EP0819016A1 - Systeme transdermique iontophoretique permettant d'administrer au moins deux substances - Google Patents

Systeme transdermique iontophoretique permettant d'administrer au moins deux substances

Info

Publication number
EP0819016A1
EP0819016A1 EP96910932A EP96910932A EP0819016A1 EP 0819016 A1 EP0819016 A1 EP 0819016A1 EP 96910932 A EP96910932 A EP 96910932A EP 96910932 A EP96910932 A EP 96910932A EP 0819016 A1 EP0819016 A1 EP 0819016A1
Authority
EP
European Patent Office
Prior art keywords
transdermal system
layer
substances
skin
storage
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP96910932A
Other languages
German (de)
English (en)
Inventor
Carlo Stefan Effenhauser
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH
Novartis AG
Original Assignee
Novartis Erfindungen Verwaltungs GmbH
Ciba Geigy AG
Novartis AG
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 Novartis Erfindungen Verwaltungs GmbH, Ciba Geigy AG, Novartis AG filed Critical Novartis Erfindungen Verwaltungs GmbH
Priority to EP96910932A priority Critical patent/EP0819016A1/fr
Publication of EP0819016A1 publication Critical patent/EP0819016A1/fr
Ceased legal-status Critical Current

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0444—Membrane
    • 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 invention relates to a transdermal system for administering at least two substances through the skin by means of an electric current according to the preamble of the independent claim.
  • transdermal systems serve to administer a substance, for example therapeutically active substances or mixtures of substances, through the skin of a living being, without using a device such as, for. B. an injection needle to mechanically clearly penetrate the outer layer of skin - the stratum comeum - and possibly also underlying skin layers.
  • Transdermal systems are therefore normally non-invasive forms of administration.
  • transdermal systems The great interest in transdermal systems is due to the fact that this form of administration has clear advantages over other customary methods.
  • undesirable side effects often occur due to incompatibilities in the gastrointestinal tract or in the liver.
  • Orally administered substances are often already decomposed in the gastrointestinal tract or in the liver or modified in such a way that the desired therapeutic effect no longer occurs ("first-pass" effect).
  • Other forms of parenteral administration such as intravenous, subcutaneous or intramuscular injections, are associated with skin penetration or skin layers and are therefore associated with a sensation of pain for the patient. Local inflammation or infection due to partial skin damage can also occur.
  • Transdermal systems are not subject to these restrictions, today, in particular in the form of a typical representative, namely the transdermal patch, they are among the common dosage forms which are widely used.
  • Transdermal systems can be roughly divided into passive and active systems.
  • the passive systems the substance to be administered diffuses through the skin from a reservoir.
  • the active systems an additional force accelerates substance transport through the skin.
  • Electrical fields that generate a current flow through the skin are particularly preferably used here.
  • the administration of a therapeutically active substance through the skin by means of an electric current is generally referred to as iontophoresis.
  • iontophoretic systems used today include at least two electrodes, one of which contacts the reservoir with the substance.
  • the other electrode often referred to as an indifferent electrode, is attached directly to the skin and is used to close the circuit through the body.
  • an electrical energy source When connected to an electrical energy source, a current flows through the skin that transports the substance into the body.
  • passive substance transport takes place accompanying such active systems.
  • a disadvantage of today's passive transdermal systems results from the fact that the diffusion process via the natural channels of the skin (sebaceous and sweat glands, inter- and transcellular transport routes, hair follicles) is very slow. It is therefore difficult, in particular, to administer a substance through the stratum comeum with a dose rate that is sufficiently high for the desired therapeutic effect by means of a passive transde ⁇ nale system.
  • the dose rate is the amount of substance that is administered through the skin per time.
  • active especially iontophoretic systems generally allow higher dosing rates.
  • the latter systems have the further advantage that the metering rate can be influenced and changed in a simple manner in a controlled manner.
  • the current as an active control element during administration, it is possible, for example, to adapt the dosing rate to the individual needs of the patient.
  • Therapeutically useful dosing schemes are also feasible, e.g. B. phases with higher dosing rates and phases with low dosing rates can alternate.
  • iontophoretic systems have the advantage that the substance to be administered is virtually “on demand”. The substance can be started or stopped simply by activating or deactivating the electrical current flow.
  • the current strength that can be used is subject to iontophoretic systems Physiological limitations, because an excessive electric current can, for example, cause burns or other irritation to the skin. Therefore, there is a need to control or increase the dosing rate in ways other than just the electric current.
  • One way to control or change the dosing rate is to administer the therapeutically active substance together with an agent which has an influence on the blood flow in the capillary vessels of the skin.
  • Such a method is disclosed for example in EP-A-0, a448,300. With this method, a composition is first generated which, in addition to the therapeutically active substance, also contains a vascular-manipulating agent. This is then followed by the iontophoretic administration of this composition.
  • the vascular manipulating agent is a vasodilator, it increases the blood flow through the capillary vessels of the skin and thus leads to a higher dosage rate for the therapeutically active substance. If the vascular-manipulating agent is a vascular-contracting agent, it reduces the blood flow through the capillary vessels, which leads to a depot effect for the therapeutically active substance. Since the vascular manipulating agent and the therapeutically active substance are administered together, this process is referred to as "coiontophoresis".
  • the concentration of the vasodilator initially shows an increase in the Dosage rate for the therapeutically active substance, which is followed by a decrease with increasing concentration of the vasodilator.
  • an optimal composition of the therapeutically active substance and the vascular manipulating agent must first be determined in a time-consuming manner so that the desired effect occurs in the co-iontophoresis of the two substances
  • the transdermal system for the administration of at least two substances through the skin by means of electric current that achieves this object is characterized by the features of independent claim 1.
  • means for spatial separation of the substances from one another are thus provided in the transdermal system, by means of which the administration of the substances begins with a time offset relative to one another.
  • This controlled sequential administration leads to a significant increase in efficiency.
  • the substance administered first can have its full effect in the skin before another substance gets into the skin.
  • a vessel-widening agent first administered can first increase the blood flow through the capillary vessels of the skin, and only then does a therapeutically effective administration take place Substance, which is then better absorbed by the already dilated blood vessels. The delay in administration thus leads to a more efficient use of the individual substances and consequently reduces the amount of substance required.
  • the metering rates for the individual substances can also be controlled. Because e.g. B. at the start of administration essentially only the first substance travels through the skin, such competitive effects as mentioned above practically do not occur.
  • Fe he can also be a controlled change in the concentrations of the substances during use, for example, a concentration of Substances in the transdermal system, which means that the substances are present in the transfer device in a higher concentration than originally in the reservoir.
  • concentration during use leads to a significant increase in the dosing rate because the substances are concentrated in the vicinity of the skin and this results in an increase in the passive transport rate, which accompanies the electrically-induced transport of the substances through the skin
  • the substances are located together in a storage layer which is contained in the reservoir.
  • the spatial separation of the substances takes place when walking through a separation layer which is contained in the transfer device.
  • the separating layer has the property that the rate of migration of the different substances is different in it. This property leads to the spatial separation and thus to the sequential administration of the substances.
  • the substances are to be additionally concentrated in this exemplary embodiment, it is particularly advantageous - as will be explained further below - if the separating layer has a higher electrical conductivity than the storage layer.
  • the reservoir comprises at least two spatially separated storage layers, each of which contains at least one substance.
  • a modification layer which spatially separates the storage layers from one another, is particularly preferably located between the storage layers.
  • a further modification layer can be provided in the transfer device, which is arranged such that it contacts the storage layer of the reservoir closest to the skin.
  • the dosing rates for the substances and the time delay between the administration of the substances can be controlled in this exemplary embodiment in particular via the thickness of the modification layers between the individual storage layers and via the migration speeds with which the substances migrate through the individual layers.
  • the different storage layers can contain the same substance in different concentrations. Due to the time delay with which the substance contained in different storage layers is administered, the metering rate can be designed to be variable in time, that is to say it can be modulated. This has the advantage that the therapeutic efficiency can be increased even further because the dosing schedule can be adapted to the time-varying needs of the patient.
  • the modification layers have a higher electrical conductivity than the storage layers.
  • Fig. 1 shows a section of a first embodiment of the transdermal system according to the invention with the essential parts and
  • Fig. 2 shows a detail of a second exemplary embodiment of the transdermal system according to the invention with the essential parts and
  • the transdermal system 1 comprises a reservoir, which in this embodiment consists of a storage layer 2, in which the substances to be administered, a first substance and a second substance, are contained together.
  • transdermal system 1 This also includes transdermal system 1, a separating layer 3 functioning as a transfer device, which is connected to both the storage layer 2 and the skin 5 of a patient during administration.
  • a first electrode 4 is provided in the transdermal system 1, which contacts the storage layer 2.
  • the representation of the corresponding counter electrode, which is often referred to as an indifferent electrode, has been omitted, since only a section is shown.
  • the system in FIG. 1 has a barrier membrane 15 which is arranged between the storage layer 2 and the separating layer 3. The functions of the intermediate layer 4a and the barrier membrane 15 will be discussed further below.
  • the storage layer 2 and the separating layer 3 consist of an electrically conductive material, so that an electrical current can flow through these layers 2 and 3.
  • the storage layer 2 is preferably made of an ionically conductive polymer material, gel or hydrogel, in which the substances to be administered are typically contained in dissolved form.
  • the separating layer 3 is also preferably made of an ionically conductive polymer material, gel or hydrogel. Both layers 2 and 3 can be made of the same material.
  • Such polymer or gel materials are per se state of the art and are frequently used in known active and passive transdermal systems.
  • the first electrode 4 and the counter electrode, not shown in FIG. 1, are also prior art per se and therefore do not require any further explanation.
  • the counterelectrode can, for example, be arranged in such a way that it surrounds the separating layer 3 in a quasi-annular manner and is in direct contact with the skin 5 during the administration, similar to that of e.g. B. is described in WO-A-93/17754 for the corresponding counter electrode.
  • the transdermal system 1 is fixed on the skin 5 of the patient such that the separating layer 3 contacts the skin 2 with its side facing away from the first electrode 4.
  • the transdermal system 1 can be designed in the form of a plaster and, for example, be coated with an adhesive layer. However, it is also possible for the separating layer 3 to be designed as an adhesive layer.
  • the attachment to the skin 5 is carried out in a manner known per se as in the case of a conventional transdermal patch.
  • the first electrode 4 and the counter electrode are connected to an electrical energy source, for example a battery, in such a way that the energy source, the two electrodes, the storage layer 2, the separating layer 3 and the skin 5 form a closed electrical circuit.
  • the substances contained in the storage layer 2 then migrate with appropriate polarity due to an electrical field between the electrodes or by means of an electrical current from the storage layer 2 through the separating layer 3 into the skin 5.
  • the first and the second substance are contained together in the storage layer 2 of the reservoir before the iontophoretic administration.
  • the two substances can be dissolved in an electrically charged form, e.g. B. as ions.
  • an electrically charged form e.g. B. as ions.
  • the electrical current circuit is closed and the polarity is appropriate, the ions begin to migrate from the storage layer 2 through the separating layer 3 into the patient's skin 5 due to the prevailing electrical field.
  • the migration rate of ions in a medium is essentially determined by the product of the local electric field strength in the medium and the electrophoretic mobility of the ions.
  • the ions of the first substance migrate through the separating layer 3 at a different migration speed than the ions of the second substance. This results in a spatial separation of the ions of the first substance from those of the second substance as it travels through the separation layer. If, for example, the ions of the first substance in the separating layer 3 have a greater migration speed than the ions of the second substance, then the former have passed through the separating layer 3 more quickly and reach the skin 5 of the patient before the ions of the second substance. As a result of this spatial separation of the two substances as they pass through the separation layer, the administration of the two substances can take place sequentially, ie at different times.
  • the time delay between the start of the administration of the first substance and the start of the administration of the second substance can be controlled via the thickness of the separation layer 3.
  • the time span mentioned is also due to the material from which the separating layer 3 is controllable, because this material influences both the electrophoretic mobility of the ions and the strength of the electric field and thus also the difference in the migration speed of the ions of the two substances.
  • the transdermal system according to the invention enables the controlled sequential administration of two or more substances.
  • This has the great advantage that the substance administered first can have its full effect in the skin before the second substance gets into the skin.
  • the transdermal system according to the invention offers the possibility of changing the concentrations of the two substances in a controlled manner.
  • the substances can be concentrated in the interface.
  • the separating layer 3 preferably has a greater electrical conductivity than the storage layer 2. If both layers 2 and 3 are made of the same material, this difference in conductivity can be realized, for example, by different degrees of crosslinking of the polymer material.
  • the separating layer 3 and the storage layer 2 form a series connection of two resistors, and since the electrical conductivity of the separating layer 3 is greater than the electrical conductivity of the storage layer 2, the voltage drop across the storage layer 2 is greater than the voltage drop across the separating layer 3. However, this means that there is a greater electric field strength in the storage layer 2 than in the separating layer 3.
  • the migration speed of the ions of a substance is essentially determined by the product of the local electric field strength and the electrophoretic mobility, it follows that the migration speed of this ion type mainly depends on the same mobility of the ions of a substance in the storage layer 2 and the separation layer 3 depends on the respective electric field strength in layers 2 and 3
  • the two types of ions, namely the ions of the first substance and that of the second substance therefore, viewed individually, have different migration speeds in the two layers 2 and 3.
  • the first exemplary embodiment can, of course, also be designed such that, in addition to the spatial separation of the substances, their concentrations are reduced in the separating layer 3. This can be realized, for example, in that the separating layer 3 has a lower electrical conductivity than the storage layer 2.
  • the electrically conductive intermediate layers 4a are also provided between the first electrode 4 and the storage layer 2 and, if appropriate, between the skin 5 and the counter electrode. They spatially separate the first electrode 4 from the storage layer 2 and the counter electrode from the skin.
  • the intermediate layers 4a prevent contamination of the storage layer 2 or the skin, because the intermediate layers 4a keep electrolysis products possibly occurring on the electrodes from the storage layer 2 or the skin during the current flow.
  • the barrier membrane 15 is located between the separating layers 3 and the storage layer 2.
  • This barrier membrane 15 has the property that its permeability can be controlled by applying an electric field. Before the application of the transdermal system, the electrical field between the electrodes is not yet switched on and thus the barrier membrane 15 has practically no permeability. If the electric field is switched on for the application of the transdermal system, the barrier membrane 15 "opens" and the substances to be administered can pass through it. Membranes such as the barrier membrane 15 are per se state of the art.
  • the transdermal system can be stored better and longer, because during storage the barrier membrane 15 leads to a more permanent separation of the storage layer 2 and the separation layer 3, which indeed have phases with different physical and chemical properties (e.g. electrical conductivity).
  • the barrier membrane 15 in the inactive transdermal system ie as long as the circuit is not yet closed, prevents substantial mass transport, for example by passive diffusion, between the individual layers.
  • the barrier membrane hinders the use of the transdermal system for the administration of the substances. So in the open state, the migration of the substances practically not.
  • the transdermal system 1 comprises a reservoir, which in this exemplary embodiment contains a first storage layer 11 and a second storage layer 13 spatially separated therefrom.
  • the first storage layer 11 contains a first substance to be administered
  • the second storage layer 13 contains a second substance to be administered.
  • a first modification layer 12 is provided between the two storage layers 11 and 13, which spatially separates the two storage layers 11 and 13 from one another.
  • the transfer device consists of a second modification layer 10 which, when the transdermal system is applied, is connected both to the skin 5 of a patient and to the first storage layer 11.
  • the four layers 10-13 mentioned form a stack-like arrangement.
  • a first electrode 4 is provided in the transdermal system 1, which contacts the side of the second storage layer 13 facing away from the skin 5.
  • the corresponding counter electrode has not been shown since only a section is shown.
  • an intermediate layer 4a is also provided between the first electrode 4 and the second storage layer 13.
  • the system in FIG. 2 has barrier membranes 15 which are arranged between the first modification layer 12 and the adjacent storage layers 11 and 13 and between the second modification layer 10 and the first storage layer 11. The functions of the intermediate layer 4a and the barrier membranes 15 will be discussed further below.
  • the two storage layers 11 and 13 and the two modification layers 10 and 12 consist of an electrically conductive material, so that an electrical current can flow through these layers 10-13.
  • the storage layers 11 and 13 are preferably made of an ionically conductive polymer material, gel or hydrogel, in which the substances to be administered are typically contained in dissolved form.
  • Modification layers 10 and 12 are also preferably made of an ionically conductive polymer material, gel or hydrogel. All four layers 10-13 can be made of the same material. Such polymer or gel materials are per se state of the art and are frequently used in known active and passive transdermal systems.
  • the transdermal system 1 is fixed on the skin 5 of the patient in such a way that the second modification layer 10 contacts the skin 5 with its side facing away from the first electrode 4.
  • the transdermal system 1 can be designed in the form of a plaster and, for example, can be coated with an adhesive layer, or the second modification layer 10 is designed as an adhesive layer.
  • the first electrode 4 and the counter electrode are connected to an electrical energy source, for example a battery, in such a way that the energy source, the two electrodes, the storage layers 11 and 13, the modification layers 10 and 12 and the skin 5 form a closed electrical circuit.
  • the first substance contained in the first storage layer 11 then migrates with appropriate polarity due to an electrical field between the electrodes or by means of an electric current from the second storage layer 11 through the second modification layer 13 into the skin 5.
  • the second substance migrates from the second Storage layer 13 through the first modification layer 12, through the first storage layer 11 and through the second modification layer 10 into the skin 5.
  • the two substances are contained in different, spatially separate storage layers 11 and 13 of the system.
  • the electrical current flows from the first electrode 4 through the second Storage layer 13, the first modification layer 12, the first storage layer 11, the second modification layer 10 and the skin 5 of the patient 5 to the counterelectrode and thus causes the substances to be transported into the skin 5. Since the ions of the first substance are present in the first storage layer 11 is contained, only have to pass through the second modification layer 10 in order to get into the skin 5, they reach the skin 5 significantly earlier than the ions of the second substance contained in the second storage layer 13, which additionally have the first modification layer 12 and the first Have to migrate through the storage layer 11 before they reach the skin 5.
  • the transdermal system thus enables the two substances to be administered sequentially.
  • the delay time between the administration of the first and the second substance can also be influenced in a controlled manner in this exemplary embodiment.
  • This delay time can be controlled, for example, via the thickness of the first modification layer 12.
  • a greater thickness of the first modification layer 12 thus leads to a longer delay time.
  • the rate of migration of an ion type in a medium depends both on the local electric field strength in the medium and on the electrophoretic mobility of the ion type in this medium.
  • the delay time which essentially depends on the time it takes for the ions of the second substance to pass through the first modification layer 12, can be controlled by the electric field strength in the first modification layer 12 and by the electrophoretic mobility of the ions of the second substance in this first modification layer 12 are influenced.
  • the electrical field strength in the first modification layer 12 can in turn, as explained further above, be controlled by the electrical conductivity of this layer 12.
  • a high electrical conductivity of the first modification layer 12 compared to the second storage layer leads to a significantly lower migration speed in this layer.
  • the second exemplary embodiment of the transdermal system according to the invention enables controlled sequential administration of the two substances.
  • the transdermal system can, for example, be designed such that the conductivity of the two modification layers 10 and 12 is significantly greater than that of the storage layers 11 and 13, which leads to a lower electric field strength and thus to a lower migration rate of the ions in the modification layers 10 and 12 leads.
  • the electrical conductivity of the individual layers 10-13 can be controlled, for example, via the degree of crosslinking of the polymer material.
  • the second substance only migrates from the second storage layer 13 through the first modification layer 12, in which it contains a has a low migration speed, that is to say where it still "waits", then migrates through the first storage layer 11 with a higher migration speed, and is then concentrated in the second modification layer 10.
  • the two substances contained in the spatially separated storage layers 11 and 13 are chemically the same and differ, for example, in that they are present in the two storage layers 11 and 13 in different concentrations.
  • the first storage layer 11 can contain the substance in a lower concentration than the second storage layer 13. Then the substance is administered from the first storage layer and, as described above, the same substance is administered from the second storage layer at a different time.
  • the substance Since the substance is contained in a higher concentration in the second storage layer, after passing through the first modification layer 12 and the first storage layer 11 in the second modification layer 10, it is also present in a higher concentration than the substance originating from the first storage layer 11. This results in at least an increase in the passive transport rate and thus an increase in the total dosing rate.
  • the electrically conductive intermediate layers 4a are also provided between the first electrode 4 and the second storage layer 13 and optionally between the skin 5 and the counter electrode. They spatially separate the first electrode 4 from the second storage layer 13 and the counter electrode from the skin.
  • the intermediate layers 4a prevent one Contamination of the second storage layer 13 or of the skin because the intermediate layers 4a keep electrolysis products possibly occurring on the electrodes from the second storage layer 13 or from the skin during the current flow.
  • barrier membranes 15 are located between the modification layers 10 and 12 and the storage layers 11 and 13 adjoining them, as described further above. In this way, the shelf life of the transde ⁇ nalen system can be improved.
  • more than two storage layers for more than two substances to be administered can also be contained in the reservoir of the transde ⁇ nalen system. It is particularly advantageous if there are further modification layers between adjacent storage layers and if necessary the individual layers are spatially separated by further barrier membranes. This is done in a manner analogous to that previously explained for the second exemplary embodiment.
  • the administration of at least two substances by iontophoretic means can thus take place in a controlled, sequential manner, that is to say at different times.
  • the first substance can develop its full effect in the skin before the second substance is administered.
  • the first substance can be a vasodilator.
  • the second substance only reaches the vessels after they have been widened by the first substance, which leads to a faster and more efficient action of the second substance.
  • the first substance can first cause a contraction of the blood vessels, which means that the subsequently administered Substance a deposit effect can be achieved.
  • the first substance is an analgesic and anti-inflammatory agent that relieves side effects and side effects of transdermal administration.

Abstract

L'invention concerne un système transdermique (1) qui permet d'administrer au moins deux substances à travers la peau à l'aide d'un courant électrique. Ce système comporte un réservoir comprenant une couche de stockage (2) pour les substances à administrer, ainsi qu'un dispositif de transfert pouvant se présenter sous forme de couche de séparation (3). Pendant le processus d'administration, ce dispositif de transfert est aussi bien en contact avec le réservoir qu'avec la peau du patient. Ce système transdermique comporte en outre des électrodes (4) qui produisent un courant servant à transporter les substances du réservoir à l'intérieur de la peau (5). Il est prévu dans ce système transdermique (1) des éléments de séparation spatiale des substances qui permettent de procéder à un mode d'administration séquentiel des substances.
EP96910932A 1995-04-07 1996-03-26 Systeme transdermique iontophoretique permettant d'administrer au moins deux substances Ceased EP0819016A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP96910932A EP0819016A1 (fr) 1995-04-07 1996-03-26 Systeme transdermique iontophoretique permettant d'administrer au moins deux substances

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP95810232 1995-04-07
EP95810232 1995-04-07
PCT/EP1996/001327 WO1996031251A1 (fr) 1995-04-07 1996-03-26 Systeme transdermique iontophoretique permettant d'administrer au moins deux substances
EP96910932A EP0819016A1 (fr) 1995-04-07 1996-03-26 Systeme transdermique iontophoretique permettant d'administrer au moins deux substances

Publications (1)

Publication Number Publication Date
EP0819016A1 true EP0819016A1 (fr) 1998-01-21

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EP96910932A Ceased EP0819016A1 (fr) 1995-04-07 1996-03-26 Systeme transdermique iontophoretique permettant d'administrer au moins deux substances

Country Status (6)

Country Link
US (1) US6032073A (fr)
EP (1) EP0819016A1 (fr)
JP (1) JPH11503043A (fr)
AU (1) AU701737B2 (fr)
CA (1) CA2217014A1 (fr)
WO (1) WO1996031251A1 (fr)

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AU701737B2 (en) 1999-02-04
US6032073A (en) 2000-02-29
CA2217014A1 (fr) 1996-10-10
WO1996031251A1 (fr) 1996-10-10
AU5397996A (en) 1996-10-23

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