DE102008060203A1 - Sheet-like device, useful for transdermal administration of e.g. rotigotine to treat Parkinson's disease, comprises an active ingredient containing layer, an active agent impermeable backing layer and a removable protective layer - Google Patents

Abstract

Sheet-like device comprises: at least an oxidation sensitive active agent and/or its base or salt containing layer (5); an active agent impermeable backing layer (4); and a removable protective layer (6). The edge of the backing layer is permanently connected with the edge of the protective layer over the open sides of the active agent layer lying between the backing layer and the protective layer. The connection is a continuous sealing of the edge type, an encapsulation against environmental factors and provides permanent anaerobic micro-environment around the active substance particle. Independent claims are also included for: (1) producing the sheet-like device, comprising providing the backing layer, the protective layer, introducing the active agent layer between these layers, guiding the edges of the backing layer over the open sides of the active agent layer and applying on the corresponding edges of the protective layer and connecting the layers under continuous sealing of the edges; and (2) means for producing the sheet-like device by the above method, where the backing layer, the protective layer and the active agent containing layer are actable by two opposing rollers, which are heat regulated. ACTIVITY : Antiparkinsonian; Muscular-Gen; Antidepressant. No biological data given. MECHANISM OF ACTION : None given.

Description

The The present invention relates to an oxidation-sensitive and for crystallization-prone active substances stabilizing sheet-like Device for the transdermal administration of such substances to the Skin and process for its preparation. In particular, the present invention a sheet-like device for the transdermal administration of oxidation-sensitive and for crystallization-prone drugs, rotigotine and / or a its pharmacologically acceptable salts or rotigotine base to the skin that recrystallizes the active substance (s) as far as prevents dose accuracy and drug safety over the functional lifetime of the device are given, as well as methods and process devices for their manufacture. Most notably The invention relates to a method for producing a sheet-like Device for the transdermal administration of rotigotine Thermal release (singulation) of active ingredient patches from a laminate, the structure and characteristics of the sheet-like Device and in the size or area a multiple of a single sheet-like Device is. In particular, the present invention relates to a Thermal release (singulation) of a sheet-like Device from a production line, eg. B. a pavement or road, with simultaneous sealing of the edges the active ingredient patch to prevent the ingress of foreign influences and to avoid recrystallization effects. After all The present invention relates to methods for producing a sheet-like device, both the procedural used components of a sheet-like Device as well as the machines used in the process and tools are electrically discharged or during the Procedure be discharged electrically.

The usual Construction of a sheet-like device for transdermal Administration of pharmaceutical agents to the skin consists of a drug-impermeable backing layer, at least a layer containing at least one active substance and a removable protective layer before use, usually the vertical sides, which when separating from an active substance plaster web arise, are not covered to the environment and as open pages are available. The separation of the sheet-like Device from a pavement path or street usually takes place by cutting or punching. Such a device will too as Transdermal Therapeutic System ("TTS"), Transdermal Delivery System ("TDS") or too referred to as active ingredient patch. Frequently, the drug-impermeable backing layer as a carrier layer and the removable before use Protective layer called release liner. These two layers are mostly present as films. The active substance-containing layer is predominant formed as a drug-matrix adhesive layer.

From Of particular interest is the oxidation-sensitive pharmaceutical Active substance Rotigotine, meanwhile significant in the Treatment of Parkinson's Disease and Restless Leg Syndrome as well as from depression and so far only in a transdermal Formulation pharmaceutically available for therapy can be made. Because this drug exclusively is available in this dosage form exists no possibility for others for the patients to avoid pharmaceutical dosage forms, if the transdermal Formulation has defects. Therefore, she has a safe Be a medicine, the u. a. containing the amount of active ingredient, accordingly the therapeutic purpose, actually to the patient emits.

Out Various transdermal therapeutic agents are known in the art Systems (TTS) for the administration of rotigotine ((-) - 5,6,7,8-tetrahydro-6- (propyl (2- (2-thienyl) ethyl) amino) -1-naphthol).

WO 94-07468 discloses a transdermal system containing a drug salt in a biphasic matrix. This two-phase matrix consists of a hydrophobic matrix polymer with a then dispersed silicate for uptake of the hydrophilic drug salt. In addition, hydrophobic solvents are used. The matrix is prepared by drying the dispersion at 70.degree. The content of rotigotine in the matrix is 2-5 wt.%.

• – Die Fertigung erfolgt in mehreren Stufen und ist somit aufwändig. Das Wirkstoffsalz muss gelöst werden, anschließend mit dem Silikat gemischt werden und schließlich mit einem Emulgator vermengt werden, um die Lösung darauffolgend mit dem in einem organischen Lösungsmittel gelösten Matrixpolymer z. B. einem Silikonkleber, zu emulgieren. Die hierbei üblicherweise verwendeten organischen Lösungsmittel können aus Heptan, Ethylacatat oder Toluol ausgewählt sein;
• – diese Emulsion ist schwierig zu handhaben;
• – eine Wirkstoffbeladung kann auf Grund der Löslichkeit des Rotigotins im jeweils verwendeten Lösungsmittelsystem nur begrenzt erfolgen. Beim Entfernen von Lösungsmittel findet während der Herstellung eine Aufkonzentrierung statt, die eine unerwünschte Kristallbildung verursachen kann. Dadurch ist die maximale Menge an Wirkstoff, die sich in die Matrix einarbeiten lässt, begrenzt. Eine niedrige Wirkstoffbeladung begrenzt jedoch die Freisetzungskapazität der Matrix pro Zeiteinheit und/oder ihre funktionale Lebenszeit;
• – das im Pflaster verbleibende Silikat bzw. Siliziumdioxid stellt eine Diffusionsbarriere für den Wirkstoff dar, die die Freigabe des Wirkstoffes negativ beeinflussen kann;
• – das anorganische Silikat beeinflusst die Wasseraufnahme des Pflasters. Porenbildung durch Herauslösen wasserlöslicher Matrixbestandteile an der Grenzfläche zur Haut können zu einer schlecht kontrollierbaren Freisetzung des Wirkstoffes führen.

The disadvantages of this system are:

• - The production takes place in several stages and is thus complex. The active substance salt must be dissolved, then mixed with the silicate and finally mixed with an emulsifier in order to subsequently mix the solution with the matrix polymer dissolved in an organic solvent, e.g. As a silicone adhesive to emulsify. The organic solvents conventionally used may be selected from heptane, ethyl acetate or toluene;
• This emulsion is difficult to handle;
• - An active ingredient loading can be limited due to the solubility of the rotigotine in each solvent system used. Upon removal of solvent, concentration takes place during production, which can cause undesirable crystal formation. This limits the maximum amount of drug that can be incorporated into the matrix. However, low drug loading limits the release capacity of the matrix per unit of time and / or their functional lifetime;
• - The remaining in the plaster silicate or silicon dioxide is a diffusion barrier for the drug, which can adversely affect the release of the drug;
• - The inorganic silicate influences the water absorption of the plaster. Pore formation by dissolving water-soluble matrix constituents at the interface with the skin can lead to a poorly controllable release of the active ingredient.

WO 99/49852 describes a Transdermal Therapeutic System (TTS) containing a pressure-sensitive adhesive system based on acrylate or silicone and in which free-base rotigotine is present. The described TTS provides therapeutic flux rates of rotigotine through human skin.

There Rotigotine in hydrophobic polymers, which includes silicone, is only slightly soluble, is in the aforementioned WO document the addition of additives to improve the dissolution behavior of the Rotigotine suggested.

Called In particular, hydrophilic polymers, such as polyvinylpyrrolidone (PVP), Copolymers of vinylpyrrolidone and vinyl acetate, polyethylene glycol, Polygropylene glycol, copolymers of ethylene and vinyl acetate and Glycerol and its esters.

WO 02/089777 and WO 02/089778 also describe a transdermal therapeutic system for administering rotigotine based on the use of solvents. According to these WO documents also surface-active substances or amphiphilic substances are added as a respective crystallization inhibitor.

EP 1 256 340 also describes a solvent-based transdermal system for the administration of rotigotine. In addition to a silicone mixture, however, the matrix in turn contains a crystallization inhibitor in the form of polyvinylpyrrolidone.

WO 04/012721 whereas, it discloses a transdermal system of a rotigotine base supersaturated matrix polymer which is free of solubilizers, crystallization inhibitors and dispersants.

WO 04/012730 discloses a backsheet and topcoat TDS in which interposed between these layers, in an adhesive matrix is rotigotine in free base form, the matrix is saturated with rotigotine, and rotigotine is present as a PVP-based microreservoir.

Finally revealed WO 04/058247 a transdermal system for the administration of rotigotine, which contains a matrix which contains the not dissolved in the matrix polymer rotigotine portion in amorphous form with particle sizes of not more than 30 microns and additionally contains antioxidants. Thus, on the one hand, the incorporation of a high content of active substance should be made possible and, on the other hand, the matrix should be free of solubilizers, crystallization inhibitors and dispersants. There is provided a rotigotine base supersaturated drug matrix which is known with the exception of an antioxidant additive of the prior art. Sufficient drug stability, which meets the requirements of modern industrial production and the distribution conditions of pharmaceutical products, is neither mentioned nor achieved.

rotigotine is a pharmaceutical because of its sensitivity to oxidation difficult to process drug. The active ingredient tends to crystallize. Rotigotine base is present as a solid in the form of crystals, the in the solvents suitable for dissolution of matrix polymers, such as hexane, ethyl acetate and toluene almost insoluble are.

To prepare a rotigotine-containing matrix, the rotigotine crystals are therefore initially dissolved in the prior art in solvents, such as ethanol, and then added to the polymer phase, for example hexane. To prepare a fine dispersion of the active ingredient-containing phase in the polymer phase, dispersants, such as. B. in the WO 99/49852 hydrophilic polymers mentioned. If the dispersants are not added as intended in this process, large drug islands may form; please refer WO 04/058247 , there 1 ,

These Active ingredient islands are suitable for causing skin irritation. she but also give rise to the risk of drug recrystallization, the reduced adhesion of the adhesive matrix to the skin of a Patients and the variation in drug loading.

To avoid drug islands should be in accordance with WO 04/058247 Rotigotine base in the form of amorphous particles or droplets finely distributed in the silicone-based matrix used there to avoid the disadvantages mentioned by the drug islands.

However, to provide a pharmaceutical dosage unit in the form of a sheet-like device for the transdermal administration of rotigotine with the requirements of modern, including industrial manufacturing and modern distribution conditions sufficient increased storage and / or transport stability and / or to ensure the dosage security of the device guaranteeing storage and / or transport stability, the known from the prior art compositions of rotigotine TTS alone are not sufficient.

These known from the prior art rotigotine compositions, be it a two-phase matrix according to WO 94/07468 , an acrylate- or silicone-based rotigotine-containing pressure-sensitive adhesive system WO 99/49852 , solvent-based transdermal systems according to WO 02/089777 . WO 02/089778 or EP 1 256 340 , an adhesive matrix of hot melt adhesive according to WO 04/012721 , an adhesive matrix with PVP-based microreservoirs with rotigotine base according to WO 04/012730 or a matrix supersaturated with rotigotine, as appropriate WO 04/058247 , have only a storage stability for clinical trials.

So mentioned the WO 04/058247 only that laboratory-produced TTS showed no sign of recrystallization under laboratory conditions and thus specially selected, but not the modern industrial manufacturing and the usual conditions for distribution, storage and transport of pharmaceutical products after storage for 6-12 months at room temperature, after 5 months storage at room temperature the release behavior was unchanged.

Also the WO 04/012721 contains only information or data obtained under special laboratory conditions. There are only a few details about the adhesive matrix in terms of its permeation properties over a period of 72 hours, but no data on the functional lifetime.

the The prior art are thus produced only under laboratory conditions, various pharmaceutical active substance-containing compositions for transdermal systems, the active substance-containing layer, especially regarding the matrix, each with different ones Aspects of their advantages over the previously known pharmaceutical formulation proposals.

The document WO 94/26346 discloses a method for producing a transdermal therapy system for the administration of active ingredients to the skin in the form of a multi-chamber or multi-channel system, wherein the upper and lower layer at individual and / or contiguous locations with displacement of the intermediate points of the active substance-containing layer and formation of Squeezed compartments or channels squeezed together and at the same time or subsequently the upper layer and lower layer at the crimping sites are permanently connected to each other.

about the prevailing in this process electrical and / or elec trostatic Conditions contains this WO-writing no Hints.

After all does not ensure the process that at the gluing or crushing points Residues of active material remain and exert an external effect, so that a reliable gluing or welding is not is reached. Anyway, the indication that a reliable Bonding or welding by pinching success, if between two slides the liquid mybiol is introduced, not on oxidation-sensitive agents or prone to crystallization containing adhesive masses are transmitted.

It persists, therefore, the usefulness of the aforementioned Compositions for modern production, which are in particular mass an industrial manufacturing marketable TTS products considered. The influence the production techniques used on the drug stability in the compositions after the time of their preparation her functional lifetime has not been studied.

Especially was not the influence of currently predominantly industrial used manufacturing and separation techniques of active ingredient Paving, TTS or TDS from production lines, such as Paving lanes or streets in terms of drug stability or the recrystallization of rotigotine in the aforementioned TTS preparations considered in the prior art. The from the production conditions resulting problems such as reduced adhesion, recrystallization more sensitive to oxidation Active substances, in particular the recrystallization of rotigotine, fluctuation the drug loading with concomitant dose inaccuracy and / or Reduction in functional lifetime has been previously related ignored for industrial production.

However, the transfer of the manufacturing process of laboratory-fabricated TTS products to industrial production - so-called scaling-up - requires an examination of new and / or other associated problems that require solution. In particular, no rotigotine-containing sheet-like device has been proposed for transdermal administration to the skin, which ensures that after its production for the duration of its functional lifetime with special consideration of the distribution channels with their climatic variations and the Einwirkun associated with transport and storage conditions on the products, recrystallizations of the active substance do not occur or, if they occur, are so slight that they are negligible in terms of medical substance law or comply with the drug legislation.

So had already in distribution rotigotine-containing drug patches due to recrystallized rotigotine active ingredient with Wirkstoffausfällungen up to 40% can either be withdrawn from the market or by means of a Cold chain are sold.

At the commercial active ingredient patches of the brand Neupro It should be noted that the formed in the drug layer Rotigotine precipitates from the cut edges surrounding the perimeter define such an active ingredient patch, and from the cutting edge the stripping away, both in the interior of the drug layer as also spread along the respective cutting edges. The rotigotine crystals have a snowflake-like appearance.

Therefore are the above formulation suggestions for Rotigotine-containing TTS with regard to their stability only sufficient for clinical trials. However, the stability is this TTS, including the conditions existing in modern manufacturing, their storage and transport stability as well as on the Distribution due to existing different effects These drug patches over a long period of time, such as she for a salable and already marketed Dosage form is required, insufficient.

If a conventional rotigotine TTS formulation in the form of a Drug patch is made, is the stability such a TTS is insufficient. This is a consequence of the pronounced Tendency of the active ingredient rotigotine or rotigotine base for recrystallization in the form of snowflake-like active substance precipitations, the previous structure of such a TTS and the conditions under which it is produced industrially so far. That's enough This does not meet the requirements for patient administration approved medicinal products in the form of TTS.

Of the Invention is based on the object, a sheet-like Device for the transdermal administration of oxidation-sensitive Active substances or agents prone to crystallization to the Skin, methods and process devices for their manufacture to provide a recrystallization or Precipitation of the containing oxidation-sensitive or for crystallization-prone active ingredient, in particular rotigotine and / or one of its pharmacologically acceptable salts or of rotigotine base in the way that prevents them in proportion in quantity to the present in the device total amount of active ingredient negligible is, respectively, ensures that the drug contained in each case the functional lifetime of the device from this to the skin a patient in therapeutically sufficient, the drug law Requirements of sufficient quantity.

These Task was solved by surprisingly it was found that a sheet-like device for the transdermal administration of an oxidation-sensitive pharmaceutical Active ingredient or a tendency to crystallize pharmaceutical Active substance containing at least one with at least one oxidation-sensitive or crystallization-prone drug or rotigotine and / or one of the pharmacologically acceptable salts of the active substances or Rotigotine-base loaded layer, a drug-impermeable backing layer and a pre-removable protective layer, in which the edge edges of the drug-impermeable Backing layer over the sides of the between backing layer and protective layer lying drug-containing layer to before Use of removable protective coating, with the edge edges the removable before use protective layer in the region of these edge edges contiguous with continuous sealing of edge edges, are permanently connected to each other, wherein the protective layer before Use is removable again.

By the continuous sealing of each Edge edges of the backing layer and the protective layer including the active substance-containing layer, the inventive Device a lasting anaerobic microenvironment around those in the drug-containing Layer existing amorphous drug particles, the environmental factors on the drug layer before application of the sheet-like Device on the patient excludes. This also applies to PVP-based Microreservoires in which rotigotine, preferably rotigotine base amorphous is dispersed.

The object of the process for the preparation of a sheet-like device for the transdermal administration of an oxidation-sensitive or crystallization-prone drug or a corresponding drug base or rotigotine and / or one of its pharmacologically acceptable salts or rotigotine base, which at least one loaded with one of the aforementioned agents Layer, an active agent-impermeable backing layer and a pre-use removable protective layer has been achieved by providing a suitable active substance impermeable backsheet and a suitable pre-removable protective layer, between which layers one having at least one oxidation-sensitive effect fabric or crystallization-prone active ingredient layer is introduced and the edge edges of the drug-impermeable layer are passed over the sides of the active ingredient-containing layer and applied to the corresponding edge edges of the removable before use protective layer and these are permanently connected to each other directly under continuous sealing.

The Solution of the task for the method of manufacture a sheet-like device for transdermal Administration of the aforementioned active substances also includes a procedure, at the junction of edge edges of drug-impermeable Back layer preferably takes place thermally, and that both the procedural used components of a sheet-like Device and the machines used in the process and tools are electrically discharged or during the Procedure be discharged electrically.

According to the invention preferred is a sheet-like device for transdermal Administration of an oxidation-sensitive drug or a for crystallization-prone drug to the skin, the at least one with at least one oxidation-sensitive active substance base or a base of a crystallization-prone drug and / or one of its pharmacologically acceptable salts Layer, a drug-impermeable backing layer and a pre-removable protective layer, in which the edge edges of the drug-impermeable Backing layer over the sides of the between backing layer and protective layer lying medicated layer, with the edge edges of the protective layer removable before use contiguous with continuous sealing of edge edges, a weld comparable, lasting with each other connected, wherein the protective layer before use removable again is.

A According to the invention particularly preferred embodiment is a sheet-like device for transdermal Administration of an oxidation-sensitive pharmaceutical agent or a crystallisation-prone active ingredient which is at least one with at least one oxidation-sensitive active substance or a prone to crystallization drug and / or one of its pharmacological acceptable salts loaded layer, a drug-impermeable Backing layer and a removable before use protective layer, at the edge edges of the drug-impermeable Backing layer over the sides of the between backing layer and protective layer containing drug-containing layer, with the edge edges of the protective layer removable before use contiguous with continuous sealing of edge edges, both an encapsulation against environmental influences as well as a permanent anaerobic microenvironment around those in the active substance-containing Layer existing drug particles forming, lasting each other connected, wherein the protective layer is removable again before use.

A another embodiment according to the invention is one, as described above in the construction sheet-like Device for the transdermal administration of the aforementioned active substances, at the edge edges of the drug-impermeable backing layer over the open sides of the between backing layer and protective layer active ingredient-containing layer until removable before use Protective layer reaching, with the edge edges of the removable before use Protective layer are incompletely connected to each other, wherein the protective layer is removable again before use.

In the inventive sheet-like device are the respective active substance impermeable backing layer and removable before use protective layer (also as a release liner referred to) in the form of films.

The Elasticity of the drug-impermeable backing layer making film is sufficient to make this over the active ingredient Adhesive layer towards the removable before use protective film to lead them to connect with this. Therefor the elasticity is sufficient in particular if the the backing layer forming film is thermally treated, preferably heated, will. It is important to ensure that the selected Temperature the temperature resistance of the film is not impaired and no temperature-related change the film enters. It is advantageous if the for use as active substance-impermeable backing layer and before use Removable protective layer selected foil from the same Material is.

in the Meaning of the invention is understood as "connected", that the compound of the drug-impermeable backing layer with the protective layer removable before use without interruption is present, d. H. the two aforementioned layers are in the according to the invention selected areas at least adjacent, preferably laminar contiguous.

For the purposes of the invention, "incomplete" is understood to mean that the connection of the edge edges of the backing layer and the protective layer is punctiform. These may be point connections in the form of successive single-point connections or successive connection paths of defined length with sections between them which do not Represent connections between backing layer and protective layer. Advantageously, the distances that are not a connection between the aforementioned layers are very short. Advantageously, they are not longer than 1 mm.

"Edge edges" are in the meaning of the invention, the edges themselves, the surface of an article in the sense of a TTS, TDS or patch drug, define its geometric shape and area. usually, such an object is quadrangular, most preferably square with rounded corners. These edges arise when the objects be separated from a large-scale paved track. They can also be referred to as cut edges, since the separation usually by cutting or punching he follows. An isolated object has one defining its scope continuous cutting edge on. Looking at the individual pages of an object, there are one cutting edge per side, in total four, present.

in the Meaning of the invention are "edge edges" but even edges in the single-digit μm range, that of the cut edges, following them parallel in their course, pointing to the inside of the pavement, the separation and / or Replacement of the drug-impermeable Back layer connected protective layer neither complicate still hamper. They are to be regarded as broadened cutting edges.

in the Meaning of the invention is understood as "permanent", that the respective edge edges of the backing layer and the protective layer of a sheet-like device during the functional lifetime of a device as long connected until they are detached from each other. "Consistently interconnected edge edges "are thus as long as available until they are used as intended for the application of a Device to the skin from each other by removing the protective layer (Release liner) of the drug-impermeable backing layer under release of the active substance-containing backing layer in Area of edge edges separated or released become. In particular, the edge edges ensure a non-destructive separation or dissolution of the aforementioned Foils without increased effort.

A Inventive planar device has an active substance-impermeable backing layer, a protectable before use layer and at least one between these layers drug-containing layer, wherein the particular composition of the active substance-containing layer also from known pharmaceutical formulations of the prior art can be selected.

For example, in the documents WO 02/089778 and WO 04/0121730 Mentioned composition and method for the preparation of rotigotine-containing transdermal articles, which can serve as a respective basis for providing a sheet-like device according to the invention for the transdermal administration of said active substances and mentioned in the claims.

A inventive embodiment provides that the active ingredient incorporated or present in the active substance-containing layer an oxidation-sensitive or crystallization-prone drug base is.

A According to the invention, preferred embodiment sees in that the active substance-containing layer is a matrix, in particular is a suitable adhesive or adhesive matrix.

All Particularly preferred according to the invention is that both the encapsulation against environmental influences as well as around the drug particles present in the matrix formed anaerobic microenvironment in a drug-containing layer the device according to the invention is present, in the drug an oxidation-sensitive or for crystallization Tending drug base is. The active substance-containing layer can be used as active ingredient-containing matrix, in particular as a drug-containing adhesive matrix be executed.

According to the invention, the degree of loading of the layer and / or matrix loaded in the apparatus with oxidation-sensitive or crystallization-tending active substance is between 0.2 and 9 mg / cm ² .

• (a) einen Anteil mit oxidationsempfindlichem oder oxidationsempfindlichen Wirkstoff von mindestens 5 Gew.%, bezogen auf die Wirkstoffschicht, und
• (b) weist einen Gehalt an oxidationsempfindlichem oder zur Kristallisation neigendem Wirkstoff von mindestens 1,0 mg/cm² auf.

According to another embodiment of the invention, the active substance-containing layer or matrix present in the device contains

• (a) an oxidation-sensitive or oxidation-sensitive active ingredient content of at least 5% by weight, based on the active ingredient layer, and
• (b) has a content of oxidation-sensitive or crystallization-tending active ingredient of at least 1.0 mg / cm ² .

in the Meaning of the invention is under "prone to crystallization Active ingredient "understood that it is an active ingredient acts, both after its completion in pure state as well as after physical and / or chemical further processing with other substances or if it contaminates with other materials which has property of crystals and / or precipitates to build.

In particular, it is understood in the sense of the invention that a "tendency to crystallization Active substance "is an active substance which, when in amorphous form, has the property of forming crystals and / or precipitates. Furthermore, for the purposes of the invention, "crystallization-tending active ingredient" is understood to mean that the active ingredient, even if only partially, forms crystal formation and / or precipitation, if it is produced amorphously, in order to achieve thermodynamic stability.

in the Meaning of the invention is under "for crystallization and / or "precipitate-prone drug" also understood that this, when in amorphous form in a pharmaceutical Preparation, in particular in a sheet-like Device is present over the duration of the functional Lifetime of the pharmaceutical preparation is so morphological changed that he released the drug from the pharmaceutical Preparation in the manner diminishes the drug release no longer the specifications of the pharmaceutical preparation or the drug corresponds.

According to the invention is very particularly preferred that the sheet-like Device is electrically discharged, so no voltage or no voltage gradient within or on the sheet-like device is available.

According to the invention Particular preference is given to a sheet-like Device for the transdermal administration of rotigotine, ((-) - 5,6,7,8-tetrahydro-6- (propyl (2- (2-thienyl) ethyl) amino) -1-naphthol), one with rotigotine and / or one of its pharmacologically acceptable ones Salts as drug-loaded layer, a drug-impermeable Backing layer and a protective layer removable before use in which the edge edges of the drug-impermeable Backing layer over the sides of the between backing layer and Protective layer lying rotigotine-containing layer until before use reaching removable protective layer, with the edge edges the protective layer separable before use remaining under continuous sealing of the edge edges interconnected with the protective layer before use is removable again.

Farther is a particularly preferred according to the invention Embodiment of a planar device for the transdermal administration of rotigotine base, containing a Rotigotine base as drug-loaded layer, a drug-impermeable backing layer and a pre-removable protective layer, in which the edge edges of the drug-impermeable Backing layer over the sides of the between backing layer and protective layer lying rotigotine-containing layer to the Reaching removable protective layer before use, with the edge edges the protective layer separable before use remaining under continuous sealing of the edge edges interconnected with the protective layer before use is removable again.

A another particularly advantageous embodiment according to the invention is a sheet-like device for transdermal Administration of rotigotine and / or one of its pharmacological acceptable salts or rotigotine base to the skin, which is a drug-loaded Layer, a drug-impermeable backing layer and a pre-removable protective layer, in which the edge edges of the drug-impermeable Backing layer over the sides of the between backing layer and protective layer with rotigotine and / or rotigotine base and / or a layer loaded with pharmacologically acceptable salts thereof reaching up to the before use removable protective coating, with the Edge edges of the protective layer removable before use contiguous with continuous sealing of edge edges, both an encapsulation against environmental influences as well as a permanent anaerobic microenvironment around those in the active substance-containing Layer existing rotigotine or rotigotine base active ingredient particles and / or the particles of a corresponding pharmacologically acceptable Having salt, remaining coherent with each other connected, wherein the protective layer before use removable again is.

After all a particularly preferred embodiment is a sheet-like Device for the transdermal administration of rotigotine and / or a its pharmacologically acceptable salts or rotigotine base the edge edges of the drug-impermeable Backing layer over the sides of the between backing layer and protective layer lying drug-containing layer to before Use of removable protective coating, with the edge edges the protective layer removable before use incomplete connected, wherein the protective layer before use removable is.

A According to the invention, preferred embodiment sees before that the rotigotine or rotigotine base-containing layer a matrix, in particular a suitable adhesive matrix. If the active ingredient-containing layer as adhesive or adhesive matrix available is, it also has the function as a basis for the serve planar device. If the active ingredient-containing layer is not formed as an adhesive layer, the sheet-like device has an additional Adhesive layer on.

Furthermore, it is very particularly preferred according to the invention that both the encapsulation against environmental influences and that in the Ma micromilieu formed trix existing drug particles in an adhesive matrix of the device according to the invention is present, in which the active ingredient is rotigotine base and / or one of its pharmacologically acceptable salts.

• WO 94/07468 , WO 99/49852 , WO 02/089777 ; WO 02/089778 , EP 1 256 340 , WO 04/012721 , WO 04/12730 sowie WO 04/058247 .

Suitable methods for the preparation of rotigotine-containing transdermal devices are, in particular, the aforementioned production instructions in the documents:

• WO 94/07468 . WO 99/49852 . WO 02/089777 ; WO 02/089778 . EP 1 256 340 . WO 04/012721 . WO 04/12730 such as WO 04/058247 ,

According to a further inventive embodiment, the degree of loading of the matrix present in the device with rotigotine is between 0.3 and 6 mg / cm ² .

• (a) einen Rotigotinanteil von mindestens 4 Gew.%, bezogen auf das Gewicht der Wirkstoffschicht, und
• (b) weist einen Rotigotingehalt von mindestens 2,0 mg/cm² auf.

In another embodiment of the invention, the rotigotine-containing matrix layer present in the device contains

• (a) a proportion of rotigotine of at least 4% by weight, based on the weight of the active substance layer, and
• (b) has a rotigotine content of at least 2.0 mg / cm ² .

advantageously, is rotigotine in the form of the active substance base with 5-20 wt.% present in the drug layer.

In a further advantageous embodiment is the respective active ingredient in the active ingredient-containing layer molecular disperse distributed, before.

In In a particularly advantageous embodiment, the rotigotine and / or one of its pharmacologically acceptable salts or rotigotine base containing device electrically uncharged or electrically discharged.

It is also advantageous if the sheet-like device has a removal aid on the protective layer which can be removed before use. Such peelers are in the DE-OS 33 44 335 A1 described. The Abziehilfen described therein may be peculiar designed cuts or predetermined breaking points. Most often, the removable before use protective layer of a substrate is cut with a very fine cut, which divides the surface of a substrate in the form of a TTS, TDS or drug plaster in two parts, usually in half. As long as the substrate is flat, it is irrelevant in most cases that the course of the very fine cut, the active substance-containing layer in contact with the environment. This is irrelevant for the stability of most active ingredients.

in the However, this case is a withdrawal aid in the form of a very fine cut in protective layer removable before use for substrates in the form of TTS, TDS or drug patches, the oxidation-sensitive and / or crystal formation or to Contain precipitating agents and / or rotigotine, not suitable. Because along the cutting edges of a respective peeling aid and pointing from these to the interior of the drug layer was the undesirable one Formation of rotigotine crystals or precipitates determine.

Under Substrate is understood here as matter, preferably in the composition a respective suitable active substance-containing layer, on the one, a Abziehhilfe comprehensive foil, is applied.

In The present invention is therefore in an advantageous embodiment Peelers used, which run as predetermined breaking points are. These can be geometric according to DE-OS be designed differently. Frequently becomes with substrates in the form of TTS, TDS or active substance patches the breaking point, largely sinusoidal, centrally from a substrate side running on the other side of the substrate, into the substrate brought in. This geometric design is called a so-called S-cut designates.

In an advantageous embodiment, the predetermined breaking points sinusoidal, geometrically according to the S-Cut, in the before use removable protective layer introduced. It is the protective layer serving foil, following the geometric shape of the S-cut, only weakened, so that the predetermined breaking point breaks along the geometric shape, if the substrate is in the form of a TTS, TDS or drug patch bent or kinked on two of its four edges before use becomes. The protective layer can then be conveniently attached to its two protruding, formed by the predetermined breaking point touch surfaces of the active substance-containing layer are deducted.

In According to the invention advantageous embodiments At least one predetermined breaking point as a removal aid for the sheet-like device formed by the serving as a removable before use protective film with a suitable cutting tool only cut, but not cut becomes. The generation of such a predetermined breaking point can according to the invention also be done thermally or by laser. In both cases This is done by placing the film along the desired Weak point is weakened. The weakening the film along the predetermined breaking point is 30% to 70%, particularly advantageous 40% to 60%, especially advantageous 50% the thickness or thickness of a film.

In the inventive sheet-like device are, according to an advantageous embodiment, the oxidation-sensitive or crystal-tending active ingredient or the corresponding active substance bases or rotigotine or rotigotine base or the corresponding respective pharmacologically acceptable salts present in amorphous form in a drug-containing layer. Ie. the morphological form of the active substance is present when the Active substance in substantial amount no crystals and / or precipitations having.

One Another object of the invention is the use of a sheet-like Device, the drug rotigotine and / or one of its pharmacological acceptable salts or rotigotine base, for the preparation of a medicament for the treatment of Parkinson's disease or of Restless Leg Syndrome.

According to the invention also the use of a device, the active ingredient rotigotine and / or one of its pharmacologically acceptable salts or rotigotine base for the manufacture of a medicament for the treatment of Depressions.

Under "sheet-shaped Device for the transdermal administration of oxidation-sensitive Active ingredients and / or a pharmacologically acceptable salts thereof and / or drug bases to the skin "is used in the sense of Invention a suitable pharmaceutical formulation or TTS, TDS or drug patches meant for transdermal Administration of the aforementioned active ingredients through mammalian skin, especially by human skin, in therapeutically relevant amount the functional lifetime are suitable.

Under "anaerobic Microenvironment "is understood in the context of the present invention, that the respective in the active ingredient-containing layer, matrix, and / or suitable adhesive matrix amorphous present, preferably disperse distributed Drug particles did not increase the stability in any significant way Manner influencing environmental, in particular air and / or moisture influence, are exposed. In particular, this also means that the active ingredient-containing layer, matrix and / or adhesive matrix around the each amorphous drug particles present in a microenvironment from the quality that is beyond the functional Lifetime of the drug particles ensures that the drug regulations are met by: drug release to specifications of drug equivalent.

Under "drug-impermeable Back layer ", which in the aforementioned device is present, a layer in the form of a suitable film understood, to which the active ingredient-containing mass and / or matrix mass and / or adhesive matrix compound is spread, or on a active ingredient-containing layer is applied, the previously on was applied before a removable protective layer, the for the ingredients of the active ingredient-containing layer and / or Matrix and / or adhesive matrix inert and sensitive to oxidation or crystallization-prone or precipitates Active ingredients, in particular for rotigotine or rotigotine base, is impermeable.

So far in the present invention terms are mentioned as word components Adhesive or adhesive-exhibit, there is no in this regard Term difference.

suitable Materials for such a backing layer are for. For example: polyesters, polyamides, polyethylenes, polypropylenes, polyurethanes, PVC or combinations of these materials. The materials are called Sheets used. The films can be siliconized and / or be provided with an aluminum layer. The thickness usually varies between 20 and 100 microns and is preferably between 30 and 40 μm, and more preferably 70 μm.

Under "before Use removable protective layer ", which in the inventive Device is present, a layer or suitable film is understood, the immediately before use of the device, so before the order on the skin, with release of the active ingredient-containing layer to Attachment to or on the skin, is removed.

These Protective layer can be made of polyester, polyethylene or Polypropylene exist. This layer can also be made with aluminum or fluorine polymers be coated. The thickness or thickness of this protective layer usually covers a range between 30 microns and 100 microns, but can be chosen lower, if technically desired. Preferably, the starch comprises a range between 50 and 70 microns.

In an embodiment of the invention, the drug-impermeable backing layer and the before Use removable protective layer of films of identical material exist in the sheet-like device available.

Under The term "matrix" is used in this patent application a pharmaceutical formulation understood that at least one comprising at least one drug loaded matrix polymer. Farther For example, the matrix polymer may be suitable for forming a dispersed system be.

Preferred ingredients for such a matrix are oxidation-sensitive active substances or oxidation-sensitive active substance bases and / or for Crystallization-prone active substances or their bases. For such a matrix, very particularly preferred ingredients are rotigotine, and / or one of its pharmacologically acceptable salts and / or rotigotine base.

Under The term "matrix polymer" is used to refer to a pharmaceutical Skilled in the production of transdermal drug forms common Understood polymers. Examples include silicones, ethyl vinyl acetates (EVA), styrene block copolymers (SXS), acrylates and methyl acrylates, Polyurethanes, vinyl acetates and gums, in particular polyolefins and polyterpenes, e.g. As polyisobutylenes, polybutadienes, neoprenes or polyisoprenes and suitable mixtures of these matrix polymers.

Especially can the active ingredient used in the invention Matrix can be a "silicon-based matrix".

Under the term "silicone-based matrix" is used in this patent application understood a matrix that at least 60 % By weight, preferably 70-95% by weight, more preferably 80-91% by weight % By weight of silicone, based on the weight of the matrix. Preferred materials for use as a silicone-based matrix are silicone pressure-sensitive adhesives. These are self-adhesive, amino-resistant, pressure-sensitive polyorganosiloxane adhesives.

suitable Polyorganosiloxane adhesives are commercially available from Dow Corning as so-called BIO-PSA pressure-sensitive adhesives available. Particularly suitable are pressure-sensitive adhesives from Dow Corning under the name BIO-PSA 7-4201 and BIO-PSA 7-4301 distributed as well as suitable mixtures of these adhesives. These mixtures silicone adhesive with strong and medium adhesion ("tack"), in particular mixtures in the ratio 40:60 to 60:40 of BIO-PSA 7-4201 and BIO-PSA 7-4301, are characterized by a particularly favorable Adhesions / Cohesionsbalance. Therefore, the use of this BIO-PSA adhesive in the inventive sheet-like Device preferred.

The known from the prior art devices in the form of a TTS, TDS or drug patches usually have one drug-impermeable backing, which is common Also referred to as a carrier layer, at least one with at least one active ingredient and / or an oxidation-sensitive and / or polymer layer loaded for crystallization-prone active ingredient, more preferably a polymer matrix adhesive layer and a pre Use removable protective coating, which often also is named as a release liner.

A Such device may also be a laminate consisting of three Layers, to be called. Because the individual layers are very thin are, - the respective thickness of a layer is in the micron rangen -, they are not recognizable as such with the naked eye. nevertheless Each layer has a scope defining a device Edge. In the present case, there are three circumferential edges.

each Layer is three-dimensional, so it also has side surfaces having.

Usually are planar devices square designed with rounded corners. In such a case are then There are four sides or side surfaces per shift.

The Side surfaces, in particular those of the active ingredient-containing Layer, are usually not against the environment completed. Thus, the active substance contained in it is over the open sides exposed to environmental influences.

A so designed device containing it sensitive to oxidation and / or prone to crystallization or precipitation Active ingredients, such as u. a. Rotigotine, one of its pharmacologically acceptable Salts or rotigotine base, is to ensure the functional Lifetime and drug safety one for marketing intended and industrially manufactured product, as explained above, not sufficient on its own. With regard to the sensitivity to oxidation and the recrystallization tendency of the active ingredients and in the Active ingredient layer or matrix given labile thermodynamic Equilibrium conditions must be manufactured permanently harmful, promoting recrystallization Manufacturing steps and environmental influences on the active substance be excluded.

Therefore is an object of the present invention, a sheet-like electrically uncharged device for transdermal administration oxidation-sensitive and / or prone to crystallization Active ingredients to the skin, the active ingredient-containing layer no Environment has open side surfaces. Especially recorded the subject of the present invention, a drug-containing layer with the active ingredients rotigotine and / or one of its pharmacological Acceptable salts or rotigotine base that are not open to the environment Has side surfaces. The inventive planar device has both an encapsulation the active ingredient-containing layer, which is also a matrix or adhesive matrix can be, against environmental influences as well an anaerobic microenvironment around the active substance-containing layer or matrix or adhesive matrix on existing drug particles and is electrically discharged.

Another object of the present invention are methods for producing a sheet-like device for transdermal administration range of oxidation-sensitive and / or crystallization-prone active ingredients and / or rotigotine and / or one of its pharmacologically acceptable salts and / or rotigotine base, which use mild manufacturing steps.

Under "mild Manufacturing steps "is in the present patent application understood that no manufacturing steps in the production, in particular in the industrial production of an inventive Find device application that, triggered by it in the germ or initially initiated, occasion for recrystallization of the active substance (s). In particular, measures are or to avoid any incidents involving an electrical charge the paving materials used and / or for the production used devices and / or machines and / or tools cause. The entire manufacturing process is to be carried out in such a way that no electrical charge, in particular a static charge, in the manufacture of the inventive device used materials and / or manufacturing tools. In the production of a novel sheet-like Device must avoid electromechanical pulses or excluded.

When Example of a in the production of an inventive planar device to be avoided measure be the usual mechanical separation of drug patches from a paved track, for example by punching or punching called.

One Inventive method for producing a sheet-like Device for transdermal administration of an oxidation-sensitive and / or prone to crystallization or precipitation pharmaceutical agent and / or rotigotine and / or a its pharmacologically acceptable salts and / or rotigotine base, the an active substance-impermeable backing layer, at least a loaded with an aforementioned drug layer of active ingredient and a protectable before use protective layer comprises, that an active substance impermeable backing layer and a pre-removable protective layer is provided that between these layers one with at least one oxidation-sensitive or prone to crystallization or to precipitations Active ingredient or rotigotine and / or one of its pharmacologically acceptable Salts and / or rotigotine base are introduced, and the edge margins the drug-impermeable backing layer over the sides of the drug-containing layer lying between the backing layer and the protective layer Layer are guided and on the corresponding edge edges the protective layer separable before use be applied and this immediately under continuous sealing be permanently connected to each other, wherein the protective layer before Use is removable.

In the process become the components of the sheet-like Device, the drug-impermeable backing layer, the active ingredient-containing layer and the protective layer which can be removed before use introduced in electrically discharged state and the implementation also necessary machinery or tools held in an electrically discharged state, which by a suitable Grounding of the same can happen.

A Grounding, for example, by means of a metal wire or a other suitable material familiar to the person skilled in the art, by the process machines and tools and the so while of the manufacturing process coming into contact materials the sheet-like device thus with the Floor to be connected.

A further procedural embodiment exists in that the components of the sheet-like Device electrically untreated introduced into the process but at the latest before separation into the respective sheet-like devices takes place, be discharged electrically.

In In another embodiment, the method is as above explained, performed in such a way that the Edge edges of the drug-impermeable backing layer over the open sides of the between backing layer and protective layer be located active ingredient-containing layer and on the corresponding edge margins of removable before use Protective layer are incompletely applied and each other be connected, wherein the protective layer before use removable is.

To In one embodiment, the process is performed without during its execution take place an electrical discharge can, performed by the edge edges of the active substance-impermeable backing layer thermal be heated so far that these over the open sides of the between the backing layer and protective layer lying active ingredient-containing layer are performed and on the thermally controlled heated edge edges the protective layer separable before use be applied and connected to each other permanently, wherein the protective layer is removable before use.

For the purposes of the invention, "thermally regulated" is understood to mean that both the films making up the layers of the planar device, the active substance-containing layer and the machines and tools used in the process are steplessly variable can be set and maintained at selected temperatures.

moderately method can guide the edges of the drug impermeable Backing layer over the open sides of the active ingredient-containing layer towards the edge edges of the removable before use Protective layer done in such a way that the first-mentioned edge edges on the open sides of the active ingredient-containing layer of an already isolated sheet-like device per open side individually or in one step at the same time all Grasping open sides, on the edge edges of the front Use removable protective layer.

A advantageous procedural embodiment provides that the sheet-like device in the form of a whole multiple of a scattered sheet-like Device constituting laminate web, the aforementioned qualitative and quantitative characteristics is placed, and one at a suitable temperature heated tool in the scope of a sheet-like Device with its scope following existing facilities provided with the tool in the way through the laminate web is driven on, that the facilities, where they are on the drug-impermeable Rear layer meet, with further propulsion in the direction of the protective layer removable before use the backing layer at the perimeter boundaries over the active agent-containing layer towards the removable protective layer before use and the former with the latter interconnected, remaining connects together and immediately a sheet-like Device forming its periphery edge edges thermally isolated from the laminate web.

Especially is advantageous if in the process, the active substance-containing layer a matrix or an adhesive matrix layer and the active ingredient an oxidation-sensitive or crystal formation or precipitation Tending drug or rotigotine and / or one of its pharmacological acceptable salts and / or rotigotine base.

In In another embodiment, the method of manufacture a sheet-like device for transdermal Administration of an oxidation-sensitive or crystallization or precipitant-prone drug containing at least one Layer loaded with a previously named active substance, a for the drug impermeable backing layer and a having a removable protective layer before use, carried out in the manner that in the respective dimensions of a production line a suitable electrically uncharged drug-impermeable backing layer and a suitable electrically uncharged before use removable Protective layer can be provided that between these layers one with at least one oxidation-sensitive or for crystallization tilting agent loaded loaded electrically charged layer becomes, whereby by thermal influence the edge edges the drug-impermeable backing layer over guided the open sides of the active ingredient-containing layer and on the corresponding edge margins of the before use removable protective layer contiguous be applied and this directly by thermal action permanently connected to one another with continuous sealing while avoiding an electromechanical or electrostatic charge can be separated by separating.

If the method on already isolated sheet-like Devices is performed, the drug-containing Layer four open sides and the edges of the edges Back and protective layer, which is the scope of a sheet-like Form device are also available in the number four.

One Another object of the present invention is a combined Bonding and separation process, the drug-impermeable backing layer under encapsulation of the active substance-containing layer and / or matrix and / or Adhesive layer contiguous with the protective layer removable before use and stays connected and capable of working on the production line existing web in sheet-like devices to separate.

This process is carried out by placing a laminate web consisting of a film of an active substance-impermeable backing layer and a film of a removable before use protective layer between the at least one active substance-containing layer containing at least one oxidation-sensitive or crystallization or precipitation-prone active ingredient, rotigotine and / or a its pharmacologically acceptable salts, or rotigotine base, is / is placed on a, preferably industrially useful, paved track and brought into contact with at least one thermally controllable, heatable roller containing devices or elevations capable of are where they meet on the side of the film of the laminate which is inclined to the roll, to guide it at the circumferential boundaries in the surface of at least one sheet-like device over the active substance-containing layer in the direction of the protective layer which can be removed before use d the backsheet contiguous with the protective layer to permanently bond to each other and immediately form a sheet-like device, forming its peripheral edge edges from the lami thermal trajectory to separate, which also from one edge edge to the opposite edge edge of a sheet-like device reaching, one, in a suitable geometric shape, predetermined breaking point, which is effected by thermal weakening or not cut through the film section, is effected on the film.

Of course the method can also be carried out in the manner that two rollers are used, the first being the contiguous ones Connection of the films of backing layer and protective layer performs and a second roller causes the predetermined breaking point. In this case, both rolls or only one can be heated.

After all is another procedural embodiment that the side facing a roller, either the drug-impermeable Backing layer or protective layer removable before use is.

Further The invention relates to the use of one of the aforementioned Process for the suppression of crystals and / or precipitates of oxidation-sensitive or for crystal formation and / or precipitation tending active ingredient, of rotigotine and / or one of its pharmacological acceptable salts or of rotigotine base in a sheet-like Contraption.

One The subject of the invention is also a machine and / or tool for producing a flat-shaped device accordingly the above description by the above Method.

All In particular, an object of the present invention is a process for thermal release of sheet-like Devices from a paved track or street for singling the sheet-like devices at the same time coherent sealing of the edges of the drug-impermeable Backing layer with protective layer removable before use the drug patch to prevent the ingress of foreign substances and to avoid recrystallization or precipitation of the or the Wikstoffs (e) in the active ingredient-containing matrix.

According to the invention All joining techniques are used, as far as they are not an occasion give that an electromechanical, especially electrostatic Charging is triggered. Exemplary for the sealing compound of said layers (drug-impermeable Backing and removable protective layer before use) may be mentioned: compound by thermal action, compound by ultrasound, connection by lasers, connection by one placed in one of said layers around the edge edges the layer on the other side facing continuous extending elevation, which in the corresponding thread-like Recess of the other layer, on which the first layer facing, corresponding Side sealingly interlocking.

Under "Connection by thermal action "is in the context of the invention understood that the connection of the edges or edge edges explained above said layers of the device by above room temperature lying heat and / or heat by means of a corresponding heated and / or heated device, machine or a tool is done.

Under "Connection by ultrasound "is understood in the sense of the invention, that the connection of the edges of said plaster layers through Ultrasound is done in a frequency range that is in relation to the existing in the device according to the invention Materials is non-destructive. The corresponding to be chosen Frequency ranges are known to the person skilled in the art.

Under "Connection by interlocking, corresponding thread-like Elevations and depressions "is in the sense of Invention understood that the continuous sealing connection the edges of the drug-impermeable backing layer with the edges of the protective layer removable before use in an analogous manner, as with aluminum foil, shielded against environmental influences, connected thin-walled Plastic deep drawing containers is known. Especially is that embodiment advantageous in which the thread-shaped depression in the form of a groove is present and the groove is present in the film layer whose film is a metal coating having. For the purposes of the present invention, an aluminum coating is advantageous. For illustrative explanation, but not exhaustive, be comparatively one filled with yoghurt and thin-walled plastic deep-drawn cup connected to aluminum foil called, in which the aluminum foil serves as a peelable lid.

at However, the connection by laser is to be noted that this Joining technique only for the backing layer and protective layer forming films can be applied with good results when the films no reflective coatings, such as an aluminum coating. According to the invention preferred be mild lasers, such as cobalt laser, their selection the expert is known, used.

According to one embodiment of the invention, the thermal connection in the form of a seal by heat and / or heat is particularly advantageous, this being by classical supply of the same and / or can be done inductively.

Especially an industrially usable process design is advantageous. This provides that at a paved road or course at least two rollers are present, each independently regulated are heated, through which a large industrial area produced, a multiple of a single sheet-like Device making up, laminate can be performed. The laminate consists of an agent-impermeable Backing layer, one loaded with at least one active substance Layer and a protective layer removable before use. in this connection a first roller has at least one suitable device, advantageously an increase or severity in the form of the Scope designed a planar device and is suitable when with the paving track Laminate comes into contact, the edges of the edges drug-impermeable layer over the drug-containing Coating, with the protective layer removable before use connected and lasting together and to separate immediately.

"Immediate" means here, that one step, without interposition and / or downstream another step, takes place.

A second roller, for the first in opposite directions, has an increase in the geometric form of a pull-off aid, which is a weakening the removable before use protective layer as a predetermined breaking point causes.

The Procedure is carried out so that during his Carrying out no electrical charging, by all materials used in the process, machines and tools are grounded.

Of course can the above arrangement on a paved road several times be arranged one behind the other.

The The following embodiments illustrate the Invention closer:

Embodiment 1

On a crystal-free surface of a commercial Rotigotine-containing active ingredient patch (TTS) brand "Neupro", consisting of drug-impermeable backing layer, active ingredient-containing matrix layer and removable before use protective layer, which has open to the environment vertical sides or side surfaces, is the area of 1 , 5 cm ² surrounding and on temperatures up to 300 ° C adjustable hot wire cutting device attached.

Under Elimination of any electrical, electromechanical and / or electrostatic influence on the materials used and the tool is heated to 150 ° C to 180 ° C, continuous Taut wire slowly perpendicular to the impermeable Back layer brought and in the vertical direction on the Removable protective layer before use. Hereby the hot wire stretches on its respective overlay on the impermeable backing layer this minimal, but sufficiently thermally, so taking along this Areas (edge edges) of the impermeable backing layer through the hot wire, this over the open, vertical Sides or side surfaces of the active substance-containing matrix layer, reaching up to the pre-use removable protective coating on top of corresponding areas (edges edges) spent the same and at the same time while continuing to drive together be permanently connected to each other under continuous sealing.

There thereby the drug-impermeable backing layer with the removable before use protective layer only to the respective edges of the cut edges is connected a permanent continuous sealing or welding of the However, layers which, however, are suitable for use with normal hands Peel force, the protective layer is removable before use.

It is a device for transdermal administration of rotigotine or rotigotine base before, oxidation-sensitive drugs, the around the drug particles present in the active ingredient-containing matrix an over their functional lifetime ensuring permanent encapsulation against environmental influences as well as a permanent anaerobic microenvironment around the drug particles comprises or comprises.

Embodiment 2

A commercial Rotigotine-containing active ingredient patch (TTS) brand "Neupro" consisting of drug-impermeable backing layer, active matrix layer and removable before use protective layer having open vertical side surfaces is sandwiched between two films that survive on all edges of the commercial product , The one film is the commercial product Scotch Pak 1109, which lies on top of the TTS and serves as a drug-impermeable backing layer, the other film is a commercially available polyester film MN 19, which lies on the underside of the TTS, as used before removable protective layer and with an aluminum layer is provided. This sandwich with 3 mm protruding foil edges is placed with the side of the protective layer on a thermally impressionable surface, which excludes an environmental impact, encapsulating compound has sufficient, following the contours of the TTS, continuous filiform recess in the form of a continuous groove, which follows the contours of the same at a distance of 1 mm to the edges of the TTS. This pad is heated to 160 ° C to 180 ° C. The overlying drug-impermeable backing layer is pressed into the continuous groove of the pad by a die having the contours of the TTS, but extending 1 mm beyond the edges of the TTS and corresponding to the continuous groove of the backing, the active-containing matrix being environmentally resistant is encapsulated and the said films are sealed together. Here, the protective film is removable from immediate use.

One Advantage of this connection is that by appropriate design the slides, z. B. in the form of a tongue, the handling the device is facilitated by the patients. Due to the obstructive tremor in Parkinson's patients, this significantly patient compliance.

Embodiment 3

The on an industrial cobbled street in its dimensions located sheet-like device in the form a TTS or active substance patch, comprising a drug-impermeable Backsheet, one with at least one oxidation-sensitive Active ingredient, such as rotigotine, one of its pharmacological acceptable salts or rotigotine base loaded drug matrix and a removable protective layer becomes one immediately before use Device fed to the two moving on the paved road above whose width encompassing, fitting rollers comprises. This effect either yourself or the propulsion of the cobbled street because of the concern on the paved road through their Propulsion moves or rolling and pavement road become independent moved or driven from each other.

The first roller has a profiling on its surface on, which corresponds to the contours of the TTS. She is able to in continuous rotation with a thermally influenced driver the drug-impermeable backing completely over the active ingredient-containing matrix on the removable before use protective layer under continuous sealing of the active ingredient-containing matrix, whereby in the region of their edge edges the one after another, immediately following rotation progress of the roller a thermally influenced cutting tool the TTS immediately isolated.

A second roller, the first counter-rotating, has a profiling in the geometric form of a pull-off aid, which is a weakening the drug-impermeable backing layer causes However, this does not cut through and thus represents a predetermined breaking point.

In In the present invention, the terms "pavement lane" and "cobblestone lane" are synonymous second hand.

Explanation of the drawings

1 , 1 shows a conventional sheet-like device in the form of a TTS or TDS or drug plaster.

In this mean the numbers

1

the active substance-impermeable backing layer;

2

the active ingredient-containing layer;

3

the removable protective layer before use (release liner)

It it can be seen that the edges and sides defining the circumference all layers are open.

2 2 shows a surface-shaped device according to the invention in the form of a TTS, TDS or active substance patch

In this mean the numbers

4

the active substance-impermeable backing layer;

5

the active ingredient-containing layer;

6

the removable protective layer before use (release liner)

14

the Edge edges of the active substance-impermeable backing layer

16

the Edge edges of the protective layer removable before use

It can be seen that the layer 4 under encapsulation of the layer 5 towards the environment with the layer 6 connected in the way that the layer 4 only with their edge edges 14 with the edge edges 16 the layer 6 connected so that the layer 6 slightly off the layer 4 can be loosened at the edge edges for attachment to the skin of a patient before use. Put on the skin, the layer remains 5 still protected against environmental influences, as it has no open sides. Thus, even when applied to the skin of a patient, crystal growth or precipitation of the respective active substance contained can be suppressed.

Experimental Procedure

Trial 1

six (6) commercial Rotigotine-containing TTS brand "Neupro" were leave as they were in the trade. They were in original packaging (TTS bag) for 15 months at room temperature (25 ° C) dark, dry and horizontal without shocks stored in a container.

she were given the designations I / 1/6 to I / 6/6.

Try 2 to 5

For Experiments 2 to 5 were respectively rotigotine-containing drug patches (TTS), the crystals at their cutting edges or Wirkstoffausfällungen showed. These cut edges are singling edges, which by industrially hitherto customary production emerged are.

Trial 2

The respective edges of the cut edges of a TTS, which had no crystals or crystal growth, facing the TTS interior were treated as follows:
The drug-impermeable backsheet was connected to a heat-wire heated to 160 ° C to 180 ° C and tensioned with the protect-before-use removable layer including the active-ingredient-containing layer.

On In this way, a total of six (6) patterns were made and with the designations II / 1/6 to II / 6/6.

These were incubated over the period of 15 months at room temperature (25 ° C) dark, dry and horizontal without shocks stored in a container. An inspection took place monthly.

Trial 3

Out one TTS at the cutting edges, but not over from the respective cut edges to the other cut edges reaching TTS range crystals or crystal growth or precipitation had the crystal-free range with a to 160 ° C. Hot-wire heated and strained to 180 ° C in the way cut out that the drug-impermeable backing layer with removable protective layer before use the active ingredient-containing layer coherent, lasting was connected with each other.

On In this way, a total of six (6) patterns were made and with the designations III / 1/6 to III / 6/6.

These were incubated over the period of 15 months at room temperature (25 ° C) dark, dry and horizontal without shocks stored in a container. An inspection of the TTS took place monthly.

Trial 4

Out one TTS in each case, which is covered by the cut edges but not above that of the respective cutting edges to the other cutting edges reaching TTS area Krristalle or Crystal growth or precipitation had and only in one very small inner area of the TTS had no crystals were with paper scissors the sites affected by crystal growth generously cut off from the TTS, leaving only a smaller, inner crystal clear area of the TTS remained. That was confirmed microscopically.

• a. mit einem auf 160°C bis 180°C erhitzten und gespannten Hitzedraht und alternativ
• b. mit einem handelsüblichen Folienschweissgerät bei 160°C gearbeitet wurde.

The freshly produced cut edges were treated in such a way that the active substance-impermeable backing layer was coherently, permanently connected to the protective layer which could be removed before use, including the active substance-containing layer, by

• a. with heated to 160 ° C to 180 ° C and stretched hot wire and alternatively
• b. was worked with a commercial film welding machine at 160 ° C.

On in each case, six (6), twelve in all (12) Pattern made.

The Patterns generated with the hot wire were named IV / a / 1/6 to IV / a / 6/6.

The with the film welder generated patterns were with the designations IV / b / 1/6 to IV / b / 6/6.

These were incubated over the period of 15 months at room temperature (25 ° C) dark, dry and horizontal in a container stored. An inspection of the TTS took place monthly.

After all six (6) additional samples were designated IV / c / 1/6 to IV / c / 6/6 according to a. generated and over the duration stored at 60 ° C for 6 months.

Trial 5

In each case a TTS that knows neither at the cut edges themselves nor at the inside of a TTS send edges of the cut edges and also did not have crystals in the inner TTS area was spent in an electric field.

After all was using a paper scissors on one side of another TTS of the aforementioned type a fresh cut edge, the commercial vis à vis, generated and spent in an electric field.

• a. Es wurden jeweils ein TTS an einer frischen sowie an einer handelsüblich ausgebotenen Schnittkante einem elektrischen Feld einer Plasmalampe in einer geeigneten Weise ausgesetzt, dass der Lichtbogen bzw. die Funkenstrecke durch das TTS an jeweils einer Stelle der handelsüblichen bzw. frischen Schnittkante schlug.

Here, once a commercial cutting edge and a freshly produced with the scissors cutting edge and the other part of the inner area of a TTS, the generated by means of a high voltage generator electric fields were exposed, with a high frequency voltage of about 25 kHz and a few kilovolts (about 12,000-12,500 kV ) worked.

• a. In each case, a TTS was exposed to an electric field of a plasma lamp in a fresh and commercially available cut edge in a suitable manner such that the arc or the spark gap struck by the TTS at respectively one point of the commercial or fresh cut edge.

• b. Schliesslich wurde ein TTS mit seinem inneren Bereich einem elektrischen Feld einer Plasmalampe in einer geeigneten Weise ausgesetzt, dass der Lichtbogen bzw. die Funkenstrecke durch den inneren Bereich des TTS schlug.

In this way, a total of two (2) samples were made and labeled V / kV / 1 and V / kV / 2.

• b. Finally, a TTS with its inner portion was exposed to an electric field of a plasma lamp in a suitable manner so that the arc hit the inner portion of the TTS.

On this way, one (1) pattern was made and named V / kV / 3 provided.

These were over the period of two (2) months at room temperature (25 ° C) dark, dry and horizontal without shocks stored in a container. An inspection of the TTS took place weekly.

analytics

The TTS of Experiments 1 to 5 were microscopically examined subjected.

It became a continuously adjustable stereomicroscope of the brand Leica, Type MZ6 with a cold light source CLS 100 and a magnification factor 3.2- up to 20 times, used. With doubler is the magnification factor 12.6- to 80-fold.

Results

Trial 1

To 15 months of storage were the TTS with the respective names I / 1/6 to I / 6/6 taken from the original packaging and examined with the naked eye and the aforementioned microscope.

Already With the naked eye could be found that of the cut edges and serving as a removal aid so-called S-cut the respective TTS away into the inner area of the TTS reaching, large area, Snow crystals or snowflakes similar, Rotigotinkristalle were present. Completely flat insignificant, very small crystal-free islands were to be found. The microscopic examination of the TTS produced the same result.

by virtue of the almost complete formation of rotigotine crystals over The entire TTS area can no longer be transdermally active to the skin of a patient in a therapeutically intended amount be delivered. Thus fulfills a TTS from the experiment 1 not the approved release specification, violates drug law Regulations and is therefore unfit for marketing.

Legally drugs need 95% of the active ingredient for the duration of his functional lifetime or as a pharmacon be effective.

Trial 2

The above the duration of 15 months was monthly inspection of the TTS with the designations II / 1/6 to II / 6/6 showed with the naked eye no crystals or crystal growth or precipitation at the cutting edges. The microscopic examination showed over the trial period that is immediately on and along the original Cut edge of the TTS a negligible, thread-like, Crystal formation of rotigotine occurred, but did not continue spread.

The negligible thread-like crystal formation will ensue attributed that used commercially TTS already infected with a few crystals or precipitations However, due to the inventive design of the TTS were suppressed in their growth according to experiment 2.

Trial 3

The above the duration of 15 months was monthly inspection of the TTS with the designations III / 1/6 to III / 6/6 showed neither to the naked eye nor with the aforementioned microscope crystals or crystal growth.

It follows that the inventive design of the TTS prevents crystal formation or crystal growth or active substance precipitation. One Such TTS thus complies with the approved release specification and is not subject to any drug regulatory concerns.

Trial 4

The above the duration of 15 months was monthly inspection of the TTS with the designations IV / a / 1/6 to IV / a / 6/6, IV / b / 1/6 to IV / b / 6/6 and IV / c / 1/6 to IV / c / 6/6 showed neither with the naked eye nor crystals or crystal growth with the aforementioned microscope.

from that it follows that the inventive embodiment of the TTS a crystal formation or a crystal growth or an active substance precipitation prevented.

A thermal exposure, as in the patterns IV / c / 1/6 to IV / c / 6/6 is done, does not affect the crystal formation when the TTS having the inventive embodiment. Without the inventive design of the already widely infected with crystals TTS cut crystal-free area of the TTS, would be the crystal formation has progressed into this area.

Also here the approved release specification is fulfilled and is not subject to drug regulatory concerns.

Trial 5

The above the duration of two (2) months weekly inspection the TTS with the designations V / kV / 1, V / kV / 2 and V / kV / 3 both showed with the naked eye as well as with the aforementioned microscope, that the the light arc or the spark gap exposed points of the commercial Cutting edge, the freshly created cutting edge and the inner crystal-free region of a TTS each starting point for a clear, unobstructed, across the surface of the TTS were spreading crystal growth.

from that follows that, in addition to the inventive design of the TTS itself, in the manufacture of a TTS in an inventive manner an electrical, electromechanical or electrostatic charging of the TTS components, in particular to avoid or exclude the films used. Especially Critical in industrial production is the step of singulation the TTS on a production line. Overall, therefore, to it Make sure that electrostatic influences on the TTS are avoided and in each step of manufacturing an electrostatic discharge is to ensure. The machines used in the manufacturing process and tools are also before use in the manufacturing process electrically discharged and during execution of the process in an electrostatically discharged state. Advantageously, the electrostatic discharge takes place over a large area.

to Crystallization or precipitating agents are in the pharmaceutical field such, over the duration their functional lifetime less than 95% drug amount release the respective pharmaceutical formulation or if they are made available as such, to less than 95% provide their desired efficacy.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - WO 94-07468 [0005]
• WO 99/49852 [0007, 0016, 0020, 0066]
• WO 02/089777 [0010, 0020, 0066]
• WO 02/089778 [0010, 0020, 0050, 0066]
• - EP 1256340 [0011, 0020, 0066]
• WO 04/012721 [0012, 0020, 0022, 0066]
• WO 04/012730 [0013, 0020]
• WO 04/058247 [0014, 0016, 0018, 0020, 0021, 0066]
• WO 94/07468 [0020, 0066]
• WO 94/26346 [0024]
• WO 04/0121730 [0050]
• WO 04/12730 [0066]
• - DE 3344335 A1 [0072]

Claims (38)

A planar device for the transdermal administration of an oxidation-sensitive pharmaceutical active substance which has at least one layer loaded with at least one oxidation-sensitive active substance and / or one of its pharmacologically acceptable salts, an active-substance-impermeable backing layer and a protective layer which can be removed before use, characterized in that the edge edges of the active-substance-impermeable backing layer overlap extending the open sides of the active-ingredient-containing layer between the backing layer and the protective layer to the protective layer which can be removed before use, are permanently connected to the edge edges of the before-removable protective layer, with continuous sealing of the edge edges, the protective layer being removable again before use. Flat-shaped device for transdermal administration of an oxidation-sensitive pharmaceutical Active substance containing at least one with at least one oxidation-sensitive Active ingredient base and / or one of its pharmacologically acceptable Salts laden layer, a drug-impermeable backing layer and a pre-removable protective layer, thereby characterized in that the edge edges of the drug-impermeable Backing layer over the open sides of the between Back layer and protective layer lying active ingredient Layer until reaching protective layer before use, with the edge edges of the protective layer removable before use continuous with continuous sealing of the edge edges are permanently connected to each other, wherein the protective layer before Use is removable again. Flat-shaped device for transdermal administration of an oxidation-sensitive pharmaceutical Active substance containing at least one with at least one oxidation-sensitive Active ingredient and / or one of its pharmacologically acceptable salts loaded layer, a drug-impermeable backing layer and a pre-removable protective layer, thereby characterized in that the edge edges of the drug-impermeable Backing layer over the open sides of the between Back layer and protective layer lying active ingredient Layer until reaching protective layer before use, with the edge edges of the protective layer removable before use contiguous with continuous sealing of edge edges, both an encapsulation against environmental influences as well as a permanent anaerobic microenvironment around those in the drug layer having existing drug particles, permanently connected are, wherein the protective layer is removable again before use. Flat-shaped device for Transdermal administration according to one of claims 1-3, characterized in that the edge edges of the active substance impermeable Backing layer over the open sides of the between Back layer and protective layer lying active ingredient Layer until reaching protective layer before use, with the edge edges of the protective layer removable before use incompletely interconnected, with the protective layer removable before use. Flat-shaped device for Transdermal administration according to one of the preceding claims, characterized in that in the active ingredient-containing layer existing active substance an oxidation-sensitive active substance base is. A sheet-like device for transdermal administration according to any one of the preceding claims, characterized in that the active substance-containing layer (a) contains an oxidation-sensitive active ingredient content of at least 5% by weight, (b) an oxidation-sensitive drug content of at least 1.0 mg / cm 2 ² has. Flat-shaped device for Transdermal administration according to one of the preceding claims, characterized in that the active substance-containing layer is a matrix or a matrix layer. Flat-shaped device for Transdermal administration according to one of claims 1 to 7, characterized in that the device is electrically discharged is. Flat-shaped device for transdermal administration of rotigotine ((-) - 5,6,7,8-tetrahydro-6- (propyl (2- (2-thienyl) ethyl) amino) -1-naphthol), the one with rotigotine and / or one of its pharmacologically acceptable ones Salts as drug-loaded layer, a drug-impermeable Back layer and a removable before use protective layer, characterized characterized in that the edge edges of the drug-impermeable Backing layer over the open sides of the between Back layer and protective layer lying active substance-containing layer reaching up to the before use removable protective coating, with the Edge edges of the protective layer removable before use continuous with continuous sealing of the edge edges are permanently connected to each other, wherein the protective layer before Use is removable again. Flat-shaped device for transdermal administration of rotigotine base containing one with rotigotine base and / or one of its pharmacologically acceptable salts as active ingredient loaded layer, a drug-impermeable backing layer and a removable before use protective layer, characterized that the edge edges of the drug-impermeable Backing layer over the open sides of the between Back layer and protective layer lying active substance-containing layer reaching up to the before use removable protective coating, with the Edge edges of the protective layer removable before use continuous with continuous sealing of the edge edges are permanently connected to each other, wherein the protective layer before Use is removable again. Flat-shaped device for transdermal administration of rotigotine, the one with rotigotine and / or one of its pharmacologically acceptable salts as active ingredient loaded layer, a drug-impermeable backing layer and a pre-removable protective layer, thereby characterized in that the edge edges of the drug-impermeable Backing layer over the open sides of the between Back layer and protective layer lying active ingredient Layer until reaching protective layer before use, with the edge edges of the protective layer removable before use contiguous with continuous sealing of the edges, both an encapsulation against environmental influences as well as a permanent anaerobic microenvironment around those in the active substance-containing Layer containing active ingredient particles having, stay together connected, wherein the protective layer before use removable again is. Flat-shaped device for Transdermal administration according to any one of claims 9-11, characterized characterized in that the edge edges of the drug-impermeable Backing layer over the open sides of the between Back layer and protective layer lying active ingredient Layer until reaching protective layer before use, with the edge edges of the protective layer removable before use incompletely interconnected, with the protective layer removable before use. Flat-shaped device for Transdermal administration according to claims 11 and 12, characterized in that in the active ingredient-containing layer existing active ingredient is rotigotine base. Area-shaped device for transdermal administration according to claims 10 to 13, characterized in that the degree of loading of the active substance-containing layer with rotigotine is between 0.3 and 6 mg / cm ² . Area-shaped device for transdermal administration according to claims 9 to 14, characterized in that the active substance-containing layer (a) contains a proportion of rotigotine of at least 4.0 wt.%, (B) a rotigotine content of at least 2.0 mg / cm ² identifies. Flat-shaped device for Transdermal administration according to claims 9 to 15, characterized in that the active substance-containing layer has a matrix or is a matrix layer. Apparatus for transdermal administration according to Claims 9 to 16, characterized in that the device electrically uncharged and / or electrically discharged. Apparatus for transdermal administration according to one of the preceding claims, characterized that the device comprises a removal aid. Apparatus for transdermal administration according to one of the preceding claims, characterized that the oxidation-sensitive active ingredient and / or its active substance base, and / or Rotigotine and / or rotigotine base in each case in amorphous form in the Device are available. Use of a sheet-like Device for transdermal administration according to one of the preceding Claims for the preparation of a medicament for treatment Parkinson's disease or Restless Leg Syndrome. Use of a sheet-like Device for transdermal administration according to one of the preceding Claims for the preparation of a medicament for treatment of depression. Process for producing a sheet-like device for the transdermal administration of an oxidation-sensitive pharmaceutical active substance and / or rotigotine and / or rotigotine base and / or one of its pharmacologically acceptable salts, comprising at least one layer loaded with at least one oxidation-sensitive active substance, an active-substance-impermeable backing layer and a Use of a removable protective layer, characterized in that an active substance impermeable backing layer and a protective layer which can be removed before use are provided, that a layer loaded with at least one oxidation-sensitive active substance is introduced between these layers and the edge edges of the active substance-impermeable backing layer are transferred over passing the open sides of the active-ingredient-containing layer between the backing layer and the protective layer, and applying them contiguously to the corresponding edge edges of the pre-use protective layer, and bonding them immediately under continuous sealing, the protective layer being removed prior to use. Method according to claim 22, characterized in that that an active substance impermeable backing layer and a pre-removable protective layer is provided that between these layers one with at least one oxidation-sensitive Active substance loaded layer is introduced and the edge edges the drug-impermeable backing layer over the open sides of the between backing layer and protective layer lying active ingredient-containing layer are performed and on the corresponding edge margins of the before use Removable protective layer incomplete and being joined together, the protective layer before use Will get removed. Method according to one of claims 22 and 23, characterized in that the edge edges of the active substance impermeable Back layer thermally controlled so far heated be that over the open sides of the between backing layer and protective layer lying active substance-containing layer out and on the thermally heated edge edges the removable before use protective layer are applied and interconnected with the protective layer removed before use becomes. Method according to one of claims 22 to 24, characterized in that the drug-loaded layer a Matrix or a matrix layer is. Method according to one of claims 22 to 25, characterized in that the drug-loaded layer a Adhesive matrix is. Method according to one of claims 22 to 26, characterized in that the drug-loaded layer as an active ingredient an oxidation-sensitive active substance base, rotigotine or rotigotine base and / or having one of its pharmacologically acceptable salts. Use of a method according to one of the claims 22 to 27 to prevent further crystal formation in the device existing oxidation-sensitive active ingredient and / or rotigotine and / or one of its pharmacologically acceptable salts. 29 procedure for producing a sheet-like device for the transdermal administration of an oxidation-sensitive pharmaceutical Active substance containing at least one with at least one oxidation-sensitive Active ingredient-loaded layer, an active substance impermeable backing layer and a removable by means of an existing peel-off before use Protective layer, characterized in that in the respective Equip a production line with a suitable electrically uncharged one drug-impermeable backing layer and a suitable electrically uncharged by means of an existing Abziehhilfe before Use removable protective layer that be provided between these layers one with at least one oxidation-sensitive Active substance loaded electrically uncharged layer is introduced wherein by thermal action, the plaster edges of the active substance-impermeable backing layer guided the open sides of the active ingredient-containing layer and on the corresponding plaster edges of the before use removable protective layer contiguous be applied and this directly by thermal action permanently connected to one another with continuous sealing while avoiding an electro-mechanical or electrostatic Charging can be separated by separating. Process according to claims 22 to 29, characterized characterized in that the active substance-loaded layer as an active ingredient an oxidation-sensitive active substance base and / or rotigotine and / or Rotigotine base and / or one of its pharmacologically acceptable Has salts. Process according to claims 22 to 30, characterized characterized in that the drug-loaded layer is a matrix. Process according to claims 22 to 31, characterized characterized in that the drug-loaded layer is an adhesive matrix is. Process according to claims 22, 23 and 25 to 31, characterized in that the connection of the edge edges the drug-impermeable backing layer with the Corresponding edge margins of removable before use Protective layer under continuous sealing by ultrasound. Process according to claims 22, 23 and 25 to 31, characterized in that the connection of the edge edges the drug-impermeable backing layer with the Corresponding edge margins of removable before use Protective layer under continuous sealing by laser action he follows. Process according to claims 22, 23 and 25 to 31, characterized in that the compound the edges of the drug-impermeable backing layer with the corresponding edges of the removable before use protective layer under continuous sealing by groove impression to form a running along the edges thread-like depression. Process according to claims 22, 23 and 25 to 31, characterized in that the connection of the edge edges the drug-impermeable backing layer with the Corresponding edge margins of removable before use Protective layer under continuous sealing by induction. Means for producing a sheet-like device according to one of claims 1 to 19 by means of a method according to one of claims 21 to 36, characterized that, by two opposing rollers, the regulated heated are, the drug-impermeable backing layer, the protective layer removable before use and the one between them befindliches active ingredient-containing layer are feasible. Agent according to claim 37, characterized in that a first roll has features that allow the singulation of a sheet-like device from a multiple the sheet-like device having laminate web causes and a second roller, in opposite to the first roller, the Training a peeling aid causes. Means according to any one of claims 37 and 38, characterized in that they are electrically discharged and / or grounded in operation for electrical discharge are.