WO2000023144A1 - Systeme et procede d'administration transdermique active de medicament - Google Patents

Systeme et procede d'administration transdermique active de medicament Download PDF

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Publication number
WO2000023144A1
WO2000023144A1 PCT/IL1998/000505 IL9800505W WO0023144A1 WO 2000023144 A1 WO2000023144 A1 WO 2000023144A1 IL 9800505 W IL9800505 W IL 9800505W WO 0023144 A1 WO0023144 A1 WO 0023144A1
Authority
WO
WIPO (PCT)
Prior art keywords
patch
membrane
drug
pharmaceutical medium
transdermal
Prior art date
Application number
PCT/IL1998/000505
Other languages
English (en)
Inventor
Alvin S. Ostrow
Geert-Henk Koops
Joseph Tannenbaum
Original Assignee
Electromagnetic Bracing Systems, Inc.
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
Priority claimed from IL11345995A external-priority patent/IL113459A/xx
Priority claimed from US09/096,469 external-priority patent/US5983134A/en
Application filed by Electromagnetic Bracing Systems, Inc. filed Critical Electromagnetic Bracing Systems, Inc.
Priority to EP98949228A priority Critical patent/EP1131131A1/fr
Priority to AU95588/98A priority patent/AU9558898A/en
Priority to US09/807,698 priority patent/US6564093B1/en
Priority to CA002347361A priority patent/CA2347361A1/fr
Publication of WO2000023144A1 publication Critical patent/WO2000023144A1/fr
Priority to IL14265401A priority patent/IL142654A0/xx

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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
    • A61N1/0432—Anode and cathode
    • A61N1/044—Shape of the electrode
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—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
    • A61N2/00—Magnetotherapy
    • A61N2/002—Magnetotherapy in combination with another treatment
    • 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

Definitions

  • the present invention relates generally to medical appliances and especially to the application of electrically charged porous patches in fluid communication with a drug medium and to a uniform system of an electrophoretic pharmaceutical delivery cuff apparatus for transdermal drug delivery.
  • Iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current.
  • iontophoretic membrane is given in US patent 5,080,646 to Theeuwes.
  • the principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current.
  • patches require a specific drug designed toward use with a particular membrane for a specified limited time of usage. Iontophoresis often requires cumbersome electrical connections to external power sources, which may be stationary or portable which can confine the patient's activity.
  • a further object of this invention is to provide a transdermal drug delivery system
  • Another further object of this invention is to provide a transdermal drug delivery system that can be worn comfortably by the patient, as a lightweight, portable design that is cost effective to manufacture and does not encumber motion by the patient.
  • Another object of this invention is the capability to deliver any drug in a fluid medium having either a positive or a negative molecular valence through the skin, iontophoretically.
  • drugs have been formulated for use in iontophoretic systems, and others are being experimented with and developed by the pharmaceutical industry for the feasibility of their delivery via iontophoresis for commercial use (e.g., nicotine, antihistamines, beta- blocker, calcium channel blockers, non-steroidal, anti-inflammatory drugs, contraceptives, anti-arrhythmic drugs, antivirals, hormones, alpha-interferon and chemotherapeutic anti- cancer agents). Therefore, it is also an object to incorporate porous membranes having pores that can accommodate molecular drug weights from one to 50,000 Daltons, or greater.
  • Yet another object of this invention is to optimally produce a selected alternating
  • the ionic drive mechanism is the force behind the electrochemical phenomenon of iontophoresis required to propel, infuse and deliver a pharmaceutical
  • EMFs electromagnetic fields
  • Magneophores in combination with drug delivery, can either increase the osmotic penetration of drugs through the skin known as "magnetophoresis", or that EMFs may help accelerate the effectiveness of exogenous drugs after being introduced into the body by transdermal or hypodermic methods.
  • Exposure to PMF (Pulsed Magnetic Field) immediately after administration of methotrexate or mitomycin C, pharmaceutical anti-tumor agents, into the cell increases eddy current stimulation induced by PMF, and the cell cycle shifts from the non-proliferative to proliferative phase, resulting in increased anti-tumor activity.
  • ECT electrochemotherapy
  • electro-infusion The combination of multiple drivers to produce an electrochemotherapeutic effect is known as "electro-infusion”.
  • biosensing component that can detect flow rate over time and the amount of permeant flow through the skin and the membrane for the control of any number of drug permeants, severally, or in combination.
  • Another object of the invention is to create a membrane electrode with a layered structure comprising:
  • a microtitration foam layer in contact with a permeant supply superior to an electrode. This foam layer is intended to prevent leakage or seepage, and to ensure
  • biosensor or biosensors interconnected with the transdermal membrane junction to the skin which are placed as to allow the permeation of pharmaceutical fluids.
  • Another object of this invention is to provide an electrophoretic cuff apparatus that can fit under a cast or brace.
  • a foam fabric can be used on the superior external surface of the apparatus, adding to patient comfort.
  • transdermal patch system for drug delivery which is non-irritating to the skin while administering a broad range of drugs.
  • a stored energy source for generating an electrical current; means for generating an electromagnetic field having at least one predetermined frequency; means for activating said energy source to generate said current producing said
  • electromagnetic field a layer of permeable foam for retaining therein a quantity of pharmaceutical medium exhibiting at least partial ionization; and an electroconductive membrane disposed under said foam layer through which the pharmaceutical medium passes, said electromagnetic field driving said ionized pharmaceutical medium by active transport through said membrane to provide drug treatment therapy via the skin.
  • the transdermal drug delivery system is provided as an unlinked patch device with an electroosmotic, electroporous membrane comprised of an inert biochemical substance which becomes actively electroosmotic when an electric charge is passed through the membrane.
  • an electric current is passed into the membrane, and it becomes electro- bioactive enabling drug solution to be passed through the electrode membrane wall to a target area on the skin surface creating an electroporative effect.
  • the patch is self-powered by an autobiofuel cell for providing the electricity for iontophoresis through the membrane.
  • the autobiofuel cell is comprised of a biochemical fuel cell substance creating a battery power source, causing an electric charge to be passed through the inert membrane which is saturated with a drug solution.
  • the autobiofuel cell is activated by pressing on an "activation button" causing a
  • An indicator is provided for indicating when
  • the battery power source is low.
  • a female jack is provided on the top surface of the patch for either giving a temporary charge to the fuel cell when the battery is low or may be used on a more long-term basis for connection to an external power source.
  • a portable 9V battery or stationary wall power pack may be supplied to accomplish the recharging.
  • the electric current from the autobiofuel cell or the external power source is passed through an intermediate electromagnetic/electroconductive separation plate, transmitting the power drivers for iontophoresis and/or magnetophoresis.
  • the combination of both iontophoresis and magnetophoresis results in electroinfusion (c) by energizing the drug reservoir membrane from the autobiofuel cell or external power source, creating an electroosmotic electro-bioactive phenomenon transferring the permeant through the membrane layer to the treatment area.
  • the separation plate prevents seepage and interaction of the autobiofuel cell fuel with the membrane and treatment area.
  • a dense coating layer is provided on the porous membrane support. Since most of the drugs that have to be delivered by the transdermal system are charged, the dense coating layer is provided with a mosaic structure such that it
  • Parameters of the patch can be altered to accommodate specific needs of specific drug solutions. These parameters include: drug concentration, current density, membrane thickness and charge density of the fixed charges in the membrane.
  • the membrane is impregnated with a substance on the epidermal delivery layer to cause hyper-permeability of the permeant through the stratum corneum (SC) of the skin and into deeper body tissue layers.
  • SC stratum corneum
  • the SC is a thin layer of highly resistant tissue with the underlying viable dermis exhibiting a much lower resistance.
  • the membrane is laced with acetylcholine, epinepherine or other stimulants to enhance permeability through the SC.
  • the dermal contact surface of the membrane is constructed out of substances close to the structure of human skin, based on the membranes used in artificial kidney membranes such as sulfonated polysulfone (PSF), so as to be non-irritating.
  • the membrane can be constructed using components of bioenegineered artificial skin compounds (such as Apligrafs from Organogenesis, Inc.). This will reduce skin rejection of polymers currently used to accomplish transdermal transport of drug solutions.
  • any commercially available transdermal membrane can be used with the patch (for example, lonClad R1010, R1030, R4010 or R4030 from Pall Corp., Port Washington, N.Y.).
  • the patch can be used to treat open or closed wounds.
  • An electrophoretic tube port is provided on the external side of the patch for injection of a needle-less syringe to provide the drug solution as needed.
  • a needle-less syringe to provide the drug solution as needed.
  • the drug solution is then transferred to and stored in a miniature reservoir in the
  • the reservoir can be provided as a foam layer for controlled microtitration.
  • the patch is provided with a connection to an external,
  • the port can be used to connect a standard IV drip bag via electrophoretic tubing.
  • the patch is provided with a biosensor for sensing when the drug is no longer present and alerting the patient or physician via an audible or visual signal.
  • a microswitch is provided to adjust and create electrical and electromagnetic frequencies of varying and alternating intensities and time cycles of a wide range to match the valences of the variety of drugs.
  • the patch would be supplied with a microprocessor for storing and controlling the various settings. Drugs may be permeated through the transdermal membrane and the skin either singularly or in multiple combination, according to the programmed settings.
  • the current density used is less than 0.5 mA/ cm 2 of the transdermal membrane electrode surface that is
  • Connections may also be provided for receiving input from the biosensors and controlling delivery from an external processor.
  • the transdermal patch of the present invention can be used in conjunction with an electrophoretic cuff apparatus which encompasses the construction of a preform applicator wrap enclosing one or more transdermal patches to pass a liquid drug medium through the skin and surface tissues.
  • the electrical current may be supplied by the autobiofuel cell or through an external source.
  • the applicator wrap is externally self-
  • the electrophoretic cuff apparatus concerns an electrotherapy
  • ⁇ ancillary treatment modalities which are provided by an optional Neuromuscular Electrostimulation, Transcutaneous Nerve Stimulation (T.E.N.S.) and Interferential Electrotherapy component.
  • the preform forms a "cuff" that can be wrapped around the body in different sizes and sections for easy treatment of large and small anatomical areas.
  • the cuff is connected to a Velcro attachment to latch on the sections, to deliver the fluid medium and electrical charge.
  • biosensors and an external pump regulated titration system can ensure precise regulation of drug flow transdermally through the skin and the transdermal membrane electrodes that act as a conduit reservoir for the flow of medicated permeants being supplied by a continuous source reservoir.
  • a pulsed or continuous electromagnetic field is created by a separate circuit.
  • the invention becomes a drug delivery apparatus with
  • the cuff apparatus When the cuff apparatus is not used for drug delivery, it can be applied and worn while the patient is exercising or conducting the activities of daily living.
  • the cuff wrap matrix is formed of waterproof, molded and flexible plastic, styrofoam or canvas-like material to accommodate a continuous hook-up for additional preform patches of various sizes and shapes, as required, to encompass the circumference of a desired target treatment area, thereby creating a "cuff or wrap around any anatomical body part.
  • the wrap is provided with a network array of electrically conductive porous polymer membrane electrode patch devices providing a "checkerboard" pattern of alternating positive and negative polarities.
  • the patches can be energized by galvanic and electromagnetic current drivers to propel permeant drugs through means of either iontophoresis, magnetophoresis or combined electromagnetophoresis.
  • a feature regarding the present invention of the electrophoretic cuff is that it can have multiple uses beyond its use for introducing drugs transdermally.
  • the present invention provides, in a versatile fashion, a variety of therapeutic benefits and applications with electrical energy modes for nerve stimulation, pain sedation and the prevention of atrophy.
  • the mode of Electrical Muscular Stimulation (EMS) can be introduced during physical therapy exercises, weight training for neurologically impaired and atrophic muscles, etc.
  • the patches within the cuff provide a consistent supply of medication, to bathe the body part in a continuous fluid within a circumference, whereas other electrical transdermal drug delivery methods are not as easily accessible or applicable.
  • This system also allows for transdermal drug treatment simultaneously to more than one location where medical attention is needed.
  • a non-medicated fluid can also be used to moisten the porous electrodes as an electrolyte, to assist electrical conductivity when the
  • the patch can apply continuous fluid medium from an optional external reservoir similar to intravenous (IN.) applicators, but without the use of a hypodermic needle.
  • the patch can be used, with or without the cuff, as an option to replace traditional methods of postoperative analgesia, such as intramuscular injections.
  • the patch has benefits for those patients who dislike hypodermic needle injections or have medical conditions making intravenous drug delivery difficult.
  • the delivery of drugs transdermally can be regulated and monitored through a computer chip and "pump" administration system that records the titration rate, amount and dosage of medication supplied.
  • the pump can vary the speed of introduction of the transdermal permeant at a desired rate.
  • the pump administration and titration mechanisms are interactively connected to biosensor detection sensors located within the transdermal membrane patch devices. Signals from the membrane electrode biosensor monitor the drug flow rate of permeant being transported through the skin as well as the membrane electrode.
  • the pump/titration regulator receives these signals from the membrane biosensor to regulate exact controlled increments of the permeant being delivered to the surface of the skin with an even flow pressure distribution in the electrophoretic tubing and membrane electrodes in the cuff delivery system.
  • a roller clamp can be used to clamp IN. tubing to control the flow of the pharmaceutical permeant.
  • Fig. 1 is a cross-section showing a transdermal patch device of the present invention divided into functional sections;
  • Fig. 2 is a diagram showing the flow of permeant through the skin surface
  • Fig 3 is a cross section of a self-powered transdermal patch device illustrating its functional sections
  • Fig. 4 is a diagram showing a schematic representation of a multi-drug system
  • transport resistance is determined by the dense charged mosaic layer
  • Fig. 5 is a diagram showing an assembly of a complete drug delivery system with the electrophoretic cuff of the invention
  • Fig. 6 is a front elevational view pictorially illustrating the electrophoretic cuff apparatus of the invention as applied to selected portions of the human body, including neck, arm, lower back and leg;
  • Fig. 7 is a perspective view of a portion of an applicator patch unit in conjunction with the apparatus of the invention illustrating a grid of transdermal patch devices;
  • Fig. 8 is a perspective view of a portion of a patch connected to other patches
  • FIG. 9a is an elevational view, in enlarged scale, of a portion of the applicator cuff, showing the electrical circuitry for energizing the transdermal patch devices;
  • Fig. 9b is a top view of a portion of an applicator wrap used in conjunction with the apparatus of the invention, illustrating a "checkerboard" pattern of positive and negative electrically charged electrodes;
  • Fig. 9c is an elevational view showing the combined lines of positive and negative electron flow, or the electrical charge of opposite polarity associated with the apparatus;
  • Fig. 10 shows a schematic drawing of a side view cross-section, showing the electrodes and supply tubes for delivering the fluid medium to the transdermal patch devices via a system of branching ducts;
  • Fig. 11 is a cross-sectional view of an electrophoretic pharmaceutical delivery system with a fluid reservoir connected to the apparatus;
  • Fig. 12 is a block diagram of the invention showing the transdermal patch system within the system components.
  • Fig. 13 shows a schematic drawing of a side view cross-section showing the electromagnetic electrodes to create the drive mechanism for magnetophoresis.
  • Transdermal patch device 20 comprises at least a three layer structure, including sealant 22, microtitration foam 24 and membrane 26. Sealant 22 is on the
  • microtitration foam 24 assists in permeant delivery timing and prevents excess permeant from running off.
  • the foam may be cultured, dehydrated and/or gamma irradiated to ensure that biological contamination is prevented.
  • the foam binds to membrane 26.
  • Membrane 26 is formed of an electrically woven fabric which is treated with antibiotic and antifungal chemicals to prevent biological contamination.
  • the membrane itself is commercially available (for example, IonClad R1010, R1030, R4010 or R4030
  • Membrane 26 can also be provided as an electroconductive porous polymer or co-polymer.
  • the large molecular weight cut-off allows drugs such as insulin (MW 6000), heparin (MW 6000-30,000), plasma factors (MW over 50,000) and anti-cancer drugs to be used with the system. Multiple drug
  • Membrane 26 acts as a reservoir and is encased in a barrier to prevent uncontrolled leakage of the drug.
  • Membrane 26 is electroconductive to provide for electrophoresis and other treatment modalities.
  • membrane 26 is provided with a substance on the epidermal delivery layer to cause hyper-permeability of the permeant through the stratum corneum (SC) of the skin and into deeper body tissue layers.
  • SC stratum corneum
  • the SC is a thin layer of highly resistant tissue with the underlying viable dermis exhibiting a much lower resistance.
  • the membrane is laced with acetylcholine, epinepherine or other stimulants to enhance permeability through
  • Biosensors 30 are disposed inferior to membrane 26, on the skin surface, and are connected to the computerized titration system to sense the flow rate of permeant through the SC. Biosensors at the junction of the trandsermal membrane and the skin surface are an integral part of the intelligent feedback titration supply sustem which controls the exact flow of drugs from the reservoir, as they detect, monitor and register drug concentration
  • the biosensor of the present invention can be provided to detect concentration of blood glucose, hormones and endogenous drugs (such as insulin). For example, in diabetics this feature is important for proper dosage and delivery of drugs such as insulin, by biosensing the blood glucose or insulin levels in the blood, so as to determine how much insulin must be administered by the intelligent feedback titration and monitoring
  • Fig. 2 depicts the flow of permeant through the skin surface 32 to an area 34 of increased concentration, in response to transdermal patch device 20. Dry skin has a low
  • Transport rate (T) can be affected by the type of membrane used, the skin type, the current density applied and the feed concentration of the drug. Calculation of the transport rate (T) can be accomplished via the formula:
  • Biosensor 30 can be constructed to comprise three electrodes which are saturated with normal saline.
  • the first biosensor electrode serves as the reference electrode and is situated far from the treatment area.
  • the second biosensor electrode is localized exactly above the treatment area and is the analyzing electrode.
  • the third biosensor electrode is near the reference electrode for comparison purposes.
  • the difference is measured between the reference electrode and the analyzing electrode.
  • the difference in millivolts between the two measurements is the actual concentration gradient.
  • the final value can be extrapolated.
  • the system needs to be calibrated for each drug.
  • FIG. 3 there is shown a cross-section of an autobiofuel powered
  • transdermal patch device 40 At least one of patch 40 is secured to skin surface 32 by adhesive tape 42. Patches 40 can be arranged as needed on adhesive tape 42 to provide circumferential treatment of a limb in a cuff format. Extending through adhesive tape 42 is electrophoretic tubing port 28 for insertion of a drug solution. Microtitration foam 24 acts as a reservoir upon insertion of the drug solution. Foam 24 assists in permeant delivery timing and prevents excess permeant from running off. The foam may be cultured, dehydrated and/or gamma irradiated to ensure that biological contamination is prevented.
  • separation plate 48 Upon depression of activator button 44, a mix of chemical compounds are released into autobiofuel cell 46 to activate the electro-conductivity of separation plate 48. For example, this can be accomplished with a suitable construction for a water activated dry- cell storage battery. Alternatively, this can be accomplished using a rechargable battery where the activator button serves as a mechanical or electrical switch to close the circuit.
  • the power drivers are supplied as separation plate 48, allowing both iontophoresis and magnetophoresis. Separation plate 48 gives a specific frequency of cathodal field designed to push the ionic drug solution through skin surface 32. In magnetophoresis, magnetic
  • Magnetic field is maintained.
  • Use of magnetic carriers has been proven effective, for example, in site specific delivery of chemotherapeutic agents in cancer therapy.
  • Use of magnetic fields increases cell permeability.
  • magnetophoresis has been shown
  • an electromagnetic field generator would allow drugs which have a large dipolar moment, a permanent charge or a ferro group to be attracted to a central
  • a power generator will generate various modulated electrical and electromagnetic field intensities, alternating polarities, timing and strengths that can be automatically, consecutively, and/or specifically programmed and are employed to correspond to the varying valences and atomic weights of pharmaceuticals for transdermal active transport through the membranes and dermal layers.
  • the range of pulse intensities and magnitudes is built into the pulse generator as the drivers.
  • the drivers are responsible for inducing the bioactivity of the membrane electrodes, the electro-introduction of drugs through the electrode, and the electro-infusion effect of accelerating drug delivery through the SC and deeper tissues.
  • Separation plate 48 additionally acts as an impermeable conductive barrier
  • membrane 26 may be composed of hypoallergenic materials close to the structure of human skin, developed from the materials used in artificial kidney membrane such as sulfonated polysulfone (PSF) or polyetheretherketone (PEEK), so as to be nonirritating.
  • PSF sulfonated polysulfone
  • PEEK polyetheretherketone
  • the membrane can use components of bioengineered artificial skin compounds (e.g. Apligrafs from Organogenesis, Inc.). This will reduce skin rejection of polymers currently used to
  • Dense coating layer 50 on membrane 26 acts as the rate determining factor in delivery of the drugs. Dense coating layer 50 is provided as a mosaic of positive and negative fixed charges to accommodate both anionic and cationic drugs. This is shown in further detail in Fig. 4. Separation plate 48 provides the push for drug solutions of various charges to transverse porous membrane 26 and reach dense coating layer 50 with its mosaic fixed charges. Drug solution 51 passes through dense coating layer 50 in a controlled fashion, to reach skin surface 32. Drug solution 51 passes through skin surface 32 and into bloodstream 52.
  • a feature of the invention (shown in Fig. 1) is that biosensors 30 are disposed inferior to membrane 26, on the skin surface, and can be connected to an indicator on the surface of patch 40 or optionally connected to an external computerized titration system to sense the flow rate of permeant through the SC.
  • autobiofuel powered transdermal patch device 40 provides a patch which extends significantly the range of drugs for which transdermal delivery is a viable
  • the patch can deliver a wide variety of types and sizes of drugs, up to 6000 Dalton or greater, without attachment to an external power source. Drugs can be administered in combination or sequentially, according to a treatment protocol.
  • the patch can be provided as a one-use disposable unit. The use of iontophoresis reduces application time even for drugs currently being used in passive patches, reducing potential irritation.
  • the patch can be supplied with a membrane which reduces irritation by being composed of
  • the patch can be used for local treatment or combined as a multiple set of patches by the use of an adhesive into any configuration, including those providing cumulative drug treatment with an electrophoretic cuff apparatus.
  • Fig. 5 shows an overview of a preferred embodiment of cuff wrap apparatus 70 as used with a standard IV drip bag and pole stand.
  • Stand 76 holds reservoir 68, allowing fluid to drip through drip chamber 78 to pump and titration regulator 72.
  • Tubing 66 leads the fluid into cuff wrap apparatus 70 to patches 20.
  • Harness wires 80 from power source 82, also leading into patches 20 provide electricity for electrophoresis, magnetophoresis, electrostimulation and pain sedation.
  • Patches 20 are comprised of sealant 22, microtitration foam 24, porous electro-conductive membrane 26 and are equipped with biosensors 30.
  • FIG. 6 there is illustrated a pictorial representation of an electrophoretic cuff system 90 in accordance with this invention.
  • the electrophoretic cuff system 90 is typically shown at selected anatomical locations on a human body.
  • System 90 is comprised of a flexible cuff 70 for wrapping around a body part or
  • a portable operating console 92 that incorporates a power supply source and a cable
  • harness 80 for conductively coupling the console 92 to the cuff wrap 70.
  • Flexible cuff wrap 70 is fabricated from a plastic and/or canvas garment-like fabric, having linked patch units 96 connected by Velcro strapping 94 as a closure for securing cuff wrap 70 against afflicted areas on the patient's body, for example, as shown in Fig. 6.
  • linked patch units 96 provide the required
  • the patch structure of unlinked patch devices 20 or autobiofuel powered transdermal patch devices 40 can be provided in a size conforming to individual patches of linked patches 96 to function in a cuff apparatus.
  • the layered structure remains the same.
  • a plurality of transdermal patch devices 20 are positioned within each patch unit 96 such that a longitudinal axis 102 of the transdermal patch devices 20 is perpendicular to a transverse axis 104 of cuff wrap 70.
  • Transdermal patch devices 20 function as a porous electroconductive membrane layer.
  • Contact surface 106 of cuff wrap 70 is intended for placement contiguous to the patient's skin 32.
  • transdermal patch devices 20, such as shown in Fig. 7, are rectangular, approximately 3/8 in. on each side and are spaced apart at point 108 approximately 2: 1 ratio center to center, to provide about four transdermal patch devices 20 per square inch within the cuff wrap 70.
  • transdermal patch devices 20 can be embedded in the plastic material during the manufacturing process, and are thus secured in place by the surrounding plastic material.
  • connectors 100 pass on top of, and are superior to, surface 110 of transdermal patch devices 20, simultaneously as they connect with the electrodes via duct system 112.
  • inside wiring 122,128 and electrophoretic tubing 66 are placed against the inside face of a waterproof substrate and/or canvas-like fabric forming the apparatus matrix, to prevent "leakage” of medicated or non-medicated fluid outside the aforementioned cuff.
  • each transdermal patch device 20 provides for a current flow through adjacent electrodes to thereby generate a "checkerboard" of electrical currents of alternate polarities, as graphically depicted in Fig. 9b. This is accomplished by conductively coupling the wiring in two circuits, as will be further described herein. It will be appreciated by those skilled in the art that the inside wiring within transdermal patch device 20 can be comprised of an electroconductive polymer membrane.
  • a wire harness 80 is conductively coupled to transdermal patch devices 20 by a set of (two-conductor) connector plugs 98, 99 that are accommodatingly received within a corresponding set of sockets 1 16, 117.
  • Electrophoretic cuff 70 can induce a pharmaceutical fluid flow when
  • electrostimulation In addition, pain sedation can be provided by nerve stimulation analgesia, and galvanic muscle strengthening can be provided by producing muscle contraction that deters the onset of atrophy in a body part.
  • the electrostimulation regimen is also effective for reversing the degenerative effects of atrophy.
  • transdermal patch devices 20 as conductive stimulator pads.
  • Transdermal patch devices 20 are applied to contact surface 106 of cuff wrap 70.
  • Connector plugs 98, 99 provide transdermal patch devices 20 with opposite charges of DC current.
  • transdermal patch devices 20 are in direct contact with the skin surface.
  • the previously described muscular electrostimulation and interferential microcurrent therapy can be used independently or in combination with the electrophoretic therapy delivery system.
  • the purpose of the iontophoresis is to utilize an electrical field to influence the transfer and metabolism of the drug medium into the patient's body, as shown in Fig.11.
  • transdermal patch devices 20 include a porous material that is connected
  • transdermal patch devices 20 will at all times be oppositely charged. In operation, transdermal patch devices 20 provide the function of receiving the pharmaceutical medium from branch tubing 66. The fluid medium is distributed throughout transdermal patch devices 20 by capillary action.
  • the application of the electrical current from power supply 82 provides an ionization effect producing a more effective delivery path to the patient.
  • a computerized chip and monitor 132 in a fluid distribution system monitors and supplies the medicated fluid from external bag reservoir 68 at various desired titration rates of ml/second through regulating pump 72. Rate of flow needed is determined by biosensor 30, and regulates fluid flow to increase efficiency to perform iontophoresis.
  • Pulse signal generator 134 receives power from power supply 82 to provide pulses to transdermal patch devices 20 for electrostimulation, magnetophoresis, electrophoresis and pain sedation.
  • transdermal patch devices 20 are supplied as electromagnetic electrodes and are arranged to create the drive mechanism for magnetophoresis.
  • Magnetic fields generate an electrical field within the tissue which is perpendicular to the magnetic field. This magnifies the electrical field strength, thereby increasing the penetration factor without increasing the externally applied current. This method produces a homogeneous potential layer.
  • PEMF pulsed electromagnetic fields
  • electro-infusion electro-infusion
  • transdermal patch devices 20 By having a multiple arrangement of transdermal patch devices 20 delivering the permeant over a large circumference, an alternating sequence is consecutively changing the infiltration area. The end result of this is avoidance of skin irritation. The living tissue is protected while ionic shift is eliminated, allowing increased penetration of ions. It is possible to transfer simultaneously several types of permeants which have inverse polarities.
  • Preferred power supply 82 is an electrochemical cell such as a commercially available nickel cadmium or lithium 9 volt rechargeable battery.
  • the battery is housed within console 92 (see Fig. 6).
  • Pulse generator 134 is included within console 92. Generator 134 supplies DC electrical power for electrostimulation and for the electrophoretic pharmaceutical delivery system.
  • pulse generator 134 can be modulated to provide a scale of electrical and electromagnetic field intensities, alternating polarities, timing and strengths that can be automatically, consecutively, and/or specifically programmed in accordance with the desired electrostimulation therapy.
  • the signals utilized in connection with the electrophoretic system include DC current modulation having trapezoidal, square and sinusoidal wave pulses from 0-50 volts
  • the pulses have a 20-30% off and 70-80% on timing for maximum effectiveness.

Abstract

L'invention concerne un système d'administration transdermique de médicament comportant au moins une pièce (20) à membrane d'électro-osmose électroporeuse (26) en matériau biochimique inerte, qui a un effet d'électro-osmose active lorsqu'une charge électrique traverse la membrane, permettant ainsi à une solution de médicament de franchir l'épiderme, de manière à créer un effet d'électroporation. La pièce peut être alimentée par un accumulateur, une source d'énergie externe (82) ou bien une cellule auto-bio-électrochimique auto-alimentée tenant lieu d'accumulateur durant la saturation de la solution de médicament. On peut utiliser des pièces multiples pour réaliser une unité de pièces reliées, en vue d'une utilisation combinée avec un manchon flexible (70), de manière à assurer le traitement sur la circonférence d'une partie du corps. Un réseau de tubes d'alimentation (66) peut être relié à un réservoir externe (68) pour assurer à chaque pièce l'alimentation lente en liquide médicamenteux. Un régulateur de titration (72) est en communication avec la pièce transdermique pour réguler le flux permanent vers la peau.
PCT/IL1998/000505 1995-04-23 1998-10-18 Systeme et procede d'administration transdermique active de medicament WO2000023144A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP98949228A EP1131131A1 (fr) 1995-04-23 1998-10-18 Systeme et procede d'administration transdermique active de medicament
AU95588/98A AU9558898A (en) 1998-10-18 1998-10-18 Transdermal active drug delivery system and method
US09/807,698 US6564093B1 (en) 1995-04-23 1998-10-18 Transdermal active drug delivery system and method
CA002347361A CA2347361A1 (fr) 1998-10-18 1998-10-18 Systeme et procede d'administration transdermique active de medicament
IL14265401A IL142654A0 (en) 1995-04-23 2001-04-17 Transdermal active drug delivery system and method

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IL11345995A IL113459A (en) 1995-04-23 1995-04-23 Electrophoretic cuff apparatus
US08/636,406 US5823989A (en) 1995-04-23 1996-04-23 Electrophoretic cuff apparatus drug delivery system
US09/096,469 US5983134A (en) 1995-04-23 1998-06-12 Electrophoretic cuff apparatus drug delivery system
US10501498A 1998-06-26 1998-06-26

Publications (1)

Publication Number Publication Date
WO2000023144A1 true WO2000023144A1 (fr) 2000-04-27

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PCT/IL1998/000505 WO2000023144A1 (fr) 1995-04-23 1998-10-18 Systeme et procede d'administration transdermique active de medicament

Country Status (2)

Country Link
EP (1) EP1131131A1 (fr)
WO (1) WO2000023144A1 (fr)

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AT409931B (de) * 2001-01-30 2002-12-27 Gluderer Lothar Erich Folien-wannenbiosteuerung
EP1438987A1 (fr) * 2003-01-16 2004-07-21 ProCare Produktions- & Handels GmbH Appareil de thérapie
WO2004060300A2 (fr) 2002-12-26 2004-07-22 Mountain View Pharmaceuticals, Inc. Conjugues polymeres de cytokines, de chimiomokines, de facteurs de croissance, d'hormones polypeptidiques et d'antagonistes de ceux-ci conservant une activite de liaison aux recepteurs
EP1545359A1 (fr) * 2002-08-23 2005-06-29 Sheiman Ultrasonic Research Foundation Pty Ltd Dispositif de nebulisation et de liberation de medicament
WO2007051243A1 (fr) * 2005-11-04 2007-05-10 Acrux Dds Pty Ltd Methode et systeme d'administration de medicament par voie transdermique
WO2011156869A1 (fr) 2010-06-17 2011-12-22 International Scientific Pty Ltd Administration d'un agent actif de soins pour la peau
WO2015092153A1 (fr) 2013-12-20 2015-06-25 Teknologian Tutkimuskeskus Vtt Oy Procédé et appareil pour le traitement de la peau
US9339836B2 (en) 2005-05-23 2016-05-17 Biosonic Australia Pty Ltd Ultrasonic atomization apparatus
US9452037B2 (en) 2010-05-25 2016-09-27 International Scientific Pty Ltd Delivery of oral care products
WO2020010389A1 (fr) * 2018-07-13 2020-01-16 International Scientific Pty Ltd Procédé et appareil pour une administration transdermique, intradermique ou transphanère améliorée de dioxyde de titane
WO2020010390A1 (fr) * 2018-07-13 2020-01-16 International Scientific Pty Ltd Procédé et appareil d'administration transdermique, intradermique ou transphanère améliorée d'acides hyaluroniques

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Publication number Priority date Publication date Assignee Title
AT409931B (de) * 2001-01-30 2002-12-27 Gluderer Lothar Erich Folien-wannenbiosteuerung
US7455686B2 (en) 2001-01-30 2008-11-25 Lothar Gluderer Device for delivering chemical/physical parameters and associated control device
US8001962B2 (en) 2002-08-23 2011-08-23 Sheiman Ultrasonic Research Foundation Pty Ltd. Nebulizing and drug delivery device
EP1545359A1 (fr) * 2002-08-23 2005-06-29 Sheiman Ultrasonic Research Foundation Pty Ltd Dispositif de nebulisation et de liberation de medicament
EP1545359A4 (fr) * 2002-08-23 2008-04-09 Sheiman Ultrasonic Res Foundat Dispositif de nebulisation et de liberation de medicament
EP2455032A1 (fr) * 2002-08-23 2012-05-23 Sheiman Ultrasonic Research Foundation Pty Ltd Dispositif de nébulisation et de libération de médicament
WO2004060300A2 (fr) 2002-12-26 2004-07-22 Mountain View Pharmaceuticals, Inc. Conjugues polymeres de cytokines, de chimiomokines, de facteurs de croissance, d'hormones polypeptidiques et d'antagonistes de ceux-ci conservant une activite de liaison aux recepteurs
EP1438987A1 (fr) * 2003-01-16 2004-07-21 ProCare Produktions- & Handels GmbH Appareil de thérapie
US9339836B2 (en) 2005-05-23 2016-05-17 Biosonic Australia Pty Ltd Ultrasonic atomization apparatus
GB2446341A (en) * 2005-11-04 2008-08-06 Acrux Dds Pty Ltd Method and system for transdermal drug delivery
WO2007051243A1 (fr) * 2005-11-04 2007-05-10 Acrux Dds Pty Ltd Methode et systeme d'administration de medicament par voie transdermique
US9452037B2 (en) 2010-05-25 2016-09-27 International Scientific Pty Ltd Delivery of oral care products
WO2011156869A1 (fr) 2010-06-17 2011-12-22 International Scientific Pty Ltd Administration d'un agent actif de soins pour la peau
US9463330B2 (en) 2010-06-17 2016-10-11 International Scientific Pty Ltd Delivery of skin care products
WO2015092153A1 (fr) 2013-12-20 2015-06-25 Teknologian Tutkimuskeskus Vtt Oy Procédé et appareil pour le traitement de la peau
CN106573142A (zh) * 2013-12-20 2017-04-19 芬兰国家技术研究中心股份公司 一种治疗皮肤的方法和装置
EP3082945A4 (fr) * 2013-12-20 2017-08-23 Teknologian Tutkimuskeskus VTT OY Procédé et appareil pour le traitement de la peau
WO2020010389A1 (fr) * 2018-07-13 2020-01-16 International Scientific Pty Ltd Procédé et appareil pour une administration transdermique, intradermique ou transphanère améliorée de dioxyde de titane
WO2020010390A1 (fr) * 2018-07-13 2020-01-16 International Scientific Pty Ltd Procédé et appareil d'administration transdermique, intradermique ou transphanère améliorée d'acides hyaluroniques

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