WO1999012606A1 - Administration par iontophorese de buprenorphine - Google Patents

Administration par iontophorese de buprenorphine Download PDF

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Publication number
WO1999012606A1
WO1999012606A1 PCT/US1997/015798 US9715798W WO9912606A1 WO 1999012606 A1 WO1999012606 A1 WO 1999012606A1 US 9715798 W US9715798 W US 9715798W WO 9912606 A1 WO9912606 A1 WO 9912606A1
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WO
WIPO (PCT)
Prior art keywords
patient
buprenorphine
buprenoφhine
current
electrolyte
Prior art date
Application number
PCT/US1997/015798
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English (en)
Inventor
John D. Denuzzio
Original Assignee
Becton Dickinson And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Becton Dickinson And Company filed Critical Becton Dickinson And Company
Priority to AU43358/97A priority Critical patent/AU4335897A/en
Priority to EP97941454A priority patent/EP0952869A1/fr
Priority to PCT/US1997/015798 priority patent/WO1999012606A1/fr
Publication of WO1999012606A1 publication Critical patent/WO1999012606A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0448—Drug reservoir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0432—Anode and cathode
    • A61N1/0436—Material of the electrode
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0444—Membrane

Definitions

  • the present invention relates to the iontophoretic transdermal delivery of buprenorphine. More specifically, the present invention concerns such delivery of buprenorphine at a flux sufficient to achieve a therapeutic dose, especially the therapeutic management of pain.
  • Buprenorphine is an opioid agonist-antagonist with partial opioid agonist activity and has,until the present invention, never been administered in vivo via iontophoretic transdermal delivery.
  • bupreno ⁇ hine is administered by injection and sublingually for the control of moderate to severe pain. It has also been used as an adjunct to anesthesia and in the treatment of opioid dependence.
  • Buprenorphine is approximately thirty (30) times more potent than morphine.
  • C 29 H 42 NO 4 Cl is Buprenorphine's chemical formula, its molecular weight is 468 (free base) and at pH ⁇ 8 buprenorphine has a charge of +1.
  • Buprenorphine has the following chemical structure:
  • analgesia is apparent within thirty minutes and lasts up to six hours.
  • a slow but prolonged response is achieved following sublingual administration.
  • the dose by i.m. or slow intravenous injection for moderate to severe pain is 300 to 600mg of buprenorphine repeated every six to eight hours as required. Doses of 200 to 400mg are given sublingual every six to eight hours.
  • buprenorphine Following intra-muscular administration, buprenorphine rapidly produces peak plasma concentrations. Absorption also takes place through buccal mucosa following sublingual administration. Buprenorphine is about 96% bound to plasma proteins.
  • Plasma elimination half-lives have ranged from 1.2 to 7.2 hours; however, there is a lack of correlation between plasma concentrations and analgesic activity. Some is metabolism in the liver to N-dealkylbuprenorphine and conjugate metabolites, but buprenorphine is excreted predominantly unchanged in the feces; there is some evidence of enteroheptic recirculation. Metabolites are excreted in the urine, but very little unchanged drug. Buprenorphine is subject to considerable first-pass metabolism following oral administration (Martindale's - The Extra Pharmacopoeia 30th ed. The Pharmaceutical Press, pg. 1067-1069, incorporated herein by reference).
  • Bupreno ⁇ hine is generally described as discussed above as a mixed agonist- antagonist acting mainly as a partial agonist at a receptors, with some antagonist activity at receptors. It has also been shown to bind , , and opioid binding sites and to have high affinity for the and receptor and lesser affinity for the receptor (Bovill JG. Which Potent Opioid? Important Criteria for Selection. Drugs 1987; 33:520-530, inco ⁇ orated herein by reference).
  • Bupreno ⁇ hine like fentanyl has high lipid solubility, but lower intrinsic activity.
  • bupreno ⁇ hine and a pure opioid agonist such as fentanyl
  • fentanyl a pure opioid agonist
  • a pure opioid agonist such as fentanyl
  • bupreno ⁇ hine binds to opioid receptors.
  • bupreno ⁇ hine had slow rates of associated and disassociation from the opioid receptor when compared with fentanyl (Boas RA, Villiger JW. Clinical Actions of Fentanyl and Bupreno ⁇ hine: The Significance of Receptor Binding. BR. J. Anaesth. 1985; 57:192-196, inco ⁇ orated herein by reference).
  • the authors estimated the transdermal delivery rate of bupreno ⁇ hine capable of inducing analgesia in humans from the pharmacokinetic parameters of the drug. Based on the parameters, the input or transdermal delivery rate can be estimated based on total body clearance and minimum effective concentration of bupreno ⁇ hine, a transdermal delivery rate of 1.9 to 2.7 g/cm 2 /L from a 20 cm 2 transdermal patch would provide adequate bupreno ⁇ hine blood levels for analgesia.
  • the article concluded that the authors believed such delivery rates achievable because most of the transdermal formulations reported in the article provided skin fluxes several times tighter than the target delivery rate. However, as indicated in the examples contained herein the passive (transdermal) delivery of bupreno ⁇ hine delivered blood levels of bupreno ⁇ hine which over a twenty-four hour period failed to deliver human therapeutic dose of bupreno ⁇ hine.
  • Iontophoresis is an attractive dosage form for the therapeutic management of pain. Its ability to rapidly deliver drugs to the systemic circulation and to control delivery profiles is particularly well-suited to the delivery of narcotic analgesics.
  • One embodiment of the present invention provides for an iontophoretic device for the iontophoretic delivery of buprenorphine.
  • the iontophoretic device has
  • an ionized substance reservoir containing an ionized or ionizable substance, in electrical communication with the current distributing member and adapted to be placed in ionic communication with the epithelial surface; and wherein said ionized or ionizable substance is bupreno ⁇ hine;
  • This device is capable of delivering an amount of bupreno ⁇ hine to a patient over a period of time which is provides a therapeutic concentration of bupreno ⁇ hine capable of providing an analgesic effect to the patient.
  • Another embodiment of the present invention is a method of non-invasively administrating a therapeutic concentration of buprenorphine to a patient.
  • Bupreno ⁇ hine is iontophoretically passed through a predetermined area of skin of the patient and a therapeutic concentration of bupreno ⁇ hine, wherein such therapeutic concentration of bupreno ⁇ hine is capable of providing an analgesic effect to the patient.
  • FIGURE 1 depicts Fig.lA an intra-muscular calibration curve based on which the delivered dose was determined and Fig. IB plasma profiles of intra-muscular doses of bupreno ⁇ hine in man and swine.
  • the human data represented is from Bullingham, et al. Clin. Pharmacol. Therap. vol. 28, no. 5, P 667, 1980, incorporated herein by reference.
  • FIGURE 2 depicts iontophoresis calibration curve formulated from the areas under the curves of intra-muscular bolus doses in swine.
  • FIGURE 3 compares the delivery from a 24-hour constant-current episode at
  • FIGURE 4 depicts the cumulative AUCs and corresponding delivered dose of the episodes in Figure 3.
  • FIGURE 5 depicts an embodiment of the iontophoretic device of this invention.
  • the present invention relates to a method of non-invasively administrating a therapeutic concentration of bupreno ⁇ hine to a patient.
  • Bupreno ⁇ hine is iontophoretically passed through a predetermined area of skin of the patient and a therapeutic concentration of bupreno ⁇ hine, wherein such therapeutic concentration of bupreno ⁇ hine is capable of providing an analgesic effect to the patient.
  • Another embodiment of the present invention relates to an iontophoretic device for non-invasively administrating a therapeutic concentration of bupreno ⁇ hine to a patient, such therapeutic concentration of bupreno ⁇ hine being capable of providing an analgesic effect to the patient.
  • This device is capable of delivering an amount of buprenorphine effective for providing an analgesic effect in the patient to whom its delivered for a selected period of time;
  • the iontophoretic device of the present invention may by way of example and not limitation include the following component and materials.
  • the iontophoretic electrode of the invention includes a current distributing member which conveys electrical current into the iontophoretic reservoirs for the delivery of an ionized substance.
  • the current distributing member is constructed of any of a large variety of electrically conductive materials, including both inert and sacrificial materials.
  • Inert conductive materials are those electrically conductive materials which, when employed in the iontophoretic devices of the invention, do not themselves undergo or participate in electrochemical reactions. Thus, an inert material distributes without being eroded or depleted due to the distribution of current, and conducts current through the generating ions by either reduction or oxidation of water.
  • Inert conductive materials typically include, for example, stainless steel, platinum, gold, and carbon or graphite.
  • the current distributing member may be constructed from a sacrificial conductive material.
  • a material may be considered sacrificial if, when employed as an electrode in an iontophoretic device of the invention, the material is eroded or depleted due to its oxidation or reduction. Such erosion or depletion occurs when the materials and formulations used in the iontophoresis device enable a specific electrochemical reaction, such as when a silver electrode is used with a formulation containing chloride ions. In this situation, the current distributing member would not cause electrolysis of water, but would itself be oxidized or reduced.
  • a sacrificial material would include an oxidizable metal such as silver, zinc, copper, etc.
  • the ions electrochemically generated via a sacrificial material would include metal cations resulting from oxidation of the metal.
  • Metal/metal salt anodes may also be employed. In such cases, the metal would oxidize to metal ions, which would then be precipitated as an insoluble salt.
  • the current distributing member may be constructed from any electrically conductive material provided an appropriate electrolyte formulation is provided.
  • the cathodic current distributing member may be constructed from a metal/metal salt material.
  • a preferred cathodic material is a silver/silver halide material.
  • a metal halide salt is preferably employed as the electrolyte.
  • the device would electrochemically generate halide ions from the electrode as the metal is reduced. Also, accompanying silver ions in a formulation would be reduced to silver metal and would deposit (plate) onto the electrode.
  • the cathode material may be an intercalation material, an amalgam, or other material which can take electrolyte cations such as sodium out of solution, below the reduction potential of water.
  • other materials may be used which permit the plating out of a metal from the appropriate electrolyte solution.
  • metals such as silver, copper, zinc, and nickel, and other materials, such as carbon, may be employed when an appropriate metal salt such as silver nitrate or zinc sulfate is in solution in the electrolyte reservoir. While such materials may develop increased resistivity as a metal plates out during use, they are not eroded or depleted during use as cathodic current distributing members. They are therefore not strictly "sacrificial" in this context.
  • the current distributing member may take any form known in the art, such as the form of a plate, foil layer, screen, wire, or dispersion of conductive particles embedded in a conductive matrix.
  • an electrolyte reservoir is arranged in electrical communication with a current distributing member.
  • electrical communication requires that electrons from the current distributing member are exchanged with ions in the electrolyte reservoir upon the application of electrical current.
  • Such electrical communication is preferably not impeded to any excessive degree by any intervening material(s) used in the construction of the iontophoretic device.
  • the resistivity of the interface is preferably low.
  • the electrolyte reservoir comprises at least one electrolyte, i.e., an ionic or ionizable component which can act to conduct current toward or away from the current distributing member.
  • the electrolyte comprises one or more mobile ions, the selection of which is dependent upon the desired application.
  • suitable electrolytes include aqueous solutions of salts.
  • a preferred electrolyte is an aqueous solution of NaCl, having a concentration of less than 1 mole/liter ( ⁇ 1 M), more preferably at about physiological concentration.
  • Other electrolytes include salts of physiological ions including, but not limited to, potassium, (K + ), chloride (Cl " ), and phosphate (PO 4 " ). The salt and its concentration may be selected as desired for particular applications.
  • Such other reservoir species include, without limitation, chelation agents (e.g., citrate ions, EDTA) surfactants (e.g., non-ionic, cationic, or anionic), buffers, ionic excipients, osmolarity adjusters (e.g., polyethylene glycols, sugars), ionic antibiotics, penetration enhancers (e.g., alkanols), stabilizers, enzyme inhibitors, preservatives, thickening agents (e.g., acrylic acids, cellulosic resins, clays, polyoxyethylenes), and the like.
  • chelation agents e.g., citrate ions, EDTA
  • surfactants e.g., non-ionic, cationic, or anionic
  • buffers e.g., ionic excipients
  • osmolarity adjusters e.g., polyethylene glycols, sugars
  • penetration enhancers e.g., alkanols
  • the electrolyte may comprise a material which is itself relatively immobile in the absence of an electric field, but which acts to deliver mobile ions in the presence of an electric field.
  • the electrolyte may more properly be termed an "ion source.”
  • ion sources according to the invention include polyelectrolytes, ion exchange membranes and resins, non-ionic buffers which become ionic upon pH change, and other known ion sources.
  • the electrolyte reservoir may contain counterions that form a soluble salt with an electrochemically generated ion.
  • a suitable counterion might be acetate or nitrate. Such counterions are useful when other means are provided for sequestering electrochemically generated ions.
  • the electrolyte reservoir can provide at least one ion of the same charge as the electrochemically generated ion, to permit current to be conducted, and at least one oppositely charged ion.
  • the reservoir structure of the iontophoretic apparatus of the invention further includes an ionized substance reservoir.
  • the ionized substance reservoir must be in ionic communication with an epithelial surface.
  • the construction of the ionized substance reservoir must be consistent with the requirements for ionic communication with the epithelial surface and electrical communication with the current distribution member. Accordingly, the structure of the ionized substance reservoir would vary, depending upon the desired application.
  • the ionized substance reservoir may include a liquid, semi-liquid, semi-solid, or solid material.
  • the ionized substance reservoir preferably further comprises means for at least substantially inhibiting the flow of the contents out of the reservoir. In such situations, the flow of the contents is desirably minimized when the device is in storage.
  • a membrane may be deployed to surround the contents of the ionized substance reservoir.
  • the flow of the contents of the reservoir may be minimized while in storage, but increased in use.
  • a surrounding membrane may increase in porosity, permeability, or conductivity upon the application of an electric field across the membrane. Examples of such membranes are disclosed in U.S. Patent Nos. 5,080,546; 5,169,382; and 5,232,438, the disclosures of which are inco ⁇ orated by reference herein.
  • the ionized substance reservoir is constructed to retain its physical integrity and to inherently resist migration and loss of the ionized substance.
  • Such embodiments include those in which the ionized substance reservoir includes a solid or semi-solid material such as a gel or other polymeric material.
  • the ionized substance reservoir includes a polymeric film in which the substance to be iontophoretically delivered is dispersed. The mobility of the substance to be delivered is substantially increased by the application of the electric field, permitting effective delivery across the target epithelial surface. Such a film need not contain any significant amount of hydrating material.
  • a cross-linked hydrogel in the electrolyte reservoir can serve as a water reservoir during iontophoresis. It may be desirable to provide the solution of active ingredient with a buffer.
  • the ion of the buffer of like charge to the drug ion should have low ionic mobility.
  • the limiting ionic mobility of this ion is preferably no greater that 1 x 10 " cm 2 /volt-sec.
  • the Ionizable Substance (Drug) for Iontophoretic Delivery An ionic drug can be delivered from either the anode, the cathode, or both simultaneously. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode or anode will be the active electrode and the negative electrode or cathode will serve to complete the electrochemical circuit. Alternatively, if the ionic substance to be delivered is negatively charged, then the negative electrode will be the active electrode and the positive electrode will be the indifferent electrode. However, it is to be understood that an anodic configuration may be used to drive positively charged chemical modifications of the bupreno ⁇ hine without departing from the spirit of the invention.
  • this invention has utility in connection with the delivery of active ingredients within the broad class of buprenorphine as well as chemical modifications of bupreno ⁇ hine.
  • the iontophoretic apparatus of the invention may also include a suitable backing film positioned on top of the electrolyte reservoir.
  • the backing film provides protection against contamination and damage to the current distributing member, if present, and the electrolyte reservoir of the apparatus.
  • the iontophoretic apparatus of the invention optionally includes a release liner which may fixed to the underside of the ionized substance reservoir by an adhesive.
  • the release liner protects the surface of the ionized substance reservoir which contact the epithelial surface from contamination and damage when the device is not in use.
  • the release liner may be peeled off to expose the epithelial contacting surface of the ionized substance reservoir for application of the device to a patient.
  • Iontophoretic devices require at least two electrodes to provide a potential to drive drug ions into the skin of a patient. Both electrodes are disposed to be in intimate electrical contact with the skin thereby completing the electrochemical circuit formed by the anode pad and cathode pad of the iontophoretic device.
  • the electrode pads may be further defined as an active electrode from which an ionic drug is delivered into the body.
  • An indifferent or ground electrode serves to complete the electrochemical circuit.
  • Various types of electrodes may be employed such as is described in United States application entitled Low-Cost Electrodes for an Iontophoretic Device , by Reddy et al., Serial No. 08/ 536, 029 filed September 29, 1995.
  • an embodiment of the iontophoretic device of this invention 50 is configured as follows: an anode patch 10, having an anode electrode compartment 11 in ionic communication with a skin contacting compartment 13.
  • the skin contacting compartment 13 and the anode electrode compartment 11 maybe separated by a compartment separation means (membrane) 17.
  • the anode electrode compartment 11 also contains an anode 14 and an electrolyte (anolyte) 15.
  • the skin contacting compartment is attached to the patient's skin 36.
  • the skin contacting compartment 23 and the cathode electrode compartment 21 maybe separated by a compartment separation means (membrane) 27.
  • the cathode electrode compartment 21 also contains an cathode 24 and an electrolyte (catholyte) 25.
  • the skin contacting compartment is attached to the patient's skin 36.
  • the criteria for deliverability with iontophoresis included physiochemical characteristics at physiological conditions (pH 7-8) such as : high hydrophilicity , high aqueous solubility, and non-neutral charge. Hydrophilicity is measures by the relative distribution of the compound in non-aqueous and aqueous phases (typically oil and water). Distribution coefficients less than 1 indicate that the molecule prefers an aqueous environment. Likewise, high distribution coefficients (D o/w > 1) indicate lipophilic tendencies.
  • iontophoresis is believed to occur along hydrophilic pathways in the skin, low distribution coefficients are often desirable; hence, high aqueous solubility is preferred. Finally, a non-neutral net charge allows the molecule to be directly influenced and transported by the electrical field (or current).
  • the physiochemical properties of bupreno ⁇ hine do not match the typically 'preferred' characteristics iontophoreable compounds; yet, we were able, as the following examples show to demonstrate high levels of delivery with rapid onset of peak plasma levels in swine. Furthermore, the iontophoretic plasma levels were several fold higher than passive delivery of bupreno ⁇ hine (even with an ethanol- enhanced formulation in the passive device).
  • the present invention has been described in connection with iontophoresis, it should be appreciated that it may be used in connection with other principles of active introduction, i.e., motive forces. Accordingly, the invention is understood to be operative in connection with electrophoresis, which includes the movement of particles in an electric field toward one or the other electric pole (anode or cathode), and electroosmosis, which includes the transport of uncharged compounds due to the bulk migration of water induced by an electric field. Also it should be appreciated that the patient or subject may include humans as well as animals.
  • Buprenorphine HC1 was loaded into the anode compartment of an iontophoretic patch, and iontophoresis was carried out on swine as listed below. Plasma samples were drawn periodically and analyzed for Bupreno ⁇ hine. The delivered dose was determined in reference to the intra-muscular calibration curve in Figure 1.
  • Cathode 100 mM sodium chloride/ Ag, AgCl cathode
  • An iontophoresis calibration curve was formed from the areas under the curves of intra-muscular bolus doses in swine ( Figure 2). This allowed estimation of intramuscular-equivalent dose delivered in the iontophoresis experiments.
  • the calibrated dose range is 4-25 g/kg: therefore, the delivered dose can be estimated only within the corresponding AUC range of 3-10 nghr/ml.
  • the therapeutic dose range is defined by the typical single and daily doses in humans; that is, 300-1000 g Bupreno ⁇ hine in 75 kg or 3-13 g/kg. This region is indicated by a shaded area.
  • Plasma levels of bupreno ⁇ hine are sustained at near-constant levels by applying current continuously over long periods.
  • Figure 3 compares the delivery from a 24-hour constant-current episode at 1.6 mA, a 1-hour episode at 1.6 mA, and passive delivery.
  • the 24-hour iontophoresis system achieves peak levels by the first sample while the passive system shows an extended lag period.
  • Figure 3 are shown in Figure 4.
  • iontophoresis achieves therapeutic levels rapidly and sustains them for long periods.
  • short episodes of iontophoresis are capable of achieving therapeutic levels quickly and in a sustained fashion.
  • bupreno ⁇ hine Since iontophoresis is generally believed to occur along hydrophilic pathways, lipophilic agents such as bupreno ⁇ hine represent a significant challenge to iontophoretic delivery.
  • bupreno ⁇ hine At physiological conditions, bupreno ⁇ hine is a monovalent cation below pH 8, and its low aqueous solubility ( ⁇ 0.1 mg/ml) and high liphophilicty (D 0/w > 50) suggest that its charge is at least partially shielded form the electrical field. Despite these 'unpreferred' characteristics, delivery is consistent with therapeutic doses in man, and peak plasma levels of drug are achieved rapidly.
  • the successful delivery buprenorphine with iontophoresis might be attributed, in part, to its initial acidic formulation and the acid environment of the outer layers of skin.
  • bupreno ⁇ hine At low pH, bupreno ⁇ hine is reasonable soluble (>10 mg/ml), with relatively low liphophilicity (D o/w ⁇ 5). During iontophoresis, bupreno ⁇ hine migrates from the patch into the so-called "acid mantle" of the skin which maintains a pH range of 4.5-6.5.
  • iontophoresis is capable of delivery buprenorphine at levels consistent with prescribed daily doses in man. In comparison to passive delivery, iontophoresis achieves peak blood levels rapidly, and the total delivered dose can be controlled by adjusting the applied current. Short episodes of iontophoresis are also effective in delivering therapeutic quantities of buprenorphine. The demonstrated control of delivery and the rapid onset of blood levels make iontophoresis attractive delivery technique for therapeutic pain-management.

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Abstract

L'invention concerne un procédé d'administration non effractive d'une dose thérapeutique de buprénorphine à un patient. On fait passer de la buprénorphine par iontophorèse à travers une zone cutanée prédéterminée du patient. La dose thérapeutique de buprénorphine administrée a un effet analgésique sur le patient pendant un long temps spécifique. Un dispositif de iontophorèse permettant une administration non effractive de la dose thérapeutique de buprénorphine à un patient, fait aussi l'objet de cette invention.
PCT/US1997/015798 1997-09-08 1997-09-08 Administration par iontophorese de buprenorphine WO1999012606A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU43358/97A AU4335897A (en) 1997-09-08 1997-09-08 Iontophoretic delivery of buprenorphine
EP97941454A EP0952869A1 (fr) 1997-09-08 1997-09-08 Administration par iontophorese de buprenorphine
PCT/US1997/015798 WO1999012606A1 (fr) 1997-09-08 1997-09-08 Administration par iontophorese de buprenorphine

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Cited By (2)

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WO2012031252A1 (fr) * 2010-09-03 2012-03-08 Abbott Laboratories Compositions de buprénorphine à dose élevée et utilisation en tant qu'analgésique
US8386029B2 (en) * 2005-03-31 2013-02-26 Encore Medical Asset Corporation Apparatus for electrotherapy drug delivery with added impurities

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US8386029B2 (en) * 2005-03-31 2013-02-26 Encore Medical Asset Corporation Apparatus for electrotherapy drug delivery with added impurities
US8781572B2 (en) 2005-03-31 2014-07-15 Encore Medical Asset Corporation Method and apparatus for electrotherapy drug delivery
US9468757B2 (en) 2005-03-31 2016-10-18 Encore Medical Asset Corporation Method and apparatus for electrotherapy drug delivery
US10478610B2 (en) 2005-03-31 2019-11-19 Encore Medical Asset Corporation Method for electrotherapy drug delivery
US11541226B2 (en) 2005-03-31 2023-01-03 Encore Medical Asset Corporation Method and apparatus for electrotherapy drug delivery
WO2012031252A1 (fr) * 2010-09-03 2012-03-08 Abbott Laboratories Compositions de buprénorphine à dose élevée et utilisation en tant qu'analgésique
AU2011295694B2 (en) * 2010-09-03 2015-02-05 Zoetis Belgium S.A. High dose buprenorphine compositions and use as analgesic
US9168251B2 (en) 2010-09-03 2015-10-27 Zoetis Belgium S.A High dose buprenorphine compositions and use as analgesic

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