BRPI0616788A2 - transdermally drug transfer systems, devices and methods, and methods employing opioid agonist and / or opioid antagonist - Google Patents

Abstract

SYSTEMS, DEVICES AND METHODS OF TRANSFER OF PHARMACEUTICALS IN TRANSDERMAL MODE, AND METHODS THAT USE OPIOID AGONIST AND / OR OPIOID ANTAGONIST. Systems, devices, and methods for transdermally transferring one or more active therapeutic agents to a biological interface. An iontophoretic drug transfer system is provided for the transdermal transfer of one or more active therapeutic agents to an individual's biological interface. The iontophoretic drug transfer system includes at least one reservoir of active agent. The at least one active agent reservoir can include a pharmaceutical composition that includes at least one opioid agonist and / or opioid antagonist.

Description

"TRANSDERMIC PHARMACEUTICAL TRANSFER SYSTEMS, DEVICES AND METHODS, AND METHODS THAT USE OPIOID AND / OR OPIOID ANTAGONISTS"

Fundamentals

Field

This disclosure is related to the field of iontophoresis and, more particularly, to device systems, and transdermal drug transfer methods employing opioid agonist and / or opioid antagonist.

Description of Related Art

Iontophoresis employs an electromotive and / or current force to transfer an active agent (e.g., a charged substance, an ionized compound, an ionic drug, a therapeutic, a bioactive agent, and the like) to a biological interface (e.g., skin, mucous membrane, and the like) by applying an electrical potential to an electrode in the vicinity of an iontophoretic chamber containing an active agent and / or its similarly charged vehicle.

Iontophoresis devices typically include an active electrode mount and an opposite electrode mount, each coupled to opposite poles or 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. Such electrode-frequency elements comprise a sacrificial element or compound, for example, silver or silver chloride. The active agent may be either cationic or anionic, and the power source may be configured to apply the appropriate return polarity based on the polarity of the active element. The iontophoresis can be advantageously used to improve or control the active agent transfer rate. The reactive 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 may be positioned to serve as a selective polarity barrier between the active agent reservoir and the biological interface. The membrane, typically only permeable with respect to an ion particle type (e.g., a charged active agent), prevents reflux of oppositely charged ions from the skin or mucous membrane.

Commercial acceptance of iontophoresis devices is dependent on a variety of factors such as manufacturing cost, shelf life, storage stability, efficiency and / or convenience of active agent transfer, biological capacity, and / or disposal issues. In addition, an iontophoresis device that is capable of transferring an active agent and which is effective in inducing analgesia or anesthesia in an individual is equally desirable.

The present disclosure is directed to overcome one or more of the disadvantages set forth above, and to provide additional related advantages.

In one aspect, the present disclosure is directed to an autonomous drug iontophoretic transfer system. The system includes at least one active personnel reservoir, an active electrode assembly that includes at least one active electrode element, a power source, and a biocompatible reinforcement. In some embodiments, the system is configured to provide modotransdermal transfer of one or more therapeutically active agents to a biological interface of an individual and induce analgesia or anesthesia in the individual for a limited period of time.

The at least one active agent reservoir includes a pharmaceutical composition 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 at least one active electrode element is operable to provide an electromotive force for conducting 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 from. at least one reservoir of the active agent to the biological interface of the individual.

The power source is electrically coupled to the active electrode assembly, and is operable to provide an electromotive force to the active electrode assembly. The biocompatible reinforcement is configured to house at least one active agent reservoir and the active electrode assembly.

In another aspect, the present invention is directed to a method for the systemic treatment of at least one condition associated with pain, neuropathic pain, acute pain, chronic pain, or cancer pain. The method includes contacting a site at a biological interface with an iontophoretic drug transfer device that includes an active electrode assembly having at least one active agent reservoir. The at least one active agent reservoir includes a pharmaceutical composition comprising at least one 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 to transdermally administer a therapeutically effective amount of the pharmaceutical composition comprising therapeutically effective amount of at least one agonistopioid and at least one opioid antagonist.

In another aspect, the present disclosure is directed to a method of treating opiate addiction and / or bringing about a substantially opiate free state in an individual in need thereof. The method includes contacting a site at a subject's biological interface with an operable iontophoretic drug transfer to iontophoretically transfer one with a pharmaceutical comprising a therapeutically effective amount of at least one opioid antagonist. The method also includes transdermally transferring a therapeutically effective amount of the pharmaceutical comprising the therapeutically effective amount of the at least one opioid antagonist.

In another aspect, the present disclosure is directed to a method of inducing anesthesia, analgesia, or hyperalgesia in an individual. The method includes positioning an active electrode and a counter electrode of an iontophoretic transfer device at a biological interface of the subject. In some embodiments, the iontophoretic drug transfer device is operable for iontophoretically transferring a pharmaceutical composition comprising an effective amount of at least one opioid agonist and at least one opioid antagonist. The method further includes iontophoretically transferring an anesthesia inducer, an analgesia inducer, or an antihyperalgesic inducing synergistic 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 of treating opiate agonist-induced narcotic / respiratory depression in an individual in need thereof. The method includes contacting a site at a subject's biological interface with an operable iontophoretic drug transfer device for iontophoretically transferring a pharmaceutical composition comprising a therapeutically effective amount of at least one opioid antagonist. The method also included transdermally transferring a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of the at least one opioid antagonist.

Brief Description of Various Drawing Views

In the drawings, identical reference numerals identify similar elements or acts. The relative sizes and positions of the elements in the drawings are not necessarily scaled. For example, the shapes of the various elements and angles are not drawn to scale, and some of these elements are arbitrarily enlarged and positioned to improve the visualization of the drawing. In addition, the particular shapes of the elements as drawn are not intended to convey any information regarding the actual shape of the particular elements, and have only been selected for ease of identification in the drawings.

Figure 1A is a front, top view of a transdermal drug transfer system according to one illustrated embodiment.

Figure IB is a top plan view of a transdermal drug delivery system according to one illustrated embodiment.

Figure 2A is a schematic diagram of an 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 positioned at a biological interface, with an optional external 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 and counter electrode assemblies and a plurality of microneedles according to one illustrated embodiment.

Figure 3A is a front bottom view of a plurality of microneedles in the form of a chord arrangement with an illustrated embodiment.

Figure 3B is a front bottom view of a plurality of microneedles in the form of one or more arrangements according to another illustrated embodiment.

Figure 4 is a flowchart according to a systemic method of treating at least one condition associated with pain, neuropathic pain, acute pain, chronic pain, or cancer pain according to an illustrated embodiment.

Figure 5 is a flow diagram of a method of inducing anesthesia, analgesia, or antihyperalgesia in an individual according to one illustrated embodiment.

Figure 6 is a flowchart of a method for depleting opiate dependence and / or bringing about a substantially opiate free state in an individual in need thereof according to an illustrated embodiment.

Figure 7 is a flowchart of a method for depleting agonist opiate-induced narcotic / respiratory depression in an individual in need of agreement with an illustrated embodiment. Figure 8 is a graph Time (min) vs. Transported Drug (g) for hydromorphone transfer through the human skin according to an illustrated embodiment.

Figure 9 is a graph of the serum parahydromorphone mass spectrum according to an illustrated embodiment.

Figure 10 is a graph Time (min) vs Hydro-morphone (ng / ml) showing hydromorphone levels in test animals following iontophoretic transfer according to one illustrated embodiment.

Detailed Description

In the following description, certain specific details are included to provide a broader understanding of the various disclosed embodiments. Those usually skilled in the relevant art, however, will recognize that embodiments may be practiced without one or more of these specific details, or with other methods, components, materials, etc. In other cases, well-known structures associated with iontophoresis devices that include, but are not limited to, voltage and / or current regulators are not shown or described in detail to avoid unnecessarily obscuring descriptions of the modalities.

Unless the concept requires otherwise, along with the specification and claims set forth below, the word "comprising" and "comprising" are to be considered in an open, inclusive sense, which is as "including, but not limited to".

Reference throughout this specification to "one embodiment" or "the embodiment" or "in another embodiment" means that an aspect, structure, or reference feature described in conjunction with the embodiment is comprised of at least one embodiment. . Thus, the emergence of phrases "in one mode" or "in one mode" or "in another mode" at various times in the course of this specification are not necessarily all referring to the same mode. Further, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

It should be noted that, as used in this specification and the appended claims, the singular forms "one", "one", and "o" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to an iontophoresis device that includes "an electrode element" includes a single electrode element, or two or more electrode elements. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the context clearly dictates otherwise.

As used herein, the term "membrane" means a boundary, layer, barrier, or material, which may or may not be permeable. The term "membrane" may also refer to an interface. Unless otherwise specified, members may take the form of a solid, liquid, or gel, and may or may not have a distinct entanglement, cross-linked, or non-cross-linked structure.

As used herein, the term "ion-selective membrane" means a membrane that is substantially ion-selective, passing certain ions as a blocker of the passage of other ions. An ion-selective membrane, for example, may take the form of a charge-selective membrane, or may take the form of a semi-permeable membrane.

As used herein, the term "charge-selective membrane" means a membrane that substantially lets passare / or substantially blocks ions based primarily on the polarity or charge carried by the ion. Charge-selective membranes are typically referred to as trochanionic membranes, and such terms are used interchangeably herein and in the claims. Charge-selective or ion-depleting membranes may take the form of a trochancation membrane, an anion exchange membrane, and / or a membranabipolar membrane. A cation exchange membrane allows substantially cations to pass through and substantially blocks osions. Examples of commercially available cation exchange membranes include those available under TokuyamaCo., Ltd.'s NEOSEPTA, CM-I, CM-2, CMMS, and CMB designations. Conversely, an anion exchange membrane substantially allows passage. anions and blocks substantially the passage of cations. Examples of commercially available anion exchange membranes include those available under the names NEOSEPTA, AM-I, AM-3, AMX, AHA, ACH, and ACS also from Tokuyama Co., Ltd.

As used herein and in the claims, the term "bipolar membrane" means a membrane that is selective at different charges or polarities. Unless otherwise specified, a bipolar membrane may take the form of a unitary membrane structure, a multiple membrane structure, or a laminate. The unitary membrane structure may include a first portion that includes cation exchange materials or groups and a second portion opposite the first part, which includes anion exchange materials or groups. The multiple membrane structure (e.g., two-film structure) may include a laminated cation exchange membrane or otherwise coupled to an anion exchange membrane. The cationic and anionic exchange membranes begin initially as distinct structures, and may or may not maintain their differentiation in the resulting bipolar membrane structure.

As used here and in; claims, the term "semipermeable membrane" means a membrane that is substantially selective based on an ion molecular size or weight. Thus, a semipermeable membrane passes substantially ions of a first molecular size or weight, while substantially blocking the passage of ions of a second molecular size or weight greater than the first molecular size or weight. In some embodiments, a semi-permeable membrane may allow passage of some molecules at a first rate, and some other molecules at a different rate than the first. In still further embodiments, the "semipermeable membrane" may take the form of a selectively permeable membrane that allows only certain selected 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 based on polarity, and not substantially selective based on the size or molecular weight of an element or compound in question.

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 based on polarity, and not substantially selective based on the size or molecular weight of an element or compound in question.

As used herein and in the claims, the term "matrix gel" means a type of reservoir, 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-gel. lattice, a jelly-like state, and the like. In some embodiments, gel matrix may result from a three-dimensional mesh or interlacing of, for example, cross-linked hydrophilic polymers in the form of a substantially water-based gel. Hydrogels may have a positive or negative net charge, or they may be neutral.

As used herein and in the claims, the term "reservoir" means any form of 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 transition 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 such are capable of retaining at least temporarily an element or compound. Typically, a reservoir serves to retain a biologically active agent prior to the discharge of such an agent by means of electromotive force and / or current within the biological interface. A reservoir may also retain an electrolyte solution.

As used herein and in the claims, the term "active people" refers to a compound, molecule, or treatment that allows a biological response to arise 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-pharmaceuticals (e.g., cosmetic, and the like), a vaccine, an immunological agent, an anesthetic or pain reliever, an antigen or a protein or peptide total such as insulin, a chemotherapeutic agent, an anti-tumor agent.

In some embodiments, the term "active agent" also refers to the active agent as well as pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts, prodrugs, metabolites, analogs, and the like. In some additional embodiment, the active agent includes at least one ionic, cationic, ionizable, and / or neutral therapeutic drug and / or pharmaceutically acceptable salts thereof. In still other embodiments, the active agent may include one or more "active cationic agents" that are positively charged, and / or capable of forming positive charges in aqueous medium. For example, many biologically active agents have functional groups that are easily convertible to a positive ion or may dissociate as a positively charged anion and a counterion in an aqueous medium.

Other active agents may be polarized or polarizable, i.e. having a polarity in one part relative to another part. For example, an active agent having an amino group may typically take the form of a solid state deamonium salt and dissociate as a free ionammonium (NH4 +) in an appropriate pH aqueous medium.

The term "active agent" may also refer to electrically neutral agents, molecules, or compounds capable of being transferred by electroosmotic flow. Electrically neutral agents are typically driven by the flow of, for example, a solvent during the electrophone. -Rese. The selection of suitable active agents is therefore contained in the experience of those usually skilled in the relevant art.

In some embodiments, one or more active agents may be selected from analgesics, anesthetics, anesthetic vaccines, antibiotics, adjuvants, immune adjuvants, immunogenic, tolerogenic, allergens, Toll-like receptor agonists, Toll-receptor antagonists. like ", immunoadjuvants, immunomodulators, immune response agents, immunostimulants, specific immunostimulators, non-specific immunostimulants, and immunosuppressants, or combinations thereof.

Non-limiting examples of such active agents include lidocaine, articaine, and others of the class -caine: morphine, hydromorphone, fentanyl, oxycodone, hydrocodone, buprenorphine, methadone, and similar opioid agonists; sumatriptan succinate, solmitriptan, naratriptan HCl, rizatr benzoate, almotriptan malate, defrovatriptan succinate and other 5-hydroxytryptamine 1 receptor subtype agonists; resiquimod, imiquidmod, and similar TLR7 and 8 agonists; domperidone, granisetron hydrochloride, ondansetron and such antiemetic drugs; dezolpidem tartrate and similar sleep inducing agents; L-dopa and other anti-Parkinson's drugs; aripiprazole, olanzapine, quetiapine, risperidone, clozapine, and siprasidone, as well as other meuroleptics; diabetic drugs such as exenatide; as well as peptides and proteins for the treatment of obesity and other ills.

Additional non-limiting examples of anesthetic agents or pain mitigates include ambucain, ametocaine, isobutyl p-aminobenzoate, amolanone, amoxecain, amylocaine, aptocaine, azacaine, bencain, benoxinate, benzocaine, N, N-dimethylalanylbenzocaine, N, N-dimethylbenzine, , beta-adrenoceptorantagonists betoxicaine, bumecain, bupivicaine, levobupivicaine, butacaine, butamben, butanilicaine, butetamine, butoxyamine, metabutoxicain, carbizocaine, carticaine, centbucridine, cepacaine, cetacaine, dicocaine, cytokine, cetacaine, dimethylacaine diperodon, diclonin, ecognin, ecogonidine, ethylaminobenzoate, etidocaine, euprocin, phenalcomine, fomocaine, heptacaine, hexacaine, hexocaine, hexylcaine, ketocaine, leucinocaine, levoxadrol, lignocaine, lotainein, methaepaine, metainaaine, metainaine octacaine, orthocaine, oxetazain, parentoxic aine, pentacaine, phenacine, phenol, piperocaine, pyridocaine, polidocanol, polycaine, prilocaine, pramoxin, procaine (Novocaine®), hydroxyprocaine, propanocaine, proparacaine, propipocaine, propoxycaine, pyrrocaine, quatacaine risocaine, rhinocaine, rhinocaine tetracaine, hydroxytetracaine, tolicaine, trapencaine, tricaine, trimecaine tropacocaine, zolamine, a pharmaceutically acceptable salt thereof, and mixtures thereof.

As used herein and in the claims, the term "individual" generally refers to any host, vertebrate, or invertebrate, and includes fish, mammals, amphibians, reptiles, birds, and particularly humans.

As used herein and in the claims, the term "α-gonist" refers to a compound that can combine with a receptor (e.g., an opioid receptor, a toll-like receptor, and the like) to produce a cellular response. Umagonist may be a ligand that binds directly to the receptor Alternatively, an agonist may combine with a receptor indirectly by forming a complex with another molecule that directly binds to the receptor or otherwise results in modification. of a total component that it directly connects to the receiver.

As used herein and in the claims, the term "antagonist" refers to a compound that can combine with a receptor (e.g., an opioid receptor, a toll-like receptor, and the like) to inhibit a cellular response. -home. An antagonist may be a ligand that binds directly to the receptor. Alternatively, an antagonist may combine with a receptor indirectly by forming a complex with another molecule that directly binds the receptor or otherwise results in modification of a compound such that it directly binds to the receptor.

As used herein and in the claims, the term "effective amount" or "therapeutically effective amount" includes an amount effective at the dosages and for time periods necessary to achieve the desired result. The effective amount of a pharmaceutical agent-containing composition may vary according to factors such as the disease's state, age, gender, and weight.

As used herein and in the claims, the term "allergenic" refers to an agent that diminishes, relieves, reduces, remedies, or extinguishes a neural sensation in an individual's body area. In some modalities, neuronal sensation is related to pain, in other respects neural sensation is related to discomfort, itching, burning, tingling, tension, temperature fluctuations (such as fever), inflammation, sore, or other neural sensations.

As used herein and in the claims, the term "a-nesthetic" refers to an agent that produces a reversible loss of sensation in an area of an individual's body. In some embodiments, the anesthetic is considered to be a "local anesthetic" because it produces a loss of sensation only in a particular area of an individual's body.

As those of ordinary skill in the art will be able to identify, some agents may act as both an anesthetic and an anesthetic, depending on the circumstances and other variables including, but not limited to, dosage, transfer method, medical condition or treatment, and genetic constitution of the drug. individual. Additionally, agents that are typically used for other purposes may possess local anesthetic or membrane stabilizing properties under certain circumstances or under particular conditions.

As used herein and in the claims, the term "immunogenic" refers to any agent that causes an immune response to arise. Examples of immunogens include, but are not limited to, natural or synthetic (including modified) peptides, proteins, lipids, oligonucleotides (including RNA), chemicals, or other agents.

As used herein and in the claims, the term "α-allergen" refers to any agent that gives rise to 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, vapors), and / or physical agents (heat, light, friction, radiation). As used here, an allergen can be an immunogen.

As used herein and in the claims, the term "adjuvant" and any deviations therefrom refers to an agent which modifies the effect of another agent while having little, if any, direct effect when given alone. For example, an adjuvant may increase the potency or efficacy of a pharmaceutical substance, or an adjuvant may alter or influence an immunoresponse.

As used herein and in the claims, the term "o-pyoid" generally refers to any agent that binds to and / or interacts with opioid receptors. Examples of opioids include endogenous opioid peptides, opioid alkaloids (eg, morphine, codeine, the like), semi-synthetic opioids (eg, heroin, oxycodone and the like), synthetic opioids ( for example buprenorphineomeperidine, fentanyl, morfinan, benzomorphine derivatives, and the like), as well as opioids having non-opioid alkaloid-related structures (e.g., pethidine, methadone, and the like).

As used herein and in the claims, the terms "carrier", "driver", "pharmaceutical carrier", "pharmaceutically acceptable carrier", or "pharmaceutically acceptable driver" may be used interchangeably, and refer to solid or pharmaceutically acceptable liquid, thinner or encapsulant, fillers or carriers, which are commonly employed in the pharmaceutical industry for the manufacture of pharmaceutical compositions. Examples of vehicles include any liquid, gel, ointment, cream, solvent, diluent, ointment fluid base, vesicles, liposomes, nisomas, ethasomes, transfersomes, virosomes, nonionic surfactant vesicles, phospholipid surfactant vesicles, mice it, and the like, which is suitable for use in contact as an individual.

In some embodiments, the pharmaceutical carrier may refer to a composition that includes and / or transfers a pharmacologically active agent, but is generally considered to be pharmacologically inactive. In some other embodiments, the pharmaceutical carrier may have some therapeutic effect when applied to a site such as a mucous membrane or skin by providing, for example, protection from the site of application of conditions such as damage, subsequent damage. , or exposure to the elements. Accordingly, in some embodiments, the pharmaceutical carrier may be used for protection without a pharmacological agent in the formulation.

The titles provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

Figures IA and IB show a representative iontophoretic drug transfer system 6 for transferring one or more active agents to an individual. System 6 includes an iontophoresis device 8 which includes active electrode and counter electrode assemblies 12, 14, respectively, and a power source 16. Electrodeactive and counter electrode assemblies 12, 14 are electrically coupled to power source 16 for provide an active agent contained in the active electrode assembly 12 by iontophoresis to a biological interface 18 (eg, a part of the skin or mucous membrane). The iontophoresis device 8 may optionally include a biocompatible reinforcement 19. In some embodiments, the biocompatible reinforcement 19 houses the iontophoresis devices 8. In some other embodiments, the biocompatible reinforcement 19 physically couples the iontophoresis device 8 to the biological interface 18 of the individual. In some embodiments, system 6 is configured to transdermally transfer one or more therapeutically effective agents to a biological interface of an individual and induce analgesia or anesthesia in the individual for a limited period of time.

As shown in Figures 2A and 2B, the active electrode assembly 12 may also comprise, from an interior 20 to an exterior 22 of the active electrode assembly 12: an active electrode element 24, an electrolyte reservoir 26 which stores an electrolyte 28, an ion-selective inner membrane30, one or more active agent inner reservoirs 34, which stores one or more active agents 36, an optional outermost ion-selective membrane 38 which optionally conceals additional active agents 40, and an optional additional active agent 42 driven by an outer surface 44 of the outermost ion-selective membrane 38. The active electrode assembly 12 may also comprise an optional external release liner 46.

In some embodiments, the one or more active agent reservoirs 34 are loadable with a vehicle and / or pharmaceutical composition for transporting, transferring, encapsulating, and / or driving the one or more active agents 36, 40, 42. In some embodiments, at least one agent reservoir 34 includes a pharmaceutical composition for inducing alalgesia or anesthesia in the subject. A pharmaceutical 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 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.

The at least one opioid agonist may be selected from endogenous opioid peptides, opium alkaloids, semi-synthetic opioids, and fully synthetic opioids, or analogs or derivatives thereof, or pharmaceutically acceptable salts thereof or solvates thereof. In some embodiments, the at least one agonistopioid is selected from (5α, 7a, 8β - (-) - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro (4,5) dec. 8-yl] -benzene-acetamide (U69, 593)), [D-Ala2, N-Me-Phe4, Gly5-Ol] enkephalin (DAMGO), delta- ([D-Pen2, D-Pen5] -encefalin ( DPDPE)), buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, heroin, hydrocone, hydromorphone, meperidine, methadone, morphine, nicomorphine, opium, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, or analogues or its analogues, or tilogos; pharmaceutically acceptable salts or solvates thereof.

At least one opioid antagonist may be selected from [(-) - (IR, 5R, 9R) -5,9-diethyl-2- (3-furylmethyl) -2'-hydroxy-6,7-benzomorphan ] (MR2266), [allyl] 2-thyr-alpha-amino isobutyric acid (Aib) -Aib-Phe-Leu-OH (ICI-174864), 4- (3-hydroxyphenyl) -34-dimethyl-alpha-phenyl -1-piperidinepropanol (LY117413), ββ-Naltrexol, 7-Benzylidenenaltrexone (BNTX), b-funaltrexamine (b-FNA), cyclazocine, cyclorfan, dezocine, diprenorphine, levorfanol, meptazinol, methiodide, methylnaltralone, nephrenalone, nephrenamine nalorphine, nalorphine dicotinate, naloxonazine, naloxone, naltrexone, naltriben (NTB), naltrindole (NTI), naltrindole isothiocyanate (NTII), N-cyclopropylmethyl-4,14-dimethoxy-morfinan-6-one (nor) binaltorfimin (nor-BNI), oxlorfan, nalbuphine, and trans-3,4-dimethyl-4-phenylpiperides or their analogs and derivatives or their pharmaceutically acceptable salts or solvates.

In some embodiments, the at least one opioid antagonist is selected from hydromorphone, or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof; and the at least one opioid antagonist is selected from naloxone, naltrexone, nalmefene, naloxone-zine, NTI, nor-BNI, LY25506, LY9935, LY255582, and LY117413, or their analogs and derivatives, or their salts or solvates pharmaceutically. acceptable.

In some embodiments, the at least one opioid antagonist is selected from hydromorphone, or analogs or derivatives, or analogs and derivatives thereof, or their pharmaceutically acceptable salts or solvates; and at least one opioid antagonist is selected from denaloxone, naltrexone, ββ-naltrexole, nalmefene, enaloxonazine, or their analogs and derivatives, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the at least one opioid antagonist is selected from paladone, Palladone® SR, hydromorphone Dilaudid® hydrochloride; and the at least one opioid antagonist is selected from Narcan®, Trexán®, Revex®, Nubian®, nalaxone hydrochloride, naltrexone hydrochloride, nalmefene hydrochloride, and nulbuphine hydrochloride. In some embodiments, the at least one opioid agonist and at least one opioid antagonist are present in effective synergistic antihyperalgesic effective amounts.

The pharmaceutical composition may also comprise at least one active agent selected from vaccines, antibiotics, adjuvants, immunological adjuvants, immunogenic, tolerogenic, allergens, toll-like receptor agonists, toll-like receptor antagonists, immunoassay. adjuvants, immunomodulators, immunoresponders, immunostimulants, specific immunostimulants, non-specific immunostimulants, and immunosuppressants, or combinations thereof.

In some embodiments, the pharmaceutical composition may include an effective amount of at least one opioid agonist, at least one opioid antagonist, and at least one active agent selected from an antihistamine drug, a vasoconstrictor drug (e.g., enephrine, adrenaline, norepinephrine, and the like), a steroid, and the like.

The pharmaceutical composition may be useful for systemic treatment of at least one condition associated with pain, neuropathic pain, acute pain, chronic pain, or cancer pain. In some embodiments, the at least one condition associated with pain, neuropathic pain, acute pain, chronic pain, or cancer pain includes: chemotherapy; alcoholism; amputation; a problem with your back, legs, or hip; diabetes, a facial nerve problem; an infection with HIV or AIDS, multiple sclerosis; spinal surgery; opiate-induced narcotic / respiratory depression; or detox opiate dependence.

The onset of acute pain induced by, for example, tissue injury typically results from stimulation of special nerve endings called nociceptors. Nociceptors respond to a variety of stimuli including burns, cuts, infection, chemical changes, pressure, and many others. other sensations that are interpreted as pain by a biological individual. By eliminating the cause of such nociceptive pain and allowing the healing process to begin, the sensitivity and pain associated with the injury or other stimulus typically dissipates. Although neuropathic pain is certainly real, the cause can be difficult to determine.

Neuropathic pain is often described as shooting, stabbing, burning or cauterization. As used herein and in the claims, such pain is called "neuropathic pain".

Conditions with which neuropathic pain may be commonly associated include, but are not limited to, herpes zoster (herpes zoster virus infection; postherpetic pain); cancer; chemotherapy; alcoholism; amputation (eg, phantom limb syndrome); back, legs, and hip problems (sciatica); diabetes, facial nerve problems (trigeminal neuralgia); HIV infection or AIDS; multiple sclerosis; and spine surgery. Chronic pain can also occur without any known injury or illness. For example, individuals may experience measures or other non-obvious stimuli. In some cases, individuals may experience chronic pain that persists for prolonged periods including months, years, even decades. Such pain results predominantly from damage to the central or peripheral nervous system.

Although the cause of neuropathic pain may be unknown, or uncontrollable, in one disclosed embodiment, treatment may include chronic progressive administration of drugs or other pain-enhancing active agents, such as active analgesic agents, anesthetic agents, and / or mitigating pain. pain. Such drugs or other active agents may be passively administered by applying one or more devices 8 to a biological interface18 (e.g., skin or mucous membrane) in or near areas where an individual is experiencing neuropathic pain. Once the device 8 is in contact with the biological interface 18, the one or more agents are transferable from the device 8 to or within the biological interface 18 to exert its pain relieving effect. Alternatively, one or more agents may advantageously be actively administered by means of a device 8 through a biological interface 18 and tissue into the systemic circulation. Accordingly, the agent may exert its therapeutic effect locally and more broadly. In one embodiment, for example, one or more active agents are administered through the area portion of a biological interface from which they can enter the bloodstream and be carried systemically within a capillary bed or other vasculature of a area experiencing pain (eg, neuropathic pain and the like). In certain embodiments, the device for the active administration of an anesthetic or pain reliever is an iontophoretic device, as described in detail herein.

As used herein and in the appended claims, "systemic circulation" typically refers to the movement of blood through a part of a cardiovascular system and / or circulatory system that carries oxygenated blood from the heart to the body and oxygen-depleted blood. Body back to the heart. Within this part of the cardiovascular system, blood may flow through vessels that include, but are not necessarily limited to, arteries, arterioles, capillaries, venules, and veins. Systemic circulation, as used here and in coatings, may also refer to the movement of fluids through an lymphatic system which collects lymph from tissues and returns them to the cardiovascular circulatory system. Lymph typically originates from blood plasma that escapes the cardiovascular system into intra-tissue spaces. "Systemic transfer", as used herein and in the claims, refers to the movement of compounds, such as active agents, from one position to another through systemic circulation.

Referring to Figures 2A and 2B, the electrodeactive assembly 12 of the iontophoretic transfer device 8 may also comprise an optional internal sealant coating (not shown) between two layers of the electrodeactive assembly 12, for example between the ion selective membrane. 30 and the active agent inner reservoir 34. The inner sealant, if present, may be removed prior to application of the iontophoretic device to the biologic surface 18. Each of the above elements or structures will be discussed in detail below.

In some embodiments, system 6 assumes the form of an iontophoretic drug transfer system. 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 an energy source 16. At least one active agent reservoir 34 includes a pharmaceutical composition for inducing analgesia. or anesthesia in the individual. 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 power source 16 and positioned in the active electrode assembly 12 to apply an electromotive force for the transport of the active agent 36, 40, 42 by means of the various others. components of the electro-active assembly 12. Under usual conditions of use, the magnitude of the applied electromotive force is generally that required to transfer one or more active agents according to an effective therapeutic dosing protocol. In some embodiments, the magnitude is selected such that it satisfies or exceeds the commonly operating electrochemical potential of the iontophoresis transfer device 8.0. At least one active electrode element 24 is operable to provide an electromotive force to drive the pharmaceutical composition ( comprising at least one anesthetic or anesthetic active agent in combination with the at least one opioid antagonist) to induce analgesia or anesthesia in the individual from at least one reservoir of the active agent34 to the individual's biological interface 18.

The active electrode element 24 may take a variety of forms. In one embodiment, the electrode element 24 may usefully take the form of a carbon-based active electrode element. This may, for example, comprise multiple layers, for example a carbon-containing polymeric matrix and a conductive sheet comprising carbon fiber or carbon fiber paper, as described in Japanese patent application 2004/317317 , deposited October 29, 2004. Carbon-based electrodes are inert electrodes because they do not experience or participate in electrochemical reactions alone. Thus, an inert electrode distributes current through the oxidation or reduction of a chemical species capable of accepting or donating an electron in the potential applied to the system, (for example, by generating ions or by reducing or oxidizing water). Additional examples of inert electrodes include stainless steel, gold, platinum, capacitive carbon or graphite.

Alternatively, an active sacrificial conductive material electrode, such as a chemical compound or Î ± -malgam, may also be used. A sacrificial electrode causes electrolysis of water, but can itself be oxidized or reduced. Typically, for an anode a metal salt / metal may be employed. In such a case, the metal may oxidize to metal ions, which may then be precipitated as an insoluble salt. An example of such an anode includes an Ag / AgCl electrode. The reverse reaction occurs at the cathode where the metal ion is reduced and the corresponding anion is released from the electrode surface. The electrolyte reservoir 26 may have a variety of shapes including any structure capable of reterelectrolyte 28, and in some embodiments may. it may still be e-electrolyte 28 itself, for example where the electrolyte 28 is in a semi-solid or solid gel form. For example, the electrolyte reservoir 26 may be in the form of a small pouch or other receptacle, membrane with pores, cavities, or interstices, particularly where the electrolyte 28 is a liquid.

In one embodiment, electrolyte 28 comprises ionic or ionizable components in an aqueous medium which may actuate to conduct current in or out of the active electrode element. Suitable electrolytes include, for example, aqueous salt solutions. Preferably, electrolyte 28 includes salts of physiological ions such as sodium, potassium, chloride, and phosphate. In some embodiments, the one or more electrolyte reservoirs 24 include an electrolyte28 comprising at least one biologically compatible antioxidant selected from ascorbate, fumarate, lactate, and malate, or salts thereof.

Once electrical potential is applied, when an inert electrode element is in use, water is electrolyzed on both the active electrode and counter electrode assemblies. In certain embodiments, such as when the active electrode assembly is an anode, water is oxidized. As a result, oxygen is removed from water while protons (H +) are produced. In one embodiment, electrolyte 28 may also comprise an antioxidant. In some embodiments, the antioxidant is selected from antioxidants that have a lower potential than that of, for example, water. In such embodiments, the selected antioxidant is preferably consumed if water electrolysis occurs. In some additional embodiments, an oxidized form of the antioxidant is used in the cathode and a reduced form of the antioxidant is used in the anode. Examples of biologically compatible antioxidants include, but are not limited to, ascorbic acid (vitamin C), tocopherol (vitamin Ε), or sodium citrate.

As noted above, the electrolyte 28 may be in the form of an aqueous solution housed within a reservoir26, or in the form of a dispersion in a hydrogel or hydrophilic polymer capable of holding substantial amounts of water. For example, a suitable electrolyte may have 0.5M disodium fumarate solution form: 0.5M polyacrylic acid: 0.15M antioxidant.

The ion-selective inner membrane 30 is generally positioned to separate the electrolyte 28 and the inner reservoir from the active agent 34 if such a membrane is included with the device. The ion-selective inner membrane 30 may have the form of a charge-selective membrane. For example, when the active agent 36, 40, 42 comprises a cationic active agent, the ion-selective inner membrane 30 may be in the form of an anion exchange membrane, selective for substantially anion passing and substantially blocking cations. Ion-selective internal membrane 30 may usefully prevent or inhibit sodium (Na +) ion transfer of electrolyte 28, thereby increasing the transfer rate and / or biological compatibility of the iontophoresis device 8.

The internal active agent reservoir 34 is generally positioned between the ion selective inner membrane 30 and the outermost ion selective membrane 38. The internal active agent reservoir 34 may have a variety of shapes including any structure capable of temporarily retaining active agent 36 For example, the active agent internal reservoir 34 may be in the form of a small pouch or other receptacle, a membrane with pores, cavities, or interstices, particularly where the active agent 36 is a liquid. The active agent reservoir 34 may also comprise a gel matrix.

Optionally, a more external ion-selective membrane 38 is positioned generally opposite along the active electrode assembly 12 from the active electrode element24. The outermost membrane 38 may, as in the embodiment shown in Figures 2A and 2B, take the form of an ion exchange membrane having pores 48 (only one shown in Figures 2A and 2B for illustration clarity) of the ion selective membrane. 38 including ionic ionic material or groups 50 (only three shown in Figures 2A and 2B for clarity of illustration). Under the influence of an electromotive current or force, the ion exchange material or groups 50 passes substantially selectively ions of the same polarity as that of the active agent 36, 40, while substantially blocking ions of opposite polarity. Thus, the outermost ion exchange membrane 38 Selective charge. Where active agent 36, 40, 42 is a cation (e.g. lidocaine), the outermost ion-selective membrane 38 may be in the form of a cation exchange membrane which thereby allows the cationic active agent to pass through while blocking the return flow from the anions present in the biological interface, such as the skin.

The outermost ion-selective membrane 38 may optionally harbor the active agent 40. Without being bound by 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 electromotive force or current. and substantially releases these ions when replaced with substitute ions of equal polarity or charge under the influence of an electromotive current or force.

Alternatively, the outermost ion-selective membrane 38 may have the form of a semipermeable or microporous membrane which is size selective. In some embodiments, such a semipermeable membrane may advantageously harbor the active agent 40, for example, by releasably releasably disposing the outer coating to retain the active agent 40 until the coating is present. external release is removed prior to use.

The outermost ion-selective membrane 38 may optionally be preloaded with additional active agent 40, such as ionized or ionizable drugs or therapeutic agents and / or polarized or polarizable drugs or therapeutic agents. Where the outermost ion-selective membrane 38 is an ion exchange membrane, a substantial amount of the active agent 40 may bind to ion exchange groups 50 in the pores, cavities or interstices 48 of the outermost ion-selective membrane 38.

Active agent 42 that fails to bind to the ion exchange material groups 50 may adhere to the outer surface 44 of the outermost ion-selective membrane 38 as the additional active agent 42. Alternatively, or additionally, the additional active agent 42 may be positively deposited on and / or adhered to at least a portion of the outer surface 44 of the outermost ion-selective membrane 38, for example by spraying. , dipping, coating, electrostatically, vapor deposition, and / or otherwise. In some embodiments, the additional active agent 42 may sufficiently cover the outer surface 44 and / or be of sufficient thickness to form a distinct layer 52. In other embodiments, the additional active agent 42 may not be sufficient in volume; thickness, or covering to form a layer in a conventional sense of such a term.

The active agent 42 may be deposited in a variety of highly concentrated forms such as, for example, solid form, quasi-saturated solution form, or formable. If in solid form, a hydration source may be provided, either integrated into the active electrode assembly 12, or applied from the outside just prior to use.

In some embodiments, active agent 36, additional active agent 40 and / or additional active agent 42 may be identical or similar compositions or elements. In other embodiments, active agent 36, additional active agent40, and / or additional active agent 42 may be different compositions or elements from each other. Thus, a first active agent type can be stored in the internal active agent reservoir 34, while a second type of active agent may be housed in the outermost ion-selective membrane 38. In such an embodiment, the first type or the second type The active agent type may be deposited on the outer surface 44 of the outermost ion-selective membrane38 as the additional active agent 42. Alternatively, a mixture of the first and second types of active agent may be deposited on the outer surface 44 of the outermost selective membrane. 38 as the additional active agent42. As an additional alternative, a third type of active agent composition or element may be deposited on the outer surface 44 of the outermost ion-selective membrane38 as the additional active agent 42. In another embodiment, a first type of active agent may be be stored in the internal active agent reservoir 34 as the active agent36 and housed in the outermost ion selective membrane 38 as the additional active agent 40, while a second type of active agent may be deposited on the outer surface 44 of the outermost ion selective membrane. 38 as the additional active agent 42. Typically, in modalities where one or more different 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 external release liner may generally be positioned overlining or overcoating more active agent 42 driven by the outer surface 44 of the outermost ion-selective membrane 38. The external release liner may protect additional active agent 42 and / or the membrane. outermost selective ion 38 during storage, prior to the application of a current or electromotive force. The external release liner may be a selectively releasable coating made of waterproof material such as release liners commonly associated with pressure sensitive adhesives.

An interface coupling means (not shown) may be employed between the electrode assembly and the biological interface 18. The interface coupling means may, for example, take the form of an adhesive and / or gel. The gel may be in the form of a moisturizing gel. The selection of bio-descriptive gels is inserted in the knowledge of those usually reversed in the relevant technique.

In the embodiment illustrated in Figures 2A and 2B, counter electrode assembly 14 comprises, from an interior 64 to an exterior 66 of the counter electrode assembly 14: an counter electrode element 68, an electrolyte reservoir 70 which stores an electrolyte 72, a membrane internal selective-ion filter74, an optional buffer reservoir 76 which holds buffer material 78, an optional outermost ion-selective membrane80, and an optional external (unshown) release liner.

Counter electrode element 68 is electrically coupled to a second pole 16b of power source 16, the second pole 16b having an opposite polarity to that of first pole 16a. In one embodiment, the counter electrode element 68 is an inert electrode. For example, the counter electrode element68 may take the form of the carbon base electrode element discussed above.

The reservoir 70 may take a variety of forms including any structure capable of holding the electrolyte72, and in some embodiments may even be the electrolyte 72 suitably, for example, where the electrolyte 72 is in a gel, semi-solid or solid form. For example, electrolyte reservoir 70 may take the form of a small pouch or other receptacle, or a membrane with pores, cavities, or interstices, particularly where electrolyte 72 is a liquid.

Electrolyte 72 is generally positioned between counter electrode element 68 and the outermost ion-selective membrane 80 in the vicinity of counter electrode element 68. As described above, electrolyte 72 may provide ions or air charges to prevent or inhibit the gas bubbles (eg hydrogen or oxygen, depending on electrode polarity) in counter electrode element 68 and can prevent or inhibit the formation of acids or bases or neutralize them, which can improve efficiency. and / or reduce the potential for biological interface irritation 18.

The internal ion-selective membrane 74 is positioned between and / or separates the electrolyte 72 from the buffer material 78. The internal ion-selective membrane 74 may be in the form of a charge-selective membrane, such as the illustrated ion-detonating membrane. substantially permits ion passages of a first polarity or charge while substantially blocking the passage of ions or charges of a second, opposite polarity. The inner ion-selective membrane 74 will typically pass ions of polarity or charge opposite to that passed through the outermost ion-selective membrane 80 while substantially blocking ions of equal polarity or charge. Alternatively, the internal ion-selective membrane 74 may be in the form of a microporous semi-permeable membrane that is size selective.

Internal ion-selective membrane 74 may prevent the transfer of undesirable elements or compounds into buffer material 78. For example, ion-selective membrane 74 may prevent or inhibit the transfer of ionshydroxyl (OH-) or chloride (C1-) from electrolyte72 into the buffer material 78.

The optional buffer reservoir 76 is generally disposed between the electrolyte reservoir and the outermost ion-selective membrane 80. The buffer reservoir 76 may have a variety of shapes capable of temporarily holding the buffer material 78. For example, the buffer reservoir 76 may take the form of a buffer. cavity, a porous membrane, or gel. Buffer material 78 may provide ions for transfer through the outermost ion-selective membrane 42 to the biological interface 18. Accordingly, buffer material 78 may comprise, for example, a salt (e.g., NaCl).

The outermost ion-selective membrane 80 of the counter electrode assembly 14 may take a variety of forms. For example, the outermost ion-selective membrane 80 may take the form of a charge-selective ion exchange membrane. outermost ion-selective membrane 80 of counter electrode assembly 14 is ion-selective with a charge or polarity opposite to that of the outermost ion-selective membrane 38 of active electrode assembly 12. The outermost ion-selective membrane 80 It is therefore a trochanion membrane, which substantially passes anions and blocks cations, thereby preventing backflow of cations from the biological interface. Examples of suitable ion exchange membranes include previously discussed membranes.

Alternatively, the outermost ion-selective membrane 80 may take the form of a semi-permeable membrane that substantially passes and / or blocks ions based on ion size or molecular weight.

The outer release liner (not shown) may generally be positioned by overlaying or covering an outer surface 84 of the outermost ion-selective membrane 80. The outer release liner may protect the outermost ion-selective membrane 80 during storage prior to storage. of applying an electromotive force or current. The external release liner may be selectively releasable waterproof coating such as release liners commonly associated with pressure sensitive adhesives. In some embodiments, the external release liner may be coextensive with the external release liner (not shown) of the active electrode assembly 12.

The iontophoresis device 8 may also comprise an inert impression material 86 adjacent the exposed sides of the various other structures forming the active electrode and counter electrode assemblies 12, 14. The demolding material 86 may advantageously provide protection. for the various structures of the electrode and counter electrode assemblies 12, 14. The envelope of the active electrode and counter electrode assemblies 12, 14 is a housing material 90.

As best seen in Figure 2B, the active electrode and counter electrode assemblies 12, 14 are positioned at the biological interface 18. The positioning of the biological interface can close the circuit, allowing current and / or force to be applied. electromotive to flow from one pole 16a of the power source 16 to the other pole 16b by means of the active electrode assembly, biological interface 18 and electrode counter-assembly 14.

In use, the outermost active electrode ion-selective membrane 38 may be placed directly in contact with the biological interface 18. Alternatively, an interface coupling means (not shown) may be employed between the outermost active electrode ion-selective membrane 22e. biological interface 18. The face coupling means may take, for example, the form of an adhesive and / or gel. The gel may be, for example, in the form of a hydration gel or a hydrogel. If used, the interfacing coupling means must be permeable to the active agent 36, 40, 42. In some embodiments, power source 16 is selected to provide sufficient voltage, current, and / or duration to ensure transfer of one or more more active agents 36, 40, 42 from reservoir 34 and via a biological interface (e.g., membrane) to impart the desired physiological effect. Power source 16 may take the form of one or more chemical battery cells, super- or ultra-capacitors, fuel cells, secondary cells, thin-film secondary cells, button cells, lithium-ion cells, zinc-air cells. , nickel metal hydride cells, and the like. Power source 16 may, for example, provide a voltage of 12.8 V DC with a tolerance of 0.8 V DC and a current of 0.3 mA. The power source 16 may be selectively electrically coupled to the active electrode and counter electrode assemblies 12, 14 by means of a control circuit, for example through carbon fiber strips. The iontophoresis device 8 may include discrete and / or integrated circuit elements to control the voltage, current, and / or energy transferred to the electrode assemblies 12, 14. For example, the iontophoresis device 8 may include a diode for provide a constant current to the electrode elements 24, 68.

As suggested above, the one or more active agents36, 40, 42 may take the form of one or more drugs, or other ionic, cationic, ionizable, and / or neutral therapeutic agents. Accordingly, the poles or terminals of the energy source 16 and the selectivity of the outermost ion-selective membranes 38, 80 and the innermost ion-selective membranes 30, 74 are consequently selected.

During iontophoresis, the electromotive force through the electrode assemblies, as described, leads to a migration of active agent charged molecules, leads to a migration of active agent charged molecules, as well as ion and other charged components via the biological interface. into the biological tissue. This migration may lead to the accumulation of active agents, ions, and / or other charged components contained in biological tissue beyond the interface. During iontophoresis, in addition to the migration of charged molecules in response to repulsive forces, there is also an electroosmotic solvent flux (eg, water) through the electrodes and the biological interface within the tissue. In certain embodiments, the electroosmotic solvent flux improves the migration of both charged and uncharged molecules. Migration stimulated by electroosmotic solvent flux can occur particularly with increasing size of the molecule.

In certain embodiments, the active agent may be a larger molecular weight molecule. In certain aspects, the molecule may be a polar polyelectrolyte. In some other aspects, the molecule may be lipophilic. In certain embodiments, such molecules may be charged, may have a low net charge, or may be uncharged under the concentrations within the active electrode. In certain respects, such active agents may poorly migrate under repulsive iontophoretic forces, in contrast to the migration of the highly charged minor active agents under the influence of these forces. Such higher molecular weight active agents can thus be transported through the biological interface into the underlying tissues primarily by the electroosmotic flow of the solvent.

In certain embodiments, the high molecular weight polyelectrolytic active agents may be proteins, polypeptides, or nucleic acids. In other embodiments, the activating agent may be mixed with another agent to form a complex capable of being transported through the biological interface by one of the driving methods described above.

In some embodiments, transdermally drug transfer system 6 includes an iontophoretic drug transfer device 8 for transdermally transferring one or more active agents 36, 40, 42 to a biological interface 18. Transfer 8 includes electrode assembly 12 which includes at least one active agent reservoir and at least one operable active electrode member for providing an electromotive force to drive an active agent from at least one active agent reservoir. The transfer device 8 may include an electrode mount 14 including at least one counter electrode member 68, and a power source 16 electrically coupled to at least one of the active electrode members and at least one of the counter electrode members. electrode 20, 68. In some embodiments, the iontophoretic transfer of drug 8 may also include one or more active agents 36, 40, 42 charged to at least one reservoir of active agent 34. As shown in Figure 2C, The transfer device 8 may also include a substrate 10 which includes a plurality of microneedles 17 in fluid communication with the active electrode assembly 12, and positioned between the active electrode assembly 12 and the biological interface 18. The substrate 10 may be positioned between the electro-active assembly 12 and the biological interface 18. In some embodiments, the at least one active electrode element 20 is operable to provide an electromotive force to conduct the reactive agent 3. 6, 40, 42 from at least one reactive reservoir 34, through the plurality of microneedles 17, and to the biological interface 18.

As shown in Figures 3A and 3B, substrate 0 includes a first side 102 and a second side 104 as opposed to the first side 102. The first side of substrate 10 includes a plurality of microneedles 17 projecting outwardly from the first side 102. The microneedles 17 may be individually provided or formed as part of one or more arrangements. In some embodiments, the microneedles 17 are integrally formed from the substrate 10. The microneedles 17 may take a solid and permeable form and / or solid and non-permeable form. In some other embodiments, solid, non-permeable microneedles may also comprise grooves along their outer faces to aid transdermal transfer 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 micro-braces may be filled with ion exchange material, ion-selective materials, permeable materials, semi-permeable materials, solid materials, and the like.

Microneedles 17 are used, for example, to transfer a variety of compositions, molecules, compounds, pharmaceutical active agents, and the like to a living organism via the biological interface, such as skin or mucous membrane. In certain embodiments, pharmaceutical compositions, molecules, compounds, active agents, and the like may be transferred to or through the biological interface. For example, in the transfer of pharmaceutical compositions, molecules, compounds, active agents, and the like through the skin, the length of the microneedles 17, either individually or in arrays 100a, 100b, and / or the depth of the insertion. It may be used to control whether the administration of a pharmaceutical composition, molecules, compounds, active agents and the like is only in the epidermis, through the epidermis to the dermis, or subcutaneously. In certain embodiments, the microneedle 17 may be useful for the transfer of high molecular weight active agents, such as those comprising proteins, peptides and / or nucleic acids, and their corresponding compositions. In certain embodiments, for example, where the fluid is an ionic solution, the microneedles 17 may provide electrical continuity between the energy source 16 and the microneedle tips 17. In some embodiments, the microneedles 17, either individually or in gears 100a, 100b may be used to dispense, transfer, and / or sample fluids through the hollow openings through the permeable or semi-permeable solid materials or through the outer slots. The microneedles 17 may also be used to dispense, transfer, and / or sample pharmaceutical compositions, molecules, compounds, active agents, and the like by 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 on a more external biological interface contact surface of a transdermal drug transfer system 6. In some embodiments, the compositions Pharmaceuticals, molecules, compounds, active agents, and the like transferred or sampled by such a system may comprise, for example, high molecular weight active agents, such as proteins, peptides, and / or nucleic acids.

In some embodiments, a plurality of microneedles 17 may be in the form of a microneedle array 100a, 100b. The microneedle array 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, irregular or irregular shapes, and the like. Microneedles 17e and microneedle arrangements 100a, 100b can be manufactured from a variety of materials including ceramic materials, elastomers, photoresist, epoxy, glass, glass polymers, glass / polymer materials, metals (for example , chrome, cobalt, gold, molybdenum, nickel, stainless steel, titanium, tungsten steel, and the like), molded plastics, polymers, biodegradable polymers, non-biodegradable polymers, organic polymers, inorganic polymers, silicone, silicon dioxide, poly-silicone, silicone rubbers, organic silicon-based polymers, superconducting materials (e.g., superconducting wafers, the like), and the like, as well as their combinations, com-pits, and / or alloys. Techniques for the manufacture of needle spikes 17 are well known in the art and include, for example, electroplating, electroplating by laser sculpted polymeric molds, laser cutting and electro polishing, laser micro-machining, micro-machining. surface machining, light lithography, X-ray lithography, LIGA techniques (eg, X-ray lithography, electro-plating and molding), injection molding, conventional silicone-based manufacturing methods (eg inductively coupled plastine cauterization, wet cauterization, and isotropic and anisotropic cauterization, solicited isotropic cauterization, siliconized anisotropic cauterization, GaAs anisotropic cauterization, isotropic micro-siliconized cauterization, isotropic micro-silicon cauterization similar), complementary symmetry / oxidometallic semiconductor (CMOS) technology, deep X-ray exposure techniques, and the like. See, for example, U.S. Patents. We. 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; 6.5 65,532; 6,603,987; 6,611,707; 6,663,820; 6.7 67.341; 6.7 90.372; 6,815,360; 6,881,203; 6,908,453; and 6,939,311. Part or all of the guidance herein may be applied to microneedle devices, their manufacture, and their use in iontophoretic applications. In some techniques, the physical characteristics of the microneedles 17 depend, for example, on anodizing conditions (eg, current density, cauterization time, HF concentration, temperature, induction adjustments, and the like) as well as properties of anodizing. substrate (e.g., doping density, doping orientation, and the like).

The microneedles 17 may be sized and shaped to penetrate the outer layers of the skin to increase its permeability and transdermal transport of pharmaceutical compositions, molecules, compounds, active agents, and the like. In some embodiments the microneedles17 are sized and shaped with the appropriate geometry and sufficient strength to fit into a biological interface (e.g., the skin or mucous membrane of an individual or the like), thereby enhancing a transinterface (e.g. transdermal) for transport of pharmaceutical compositions, molecules, compounds, active agents, and the like.

Figure 4 shows a representative method 400 for the systemic treatment of at least one condition associated with pain, neuropathic pain, acute pain, chronic pain, or cancer pain.

At 402, the method includes contacting a position on a biological interface 18 with an iontophoretic drug transfer device 8 including an electrode assembly 12 having at least one active agent reservoir 34. At least one active agent reservoir 34 includes a pharmaceutical composition comprising at least one therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist.

In some embodiments, the at least one agonistopioid is selected from endogenous opioid peptides, opium alkaloids, semi-synthetic opioids, and fully synthetic opioids, or analogs or derivatives thereof, or their pharmaceutically acceptable salts or solvates.

In some embodiments, the at least one agonistopioid is selected from (5α, 7a, 8β - (-) - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro (4,5) dec. 8-yl] -benzene-acetamide (1169, 593)), [D-Ala2, N-Me-Phe4, Gly5-Ol] enkephalin (DAMGO), delta- ([D-Pen2, D-Pen5] -encefalin ( (DPDPE)), buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, heroin, hydrdrone, hydromorphone, meperidine, methadone, morphine, nicomorphine, opio, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, or anilidine, or tiláldine or its derivatives or pharmaceutically acceptable salts or solvates thereof.

In some embodiments, the at least one opioid antagonist is selected from [(-) - (1R, 5R, 9R) -5,9-diethyl-2- (3-furylmethyl) -2'-hydroxy-6,7 - benzomorphan] (MR2266), [allyl] 2-tir-alpha-amino-isobutyric acid (Aib) -Aib-Fe-Leu-OH (ICI-174864), 4- (3-hydroxyphenyl) -34-dimethyl-alpha -phenyl-1-piperidinepropanol (LI117413), δβ-Naltrexole, 7-Benzylidenenaltrexone (BNTX), b-funaltrexamine (b-FNA), cyclazocine, cyclorfan, dezocine, diprenorphine, levorfanol, meptazinol, methiodide, methylnaltrex, nalmexone, nalorphine, nalorphine dicotinate, naloxonazine, naloxone, naltrexone, naltriben (NTB), naltrindole (NTI), naltrindole isocyanate (NTII), N-cyclopropylmethyl-4,14-dimethoxy-morfinan-6-one nor-binaltorphinine (nor-BNI), oxylorfan, nalbuphine, and trans-3,4-dimethyl-4-phenylpiperides, or their analogs or derivatives, or their pharmaceutically acceptable salts or solvates.

In some embodiments, the at least one opioid antagonist is selected from hydromorphone, or derivatives thereof, or pharmaceutically acceptable salts or solvates thereof; and the at least one opioid antagonist is selected from naloxone, naltrexone, nalmefene, naloxonazine, NTI, nor-BNI, LY25506, LY9935, LY255582, or LY117413, or derivatives thereof, or their pharmaceutically acceptable salts or solvates.

In some embodiments, the at least one opioid antagonist is selected from hydromorphone, or analogs or derivatives thereof, or pharmaceutically acceptable salts or solvates thereof; and the at least one opioid antagonist is selected from naloxone, naltrexone, ββ-naltrexole, nalmefene, and naloxonazine, or analogs or derivatives thereof, or their pharmaceutically acceptable salts or solvates. In some embodiments, the at least one opioid antagonist is selected from paladone, Palladone® SR, hydromorphone Dilaudid® hydrochloride; and the at least one opioid antagonist is selected from Narcan®, Trexan®, Revex®, Nubian®, nalaxone hydrochloride, naltrexone hydrochloride, nalmefene hydrochloride, and nulbuphine hydrochloride.

In still some additional embodiments, at least one opioid agonist and at least one opioid antagonist are present in synergistic antihyperalgesic amounts.

In some embodiments, the at least one condition associated with pain, neuropathic pain, acute pain, chronic dro, or cancer pain includes: chemotherapy; alcoholism; amputation (eg phantom limb pain); a problem born, legs, or hip (sciatica); diabetes; a problem facial nerve (trigeminal neuralgia); an infection with HIV or AIDS; multiple sclerosis; spinal surgery; opiate-induced narcotic / respiratory depression; or detoxification of opiate addiction.

In some embodiments, the pharmaceutical composition further comprises at least one selected active agent of vaccines, antibiotics, adjuvants, immune adjuvants, immunogenic, tolerogenic, allergens, Toll-like receptor agonists, Toll-like receptor antagonists. , immunoadjuvants, immunomodulators, immune response agents, immunostimulants, specific immunostimulants, non-specific immunostimulants, and immunosuppressants, or combinations thereof.

At 404, the method also includes applying a sufficient amount of current to the active electrode assembly 12 to transdermally deliver a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of at least one agonistopioid and at least antagonist. opioid. In some instances, applying a sufficient amount of current to the active electrode assembly 12 comprises providing sufficient voltage and current over a period of time to the active electrode assembly 12 to transfer a therapeutically effective amount of the pharmaceutical composition comprising the active electrode assembly. The therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist from at least one reservoir of active agent 34 to the site at the biological interface 18. In some embodiments, applying a sufficient amount of current comprises providing a sufficient voltage and current over a period of time to the active electrode assembly 12 to substantially achieve prolonged or controlled transfer of the pharmaceutical composition comprising the therapeutically effective amount of at least one o-pyoid agonist and at least one antagonist. opioid for an extended period of time, d and in order to produce α-anesthetic, analgesic, or antihyperalgesic therapy in an individual.

Figure 5 shows a representative method of inducing anesthesia, analgesia, or antihyperalgesia in an individual.

At 502, the method includes positioning an active electrode and counter electrode of an iontophoretic transfer device at a subject's biological interface. In some embodiments, the iontophoretic drug transfer device 8 is operable for transferring formaphthoretic to a pharmaceutical composition comprising an effective amount of at least one opioid agonist and at least one opioid antagonist.

At 504, the method further includes iontophoretically transferring a synergistic anesthetic inducing, analgesic inducing, or antihyperalgesic inducing amount of a pharmaceutical composition comprising at least one opioid agonist and at least one opioid antagonist.

Figure 6 shows a representative method 600 for denying opiate dependence and / or bringing about a substantially opiate free state in an individual in need thereof.

At 602, the method includes contacting a site in a subject's biological interface 18 with an operable iontophoretic drug transfer 8 for i-ontophoretically transferring a pharmaceutical composition comprising a therapeutically effective amount of at least one opioid antagonist.

At 604, the method additionally includes transdermally transferring a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of the at least one opioid antagonist.

At 606, the method further includes providing sufficient voltage and current to transfer the therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of the at least one opioid antagonist to the site at the subject's biological interface 18 so as to bring about substantially free state. of opiate.

Figure 7 shows a representative method of treating opiate agonist-induced narcotic / respiratory depression in an individual in need thereof.

At 702, the method includes contacting a site in a subject's biological interface 18 with an operable iontophoretic drug transfer device 8 to iontophoretically transfer a pharmaceutical comprising a therapeutically effective amount of at least one opioid antagonist.

At 704, the method further includes transdermally transferring a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of the at least one opioid antagonist.

Figure 8 shows a graph Time (min) vs. Transported Drug (g) for the transfer of hydromorphone through human skin according to an i-polished embodiment. A Franz cell assembly using dermatomedical human skin as the central chamber barrier was used to demonstrate transport across human skin. Hydromorphone was diluted in 1 mg / mL water and placed in contact with the anode side of an iontophoretic transfer device 8. A current density of 0.33mA / cm2 was applied to the cell and definite moments were taken as shown. in the graph Time (minutes) vs. Carrier Drug (g). Samples were analyzed for the presence of hydromorphone and labeled as a function of time. As shown in Figure 9, mass spectral analysis was performed on serum samples from midday pigs following iontophoretic transfer of hydromorphine. according to an illustrated embodiment. 250 μΐ plasma were combined with 1.25 mL borate buffer (11 g sodium borate and 6.5 g boric acid per liter water) at pH 8.9. 5 ng of internal standard (hydromorphone-d6) was added and mixed. SPE tubes (Varian Inc. Harbor City, CA) were prepared by washing with 2 mL methanols followed by 2 mL deionized water. The samples were applied and pulled by vacuum. The SPE tubes were then washed with 2 mL deionized water, 2 mL 10 mM deammonium acetate pH = 4, and 2 mL methanol. The SPE tubes were then dried under high vacuum for 5 minutes. The material was eluted with 2 mL methylene chloride: isopropyl alcohol: 80: 20: 2 ammonium hydroxide. The eluent was evaporated at 40 ° C under a stream of air. The residue was then reconstituted in 75 µL of mobile phase HPLC and injected into an HPLC column. HPLC-MS is an Agilent Technologies (Palo Alto, CA) 1100 series including binary pump, degassing module, autosampler, column housing, and mass spectrometer. The column was a Zorbax SB-C18 150 mm χ 2.1 mm χ 5 μ (Agilent Technologies, Palo Alto, CA.). The column was kept at 30 ° C. The mobile phase consisted of 10 mM deammonium acetate pH = 4: acetonitrile 91: 9. The flow rate was 0.25 mL / min. The mass spectrometer was operated as ESI + using selected monitoring (YES) for maximum sensitivity. The monitored ions were m / z 286 for hydromorphone and m / ζ 292 for hydromorphone-dô. The lower limit of quantitation for 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 graph Time (min) vs. hydromorphone (ng / ml) of an in vivo piglet experiment according to one illustrated embodiment. For the electrode, a carbon base on polyethylene film was used. The bandage reinforcement material was 3M (medical cell closed polyolefin foam reinforcement, product # 9773). The shell material was polyester fabric (Textile Development Associates, # PETNF322.3030), 17 mm diameter, and 2 mm nominal thickness. The discs were specially treated by saturating with 2% w / v hydroxypropyl cellulose solution (Klucel, MF Pharm, HerculesCorp.) And dried in a convection oven. The transfer solution was prepared by dissolving 21 mg hydromorphone hydrochloride (Sigma Chemical Co., Lot # 024K1167) in 10 mL buffer containing 0.155 M Na deascorbate, pH 4.55) to yield 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 buffer and drug concentrations were made on the same day as the experiment. The bandage was made by placing the screen printed electrode (TTI) on the back of the reinforcement material. Above this, two layers of reinforcement material with 17 mm holes punched to cover the carbon electrode were placed. In the holes, HPC-treated reservoir discs were placed. An aliquot (325 μΐ *) of either drug or counter-solution was placed in the appropriate reservoir and left to hydrate the coated polyester fabric. (For control bandages, as-corbate buffer alone was used on the transfer side). After hydration (~ 2 minutes), the transfer paper of the foamed reinforcing material was removed and the reservoir disc was covered by a protective hydrophilic membrane. Another coating of binding paper (3M) was then placed over the reservoirs until use.

The bandages were triggered by 8-channel potentios-tat / galvanostat (Solartron Analytical Model 1480) running cell test software (Solartron Analytical) for instrumental control and data acquisition. The drug transfer electrode was connected to the anode (+) and the counter electrode was connected to the cathode (-). The current was transferred under a controlled current protocol at 1 mA (bandage area 2.27 cm 2, current density 0.44 mA / cm 2) for 45 minutes duration. The instrument captured the total voltage drop through the bandage reflecting the sum of the voltages (resistance to current flow) through each electrode, the skin at both interfaces and the underlying fabric. Samples were collected at the indicated times and analyzed as shown in Figure 10.

The above description of the illustrated embodiments, including what is described in the Summary, is not intended to be exhaustive or to limit the claims to the precise forms disclosed. While specific embodiments and examples are described herein for illustrative purposes, various equivalent modifications may be made without departing from the spirit and scope of the coating, as will be identified by those ordinarily skilled in the relevant art. The guidelines provided herein may be applied to other agent transfer device systems, not necessarily to the representative iontophoresis activating agent system and device described herein. For example, some embodiments may include additional structure. For example, some embodiments may include a control circuit or subsystem for controlling the voltage, current, or energy 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. Outer electrode-active ion-selective 22 and biological interface 18. Some embodiments may include additional ion-selective membranes, ion exchange membranes, semipermeable membranes and / or porous membranes, as well as additional reservoirs for electrolytes and / or tampons.

Several electrically conductive hydrogels are known and used in the medical field to provide an electrical interface to the skin of an individual or within a device to couple an electrical stimulus to the individual. Hydrogels moisturize the skin, thereby protecting against burns due to electrical stimulation through the hydro gel, while swelling the skin and allowing more efficient transfer of an active component. Examples of such 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; 5.2 90.585; 6.7 97.27 6; 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 their entirety. Additional examples of such hydrogels are disclosed in U.S. Patent Applications Nos. 2004/166147; 2004/105834; and 2004/247655, incorporated herein by reference in their entirety. Trademarks of various hydrogels and hydrogel sheets include CorplexTM by Corium, TegagelTM by 3M, PuraMatrixTM by BD; VigilonTM by Bard; ClearSiteTM by Conmed Corporation; FlexiGelTM by Smith &Nephew; Derma-GelTM by Medline; Nu-GelTM by Johnson &Johnson; and CuragelTM by Kendall, or deacrylhydrogel films available from Sun Contact Lens Co., Ltd.

In certain embodiments, compounds or compositions may be transferred by an iontophoresis device comprising an active electrode assembly and a counter electrode assembly electrically coupled to a power source to transfer an active agent into or via a biological interface. The active electrode assembly includes the following: a first electrode element connected to a positive electrode of the power source; an active agent reservoir having a drug solution that is in contact with the first electrode element and to which a voltage is applied via the first electrode element; a contact element of the biological interface, which may be a microneedle arrangement and is placed against the front surface of the active agent reservoir; and a first cover or container accommodating such elements. The counter electrode assembly includes the following: a second electrode element connected to a negative electrode of the voltage source; a second holding portion holding an electrolyte which is in contact with the second electrode element and to which voltage is applied by means of the second electrode element; and a second cover or container accommodating such elements.

In certain embodiments, compounds or compositions may be transferred by an iontophoresis device comprising an active electrode mount and a counter electrode mount electrically coupled to a power source to transfer an active agent into or through an electrode. biological interface. The active electrode assembly includes the following: a first electrode element connected to a positive electrode from the voltage source; a first electrolyte reservoir having an electrolyte which is in contact with the first electrode element and to which a voltage is applied via the first electrode element, a first ion exchange membrane that is placed on the front surface of the first portion supports the electrolyte; an active agent reservoir that is placed against the front surface of the first ion exchange membrane, a contact element with the biological interface, which may be a microneedle arrangement, and is placed against the front surface of the active agent reservoir; and a first cover or container that accommodates these elements. Counter electrode assembly includes the following: a second electrode element connected to a negative electrode from the voltage source; a second electrolyte supporting portion having an electrolyte which is in contact with the second electrode element to which a voltage is applied via the second electrode element; a cation exchange membrane that is placed on the front surface of the second electrolyte reservoir; a third electrolyte reservoir that is placed against the front surface of the trochantic membrane and holds an electrolyte to which a voltage is applied by the second electrode element by means of the second electrolyte supporting part and the cation exchange membrane; a second anion exchange membrane placed against the front surface of the third electrolyte reservoir; a second cover or container that accommodates these elements.

The various embodiments described above may be combined to provide additional embodiments. All US Patents, US Patent Application publications, foreign patents, foreign patent applications and non-patent publications referred to in that specification and / or listed in the Application Data Sheet are incorporated herein by reference, in including, but not limited to: Japanese Patent Application Serial No. H03-86002, filed March 27, 1991, having Japanese Publication No. H04-297277, issued on March 3, 2000as Japanese Patent No. 3040517 ;

Japanese Patent Application Serial No. 11-033076, filed February 10, 1999, having Japanese Publication No. 2000-229128;

Japanese Patent Application Serial No. 11-033765, filed February 12, 1999, having Japanese Publication No. 2000-229129;

Japanese Patent Application Serial No. 11-041415, filed February 19, 1999, having Japanese Publication No. 2000-237326;

Japanese Patent Application Serial No. 11-041416, filed February 19, 1999, having Japanese Publication No. 2000-237327;

Japanese Patent Application Serial No. 11-042752, filed February 22, 1999, having Japanese Publication No. 2000-237328;

Japanese Patent Application Serial No. 11-042753, filed February 22, 1999, having Japanese Publication No. 2000-237329;

Japanese Patent Application Serial No. 11-099008, filed April 6, 1999, having Japanese Publication No. 2000-288098;

Japanese Patent Application Serial No. 11-099009, filed April 6, 1999, having Japanese Publication No. 2000-288097;

PCT patent application WO 2002JP4696, filed May 15, 2002, having PCT Publication No. WO003037 425; U.S. patent application Serial No. 10/488970, filed March 9, 2004;

Japanese patent application 2004/317317, filed October 29, 2004;

U.S. provisional patent application Serial No. 60 / 627,952, filed November 16, 2004;

Japanese Patent Application Serial No. 2004-347814, filed November 30, 2004;

Japanese Patent Application Serial No. 2004-357313, filed December 9, 2004;

Japanese Patent Application Serial No. 2005-027748, filed February 3, 2005;

Japanese Patent Application Serial No. 2005-081220, filed March 22, 2005;

U.S. Provisional Patent Application No. 60 / 722,136 filed September 30, 2005;

U.S. Provisional Patent Application No. 60 / 754,688 filed December 29, 2005;

U.S. Provisional Patent Application No. 60 / 755,199 filed December 30, 2005; and

U.S. Provisional Patent Application No. 60 / 755,401 filed December 30, 2005.

Those skilled in the relevant art may readily appreciate that the present disclosure comprises methods of treating an individual by any compositions and / or methods described herein.

Aspects of the various embodiments may be modified, if necessary, to employ systems, patent circuits, and patent applications, applications, and publications to provide further additional embodiments, including those patents and applications identified herein. While some modalities may include all membranes, reservoirs, and other structures discussed above, other modality may omit some of the membranes, reservoirs, or other structures. Still other embodiments may employ additional membranes, reservoirs, and structures generally described herein. Even the additional embodiments may omit some of the membranes, reservoirs and structures described above while employing additional demembranes, reservoirs and structures generally described herein.

These and other changes may be made in light of the detailed description presented above. In general, in the claims set forth below, the terms used are not to be construed as limiting the specific embodiments disclosed in the specifications and claims, but should be considered to include all systems, devices and / or methods operating in accordance with the foregoing. King-vindications. Accordingly, the invention is not limited by disclosure, but on the contrary, its scope is determined entirely by the claims set forth below.

Claims (21)

1. Method for systemic treatment of at least one condition with pain, neuropathic pain, acute pain, chronic pain, or cancer pain, characterized by the fact that it comprises: contacting a site at a biological interface with a drug transfer device iontophoretically, the i-ontophoretic drug transfer device comprising an active electrode assembly having at least one active agent reservoir, or at least one active agent reservoir including a pharmaceutical composition comprising at least an amount thereof. -epatically effective for at least one opioid agonist and at least one opioid antagonist; Applying a sufficient amount of current to the active electrode assembly to transdermally administer 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. Method according to claim 1, characterized in that applying a sufficient amount of current to the active electrode assembly comprises: providing sufficient voltage, current, or current for a predetermined interval of time to the active electrode assembly to transferring a therapeutically effective amount of the pharmaceutical composition comprising the therapeutically effective amount of the at least one opioid agonist and at least one opioid antagonist, from at least one active agent reservoir to the site on the biological interface. A method according to claim 1, characterized in that a sufficient amount thereof comprises: providing sufficient voltage and current over a period of time to the active electrode assembly to substantially achieve prolonged transfer or controlled transfer of the composition. A pharmaceutical composition comprising a therapeutically effective amount of at least one opioid agonist and at least one opioid antagonist over an extended period of time so as to produce anesthetic, analgesic, or antihyperalgesic therapy in an individual. . A method according to claim 1, characterized in that the 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 thereof or solvates thereof. A method according to claim 1, characterized in that the at least one agonistopioid is selected from (5α, 7α, 8β - (-) - N-methyl-N- [7- (1-pyrrolidinyl). ) -1-oxaspiro (4,5) dec-8-yl] -benzene-acetamide (U69,593)), [D-Ala 2, N-Me-Phe 4, Gly5-Ol] encefalin (DAMGO), delta- ( [D-Pen2, D-Pen5] -encefalin (DPDPE)), buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, heroin, hydrocone, hydromorphone, meperidine, methadone, morphine, nicomorphine, opium, oxycodone, oxymmorphine, pentazocine, propoxyphene, and tilidene, or analogs or derivatives thereof, or pharmaceutically acceptable salts or solvates thereof. A method according to claim 1, characterized in that the at least one opioid antagonist is selected from [(-) - (IR, 5R, 9R) -5,9-diethyl-2- (3- furylmethyl) -2'-hydroxy-β, 7-benzomorphan] (MR2266), [allyl] 2-thyr-alpha-isobutyric acid (Aib) -Aib-Phe-Leu-OH (ICI-174864), 4- (3-hydroxyphenyl) -34-dimethyl-alpha-phenyl-1-piperidinepropanol (LY117413), ββ-Naltrexol, - 7-Benzylidenenaltrexone (BNTX), b-funaltrexamine (b-FNA), cyclazocine, cyclorfan, dezocine, diprenorphine, levorfanol, meptazinol, methiodide, methylnaltrexone, nalida, nalmefene, nalmexone, nalorphine, nalorphine dicotinate, naloxonazine, naloxone, naltrexone, naltriben (NTB), naltrindole (NTI), niothiocycline (NTI), nitrylthipropion, , 14-dimethoxy-morfinan-6-one (cyprodime), norbinaltorphinine (nor-BNI), oxlorfan, nalbuphine, and trans-3,4-dimethyl-4-phenylpiperides, or their analogs and derivatives, or salts thereof or pharmaceutically acceptable solvates. A method according to claim 1, characterized in that the at least one opioid antagonist is selected from hydromorphone, or analogs or derivatives, or pharmaceutically acceptable salts or solvates thereof; and the at least one opioid antagonist is selected from naloxone, naltrexone, nalmefene, naloxone-zine, NTI, nor-BNI, LY25506, LY9935, LY255582, and LY117413, or their analogs and derivatives, or their salts or solvates pharmaceutically. acceptable. A method according to claim 1, characterized in that the at least one opioid antagonist is selected from hydromorphone, or analogs or derivatives, or analogs and derivatives thereof, or pharmaceutically acceptable salts or solvates thereof; and the at least one opioid antagonist is selected from naloxone, naltrexone, ββ-naltrexole, nalmefene, and naloxonazine, or their analogs and derivatives, or pharmaceutically acceptable salts or solvates thereof. A method according to claim 1, characterized in that the at least one opioid antagonist is selected from paladone, Palladone® SR, Dilaudid® and hydromorphone hydrochloride; and the at least one opioid antagonist is selected from Narcan®, Trexan®, Revex®, Nubian®, nalaxone hydrochloride, denaltrexone hydrochloride, nalmefene hydrochloride, and denulbuphine hydrochloride. A method according to claim 1, characterized in that the at least one condition associated with pain, neuropathic pain, acute pain, chronic pain, cancer pain includes: chemotherapy; alcoholism; amputation, a problem with the back, legs, or hip; diabetes; a facial nerve problem; an infection with HIV or AIDS; multiple sclerosis; spinal surgery; opiate-induced narcotic / respiratory depression; or detox opiate dependence. A method according to claim 1, characterized in that it further comprises at least one active agent selected from vaccines, antibiotics, adjuvants, immunological adjuvants, immunogens, allergens, receptor agonists. Toll-like, Toll-like receptor antagonists, immunoadjuvants, immuno-modulators, immunoresponders, immunostimulators, specific immunostimulators, non-specific immunostimulants, and immunosuppressants, or combinations of those mentioned. A method according to claim 1, characterized in that at least one opioid agonist and at least one opioid antagonist are present in effective antihyperalgesic synergistic amounts. 13. Autonomous iontophoretic drug transfer system for providing transdermal transfer of one or more active agents to an individual's biological interface and inducing analgesia or anesthesia in the subject for a limited period of time, CHARACTERIZED by the factor comprising: at least an active agent reservoir, or at least one active agent reservoir including a pharmaceutical composition for inducing analgesia or anesthesia in the individual, the pharmaceutical composition for inducing analgesia or anesthesia in the subject comprising at least one analgesic or anesthetic agent in combination with at least at least one opioid antagonist; an active electrode assembly comprising at least one active electrode element, the at least one electro-active element operable to provide an electromotive force for conducting the pharmaceutical composition to induce analgesia or anesthesia in the subject comprising at least one analgesic agent or anesthetic in combination with at least one opioid antagonist from at least one active agent reservoir for the individual's biological interface, a power source electrically coupled to the active electrode assembly, the power source operable to provide an electromotive force to the active electrode assembly; It is a biocompatible reinforcement configured to confine at least one active agent reservoir and the active electrode assembly. A system according to claim 13, characterized in that the at least one opi-side agonist is selected from endogenous opioid peptides, opium alkaloids, semi-synthetic opioids, and fully synthetic opioids, or analogs or derivatives. or pharmaceutically acceptable salts thereof or solvates thereof. A system according to claim 13, characterized in that the at least one opioid antagonist is selected from naloxone, naltrexone, 6β-naltrexole, nalmefene, and naloxonazine or their pharmaceutically acceptable salts or solvates or solvates thereof. . A system according to claim 13, characterized in that the at least one opioid antagonist is selected from hydromorphone, or analogs or derivatives, or analogs and derivatives thereof, or pharmaceutically acceptable salts or solvates thereof; and the at least one opioid antagonist is selected from naloxone, naltrexone, ββ-naltrexole, nalmefene, and naloxonazine, or their analogs and derivatives, or pharmaceutically acceptable salts or solvates thereof. A 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, cell. and nickel metal hydride cell. A system according to claim 13, characterized in that it further comprises: a circuit operable to manage an obligatory cycle associated with the transfer of a therapeutically effective amount of the pharmaceutical composition to induce analgesia or anesthesia. in the subject comprising at least one analgesic or anesthetic active agent in combination with the at least one opioid antagonist for a predetermined period. A system according to claim 13, characterized in that the system is operable for transdermally transferring at least one opioid agonist and at least one opioid antagonist in effective antihyperalgesic synergistic amounts. A system according to claim 13, characterized in that it further comprises: an external adhesive surface for physically coupling the autonomously iontophoretically deformed drug transfer system to the biological interface of the subject. A system according to claim 13, characterized in that it further comprises: a controller electrically coupled to the power source, a counter electrode assembly comprising at least one electrode coupled electrically coupled to the power source; and one or more electrolyte reservoirs, the one or more electrolyte reservoirs including an electrolyte comprising at least one biologically compatible antioxidant selected from ascorbate, fumarate, lactate, and malate, or salts thereof.