microneedles 17 may take the form of an array of microneedles 100a, 100b. The array of microneedles 100a, 100b may be arranged in a variety of configurations and patterns including, for example, a rectangle, a square, a circle (as shown in Figure 3A), a triangle, a polygon, regular shapes or irregular and similar. The microneedles 17 and the Microneedle arrays 100a, 100b can be manufactured from a variety of materials including ceramic, elastomers, epoxy photoresist, glass, glass polymers, glass / polymer materials, metals (e.g., chromium, cobalt, gold, molybdenum, nickel, stainless steel, titanium, tungsten iron and the like), molded plastics, polymers, biodegradable polymers, non-biodegradable polymers, organic polymers, inorganic polymers, silicon, silicon dioxide, polysilicon, silicon rubbers, organic polymers based on silicon , superconducting materials (e.g., superconducting wafers and the like) and the like, as well as combinations, compounds and / or alloys thereof. The techniques for manufacturing the microneedles 17 are well known in the art and include, for example, electrodeposition, electrodeposition on polymeric drilled with laser beam, laser cutting and electropolishing, microtoring with laser beam, microtoring of surfaces, smooth lithography, X-ray lithography, LIGA techniques (eg X-ray lithography, galvanizing and molding), injection molding, conventional silicon-based manufacturing methods (eg inductively coupled plasma etching, wet etching, isotropic and anisotropic etching) , silicon isotropic engraving, anisotropic silicon etching, Gais anisotropic etching, deep ion etching, silicon isotropic etching, silicon bulk microgravure and the like), metal oxide semiconductor / complementary symmetry technology (CMOS), deep-beam exposure techniques X and similar. See, for example, US Pat. Nos. 6,256,533; 6,312,612; 6,334,856; 6,379,324; 6,451,240; 6,471,903; 6,503,231; 6,511,463; 6,533,949; 6,565,532; 6,603,987; 6,611,707; 6,663,820; 6,767,341; 6,790,372; 6,815,360; 6,881,203; 6,908,453; and 6,939,311. Some or all of the teachings in this document can be applied to microneedle devices, their manufacture and their use in iontophoretic applications. In some techniques, the physical characteristics of the microneedles 17 depend on, for example, anodization conditions (e.g., current density, etching time, HF concentration, temperature, deviation settings and the like) as well as the properties of the substrate (eg, doping density, doping orientation and the like). The microneedles 17 can be adjusted with respect to size and shaped to penetrate the outer layers of the skin to increase their permeability and transdermal transport of pharmaceutical compositions, molecules, compounds, active agents and the like. In some embodiments, the microneedles 17 are dimensioned with respect to size and are formed with an appropriate geometry and sufficient strength to be inserted into a biological interface (e.g., the skin or mucous membrane in a subject and the like) and increase thereby a trans-interface transport (eg, transdermal) of pharmaceutical compositions, molecules, compounds, active agents and the like. Figure 4 shows an exemplary method 400 for the systemic treatment of at least one condition associated with pain, neuropathic pain, acute pain, chronic pain or pain from cancer. In 402, the method includes contacting a location at a biological interface 18 with an iontophoretic drug delivery device 8 that includes an active electrode assembly 12 having at least one active agent reservoir 34. At least one reservoir of active agent 34 includes a pharmaceutical composition that includes at least a therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist. In some embodiments, at least one opioid agonist is selected from endogenous opioid peptides, opioid alkaloids, semisynthetic opioids, and opioids. fully synthetic or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, at least one opioid agonist is selected from (5a, 7a, 8β- (-) - N -methyl- N- [7- (1-pyrrolidinyl) -1-oxaespiro (4,5) dec-8 -yl] -benzene-acetamide (U69,593)), [D-Ala2, N-Me-Phe4, Gly5-ol] encephalitis (DAMGO), delta- ([D-Pen2, D-Pen5] -encephalin (DPDPE)], buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, meperidine, methadone, morphine, nicomorphine, opium, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene and tilidine, or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, at least one opioid antagonist is selected from [(-) - (IR, 5R, 9R) -5,9-diethyl-2- (3-furyl-methyl) -2'-hydroxy-6,7 -benzomorphan] (MR2266), [allyl] 2-tir-alpha-amino-isobutyric acid (Aib) -Aib-Phe-Leu-OH (ICI-174864), 4- (3-hydroxyphenyl) -34-dimethyl-alpha -phenyl-l-piperidinepropanol (LY117413), dß-Naltrexol, 7-Benzylidene naltrexone (BNTX), b-funaltrexamine (b-FNA), cyclazocine, cyclorfan, dezocin, diprenorphine, levorphanol, meptazinol, methiodide, methylnaltrexone, nalida, nalmefene, nalmexone, nalorphin, nalorphin dinicotinate, naloxonazine, naloxone, naltrexone, naltriben (TB), naltrindol (NTI), naltrindol isothiocyanate (NTII), N- cyclopropylmethyl-4,14-dimethoxy-morphinan-6-one (cyprodim), nor-binaltorphimine (nor-BNI), oxollorphane, nalbuphine and trans-3,4-dimethyl-4-phenylpiperides or analogs or derivatives, or salts or solvates pharmaceutically acceptable thereof. In some embodiments, at least one opioid antagonist is selected from hydromorphone or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof; and at least one opioid antagonist is selected from naloxone, naltrexone, nalmefene, naloxonazine, NTI, nor-BNI, LY25506, LY9935, LY255582 and LY117413, or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, at least one opioid antagonist is selected from hydromorphone or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof; and at least one opioid antagonist is selected from naloxone, naltrexone, 6β-naltrexol, nalmefene and naloxonazine or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, at least one opioid antagonist is selected from palladium, Palladone SRMR, Dilaudid ™, and hydromorphone hydrochloride; and at least one opioid antagonist is selected from Narcan ™, Trexan ™, Revex®, Nubian ™, hydrochloride, nalaxone, hydrochloride naltrexone, nalmefene hydrochloride and nulbufine hydrochloride. In still some additional embodiments, at least one opioid agonist and at least one opioid antagonist are present in effective, anti-hyperalgesic, synergistic amounts. In some modalities, at least one condition associated with pain, neuropathic pain, acute pain, chronic pain or pain from cancer includes: cancer; chemotherapy; alcoholism; amputation (for example, phantom limb syndrome); a back, leg or hip problem (sciatica); diabetes; a problem of facial nerves (trigeminal neuralgia); an HIV infection or AIDS; multiple sclerosis; spinal surgery; narcotic / respiratory depression induced by opiates; or detoxification of opioid dependence. In some embodiments, the pharmaceutical composition further comprises at least one active agent selected from vaccines, antibiotics, adjuvants, immunological adjuvants, immunogens, tolerogens, allergens, Toll-like receptor agonists and Toll-like receptor antagonists, immuno-adjuvants, immune modulators, immuno-response agents, immuno-stimulators, specific immuno-stimulators, non-specific immuno-stimulators and immuno-suppressors or combinations thereof. In 404, the method further includes applying a sufficient amount of current to the active electrode assembly 12 for transdermally administering a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist. . In some embodiments, the application of a sufficient amount of current to the active electrode assembly 12 comprises providing a voltage and current sufficient for a time interval to the active electrode assembly 12 to deliver a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist, from at least one deposit of active agent 34 to the location at the biological interface 18. In some embodiments, the application of a sufficient amount of current comprises providing a sufficient voltage and current for a period of time to the active electrode assembly 12 to substantially achieve sustained delivery or controlled delivery of the pharmaceutical composition comprising the therapeutically effective amount of at least one agonist opioid and at least one opioid antagonist, over an extended period of time, to produce an anesthetic, analgesic or anti-hyperalgesic therapy in a subject. Figure 5 shows an exemplary method 500 for inducing anesthesia, analgesia or anti-hyperalgesia in a subject. In 502, the method includes placing an active electrode and a counter electrode of an iontophoretic delivery device at a biological interface of the subject. In some embodiments, the iontophoretic drug delivery device 8 is operable to iontophoretically deliver a pharmaceutical composition comprising an effective amount of at least one opioid agonist and at least one opioid antagonist. In 504, the method further includes iontophoretically delivering a synergistic anesthetic-inducing, analgesic-inducing or anti-hyperalgesic inducing amount of a pharmaceutical composition comprising at least one opioid agonist and at least one opioid antagonist. Figure 6 shows an exemplary method 600 for treating opioid dependence and / or for producing a substantially free opioid state in a subject in need thereof. In 602, the method includes contacting a location at a biological interface 18 of the subject with an iontophoretic drug delivery 8 that is operable to iontophorically deliver a pharmaceutical composition comprising a therapeutically effective amount of at least one opioid antagonist. In 604, the method further includes administering via transdermal route a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid antagonist. In 606, the method further includes providing a voltage and current sufficient to deliver the therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid antagonist to the location at the biological interface 18 of the subject, to produce the state substantially free of opiates. Figure 7 shows an exemplary method 600 of the method for treating narcotic / respiratory depression induced by an opiate agonist in a subject in need thereof. In 702, the method includes contacting a location at a biological interface 18 of the subject with an iontophoretic drug delivery device 8 that is operable to iontophoretically deliver a A pharmaceutical composition comprising a therapeutically effective amount of at least one opioid antagonist. In 704, the method further includes administering via transdermal route a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid antagonist. Figure 8 shows a diagram of Time (minutes) vs. Transported Drug ^ g) for the supply of hydromorphone through human skin according to an illustrated modality. A configuration of Franz cells using human skin with dermatome as the barrier to the central chamber was used to demonstrate transport through human skin in a workbench environment. The hydromorphone is; diluted in water to 1 mg / ml and placed in contact with the anode side of an iontophoresis delivery device 8. A current density of 0.33 mA / cm2 was applied to the cell and the time points taken were demonstrated in the Time diagram (minutes) vs. Transported drug ^ g). The samples were analyzed for the presence of hydromorphone and placed in a diagram as a function of time. As shown in Figure 9, a mass spectrum analysis was performed on guinea pig serum samples after the iontophoretic delivery of hydromorphone according to an illustrated embodiment. 250 μ? of plasma were combined with 1.25 ml of borate buffer (11 g of sodium borate and 6.5 g of boric acid per liter of water) at pH = 8.9. 5 ng of the internal standard (hydromorphone-d6) were added and mixed. SPEMR tubes (Varian Inc. Harbor City, CA) were prepared by washing with 2 ml of methanol followed by 2 ml of deionized water. The samples were applied and attracted through under vacuum. The SPEMR tubes were then washed with 2 ml of deionized water, 2 ml of 10 m ammonium acetate pH = 4 and 2 ml of methanol. The SPEMR tubes were then dried under high vacuum for 5 minutes. The material was eluted with 2 ml of methylene chloride: isopropyl alcohol: ammonium hydroxide 80: 20: 2. The eluent was evaporated at 40 ° C under a stream of air. The residue was then reconstituted in 75 μ? of the CLAR mobile phase and injected into a CLAR column. The CLAR-EM is the 1100 series of Agilent Technologies (Palo Alto, CA.) that includes a binary pump, degassing module, automatic sampler, column compartment and mass spectrometer. The column was a Zorbax SB-C18MR 150 mm x 2.1 mm x 5 μ column (Agilent Technologies, Palo Alto, CA.). The column was maintained at 30 ° C. The mobile phase consisted of 10 mM ammonium acetate pH = 4: acetonitrile 91: 9. The flow speed was 0.25 ml / minute The mass spectrometer was operated in the ESI + mode using the specific ion control (SIM) for maximum sensitivity. The monitored ions were m / z 286 for hydromorphone and m / z 292 for hydromorphone-d6. The lowest limit of quantification of this assay is 0.2 ng / ml and the lower limit of detection is 0.1, ng / ml based on a sample size of 0.25 ml. Figure 10 shows a diagram of Time (minutes) vs. Hydromorphone (ng / ml) of an in vivo experiment of guinea pigs according to an illustrated modality. For the electrode, a carbon base was used on polyethylene film. The patch backing material was 3M (medical backing of closed cell polyolefin foam, product # 9773). The reservoir material was polyester fabric (Tex.tile Development Associates, # PETNF322.3030), 17 mm in diameter and 2 mm nominal thickness. The discs were specially treated by means of saturation with a 2% w / v solution of hydroxypropylcellulose (Klucel, MF Pharm, Hercules Corp.) and dried in a convection oven. The supply solution was prepared by dissolving 21 mg of HC1 from hydromorphone (Sigma Chemical Co., Lot # 024K1167) in 10 mL of buffer solution containing 0.155 M Na Ascorbate, pH 4.55) to provide a final concentration of 2.1 mg / mL. (USP Sodium Ascorbate, Spectrum Chemical Co., Product # S1349, Lot # UH0989 and USP Ascorbic Acid, Spectrum Chemical Co., Product # AS105, Lot # UI0026). The counter electrode solution was 0.5 M Disodium Fumarate (Fluka, Product # 47970, Lot # 443411/1). All of the buffer and drug solution was made on the same day of the experiment. The patch was made by placing the screen-printed electrode (TTI) on a backing of the backing material. On this, two layers of the backing material with perforated 17 mm holes were placed to cover the carbon electrode. In the holes, deposit discs treated with HPC were placed. An aliquot (325 μL) of either the drug or the counter-solution was placed in the appropriate reservoir and the coated polyester fabric was allowed to hydrate. (In the case of control patches, the ascorbate buffer solution alone was used on the supply side). After hydration (~ 2 minutes), the release paper of the foam backing material was removed and the reservoir disc was covered by a protective hydrophilic membrane. Another release paper liner (3) was then placed on the reservoirs until use. The patches were fed by a potencioestato / galvanostato of 8 channels (Solartron Analytical Model 1480) that executed the computer program Cell Test (Solartron Analytical) for instrument control and data acquisition. The drug delivery electrode was connected to the anode (+) and the counter electrode was connected to the cathode (-). Current was supplied under a current-controlled protocol at 1 mA (patch area 2.27 era2, current density 0.44 mA / cm2) for a duration of 45 minutes. The instrument captured the total voltage drop across the patch reflecting the sum of the voltages (resistance to current flow) through each electrode, the skin at both interfaces and the underlying tissue. The samples were collected at the indicated time points and analyzed as shown in Figure 10. It is not proposed that the above description of the illustrated modalities, including what is described in the Summary of the Invention, be exhaustive or limit the claims to the precise forms that are disclosed. Although the specific embodiments and examples are described in this document for illustrative purposes, various equivalent modifications may be made without departing from the spirit and scope of the invention, as will be recognized by those skilled in the relevant field. The teachings provided in this document can be applied to other systems and agent delivery devices, not necessarily the exemplary iontophoresis active agent system and devices that are generally described above. For example, some modalities may include an additional structure. For example, some embodiments may include a control circuit or subsystem for controlling a voltage, current or power applied to the active electrode and counter electrode elements 20, 68. Also for example, some embodiments may include an interface layer interposed between the membrane selective ion of external active electrode 22 and biological interface 18. Some embodiments may comprise additional ion selective membranes, ion exchange membranes, semipermeable membranes and / or porous membranes, as well as additional deposits for electrolytes and / or buffers. Several electrically conductive hydrogels have been known and used in the medical field to provide an electrical interface for the skin of a subject or within a device for coupling electrical stimuli in the subject. The hydrogels hydrate the skin, thus protecting it against burning due to electrical stimulation through the hydrogel, while swelling the skin and allowing a more efficient transfer of an active component. Examples of these hydrogels are disclosed in U.S. Patent Nos. 6,803,420; 6,576,712; 6,908,681; 6,596,401; 6,329,488; 6,197,324; 5,290,585; 6,797,276; 5,800,685; 5,660,178; 5,573,668; 5,536,768; 5,489,624; 5,362,420; 5,338,490 and 5,240,995, incorporated herein by reference in its entirety. Additional examples of these hydrogels are disclosed in U.S. Patent Applications Nos. 2004/166147; 2004/105834 and 2004/247655, incorporated herein by reference in its entirety. The product brand names of various hydrogels and hydrogel sheets include Corium Corplex ™; Tegagel ^ 3M; PuraMatrixMR from BD; Bard's Vigilon ™; ClearSite ^ by Conmed Corporation; FlexiGelMR from Smith & Nephew; Derma-Gel ^ by Medline; Nu-Gel ™ from Johnson & Johnson; and Curagel ™ from Kendall or acrylhydrogel films available from Sun Contact Lens Co., Ltd. In certain embodiments, the compounds or compositions may be delivered by means of an iontophoresis device comprising an active electrode assembly and a counter electrode assembly, coupled electrically to a power source for delivering an active agent to, at or through a biological interface. The active electrode assembly includes the following: a first electrode member connected to a positive electrode of the power source; an active agent deposit that has a drug solution that is in contact with the first electrode member and to which a voltage is applied via a first electrode member; a contact member with the biological interface, which may be a microneedle array and placed against the front surface of the active agent reservoir; and a first cover or container that accommodates these members. The counter electrode assembly includes the following: a second electrode member connected to a negative electrode of the voltage source; a second electrolyte support part that retains an electrolyte that is in contact with the second electrode member and to which a voltage is applied via the second electrode member; and a second cover or container that accommodates these members. In certain other embodiments, the compounds or compositions may be delivered by means of an iontophoresis device comprising an active electrode assembly and a counter electrode assembly, electrically coupled to a power source for delivering an active agent to, on or through a biological interface. The active electrode assembly includes the following: a first electrode member connected to a positive electrode of the voltage source; a first electrolyte reservoir that has an electrolyte which is in contact with the first electrode member and to which a voltage is applied via the first electrode member; a first anion exchange membrane which is placed on the front surface of the first electrolyte support part; an active agent reservoir which is placed against the front surface of the first anion exchange membrane; a contact member with the biological interface, which may be a microarray array and placed against the front surface of the active agent reservoir; and a first cover or container that accommodates these members. The counter electrode assembly includes the following: a second electrode member connected to a negative electrode of the voltage source, a second electrolyte support part having an electrolyte that is in contact with the second electrode member and to which it is applied a voltage via the second electrode member; a cation exchange membrane which is placed on the front surface of the second electrolyte reservoir; a third electrolyte reservoir which is placed against the front surface of the cation exchange membrane and which holds an electrolyte to which a voltage from the second electrode member is applied via the second electrolyte support part and the cation exchange membrane; a second membrane of anion exchange placed against the front surface of the third electrolyte reservoir; and a second cover or container that accommodates these members. The various embodiments described above can be combined to provide additional modalities. All US patents, publications of US patent applications, US patent publications, foreign patents, foreign patent applications and publications that are not patents referred to in this specification and / or listed in the Application Data Sheet are incorporated herein. by way of reference, in its entirety, including but not limited to: Japanese Patent Application Serial No. H03-86002, filed on March 27, 1991, which has Japanese Publication No. H04-297277, issued on March 3, 1991 March 2000 as Japanese Patent No. 3040517; Japanese Patent Application Serial No. 11-033076, filed February 10, 1999, which has Japanese Publication No. 2000-229128; Japanese Patent Application Serial No. 11-033765, filed February 12, 1999, which has Japanese Publication No. 2000-229129; Japanese Patent Application Serial No. 11-041415, filed February 19, 1999, which has Japanese Publication No. 2000-237326; Japanese Patent Application Serial No. 11-041416, filed on February 19 of 1999, which has Japanese Publication No. 2000-237327; Japanese Patent Application Serial No. 11-042752, filed February 22, 1999, which has Japanese Publication No. 2000-237328; Japanese Patent Application Serial No. 11-042753, filed on February 22, 1999, which has Japanese Publication No. 2000-237329; Japanese Patent Application Serial No. 11-099008, filed on April 6, 1999, which has Japanese Publication No. 2000-288098; Japanese Patent Application Serial No. 11-099009, filed on April 6, 1999, which has Japanese Publication No. 2000-288097; PCT Patent Application O 2002JP4696, filed May 15, 2002, which has PCT Publication No. WO03037425; US Patent Application Serial No. 10/488970, filed March 9, 2004; Japanese Patent Application No. 2004/317317, filed on 29 'October 2004; US Provisional Patent Application Serial No. 60 / 627,952, filed November 16, 2004; Japanese Patent Application Serial No. 2004-347814, filed on November 30, 2004; Japanese Patent Application Serial No. 2004-357313, filed December 9, 2004; Japanese Patent Application Serial No. 2005-027748, filed on February 3, 2005; Japanese Patent Application Serial No. 2005-081220, filed on March 22, 2005; Patent request Provisional North American No. 60 / 722,136 filed on September 30, 2005; US Provisional Patent Application No. 60 / 754,688 filed December 29, 2005; US Provisional Patent Application No. 60 / 755,199 filed December 30, 2005 and Provisional US Patent Application No. 60 / 755,401 filed December 30, 2005. As a person skilled in the relevant art would readily appreciate, the present description comprises methods for treating a subject by means of any of the compositions and / or methods described herein. Aspects of the various modalities may be modified, if necessary, to employ systems, circuits and concepts of the various patents, applications and publications to provide yet additional modalities, including those patents and applications identified in this document. While some embodiments may include all of the membranes, deposits and other structures described above, other embodiments may omit some of the membranes, deposits or other structures. Still other embodiments may employ membranes, deposits and additional structures of those described in general above. Still further modalities may omit some of the membranes, deposits and structures described above while they use membranes, deposits and additional structures of those described in general above. These and other changes can be made in view of the above detailed description. In general, in the following claims, the terms used should not be considered as limiting for the specific embodiments disclosed in the specification and the claims, but should be considered to include all the systems, devices and / or methods that operate according to the claims. Accordingly, the invention is not limited by the description, but instead its scope must be determined completely by the following claims.

Claims (21)

1

CLAIMS 1. A method for the systemic treatment of at least one condition associated with pain, neuropathic pain, acute pain, chronic pain or cancer pain, characterized in that it comprises: contacting a location in a biological interface with a device iontophoretic drug delivery, the iontophoretic drug delivery device comprises an active electrode assembly having at least one active agent reservoir, at least one active agent reservoir includes a pharmaceutical composition comprising at least a therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist; and applying a sufficient amount of current to the active electrode assembly to be administered by the way; transdermally a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist. The method according to claim 1, characterized in that the application of a sufficient amount of current to the active electrode assembly comprises: providing a sufficient voltage or current for a predetermined time interval

to the active electrode assembly for delivering a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist, from at least one deposit of active agent to the location in the biological interface. 3. The method according to claim 1, characterized in that the application of a sufficient amount of current comprises: providing a voltage and current sufficient for a time interval to the active electrode assembly to achieve substantially a sustained supply or controlled delivery of The pharmaceutical composition comprising the therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist, for an extended period of time, to produce an anesthetic, analgesic or anti-hyperalgesic therapy in a subject. The method according to claim 1, characterized in that at least one opioid agonist is selected from endogenous opioid peptides, opium alkaloids, semi-synthetic opioids and fully synthetic opioids or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof .

8

5. The method according to claim 1, characterized in that at least one opioid agonist is selected from (5a, 7a, 8β- (-) - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaespiro ( 4,5) dec-8-yl] -benzene-acetamide (U69,593)), [D-Ala2, N-Me-Phe, Gly5-ol] encephalitis (DAMGO), delta- ([D-Pen2, D -Pen5] -enkephalin (DPDPE)), buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, meperidine, methadone, morphine, nicomorphine, opium, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene and tilidine, or the like or derivatives, or pharmaceutically acceptable salts or solvates thereof.

6. The method according to claim 1, characterized in that at least one opioid antagonist is selected from [(-) - (IR, 5R, 9R) -5, 9-diethyl-2- (3-fuiryl-methyl) -2 '-hydroxy-6,7-benzomorphan] (MR2266), [allyl] 2-tir-alpha-amino-isobutyric acid (Aib) -Aib-Phe-Leu-OH (ICI-174864), 4- (3 -hydroxyphenyl) -34-dimethyl-alpha-phenyl-1-piperidinepropanol (LY117413), d-Naltrexol, 7-Benzylidene naltrexone (BNTX), b-funaltrexamine (b-FNA), cyclazocine, cyclochlorphan, dezocin, diprenorphine, levorphanol , meptazinol, methiodide, methylnaltrexone, nalida, nalmefene, nalmexone, nalorphine, nalorphine dinicotinate, naloxonazine, naloxone, naltrexone, naltriben (TB), naltrindol (NTI), naltrindol isothiocyanate (TII), N-

cyclopropylmethyl-4,14-dimethoxy-morphinan-6-one (cyprodim), nor-binaltorphimine (nor-BNI), oxollorphane, nalbuphine and trans-3,4-dimethyl-4-phenylpiperides or analogs or derivatives, or salts or solvates pharmaceutically acceptable thereof. The method according to claim 1, characterized in that at least one opioid antagonist is selected from hydromorphone or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof; and at least one opioid antagonist is selected from naloxone, naltrexone, nalmefene, naloxonazine, NTI, nor-BNI, LY25506, LY9935, LY255582 and LY117413 or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. The method according to claim 1, characterized in that at least one opioid antagonist is selected from hydromorphone or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof; and at least one opioid antagonist is selected from naloxone, naltrexone, 6β-naltrexol, nalmefene and naloxonazine or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. 9. The method according to claim 1, characterized in that at least one

Opioid antagonist is selected from PALADONE, PALLADONE SRMR, DILAUDIDMR and hydromorphone hydrochloride; and at least one opioid antagonist is selected from NARCAN ™, TREXA ™ MR, REVEX ™, NUBIAN ™, nalaxone hydrochloride, naltrexone hydrochloride, nalmefene hydrochloride and nulbuphine hydrochloride. The method according to claim 1, characterized in that at least one condition associated with pain, neuropathic pain, acute pain, chronic pain or cancer pain includes: cancer; chemotherapy; alcoholism; amputation; a back, leg or hip problem; diabetes; a problem of facial nerves; an HIV infection or AIDS; multiple sclerosis; spinal surgery; narcotic / respiratory depression induced by opiates; or detoxification of opioid dependence. The method according to claim 1, characterized in that the pharmaceutical composition further comprises at least one active agent selected from vaccines, antibiotics, adjuvants, immunological adjuvants, immunogens, tolerogens, allergens, Toll-like receptor agonists and receptor antagonists. Toll type, immuno-adjuvants, immuno-modulators, immuno-response agents, immuno-stimulators, specific immuno-stimulators, immuno-stimulators

non-specific stimulators and immunosuppressants or combinations thereof. The method according to claim 1, characterized in that at least one opioid agonist and at least one opioid antagonist are present in effective, anti-hyperalgesic, synergistic amounts. 13. An autonomous iontophoretic drug delivery system for providing a transdermal delivery of one or more therapeutic active agents to a biological interface of a subject and inducing analgesia or anesthesia in the subject for a limited period of time, characterized in that it comprises: at least one deposit of active agent, at least one deposit of active agent includes a pharmaceutical composition for inducing analgesia or anesthesia in the subject, the pharmaceutical composition for inducing analgesia or anesthesia in the subject comprises at least one analgesic active agent or anesthetic in combination with at least one opioid antagonist; an active electrode assembly that includes at least one active electrode element, at least one active electrode element that is operable to provide an electromotive force to drive the pharmaceutical composition to induce analgesia or anesthesia in the subject comprising less an agent

analgesic or anesthetic active in combination with at least one opioid antagonist, of at least one deposit of active agent, at the biological interface of the subject; a power source electrically coupled to the active electrode assembly, the power source is operable to supply an automotive force to the active electrode assembly; and a biocompatible backing configured to coat at least one active agent reservoir and the active electrode assembly. The system according to claim 13, characterized in that at least one opioid agonist is selected from endogenous opioid peptides, opium alkaloids, semi-synthetic opioids and fully synthetic opioids or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof . The system according to claim 13, characterized in that at least one opioid antagonist is selected from naloxone, naltrexone, β-naltrexol, nalmefene and naloxonazine or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. 16. The system according to claim 13, characterized in that at least one opioid antagonist is selected from hydromorphone or

analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof; and at least one opioid antagonist is selected from naloxone, naltrexone, 6β-naltrexol, nalmefene and naloxonazine or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof. The system according to claim 13, characterized in that the power source includes at least one of a chemical battery cell, super- or ultra-capacitor, fuel cell, secondary cell, thin film cell, cell in Button shape, lithium ion cell, zinc-air cell and metal nickel-hydride cell. The system according to claim 13, characterized in that it further comprises: an operable circuit for managing a work cycle associated with the delivery of a therapeutically effective amount of the pharmaceutical composition for inducing analgesia or anesthesia in the subject comprising thereby minus an analgesic or anesthetic active agent in combination with at least one opioid antagonist for a predetermined period. The system according to claim 13, characterized in that the system is operable to supply transdermally at least

an opioid agonist and at least one opioid antagonist in effective amounts, anti-hyperalgesic, synergistic. The system according to claim 13, characterized in that it further comprises: an outer adhesive surface for physically coupling the autonomous iontophoretic drug delivery system to the biological interface of the subject. The system according to claim 13, characterized in that it further comprises: a controller electrically coupled to the power source; a counter electrode assembly including at least one counter electrode element electrically coupled to the power source; and one or more electrolyte reservoirs, one or more of the electrolyte reservoirs include an electrolyte comprising at least one biologically compatible antioxidant selected from ascorbate, fumarate, lactate and malate or salts thereof.