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WO1999052590A1 - Systeme d'application transdermal (tds) dote d'un reseau d'electrodes - Google Patents

Systeme d'application transdermal (tds) dote d'un reseau d'electrodes Download PDF

Info

Publication number
WO1999052590A1
WO1999052590A1 PCT/EP1999/002425 EP9902425W WO9952590A1 WO 1999052590 A1 WO1999052590 A1 WO 1999052590A1 EP 9902425 W EP9902425 W EP 9902425W WO 9952590 A1 WO9952590 A1 WO 9952590A1
Authority
WO
WIPO (PCT)
Prior art keywords
application system
electrodes
tds
film
active substance
Prior art date
Application number
PCT/EP1999/002425
Other languages
German (de)
English (en)
Inventor
Wilfried Fischer
Rüdiger HAAS
Clifton Zimmermann
Original Assignee
Paedipharm Arzneimittel Gmbh
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 Paedipharm Arzneimittel Gmbh filed Critical Paedipharm Arzneimittel Gmbh
Publication of WO1999052590A1 publication Critical patent/WO1999052590A1/fr
Priority to US09/685,782 priority Critical patent/US6757560B1/en
Priority to US10/820,553 priority patent/US7383083B2/en

Links

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

Definitions

  • TDS Transdermal application system
  • TDS Transdermal delivery systems
  • previously implemented application areas e.g. hormones, high blood pressure, pain, nicotine replacement
  • TDS have already achieved a sales volume of over US $ 2 billion worldwide.
  • permeability limits that result from the chemical-physical properties of the substances to be applied.
  • Many known active substances are suitable for transdermal application as soon as a system is available that e.g. the permeability of larger molecules.
  • the additional market potential is enormous. For this reason, there have been technical approaches to improve the permeability of substances for some years, e.g. the use of absorption promoters in passive TDS or iontophoretic systems.
  • TDS take advantage of the passive concentration-dependent diffusion along the concentration gradient between the TDS and the stratum corneum of the skin for the active ingredient transport through the skin.
  • this mechanism only succeeds in driving very small molecules through the skin.
  • Larger, more complex molecules such as insulin, LH-RH etc. require an additional driving force to get through the skin into the bloodstream.
  • One method of applying an additional diffusion-increasing force is iontophoresis, ie the transport of molecules by means of an applied electric field. For this purpose, an electrical potential difference is generated between the active substance carrier and the patient. The molecules in ion form are then driven out of the conductive active substance reservoir into the skin by electrostatic repulsion.
  • the time course of the release of the active substance can be precisely controlled by appropriately controlling the driving electromotive force. This is a critical parameter, particularly in the case of an iontophoretic insulin system. Because of the small therapeutic breadth of the active ingredient, it is absolutely necessary that the liberation from the system controls the permeation through the skin.
  • External control units are supplied for iontophoretic systems, which are connected to the system by cables.
  • Devices are also known from the patent literature, which consist of integrated control units in conjunction with an active substance reservoir and electrodes (see below).
  • Iontophoretic transdermal therapeutic systems as are known, for example, from DE 3703321 C2, WO 92/04938, WO 87/04936, US 3,991,755, US 4,141,359 or WO 91/16077, generally consist of a combination of two electrodes, one or both electrodes are each connected to an active substance reservoir. By applying a voltage to both electrodes, after applying the iontophoretic system to the skin, ionized active substance molecules are forced through skin by electrostatic repulsion through the electrode charged with the active substance in the same sense.
  • the basic structure of ionophoretic systems always includes a cathode and an anode, which serve to generate a direct current flow through the body. Accordingly, the electrodes must be arranged at such a geometric distance from one another that no short circuit can occur on the surface of the skin.
  • the electrodes are directly connected to aqueous buffer solutions, which can be immobilized in gels. The electrical contact to the skin takes place via these aqueous preparations. Ion-containing liquid from it can spread along the surface of the skin and thus cause a direct current flow between the electrodes. This requires a certain minimum size of such a system in order to be able to insulate the electrodes.
  • iontophoretic systems are operated with pulsed DC voltage or AC voltage, the type of Pulse (shape, height, length) affect the tolerance and effectiveness of the iontophoretic system.
  • the field is generated over a large area over the entire TDS and can only be roughly controlled, if at all. This means that the entire system is either active or switched off. Since the skin needs recovery phases between the tension applications, for example around If the reservoir built up under the iontophoresis is emptied again, there is a non-constant release of the active ingredient and thus fluctuating blood levels.
  • iontophoretic TDS The current technical versions of iontophoretic TDS are very complex and expensive. Precious metal coated metal disks are mostly used as electrodes, e.g. as counter electrodes. Normal electrodes, all measures to avoid possible polarizations. As stated above, the electrode gels must be attached insulated from each other and must not leak. All in all, the current iontophoretic TDS are large, expensive and not very flexible in terms of their control options. However, in order to make the advantages of voltage-controlled active substance permeation generally usable, it is necessary to have simple, inexpensive to manufacture and flexible TDS.
  • the object of the present invention is to provide an "intelligent" electrically controlled TDS which avoids the disadvantages described above.
  • the invention now relates to a transdermal application system (TDS)
  • a carrier film which carries a substance / active substance reservoir for receiving a substance / active substance on one side and is provided with an electrode grid
  • the application system according to the invention can be characterized by a carrier film with a thickness in the range from 10 to 1000 ⁇ m.
  • the application system according to the invention can be characterized in that the active substance reservoir is formed by a pressure-sensitive pressure sensitive adhesive, a gel or an immobilized solution for the active substance.
  • the application system according to the invention can be characterized in that the carrier foil carries a grid of electrode pairs, the electrodes of each pair being arranged on opposite sides of the carrier foil. Furthermore, the application system according to the invention can be characterized in that the electrode grid is printed.
  • each pair of electrodes can be controlled individually.
  • the application system according to the invention can be characterized in that the electrode pairs can be controlled in groups.
  • the application system according to the invention can be characterized in that electrodes which can be charged in the same direction or in opposite directions are arranged on each of the two sides of the application system.
  • the application system according to the invention can be characterized in that the microchip is firmly welded to the film carrier.
  • the application system according to the invention can be characterized in that the microchip is a recipe-programmable chip.
  • the application system according to the invention can be characterized in that the battery is a button or foil battery.
  • the application system according to the invention can be characterized in that the battery in a pocket of the film carrier is provided.
  • the proposed "grid” TDS represents a new category of transdermal application systems.
  • the grid “TDS” consists primarily of four components:
  • the size of the grid-TDS will not be different from the forth ⁇ conventional passive TDS (some 10 cm 2).
  • the carrier film is given a pattern of punctiform pairs of electrodes by double-sided printing (etching), the geometry of which is designed in such a way that a concentrated electric field is produced in the area of the two antipodes.
  • the field geometry and the level of the applied potential difference are designed in such a way that the active substance ions are driven out of the active substance matrix into the skin.
  • the control of the individual Electrodes are grid-shaped, systematic or. via a random generator.
  • a welded-on microchip with (optionally) electromagnetically rewritable memory is located on the edge of the carrier film.
  • This chip controls the above-mentioned electrodes to re ⁇ zept restroom, wherein the (optional) individual patient parameters can be taken into account in the course of therapy.
  • the patient or the attending doctor receives a card reader and writer. Before each treatment, the individual patient data are transferred to the chip memory via the reader. Depending on the data entered, the patient now receives the active ingredients in an optimal dosage via the patch programmed in this way.
  • One or more Li-button lines or corresponding foil batteries are used as the energy source.
  • the carrier film receives a pocket in the immediate vicinity of the microchip with corresponding connections into which the battery can be inserted.
  • the performance of such a cell will, depending on the active ingredient and the duration of use, be sufficient for one or more TDS applications, so that the batteries can generally be used several times.
  • the grid TDS consists of a large number of electrode pairs that are printed on the top and bottom of the carrier film of the TDS (electrode grid).
  • This electrode design makes it possible to produce large quantities very inexpensively using standard printing processes.
  • the printed film does not lose its flexibility.
  • the distance between the counter electrodes is very precisely determined by the thickness of the film.
  • the distance of the electrode pairs in the lateral direction can be varied very easily by the printing pattern.
  • the distance between the electrode pairs is designed so that the individual pairs can be controlled separately.
  • the electrode area is
  • the type of application of the electric field in the electrode raster TDS allows for the first time a variable change of state of any surface of the TDS. Parts of the TDS can be positively charged, while others are negative or uncharged. A recurring pattern of the distribution of the electric field can be built up via the TDS, which can be linear or flat along the electrode pairs. This makes it possible to adapt very individually to the field strength requirements. 10
  • a fundamental difference to iontophoretic systems is that ionized molecules migrate along the field lines within the drug reservoir. This can be done in media with low electrical or lack of conductivity. This makes it possible to arrange electrodes charged in opposite directions without a special insulator within one level of the TDS. If the strength of the electric field has been chosen so large that it can penetrate the skin with sufficient strength, the penetration of charged active substance molecules into the skin is influenced, in general a penetration enhancement is desired.
  • the electrode pairs can be operated with constant or pulsed DC voltage or AC voltage of different waveforms.
  • Films made of, for example, polyester, polyethylene or polypropylene with thicknesses of 10 to 1000 ⁇ m can be used as carrier films.
  • the electrodes made of copper, silver, gold, platinum or other conductive materials can be applied to the carrier film by means of appropriate printing processes such as gravure printing, screen printing or etching.
  • the active substance reservoir can be a pressure sensitive pressure sensitive adhesive containing an active substance, a gel containing an active substance or an immobilized active substance solution, the pH value of which enables the active substance in question to be ionized.
  • Substances from the class of opioids, antiasthmatics, regulatory peptides, parasympathomimetics, parasympatholytics or local anesthetics can be used as active ingredients, without being limited to these.
  • concentrations of the active substances in the reservoirs can be varied within wide limits, and they depend to varying degrees on the desired release rate and the necessary permeation through the skin. Typical concentrations are in the range of 0.1 to 10% of the total mass of the reservoir.
  • the skin permeation of the active substances in question can be influenced by adding conventional permeation promoters.
  • the electrodes are isolated from each other by the foil. Each electrode is provided with a lead printed on the foil, which is also silver-plated.
  • the supply lines which are insulated from one another, are each electrically conductively connected to a control device (controller).
  • the controller generates pulsating DC voltages in the range up to 7.5 V, whereby the frequency of the voltage can be varied from 0 to 2 kHz. Sine half-waves, triangular or rectangular pulses can be used as the pulse shape.
  • the controller can also be printed on the carrier film or can be accommodated in an external housing together with the required energy source. In the latter case, the electrodes are connected to the controller via flexible wiring. Each pair of electrodes can be controlled individually.
  • An ionic dye (as a model for an ionic drug) is dissolved in the solution of a pressure sensitive pressure sensitive adhesive (Duro-Tak 287-2097, uncrosslinked acrylate adhesive without functional groups) so that its concentration in the dry matter is 0.25%.
  • a pressure sensitive pressure sensitive adhesive Duro-Tak 287-2097, uncrosslinked acrylate adhesive without functional groups
  • a pressure-sensitive adhesive layer from the dye / adhesive solution described above is applied to one side of the electrode-carrying film using coating processes known to those skilled in the art and the solvent is evaporated using warm air.
  • a polyester film is provided with an upper electrode field facing away from the adhesive-containing side.
  • the underside is printed with ring-shaped electrodes, the rings being exactly opposite the flat electrodes.
  • the ring-shaped electrodes are connected together and are therefore not individually controllable. These electrodes represent the zero potential. Circular pieces with 8 electrodes and an area of 5 cm 2 are punched out of the film.
  • 500 mg agarose are dissolved together with 200 mg hydromorphone hydrochloride in 9.3 g water at 90 ° C.
  • the solution is cooled to 65 ° C. and spread out with a preheated application knife to form a 0.4 mm thick layer and allowed to cool.
  • circular 5 cm 2 pieces are punched out of the gel layer and fastened on the underside of the electrode field foils described above by means of a clamping ring so that no air pockets can occur between the gel layer and the foil.
  • the active substance flow in the hydrogel can be influenced as follows by varying the voltage (2 to 200 V): If the electrodes on the underside of the electrode holder 14
  • the diffusion of the hydromorphone hydrochloride increases away from the electrode field.
  • the active substance ions migrate towards the electrode foil. This reduces the amount of active ingredient released into the environment.
  • the strength of the active substance movement can be modulated by temporarily activating / deactivating individual pairs of electrodes.
  • the stamped electrode grid film from Example 2 is covered with a protruding film (Hostaphan MN 19), which is coated on one side with a self-adhesive pressure sensitive adhesive (Duro-Tak 287-2287), in such a way that a uniform adhesive ring results.
  • a protruding film Hostaphan MN 19
  • a self-adhesive pressure sensitive adhesive Duro-Tak 287-2287
  • a thin polyurethane foam film (approx. 0.5 mm thick) is coated with a self-adhesive pressure sensitive adhesive using a conventional coating process and covered with a siliconized protective film. Circular pieces with a diameter of 5 cm are punched out of the laminate, into each of which circular holes with a diameter of 2.5 cm are punched. Completely assembled electrode grid foils are inserted into the openings.
  • the finished electrode grid TTS can be glued to the skin after removing the protective film.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (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)
  • Bioinformatics & Cheminformatics (AREA)
  • Electrotherapy Devices (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un système d'application transdermal (TDS) doté d'un champ réseau commandé électriquement et comprenant: 1) un film support pourvu d'une matrice principe actif, appliquée d'un côté, et d'un réseau d'électrodes imprimé; 2) une micropuce réinscriptible, solidement soudée au film support; 3) un ensemble de boutons ou de films placé dans une poche du film support et servant de source d'énergie réutilisable; 4) un appareil de lecture et d'écriture destiné à l'écriture de la micropuce.
PCT/EP1999/002425 1998-04-09 1999-04-09 Systeme d'application transdermal (tds) dote d'un reseau d'electrodes WO1999052590A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/685,782 US6757560B1 (en) 1999-04-09 2000-10-10 Transdermal delivery system (TDS) with electrode network
US10/820,553 US7383083B2 (en) 1998-04-09 2004-04-08 Transdermal delivery system (TDS) with electrode network

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19816143.3 1998-04-09
DE1998116143 DE19816143A1 (de) 1998-04-09 1998-04-09 Transdermales Applikationssystem (TDS) mit Elektrodenraster

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/685,782 Continuation-In-Part US6757560B1 (en) 1998-04-09 2000-10-10 Transdermal delivery system (TDS) with electrode network

Publications (1)

Publication Number Publication Date
WO1999052590A1 true WO1999052590A1 (fr) 1999-10-21

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Application Number Title Priority Date Filing Date
PCT/EP1999/002425 WO1999052590A1 (fr) 1998-04-09 1999-04-09 Systeme d'application transdermal (tds) dote d'un reseau d'electrodes

Country Status (2)

Country Link
DE (1) DE19816143A1 (fr)
WO (1) WO1999052590A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001039748A3 (fr) * 1999-12-03 2002-01-03 Qinetiq Ltd Produit pharmaceutique administrable oralement et procede de fabrication correspondant
WO2001041736A3 (fr) * 1999-12-10 2002-01-31 Massachusetts Inst Technology Dispositifs a puces pour l'administration de molecules et procedes de fabrication correspondants
US6730072B2 (en) 2000-05-30 2004-05-04 Massachusetts Institute Of Technology Methods and devices for sealing microchip reservoir devices
EP1457233A1 (fr) * 2003-03-12 2004-09-15 Novosis AG Système d'administration de médicaments transdermique avec electrode à mailles
DE102007020799A1 (de) 2007-05-03 2008-11-06 Novosis Ag Transdermales therapeutisches System mit Remifentanil
DE102007058504A1 (de) 2007-12-05 2009-07-09 Acino Ag Transdermales therapeutisches System mit einem Gehalt an einem Modulator für nikotinische Acetylcholinrezeptoren (nAChR)
EP1688132A3 (fr) * 1999-12-10 2009-10-07 Massachussetts Institute of Technology dispositifs à puces pour l'administration de molécules et procédés de fabrication correspondants
US7985386B2 (en) 2000-03-02 2011-07-26 Microchips, Inc. Implantable medical device for diagnostic sensing
EP4259239A1 (fr) * 2020-12-14 2023-10-18 LTS LOHMANN Therapie-Systeme AG Système d'administration de principe actif

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10015928B4 (de) * 2000-03-30 2004-12-09 Hafner, Dieter, Dr. Träger für ein Arzneimittel und Verfahren zur Überprüfung der Unversehrtheit dieses Trägers
DE10015930A1 (de) * 2000-03-30 2001-10-18 Dieter Hafner Träger für ein Arzneimittel

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US3991755A (en) 1973-07-27 1976-11-16 Medicon, Inc. Iontophoresis apparatus for applying local anesthetics
US4141359A (en) 1976-08-16 1979-02-27 University Of Utah Epidermal iontophoresis device
WO1987004936A1 (fr) 1986-02-12 1987-08-27 Key Pharmaceuticals, Inc. Procede et appareil d'administration iontophoretique de medicaments
US4931046A (en) * 1987-05-15 1990-06-05 Newman Martin H Iontophoresis drug delivery system
US4942883A (en) * 1987-09-29 1990-07-24 Newman Martin H Drug delivery device
DE3703321C2 (fr) 1986-09-01 1991-08-29 Transcutan Gmbh, 7640 Kehl, De
WO1991016077A1 (fr) 1990-04-18 1991-10-31 Medtronic, Inc. Procede ameliore d'administration de medicaments par iontophorese
WO1992004938A1 (fr) 1990-09-25 1992-04-02 Rutgers, The State University Of New Jersey Dispositif iontotherapeutique, dispositif d'electrode pour reservoir, procede et dose unitaire
WO1993003790A1 (fr) * 1991-08-26 1993-03-04 Rutgers, The State University Of New Jersey Procede et dispositif ionotherapeutiques
EP0532451A1 (fr) * 1991-09-12 1993-03-17 S.I. SCIENTIFIC INNOVATIONS Ltd. Dispositif pour l'administration transcutanée d'un médicament
WO1994016765A1 (fr) * 1993-01-28 1994-08-04 Scientific Innovations Ltd. Applicateur pour l'apport transcutane de medicament
US5415629A (en) * 1993-09-15 1995-05-16 Henley; Julian L. Programmable apparatus for the transdermal delivery of drugs and method
FR2726769A1 (fr) * 1994-11-16 1996-05-15 Lhd Lab Hygiene Dietetique Dispositif ionophoretique d'administration transdermique de medicaments et ensemble jetable formant partie d'un tel dispositif

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IT1244030B (it) * 1989-12-21 1994-06-28 Elan Corp Plc Dispostitivo in due parti per la somministrazione controllata di un ingrediente

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3991755A (en) 1973-07-27 1976-11-16 Medicon, Inc. Iontophoresis apparatus for applying local anesthetics
US4141359A (en) 1976-08-16 1979-02-27 University Of Utah Epidermal iontophoresis device
WO1987004936A1 (fr) 1986-02-12 1987-08-27 Key Pharmaceuticals, Inc. Procede et appareil d'administration iontophoretique de medicaments
DE3703321C2 (fr) 1986-09-01 1991-08-29 Transcutan Gmbh, 7640 Kehl, De
US4931046A (en) * 1987-05-15 1990-06-05 Newman Martin H Iontophoresis drug delivery system
US4942883A (en) * 1987-09-29 1990-07-24 Newman Martin H Drug delivery device
WO1991016077A1 (fr) 1990-04-18 1991-10-31 Medtronic, Inc. Procede ameliore d'administration de medicaments par iontophorese
WO1992004938A1 (fr) 1990-09-25 1992-04-02 Rutgers, The State University Of New Jersey Dispositif iontotherapeutique, dispositif d'electrode pour reservoir, procede et dose unitaire
WO1993003790A1 (fr) * 1991-08-26 1993-03-04 Rutgers, The State University Of New Jersey Procede et dispositif ionotherapeutiques
EP0532451A1 (fr) * 1991-09-12 1993-03-17 S.I. SCIENTIFIC INNOVATIONS Ltd. Dispositif pour l'administration transcutanée d'un médicament
WO1994016765A1 (fr) * 1993-01-28 1994-08-04 Scientific Innovations Ltd. Applicateur pour l'apport transcutane de medicament
US5415629A (en) * 1993-09-15 1995-05-16 Henley; Julian L. Programmable apparatus for the transdermal delivery of drugs and method
FR2726769A1 (fr) * 1994-11-16 1996-05-15 Lhd Lab Hygiene Dietetique Dispositif ionophoretique d'administration transdermique de medicaments et ensemble jetable formant partie d'un tel dispositif

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001039748A3 (fr) * 1999-12-03 2002-01-03 Qinetiq Ltd Produit pharmaceutique administrable oralement et procede de fabrication correspondant
AU769952B2 (en) * 1999-12-03 2004-02-12 Psimedica Limited Orally administrable pharmaceutical product and method of fabrication therefor
WO2001041736A3 (fr) * 1999-12-10 2002-01-31 Massachusetts Inst Technology Dispositifs a puces pour l'administration de molecules et procedes de fabrication correspondants
US6808522B2 (en) 1999-12-10 2004-10-26 Massachusetts Institute Of Technology Microchip devices for delivery of molecules and methods of fabrication thereof
EP1688132A3 (fr) * 1999-12-10 2009-10-07 Massachussetts Institute of Technology dispositifs à puces pour l'administration de molécules et procédés de fabrication correspondants
US7985386B2 (en) 2000-03-02 2011-07-26 Microchips, Inc. Implantable medical device for diagnostic sensing
US6730072B2 (en) 2000-05-30 2004-05-04 Massachusetts Institute Of Technology Methods and devices for sealing microchip reservoir devices
EP1457233A1 (fr) * 2003-03-12 2004-09-15 Novosis AG Système d'administration de médicaments transdermique avec electrode à mailles
DE102007020799A1 (de) 2007-05-03 2008-11-06 Novosis Ag Transdermales therapeutisches System mit Remifentanil
DE102007058504A1 (de) 2007-12-05 2009-07-09 Acino Ag Transdermales therapeutisches System mit einem Gehalt an einem Modulator für nikotinische Acetylcholinrezeptoren (nAChR)
EP4259239A1 (fr) * 2020-12-14 2023-10-18 LTS LOHMANN Therapie-Systeme AG Système d'administration de principe actif

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Publication number Publication date
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