WO1995009031A1 - Dispositif d'ionophorese, reservoir et procede de fabrication - Google Patents

Dispositif d'ionophorese, reservoir et procede de fabrication Download PDF

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Publication number
WO1995009031A1
WO1995009031A1 PCT/US1994/010960 US9410960W WO9509031A1 WO 1995009031 A1 WO1995009031 A1 WO 1995009031A1 US 9410960 W US9410960 W US 9410960W WO 9509031 A1 WO9509031 A1 WO 9509031A1
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WO
WIPO (PCT)
Prior art keywords
reservoir
water soluble
soluble polymer
cross linked
linked water
Prior art date
Application number
PCT/US1994/010960
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English (en)
Inventor
Preston Keusch
Scott E. Smith
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 AU78454/94A priority Critical patent/AU7845494A/en
Publication of WO1995009031A1 publication Critical patent/WO1995009031A1/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

Definitions

  • the present invention generally relates to iontophoretic systems for delivering medicaments such as therapeutic drugs and medicines to patients transdermally, i.e., through the skin, and more specifically relates to an iontophoretic drug delivery device and a reservoir for use in the same.
  • the present invention relates to a method for making the reservoir for use in such an iontophoretic drug delivery device.
  • Transdermal drug delivery systems have, in recent years, become an increasingly important means of administering drugs. Such systems offer advantages clearly not achievable by other modes of administration such as avoiding introduction of the drug through the gastro-intestinal tract or punctures in the skin to name a few.
  • Passive and Active transdermal drug delivery systems
  • Passive systems deliver drug through the skin of the user unaided, an example of which would involve the application of a topical anesthetic to provide localized relief, as disclosed in U.S. Patent No. 3,814,095 (Lubens) .
  • Active systems deliver drug through the skin of the user, such as a patient, using iontophoresis, which according to Stedman's Medical Dictionary, is defined as "the introduction into the tissues, by means of an electric current, of the ions of a chosen medicament.”
  • absorbent pads or porous solid sheet that can be filled with drug solution as the drug reservoir.
  • These absorbent pads or porous sheets have three major disadvantages. First, they must be filled with the drug solution after removal from the package since these pads or porous sheets do not hold the drug solution as the solution is subject to removal and leakage under pressure or flexure. In addition, even after the inconvenient addition of the drug solution and after removal from the package, the absorbent pad or porous sheet reservoir remain subject to leakage and smearing of the drug solution due to pressure or flexure upon the skin. Furthermore, absorbent pads or porous solid sheets can not provide the electrical continuity to complete intimate contact since they lack adhesivity and flexibility with the skin and its contours.
  • prior drug reser-voirs have included pastes and unformed viscous semi-solid gels such as agar that have both solid and liquid characteristics as described, for example, in U.S. Patent No. 4,383,529
  • the semi-solid reservoir disclosed in Webster flows under shear or stress.
  • this disclosed reservoir may melt upon exposure to modest elevated temperatures.
  • a iontophoretic drug delivery device particularly suited for use to deliver at least one medicament, particularly in a high dose efficiency can be constructed in accordance with the present invention by the incorporation of an aqueous swollen cross linked water soluble polymeric drug delivery reservoir.
  • the device of the present invention can easily fit over any contour of the body and provide excellent electro coupling with the electrode and the skin, while still being capable of flexing and adhering to the skin.
  • the device of the present invention can be applied over a range of temperatures and is stable for over two years at controlled room temperature to provide a commercially suitable shelf-life.
  • the iontophoretic drug delivery device of the present invention for delivering at least one medicament to an applied area of a patient, such as the skin, mucus membrane and the like, includes electrode assembly means for driving a medication into the applied area of the patient to be absorbed by the body of the patient and a reservoir situated in electrically conductive relation to the electrode assembly means, with the reservoir including an aqueous swollen cross linked water soluble polymer, with the reservoir containing the at least one medicament.
  • the device of the present invention also includes a structurally reinforcing member situated within the reservoir including the aqueous swollen cross linked water soluble polymer, with the structurally reinforcing member having an open area.
  • the structurally reinforcing member is a thermoplastic polymeric scrim and the aqueous swollen cross linked water soluble polymer is cross linkable by high energy irradiation.
  • the aqueous swollen cross linked water soluble polymer is selected from the group including polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol and polyacrylamide.
  • the at least one medicament includes Lidocaine and the reservoir includes a vasoconstrictor, stabilizers and glycerin.
  • the reservoir further includes additives and conductive salts, with the additives selected from the group including glycerin, propylene glycol and polyethylene glycol.
  • the composition of the polyethylene oxide is from 1% to 6% and the composition of the polyvinyl pyrrolidone is from 15% to 40%, with the compositions being irradiation cross linked in aqueous solution.
  • the reservoir of the present invention for use in an iontophoretic drug delivery device having an electrode assembly for delivering at least one medicament through an applied area of a patient, such as the skin, mucus membrane and the like, includes a layer of a aqueous swollen cross linked water soluble polymer material capable of being electrically conductive with the electrode assembly and the aqueous swollen cross linked water soluble polymer material including at least one medicament for delivery through an applied area of a patient, such as the skin, mucus membrane and the like.
  • the reservoir also includes a structurally reinforcing member situated within the layer of aqueous swollen cross linked water soluble polymer material, with the structurally reinforcing member having an open area.
  • the structurally reinforcing member is a scrim of a aqueous insoluble thermoplastic polymeric material and the aqueous swollen cross linked water soluble polymer material is cross linked by high energy irradiation.
  • the aqueous swollen cross linked water soluble polymer is selected from the group including polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol and polyacrylamide.
  • the at least one medicament in the reservoir of the preferred embodiment is Lidocaine and the aqueous swollen cross linked water soluble polymer includes a vasoconstrictor, stabilizers and glycerin.
  • the reservoir includes additives and conductive salts, with the additives selected from the group including glycerin, propylene glycol and polyethylene glycol.
  • the composition of the polyethylene oxide is from 1% to 6% and the composition of the polyvinyl pyrrolidone is from 15% to 40%, with the compositions being irradiation cross linked in aqueous solution.
  • the method of the present invention for making a reservoir for use in an iontophoretic drug delivery device includes the steps of providing a structurally reinforcing member, coating the reinforcing member with a viscous water soluble polymer solution, and cross linking the layer by high energy irradiation.
  • the step of coating includes the steps of applying a layer of the viscous solution to one side of the reinforcing member, applying a layer of the viscous solution to one side of a release liner and laminating the release liner and the reinforcing material together such that both surfaces of the reinforcing member are coated with the viscous solution.
  • the viscous solution is applied to the reinforcing member and the release liner to a thickness of Ca. 5 mil to 30 mil.
  • the method includes the step of applying a final release liner to the remaining exposed viscous solution coated surface of the reinforcing member to form a laminate and cross linking the viscous solution and includes the step of replacing the final release liner with an electrode.
  • the method includes the step of adding at least one medicament to the viscous water soluble polymer solution, with the medicament including Lidocaine and the polymer includes a vasoconstrictor, stabilizers and glycerin. Further, the method includes the step of cutting the laminate into a suitable shape and area for use in the iontophoretic drug delivery device.
  • Figure 1 is a schematic view of the iontophoretic drug delivery device of the present invention illustrating placement of the device on a user;
  • Figure 2 is a cross sectional view of the device of the present invention.
  • FIGS 3A, 3B, 3C and 3D are schematic views of the various steps of the method for making the reservoir of the present invention.
  • Figure 4 is a logic flow diagram depicting the various steps of the method for making the reservoir of the present invention.
  • the iontophoretic drug delivery device of the present invention is illustrated in Figures 1 and 2, and generally includes the designation 10.
  • the device 10 of the present invention includes an electrode assembly 12, having at least one electrode and at least one reservoir, with the reservoir and electrode held or contained within a suitable structure 16, with a skin adhesive 18.
  • a power source 19 is provided in circuit with the electrode assembly 12 for supplying a source of electrical current. It should be appreciated that a return electrode and reservoir may be combined into a single electrode assembly 12 or separately provided as illustrated in Figure 1.
  • the device is divided or otherwise separated into two portions 20 and 22, with the electrode assembly 12 including two electrodes 24 and 26.
  • One portion 20 includes the electrode 24 and a reservoir 28, with the reservoir being situated adjacent and coupled to the electrode 24 and holding at least one medicament or drug 30, preferably in ionized or ionizable forms, to be delivered iontophoretically.
  • the other portion 22 includes the electrode 26 and a reservoir 32, with the reservoir being situated adjacent to the electrode 26 and holding an electrolyte 34.
  • the particular electrolyte is not essential to the present invention and is merely a matter of choice. However, in this embodiment the electrolyte may include sodium chloride in an aqueous solution, matrix or the like as explained in greater detail hereinbelow.
  • FIG. 2 A schematic diagram of the first portion 20 of the device 10 is illustrated in Figure 2.
  • the medicament 30 to be delivered through the skin is a cation and the reservoir 28 is connected to the electrode 24, which acts as an anode.
  • the return electrode 26 (cathode) may be constructed in the manner as the working electrode 24. If the drug is an anion, then the drug containing reservoir would be connected to the cathode and the return reservoir would be connected to the anode.
  • the device can be situated on the area of the patient to which the medicament is to be applied (the applied area) and a voltage impressed across the electrodes 24, 26 of the electrode assembly 12 to cause current to flow through the skin 60 of the patient to drive the ionic medicament locally into the skin and the tissue or to be absorbed systematically by the body of the patient. It should also be appreciated that the device of the present invention can be applied to other areas of the body such as mucus membranes and the like depending upon the desired therapy and medicaments to be delivered.
  • the reservoir 28 containing the medicament includes an aqueous swollen cross linked water soluble polymer, which for simplicity is hereinafter referred to as a cross linked water soluble polymer.
  • the cross linked water soluble polymer can be incorporated into the reservoir as a homogeneous solid cut or molded sheet 40 of suitable shape and area which can be attached to the electrode as illustrated in Figures 1 and 2.
  • the reservoir 32 (cathode) may also be made of the same material as the reservoir 28 containing the medicament, i.e., to include the cross linked water soluble polymer sheet 40 illustrated in Figures 3A-3D.
  • the cross linked water soluble polymer sheet 40 containing either the medicament and/or the electrolyte serves as the reservoirs 28, 32 and the electrical coupling to the skin while being able to conform to all contours of the body.
  • the reservoir may include additives selected from the group including glycerin, propylene glycol and polyethylene glycol and conductive salts.
  • cross linked water soluble polymer material may be made from a variety of commercially available water soluble polymers known to those skilled in the art as long as it is of low bioburden, is electrically conductive, readily conforms to the contours of the body, is capable of being cross linked and can hold or otherwise retain the drug solution under pressure and flexure.
  • Cross linked water soluble polymers are preferred reservoirs as they provide a comfortable interface with good electrical coupling and excellent biocompatibility.
  • Examples of such cross linked water soluble polymers are irradiated cross linked polyethylene oxide (PEO) , with from 94% to 99% water, polyvinyl pyrrolidone (PVP) , polyvinyl alcohol (PVA) , and polyacrylamide.
  • PEO polyethylene oxide
  • PVP polyvinyl pyrrolidone
  • PVA polyvinyl alcohol
  • the cross linked water soluble polymer sheet 40 by nature of its preparation by irradiation cross linking is of low bioburden and is non toxic, non irritating and non sensitizing to the skin. This is particularly assured by the fact that no chemical cross linking agents or organic solvents are required to synthesize the cross linked water soluble polymer material. It should be appreciated, that the techniques of irradiation cross linking the water soluble polymer material are well known in the art.
  • the cross linked water soluble polymer sheet 40 may include a netting material 42 such as an inert polyethylene scrim of the type known as DelnetTM, which is commercially available from Applied Extrusion Technologies Inc.
  • the scrim utilized for this application is preferably an open web, water insoluble material that does not change the conductivity or ionic flow of the materials in the water soluble polymer.
  • the cross linked water soluble polymer sheet 40 can be formed from a solution 44 of premixes after dispersion and full solution, with the solution then applied on both sides of the scrim 42 to a thickness of Ca.
  • cross linked water soluble polymer sheet may vary depending upon, e.g., the medicament to be delivered, the applied area and the like, from a very thin sheet, i.e., film, for high drug efficiency to a very thick sheet for minimization of sensation when an electrical current is applied.
  • the cross linked water soluble polymer sheet 40 is formed by providing the release liner 46 and the scrim 42, applying or otherwise coating a release liner or other backing material 46 with one-half of the viscous solution 44 of water soluble polymer to form a layer 44A ( Figure 3B) and coating or otherwise applying the other half of the viscous solution 44 to one side of the scrim 42 to form a layer 44B ( Figure 3C) .
  • the coated liner 46 is then laminated to the coated scrim 42 such that the scrim has the viscous solution on both sides ( Figure 3D) .
  • a final liner or other backing material 48 is then applied to the exposed surface, with the cross linked water soluble polymer sheet 40 sandwiched between the two release liners 46, 48 to form a laminate 50, which in the preferred embodiment is then exposed to high energy irradiation to cross link the water soluble polymer solution.
  • the final release liner 48 can be applied to the coated scrim prior to lamination with the coated liner 46.
  • the scrim 42 itself imparts structural support and mechanical strength to the final cross linked water soluble polymer sheet to prevent shearing. Thereafter, the laminate 50 can be easily handled and cut or otherwise formed into the desired shape for the particular reservoir 28, 32. In this way, the release liner 46 can be subsequently removed and the exposed surface of the cross linked water soluble polymer adhered to the electrode 24, 26, or removed and the medicament 30 added and the release liner replaced or adhered to the electrode. Also, the release liner 48 can remain until being removed for application of the device 10 to the applied area of the patient.
  • the release liner 48 (or 46) can be replaced by the electrode in the form of a thin metal sheet or polymer sheet coated with a conductive ink or metal foil laminated to the polymeric sheet.
  • the reservoir can be coupled to the electrode in one step.
  • a conductive scrim may be incorporated into the reservoir with the scrim being placed asymmetrically with in the reservoir by placing different thicknesses of the viscous solution on each side of the scrim.
  • the use of an easily handled cross linked water soluble polymer sheet as the reservoir 28, 32 to replace a paste, semi-solid gel or an absorbent pad has many advantages over existing coupling reservoirs.
  • the cross linked water soluble polymer is solid and shape retaining and it exhibits no leakage of medicament or electrolyte under flexure or applied pressure. It is also drapeable and flexible and adhesive to the skin. This assures that the cross linked water soluble polymer maintains the required medicament and electrolyte concentration as well as reproducible delivery by its adherence and conformability to the contours of the skin or other applied area.
  • the cross linked water soluble polymer Due to its high water content, the cross linked water soluble polymer is highly conductive to ionic transport, yet it possesses sufficient mechanical strength for processing and use. Also, despite its high water content, the cross linked water soluble polymer is a single phase solid solution which does not synerese liquid upon applied pressure or flexure. The ability of the cross linked water soluble polymer to retain aqueous solution and its stability over extremes of ambient temperature, allow the iontophoretic drug delivery device 10 to be prepackaged and stored as a ready to use device, eliminating the need for loading a drug solution after opening and assembly.
  • the various reservoirs 28, 32 formed from the cross linked water soluble polymer sheet 40 are easily and stably coupled with the electrically conductive electrodes 14, 26 to form a highly electrically conductive electrode assembly 12.
  • the medicament can either be added to the viscous water soluble polymer solution or subsequently added after cross linking depending upon the application and/or the medicament to be administered.
  • the two portions of the device 20, 22 are placed over the applied area, i.e., the portion of the skin where the medicament is to be delivered such as the arm as illustrated in Figure 1 with other electrode 32, i.e., the return electrode, placed on the skin 60 at an appropriate location relative to the first or working electrode 14.
  • the cross linked water soluble polymer 40 in the preferred embodiment of the present invention is self-adhering to the skin of the patient and therefore provides intimate contact for ionic transport. Accordingly, the cross linked water soluble polymer sheet 40 contained in the drug reservoir 28 and used for the electrolyte reservoir 32 may also act as an adhesive, eliminating the need in prior , devices for an adhesive layer or the like.
  • the following formulations for the cross linked water soluble polymer sheet 40 were used in connection with the device of the present invention for the reservoirs in the iontophoretic delivery of a topical anesthetic and a vasoconstrictor, with the device 10 including one active electrode 24 having a surface area between 2-10 cm 2 and one to three return electrodes 26 having a total surface area between 1-5 cm 2 .
  • the electrode reservoir 28 was comprised of the following active and inert components to a thickness of between 10-50 mils by making a viscous stock solution containing the medicaments and the excipients that was 3 times more concentrated than the intended final formulation. The stock solution was then added to preexisting sheets and allowed to diffuse and equilibrate in the sheets.
  • the Lidocaine is an anesthetic
  • the L-Adrenaline is a vasoconstrictor
  • the composition of polyethylene oxide (PEO) is 2.67% and known as WSR-301 from Union Carbide Corp.
  • PEO polyethylene oxide
  • WSR-301 from Union Carbide Corp.
  • the concentration of the PEO may vary from approximately 1-6% w/w.
  • Epinephrine can be substituted for the L-Adrenaline.
  • PVP polyvinyl pyrrolidone
  • PEO polyvinyl pyrrolidone
  • PVA polyvinyl alcohol
  • Drug, medication, medicament and active compound have been used herein to mean any pharmaceutical agent, such as therapeutic compounds, diagnostic agents and the like.
  • electroactive introduction i.e., motive forces, such as electrophoresis which includes the movement of particles in an electric field toward one or other electric pole, anode, or cathode and electro-osmosis which includes the transport of uncharged compounds due to the bulk flow of water induced by an electric field.
  • motive forces such as electrophoresis which includes the movement of particles in an electric field toward one or other electric pole, anode, or cathode and electro-osmosis which includes the transport of uncharged compounds due to the bulk flow of water induced by an electric field.
  • electrophoresis which includes the movement of particles in an electric field toward one or other electric pole, anode, or cathode
  • electro-osmosis which includes the transport of uncharged compounds due to the bulk flow of water induced by an electric field.
  • the patient may include humans as well as animals.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Electrotherapy Devices (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Dispositif ionophorétique (10) d'administration de médicaments qui comporte un ensemble électrode (12) situé en contact électrique avec au moins un réservoir (28) contenant un polymère hydrosoluble réticulé aqueux gonflé choisi dans le groupe constitué de l'oxyde de polyéthylène (PEO), de la polyvinylepyrrolidonne (PVP) et du polyacrylamide. Ledit polymère hydrosoluble gonflé aqueux est réticulé par exposition à un rayonnement à haute énergie. Au moins un des réservoirs contient au moins un médicament à administrer et l'un des réservoirs comprend un électrolyte. De plus, le procédé de la présente invention consiste à placer un élément de renforcement (42) structural, à recouvrir ledit matériau de renforcement d'une solution polymère hydrosoluble visqueuse et à réticuler ladite solution.
PCT/US1994/010960 1993-09-30 1994-09-28 Dispositif d'ionophorese, reservoir et procede de fabrication WO1995009031A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU78454/94A AU7845494A (en) 1993-09-30 1994-09-28 Iontophoretic device, reservoir and method of making

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/129,222 1993-09-30
US12922293A 1993-10-04 1993-10-04

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WO1995009031A1 true WO1995009031A1 (fr) 1995-04-06

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0748636A2 (fr) * 1995-06-14 1996-12-18 Takeda Chemical Industries, Ltd. Interface pour iontophorèse
WO1997007854A1 (fr) * 1995-08-29 1997-03-06 Becton Dickinson And Company Dispositif d'administration de medicament par iontophorese comportant un circuit de conversion continu-continu a grande efficacite
US6375990B1 (en) 1997-10-09 2002-04-23 Emory University Method and devices for transdermal delivery of lithium
JP2002525307A (ja) * 1998-09-28 2002-08-13 ベクトン・ディキンソン・アンド・カンパニー ピペリジン誘導体を含むイオントフォレーゼ装置

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4706680A (en) * 1986-06-30 1987-11-17 Nepera Inc. Conductive adhesive medical electrode assemblies
US4786277A (en) * 1986-11-21 1988-11-22 Trustees Of Boston University Electrodes, electrode assemblies, methods, and systems for tissue stimulation
US5006108A (en) * 1988-11-16 1991-04-09 Noven Pharmaceuticals, Inc. Apparatus for iontophoretic drug delivery
US5087242A (en) * 1989-07-21 1992-02-11 Iomed, Inc. Hydratable bioelectrode
US5224928A (en) * 1983-08-18 1993-07-06 Drug Delivery Systems Inc. Mounting system for transdermal drug applicator
US5250022A (en) * 1990-09-25 1993-10-05 Rutgers, The State University Of New Jersey Iontotherapeutic devices, reservoir electrode devices therefore, process and unit dose

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5224928A (en) * 1983-08-18 1993-07-06 Drug Delivery Systems Inc. Mounting system for transdermal drug applicator
US4706680A (en) * 1986-06-30 1987-11-17 Nepera Inc. Conductive adhesive medical electrode assemblies
US4786277A (en) * 1986-11-21 1988-11-22 Trustees Of Boston University Electrodes, electrode assemblies, methods, and systems for tissue stimulation
US5006108A (en) * 1988-11-16 1991-04-09 Noven Pharmaceuticals, Inc. Apparatus for iontophoretic drug delivery
US5087242A (en) * 1989-07-21 1992-02-11 Iomed, Inc. Hydratable bioelectrode
US5250022A (en) * 1990-09-25 1993-10-05 Rutgers, The State University Of New Jersey Iontotherapeutic devices, reservoir electrode devices therefore, process and unit dose

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0748636A2 (fr) * 1995-06-14 1996-12-18 Takeda Chemical Industries, Ltd. Interface pour iontophorèse
EP0748636A3 (fr) * 1995-06-14 1997-06-04 Takeda Chemical Industries Ltd Interface pour iontophorèse
US6743432B1 (en) 1995-06-14 2004-06-01 Hisamitsu Pharmaceutical Co., Inc. Interface for iontophoresis
WO1997007854A1 (fr) * 1995-08-29 1997-03-06 Becton Dickinson And Company Dispositif d'administration de medicament par iontophorese comportant un circuit de conversion continu-continu a grande efficacite
US6375990B1 (en) 1997-10-09 2002-04-23 Emory University Method and devices for transdermal delivery of lithium
JP2002525307A (ja) * 1998-09-28 2002-08-13 ベクトン・ディキンソン・アンド・カンパニー ピペリジン誘導体を含むイオントフォレーゼ装置

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