Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
2000-10-10
2004-06-29
Casler, Brian L. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C604S501000
Reexamination Certificate
active
06757560
ABSTRACT:
1. STATE OF THE ART
In the pharmaceutical industry's permanent search for optimization of the administration of medicaments, transdermal delivery systems (TDSs) today occupy a significant position. In the areas of use realised so far (e.g. hormones, hypertension, pain, nicotine replacement), TDSs have already reached a worldwide turnover in excess of $ 2 billion. With all of the advantages of TDSs for patients and for the health cost system, the possibility of using such delivery systems is currently still restricted by permeability limits, which stem from the physico-chemical properties of the substances to be delivered. Many known active ingredients will be possible candidates for transdermal delivery as soon as a system is available that, for example, brings about permeability to larger molecules. The additional market potential is enormous. For some years there have therefore been technological attempts to improve the permeability to substances, for example the use of absorption enhancers in passive TDSs, or iontophoretic systems.
In order to transport a substance/active ingredient through the skin, customary TDSs make use of passive concentration-dependent diffusion along the concentration gradient between the TDS and the stratum corneum of the skin. Only very small molecules, however, can be forced through the skin using that mechanism. Larger, more complex molecules, such as insulin, LH-RH etc., require an additional driving force in order to pass through the skin into the bloodstream.
One method of applying an additional diffusion-increasing force is iontophoresis, that is to say the transport of molecules by means of an applied electrical field. For that purpose, a difference in electrical potential is generated between the substance/active ingredient carrier and the patient. The molecules, present in ionic form, are then driven from the conductive substance/active ingredient reservoir into the skin by means of electrostatic repulsion. The release of the substance/active ingredient over time can be accurately controlled by corresponding control of the driving electromotive force. This is a critical variable, especially in the case of an iontophoretic insulin system. Owing to the small therapeutic range of the active ingredient in that case, it is absolutely necessary that the permeation through the skin is controlled by the release from the system.
Supplied with iontophoretic systems are external control devices which are connected to the system by cable. Also known from the patent literature are arrangements that consist of integrated control units associated with a substance/active ingredient reservoir and electrodes (see below).
Iontophoretic transdermal therapeutic systems, as known, for example, from DE 3 703 321 C2, WO 92/04938, WO 87/04936, U.S. Pat. No. 3,991,755, U.S. Pat. No. 4,141,359 or WO 91/16077, generally consist of a combination of two electrodes, wherein one electrode or both electrodes is/are each connected to a substance/active ingredient reservoir. By means of a voltage applied to both electrodes it is then possible, once the iontophoretic system has been applied to the skin, for ionised substance/active ingredient molecules to be forced through the skin by means of electrostatic repulsion from the electrode that is charged in the same sense as the substance/active ingredient.
U.S. Pat. No. 5,415,629 describes an iontophoretic transdermal active-ingredient-delivery system having an “ionosonic applicator working electrode” or “applicator electrode” 10 that has a skin-contacting face 17. It is clearly to be inferred that the electrode is in contact with the skin. The active ingredient thus migrates iontophoretically, in a field lying between electrode and skin, into the skin. Measures for the avoidance of tunnelling are claimed, since the density of the field lines on the skin can vary, especially when the skin is damaged.
EP 0 532 451 relates to a transdermal active-ingredient-delivery system having a pair of electrodes in which both electrodes are in contact with the layer containing the active ingredient. The two electrodes are arranged spaced from each other, an insulating layer, which contains the active ingredient, covering the gap formed by the two electrodes. The active ingredient thus moves in the electric field formed between the two electrodes.
The basic construction of iontophoretic systems always comprises a cathode and an anode, which serve to generate a direct flow of current through the substance body. Accordingly, the geometric spacing between the electrodes must be such that there can be no short-circuiting at the skin surface. The electrodes in such arrangements are in direct contact with aqueous buffer solutions, which can be immobilised in gels. The electric contact with the skin is through those aqueous preparations. Ion-containing liquid therefrom is able to spread along the surface of the skin and thus bring about a direct flow of current between the electrodes. Such a system therefore has to be of a certain minimum size in order to be able to give rise to insulation of the electrodes.
In order to avoid burns to the skin tissue, prevent polarisation of the electrodes and hydrolysis of tissue water (down to approximately 1.7 V), which can result in a painful shift in pH, iontophoretic systems are operated with a pulsed direct voltage or alternating voltage, the nature of the pulse (form, height, length) influencing the compatibility and effectiveness of the iontophoretic system. The field is generated over a wide area over the entire TDS and can be regulated only roughly, if at all. The entire system is therefore either active or switched off. Since the skin requires phases of recovery between voltage applications, for example in order for the reservoir built up during the iontophoresis to be emptied again, the result is that the release of active ingredient is not continuous and consequently also blood levels vary.
The current commercial forms of iontophoretic TDSs are very complex and expensive. The electrodes used are usually noble-metal-coated metal discs, and the counter-electrodes are, for example, standard electrodes, all measures for avoiding the possible occurrence of polarisation. The electrode gels must, as stated hereinabove, be so arranged as to be isolated from each other and must not leak. All in all, the iontophoretic TDSs currently available are large, expensive and not very flexible with regard to the possibility of their being controlled. To harness the advantages of voltage-controlled substance/active ingredient permeation generally, however, requires simpler and more flexible TDSs that are less expensive to produce.
Electroporation, which has been described recently and which operates with very brief (a few ms) and very high voltages (100-200 V), is not discussed herein.
2. DESCRIPTION OF THE INVENTION
The problem underlying the invention is to make available an “intelligent” electrically controlled TDS that avoids the disadvantages described hereinabove.
The invention relates to a transdermal delivery system (TDS) having
(i) a carrier layer which, on one side, carries a substance/active ingredient reservoir for accommodating a substance/an active ingredient and is provided with an electrode network,
(ii) an optionally rewritable microchip, which is fixed to the carrier layer,
(iii) an optionally reusable battery and
(iv) a reading and writing device for writing to the microchip.
According to one embodiment, the invention relates to a transdermal delivery system (TDS) having
(i) a carrier layer which, on one side, carries a substance/active ingredient reservoir for accommodating a substance/an active ingredient and is provided with an electrode network,
(ii) a battery
(iii) a microchip that (a) is fixed to the carrier layer or (b) is accommodated with the battery in an external housing and is connected to the electrodes of the electrode network by a flexible wiring system, and
(iv) a reading and writing device for writing to the microchip,
which is characterised in that the carrier layer carries a ne
Fischer Wilfried
Haas Ruediger
Zimmermann Clifton
Casler Brian L.
Maiorino Roz
Marshall & Gerstein & Borun LLP
Novosis Pharma AG
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