DD279404A5 - FLAECHENFOERMIGES, THERAPEUTIC SYSTEM, METHOD FOR THE PRODUCTION THEREOF AND ITS USE - Google Patents

Abstract

The invention relates to a surface-therapeutic system for the administration of active ingredients to the skin, with active substance reservoir (s) with active ingredient delivery surfaces and Hautadhaesionsflaechenabschnitten arranged on the skin side. According to the invention, the active substance delivery area sections to be brought into contact with the skin and the skin side (s) skin adhesion area sections are at the same level. The surface-active therapeutic system according to the invention is used for local or systemic transdermal drug administration in human or veterinary medicine or in cosmetics. The invention also relates to processes for the preparation of the surface therapeutic system. Fig. 2

Description

Field of application of the invention

The invention relates to a sheet-like therapeutic system for the administration of active ingredients to the skin, with active substance reservoir (s) with active substance delivery surfaces and with pressure-sensitive adhesive areas arranged on the skin side; a method for producing the sheet-like therapeutic system and its use.

The invention thus relates to a transdermal therapeutic system for administering medicinal agents or even cosmetically active substances to human or animal skin.

Characteristic of the known state of the art

A therapeutic system is a drug-containing device or dosage form that delivers one or more drugs at a predetermined rate continuously to a specified site of use for a specified period of time.

These systems are therapeutic precision instruments, whose construction requires extraordinary measures to ensure the continuous Wirkstoh ^r ieisetzung.

Therapeutic systems have already been developed for a wide variety of application sites, including the skin, whereby systemic effects can be achieved in addition to topical ones. The variety of active ingredients that can be administered in this way and their different chemical, physical and pharmacological properties make it impossible to cover all therapeutic problems with just one system.

Numerous sheet-like therapeutic systems have already become known for administering medicinal active substances to the skin, a summary of which can be found, for example, in Klaus Heilmann: Therapeutic Systems, Ferdinand Enke Verlag, Stuttgart, 1977. In all cases, the systems of the prior art were able to achieve a completely satisfactory effect.

In this case, a common structure of such a transdermal therapeutic system is a drug reservoir in which the active ingredient is in solid, liquid or dissolved form and a pressure-sensitive adhesive layer, by which the system is closely connected to the skin.

This principle finds its limits where the active ingredient does not diffuse through the pressure-sensitive adhesive layer or a chemical reaction between active ingredient and pressure-sensitive adhesive occurs, or the active ingredient in the pressure-sensitive adhesive is not or only slightly soluble. In these cases, attempts have been made to bring a non-pressure-sensitive active substance-containing reservoir or the active ingredient itself into direct contact with the skin and to fix this reservoir or the active ingredient itself by additional measures on the skin. For this purpose, for example, separate pressure-sensitive adhesive strips or the integration of the reservoir or the drug in a patch are such that the reservoir or the drug is surrounded all around by a pressure-sensitive adhesive edge

(see, for example, DE-OS 2902183). If the contact area exceeds a certain size, the constant contact with the skin required for controlled therapy is no longer guaranteed with prolonged wearing time, which can be days, even weeks, because of the unavoidable body and muscle movements.

In DE-OS 3202775 has now been proposed to distribute the active ingredient grid-like on a pressure-sensitive adhesive surface. The adhesive surface is in principle then large enough to fix the active ingredient on the skin and should theoretically allow a surface fixation of the drug reservoir. However, since the active ingredient is on the adhesive layer, not at the same level with the same, it is constantly under tension after sticking to the skin. For this reason, the bonded spots in the inevitable body and muscle movements very easily dissolve again, affecting the constant contact of the drug surface with the skin by pressure change occurring and thus prevent any controlled release of the drug.

From DE-OS 3423328 a self-adhesive patch with separate drug segments has become known, are arranged in the dome-shaped drug segments and adhesive segments on a non-adhesive pad. It is suggested that adhesive segments and drug segments should have the same height. When applying the patch, the size of the skin contact segments and thus the amount of active ingredient released depends on the pressure on the patch. As a therapeutic system, this patch is useless.

In DE-OS 3319469 it has been proposed to deposit the active ingredient in the pores of a microporous film, which may be partially or completely coated with a pressure-sensitive adhesive for fixing to the skin. Also in this embodiment, the contact of the active ingredients in the pore openings is impaired with the skin, since the pore openings are not at the same level with the pressure-sensitive adhesive areas and therefore contact between the active ingredient and the skin surface is prevented by the pressure-sensitive adhesive layer. Even with this system, therefore, a controlled administration of drugs is impossible.

Object of the invention

The object of the invention is to provide an improved therapeutic system for the administration of active ingredients to the skin.

Explanation of the essence of the invention

The invention has for its object to provide a sheet-like therapeutic system for the administration of drugs to the skin, which regardless of ler Mwendigen size of Wirkstoffabgabefiäche even with prolonged wearing time of the system the lasting contact of the active substance. bonder surface ensures the skin.

The object is achieved in a generic planar therapeutic system in which the active substance delivery area section (s) to be brought into contact with the skin are at the same level. The system according to the invention is particularly advantageous for the administration of active substances which react unfavorably with pressure-sensitive adhesive substances or which do not diffuse through a skin-adhesive layer.

In an advantageous development of the inventive idea, the active substance delivery area sections are distributed uniformly or unevenly in the skin contact area. It may be particularly advantageous if the drug delivery area sections are round or angular. In the skin contact area, skin adhesion surface portions may be regularly or irregularly distributed. The Hautadhäsionsflächenabschnitte may be round or square. Eb may also be particularly preferred for true-to-life forms of application, however, in that the skin adhesion and active substance delivery surface sections are arranged in a strip-like manner in alternation. In a particularly preferred embodiment of the invention, the skin contact surface may have a surrounding skin adhesion margin. The system according to the invention may further comprise a skin-facing flexible backing layer and optionally a removable protective layer. In addition, it may have an apertured support layer to improve the mechanical stability. The backing layer may consist essentially of paper, a textile Flächengerjjlde, a metal or plastic film or laminates thereof. Between the support layer and the drug reservoir, a pressure-sensitive adhesive layer can be wholly or partially present. The drug reservoir may have one or more drug (s) having topical or systemic activity.

The active substance (s) is preferably selected from the group of cardiac glycosides from Digitalis lanata β-acetyldigoxin; Vasodilators, e.g. Pentaerythrityl tetranitrate, cinnarizine or nitroglycerin, the niusculotropic spasmolylics, eg moxaverin HCl; Coronary therapy, e.g. As oxyfedrine HCI, coronary dilators, z. N- (3,3-diphenylpropyl) -alpha-methyl-benzylamine HCl (fendiline), antihistaminics such as clemastine or antiemetic dimethhydrinate, analeptics such as caffeine; Analgesics, such as phenazone chloral hydrate; Hypnotics such as chlorobutanol, musculotropic vasodilators such as nicotinic acid, vitamin B6 such as pyridoxine, broncholytica, cardiaca, diuretics, phosphodiesterase inhibitor theophylline and compounds thereof, e.g., choline theophyllinav, theophylline-ethylenediamine, theophyllin sodium glycinate, theophylline sodium salicylate; and theophylline derivatives, broth theophylline, chlortheophylline, ethenylphylline, diprophylline etofylline and poxyphylline, and rubefacients, such as nicotinic acid β-butoxyethyl ester and / or nonylic acid vanillylamide; Antiphlogistica, such as ethylene glycol monosalicylate or difithylamine salicylate. Preferred active substances are amphetaminil, betahistine, beta-acetyldigoxin, bopindolol, buprenorphine, clemastine, diclofenac, diitiazen, dimenhydrinate, diethylamine salicylate, ethylene glycol monosalicylate, 5-fluorouracil, glibenclamide, hydromorphone, ibuprofen, isopropyl 4- (2,1,3-benzoxadiazole). 4-yl) -M-dihydro-B-methoxycarbonyl ^. -Dimethyl-S-pyridine-carboxy-lat, ketotifen, L-thyroxine, nicotine, nicotinic acid-ßbutoxyethylester, Nonylsäurevanillylamid, pindolol, salbutamol, tamoxifen, tizanidine, and their Bases, salts and derivatives. The active compounds can also be used in a meaningful combination with each other, preferred are:

A. Cardiac glycoside from Digitalis lanata β-acetyldigoxin in combination with

1. a vasodilator, z. Pentaerythrityl tetranitrate or nitroglycerin,

2. a musculotropic spasmolytic, z. B. Moxaverin HCI

3. a Coronarlherapeuticum, z. B. oxyfedrine HCI or

4. oine coronary dilator, z. B. N- (3,3-diphenylpropyl) -alpha-methyl-benzylamine HCl (Fendilin)

Antihistaminic, clemastine, in combination with a glucocortiocoid, e.g. Dexamethasone orlocortolone-i-pivalate;

C. Antihistaminicum, such as antiemetic dimenhydrinate in combination with a

1. Vasodilator, Antihistaminicum, z. Cinnarizine,

2. Analectic, e.g., caffeine,

3. analgesic, antipyretic, e.g. Phenazone chloral hydrate;

4. Hypnotic, anesthetic, antiseptic, z. For example, chlorobutanol;

5. Musculotropic vasodilator, lipid-lowering agent, eg. B. nicotinic acid, or

6. Vitamin B6, e.g. Pyridoxine.

D. Broncholyticum, Cardiacum, Diureticum, Phosphor diesterase Theophylline - in combination with others

1. Theophylline compounds, such as: choline theophyllinate TheophyMin-ethylenediamine Theophylline sodium glycinate Theophylline sodium salicylate, or

2. Theophylline derivatives. How: Broth theophylline Chlortheophyllin Etaminphyllin diprophylline

Etofylline proxyphylline

E. Rubefacients, such as nicotinic acid β-butoxyethyl ester and / or nonylic acid vesnillylamide - in combination with antiphlogistic, e.g. Ethylene glycol monosalicylate or diethylamine salicylate.

A particular advantage obtainable by such drug combinations is that, ideally, multiple drugs may be administered simultaneously, optionally at different delivery rates, that are not mixed - whether processed or stored for reactions with each other or different physical properties. The manufacturing steps explained later allow problem-free separate incorporation of the active ingredients.

Particularly preferred active substances which can be used in the system according to the invention are:

Amphetaminil, betahistine, β-acetyldigoxin, bopindolol, buprenorphine, clemastine, diclofenac, diitiazene, dimenhydrinate, diethylamine salicylate, ethylene glycol monosalicylate, 5-fluorouracum, glibenclamide, hydromorphone, ibuprofen, isopropyl-4- (2,1,3-benzoxadiazole) - yD-i ^ -dihydro-B-methoxycarbonyl ^.-dimethyl-S-pyridine-carboxylate, ketctifen, L-thyroxine, nicotine, nicotinic acid-β-butoxyethyl ester, nonylic acid-vanillylamide, pindolol, salbutamol, tamoxifen, tizanidine, theophylline, and the bases, salts and derivatives of the abovementioned preferred active compounds.

The invention also relates to methods for producing the sheet-like therapeutic system, comprising the following steps:

Presenting a repellent base; Creating a skin adhesion layer on the substrate, laminating a support material; Perforation of the laminate thus formed, replacement of the repellent pad with a removable protective layer; Coating of the protective layer-free surface with active substance-containing reservoir mass; Laminating the possibly

Pressure-sensitively treated backing layer and packaging.

In a particularly preferred development of this method, after the perforation of the laminate, a coating with the active substance-containing reservoir mass is carried out by lamination with a reservoir layer containing active substance produced under pressure or under pressure / heat.

In a further particularly preferred method, skin adhesion sections are applied to a protective layer underlay, these skin adhesion layer sections and the protective layer underlay are coated with active substance-containing backing material, a backing layer optionally coated with adhesive bonding is laminated and the finished system is assembled.

The invention is also concerned with the use of the system for local or systemic transdermal)

Drug administration in human or veterinary medicine or cosmetics.

Due to the fact that, according to the invention, the therapeutically required active substance delivery surfaces alternately with

Adhesive surfaces are in one plane, a satisfactory long-lasting intimate contacting of the drug delivery reservoir with the active substance receiving skin surface can be done, which alone the continuous drug delivery, as it is therapeutically desirable guaranteed.

In the following, the invention will now be explained with reference to embodiments and the accompanying drawings. Showing:

1 shows schematically the skin contact surface of a section of a planar therapeutic system according to the invention;

2 shows a cross section along the line I-L of Figure 1 in magnification ..;

3 shows a section of the skin contact surface of a further preferred embodiment of the invention; Fig. 4: schematically enlarges the cross section along line II-II of Fig. 3; Figure 5: the skin contact surface of a plaster-like embodiment of the invention; 6 shows the skin contact surface of a further pear-like embodiment of the invention; and FIG. 7 shows a representation of the in vitro release of keto-sulfur and bopindolol from therapeutic systems according to the invention.

According to the invention, the subdivision of the skin contact layer is based on two basic principles:

Principle A:

The active substance delivery areas are occasionally distributed in a possibly also drug-containing Hautadhäsionsfläche.

Principle B:

A drug delivery area is interrupted by a possibly also drug-containing Hautadhäsionsfläche.

Embodiments of the invention according to principle A are shown in Figures 1, 2 and 6; whereas in FIGS. 3, 4 and 5, embodiments which correspond to principle B are shown.

In FIGS. 1 and 2, circular active substance delivery surfaces 2 are symmetrically distributed in a pressure-sensitive adhesive skin adhesion surface 1. Of course, this embodiment is to be taken only as an example and not limiting for the inventive concept, because the arrangement of drug delivery surfaces, their size, their geometric shape and their distance from each other are variable and depend on the therapeutic and physical requirements.

In rig. 2, the section along the line 1-l in FIG. 1 is shown. Under a backing layer 3, a pressure-sensitive adhesive layer 4 is arranged, which ensures cohesion with a drug reservoir layer F. The reservoir layer 5 is superimposed by a perforated support layer 6 which has a skin adhesion layer 1 on the skin side. The resulting by perforation cavities are completely filled by the material of the drug reservoir 5, which also forms the drug delivery sections 2, so that alternate at the skin contact surface drug delivery surfaces 2 and skin adhesion sections 1 at the same level.

FIG. 6 shows a plaster-like embodiment of the principle A, with isolated active substance delivery surfaces 13 being distributed symmetrically in the middle region of an otherwise pressure-sensitive Pfiaster-like section as circular points. In the edge region, a circumferential, continuous adhesive adhesion edge 12 is provided, which ensures a secure edge bonding with the skin when the plaster is applied.

Figures 3 and 4 illustrate before jgte embodiments of the principle B. In this case, a drug delivery surface 8 is interrupted by symmetrically arranged sechb ^^ ige Hautadhäsionsabschnitte 7. Again, the arrangement of Klebebereiuhe, the distance from each other, their size and their geometric shape are variable and can be modified according manufacturing requirements. The construction of the system seen in FIG. 3 from the skin contact surface is shown by the greatly enlarged cross section along line H-II shown in FIG. In this case, a backing layer 9 adjoins an adhesion-limiting intermediate layer 10, which in turn is in contact with a reservoir layer 11.

To a certain extent admitted into the reservoir layer 11 are skin adhesion points 7, which terminate with the surface of the active substance reservoir 8 lying in a plane towards the skin. The adhesive dots 7 are surrounded all around by the drug delivery surface 8.

FIG. 5 shows a further exemplary embodiment of the principle B of the invention, in the form of an application-ready Df vaster-shaped section. The Hautadhäsionsabschnitte are designated 12 and the drug delivery surfaces with 13.

In this embodiment, the active substance delivery surface is symmetrically penetrated by square skin adhesion points and surrounded on all sides by a peripheral skin adhesion margin. Again, it is particularly advantageous that edge gluing problems of the plaster-like systems of the invention can be avoided thereby.

The new sheet-like therapeutic systems according to the invention are very variable in their application possibilities, since they-apart from special embodiments, as shown for example in Figures 5 and 6 can be produced as rapportfreie web and thus divided into almost any blanks. Thus, the application can be done, for example, as a patch, strip or even as a bandage. With arbitrary splitting of the webs, it is possible that cut edges arise that are not completely covered with pressure-sensitive adhesive. It should therefore be ensured that the cutting lines always lead through such pressure-sensitive adhesive strips, rings o.

The hautadhäsionsmaterialfreien sections can be kept so small by appropriate choice of the geometric Desnigs of the system that no detachment occurs from the edge even with prolonged wearing time of the plaster. The area of tolerable skin adhesive material free sections depends on the choice of skin adhesive material. A special case in this context is a therapeutic system de r, in which the active substance delivery area is distributed in a strip-like manner in the skin adhesion surface or the skin adhesion surface in strip form in a drug delivery area. Here, the cut may only lie parallel to the strip direction within a pressure-sensitive adhesive strip in order to avoid a completely tack-free edge in this direction.

The new system is particularly suitable for the administration of medical or ko imetischen drugs to the skin, which are not or hardly applicable from pressure-sensitive adhesive systems. It can also be alia easy too

Applicant agents are used, which are able to migrate alone or with adjuvants into the skin. )

It has already been shown that the system is particularly suitable for administering active substances such as ketotifen or bopindolol.

The drug reservoir layer can be prepared in a manner known per se, for example by dissolving the active ingredient in a matrix, dispersing the active ingredient in a matrix or distributing the active ingredient in a matrix in microencapsulated form; Distributing the adsorbed on an inert carrier drug in a matrix. Of course, the drug reservoir can also consist of pure active ingredient or substantially pure active ingredient. The matrix itself may consist of low or high molecular weight, natural or synthetic substances, while its selection depends on the properties of the active ingredient to be administered and the therapeutic requirements known to those skilled in the art. In connection with ketotifen and bopindolol, for example, a matrix based on water-swellable polyacrylates has proven particularly useful.

In addition to the matrix constituents and active ingredients, the active substance reservoir layer may contain further suitable additives known or obvious to a person skilled in the art on the basis of his specialist knowledge, such as, for example, solubilizers, plasticizers, stabilizers, fillers and enhancers. The thickness of the reservoir layer, d. H. the distance between the backing layer, if necessary, pressure-sensitively coated backing layer is determined mainly by the therapeutic requirements of the system; it is preferred that the total thickness of the system is between 40pm and 5mm, preferably between 80pm and 1.2mm. In special cases, the reservoir consists only of the complete or partial filling of the pore openings in the laminate of backing and skin adhesion layer, so that the pressure-sensitively coated backing layer is in direct association with the backing layer. Also in these variants, the drug delivery surfaces lie in a plane with the Hautadhäsionsflächen, as required by the invention.

The backing layer covering the reservoir on the skin-remote side may be permeable or impermeable. It must be flexible and serves primarily for further mechanical stabilization of the system. If the parts of the reservoir or of the incorporated active ingredients are volatile, the backing layer must be impermeable to these substances. It can be single or multi-layered. Substances that can be used to make them are polymeric substances such as polyethylene, polypropylene, polyethylene terephthalate and polyamides. As other materials and metal foils, such as aluminum foil, alone or coated with a polymeric substrate can be used. Permeable backing layers are, for example, textile fabrics, such as woven and nonwoven fabrics or even porous polymer materials. The required thickness of the backing layer depends on the material chosen, but should be in the range of 5 to 15 microns, preferably 10 to 60 microns. If the self-tackiness of the reservoir layer is insufficient for a permanent bond with the backing layer, the bonding is accomplished by means of a pressure-sensitive adhesive interlayer, wherein the adhesive forces between the back and intermediate layer must be greater than those between the skin contact surface and the skin. These are all physiologically acceptable, to active substances and other constituents of the reservoir inert adhesive g ^ is, for example, based on rubber, rubber-like synthetic homo-, co- or block polymers, P <yacrylsäure, esters and their copolymers, polyurethanes and silicones. The thickness of the pressure-sensitive adhesive interlayer 10 is preferably between 10 and 100 pm and particularly preferably between 20 and 40 pm. In Aiisführungsformen according to the invention according to principle A- where drug delivery surfaces are arranged in a Hautadhäsionsschicht - it has proved to be advantageous if the adhesion layer is applied to a support layer which is in contact with the active substance reservoir. Arrangements without this support layer are of course possible and may be advantageous for particularly durable drug reservoir layers. The support layer has openings, preferably through pores, which are completely or partially filled to the skin contact surface with a drug delivery composition. Suitable materials for this flexible support layer are, for example, paper, plastic and metal foils or textile fabrics. The layer thickness should be between 5 pm and 2 mm, preferably between 10 pm and 500 pm. If a secure bond between the reservoir and support active layer can not be ensured by the self-tackiness of the reservoir, it can be brought about by attaching an additional pressure-sensitive adhesive layer between the support material and the drug reservoir layer, whereby the adhesive forces within the overall system must be greater than those between the skin contact surface and the skin. The pressure-sensitive adhesive layer may cover the entire contact area between the active substance reservoir and support layer or be limited to the surfaces of the support layer parallel to the skin. The pressure-sensitive adhesive to be used in this case, like the pressure-sensitive adhesive of the intermediate layer between the reservoir and backing layer, must cause a greater adhesion within the system than between the skin and the skin-contacting surface. The thickness of this adhesive layer moves sic ^{u is} preferably between 10 and 100 pm, particularly preferably between 20 and 40μιτι.

To protect the skin contact surface and possibly also to prevent the escape of components of the drug reservoir on the exposed surfaces of the drug delivery area, the system according to the invention is covered on the skin contact side by a detachable before application layer. It may be made of the same materials as used to make the backing layer, provided that they are made releasable, for example, by applying a silicone layer. Other removable protective layers, as are well known to those skilled in the art, are for example polytetrafluoroethylene. Handicrafted paper, cellophane, polyvinylchloride u. Ä. For ease of detachability, the protective layer may be provided in a conventional manner with Abziehhilfen. The thickness of the protective layer is not essential since it does not affect the wearing comfort because of the removal before application. It can usefully be between 10 and 500 μm, preferably between 20 and 150 μm; but it can also be very stiff - to prevent kinking of the system before application.

The inventive method for the preparation of the new therapeutic system is a combination of known process steps. To prepare a therapeutic system according to the invention according to the principle A-isolated active substance delivery surfaces in an adhesion surface-a repellent base is coated with skin adhesive material and coated in a second step, the support layer. The laminate thus obtained is then perforated by known methods, for example by punching or with the aid of a spiked or anilox roller, wherein the geometrically desired openings can be determined by the choice of the tool. In this Perforationsvorgang., Which may possibly also be carried out at elevated temperature, are in each case perforated support and adhesive layer and embossed the repellent pad or even perforated. The latter is removed in a further step and replaced by the removable protective layer. Subsequently, the drug reservoir layer is applied to the perforated Hautadhäsionsschicht side of the laminate in a conventional manner

 If it is applied as a solution, the solvent must be evaporated before further process steps. The

Consistency of the mass applied to the active substance reservoir is initially adjusted so that its complete penetration into the openings of the laminate is ensured. By laminating a possibly provided with a pressure-sensitive adhesive layer (corresponds to the intermediate layer) backing layer, the system is continued. The sheet material obtained in this way can now be made up and packaged, as described above, in consideration of therapeutic requirements.

A preferred development of this method consists in that the active substance reservoir layer is produced on a backing layer, optionally provided with a pressure-sensitive adhesive layer, and applied by laminating under pressure or under pressure and heat to a laminate of support layer and skin adhesion layer.

If an additional pressure-sensitive adhesive layer is necessary for the bond between the reservoir and the proof layer, then this is applied to the support layer before perforation of the laminate of the support and skin adhesion layer. The laminate obtained in this way can be supplied to the perforation directly or after being covered with a redetachable auxiliary layer (for example silicone paper).

Before applying or laminating the reservoir layer, the auxiliary layer is then pulled off again.

When using Stützmateria'ien, which are already provided by the manufacture with suitable openings, such as fabrics (such as woven or nonwoven fabrics) to modify the manufacturing process insofar as in the first step, the support material on one side (for example by spraying) or on all sides (for example by immersion) is provided with a Haftkiebebelag i'nd is placed on the removable protective layer. The further method steps correspond to those shown above after the perforation, wherein an exchange of the repellent base can be dispensed with.

The preparation of planar therapeutic systems according to the principle A without support material layer can be effected by the drug delivery surfaces in the desired arrangement, for example by means of a screen printing process, produced on a protective layer, coated with pressure-sensitive adhesive and covered with the backing layer.

Two-dimensional systems according to the invention according to the principle B - a drug delivery surface interrupted by skin adhesion surface portions - can be produced according to the invention by the combination of the following steps:

Producing Hcutadhäsionsflächen in the desired arrangement by means of, for example, a screen printing on a repellent base, which preferably serves as a protective layer; Coating with drug-containing reset voirmasse; Laminating the optionally provided with a pressure-sensitive adhesive layer backing and packaging. Again, the o.g. Variant of generating the reservoir layer can be selected on a possibly coated with a tack adhesive layer backing layer.

The preferred embodiments of the system according to the invention shown in FIGS. 5 and 6 can likewise be produced by the described methods; wherein in the case of patches according to FIG. 5, only the material applying the skin adhesive material (for example a screen printing stencil) has to be designed accordingly, whereas in the case of patches according to FIG. 6 the perforation tool must be structured accordingly. In both cases, the specified repeat must be taken into account in the case of assembly.

embodiment

The invention will now be explained in more detail with reference to the following examples.

Example ', · Therapeutic system according to principle A:

For the preparation, a layer of an acrylate copolymer solution (DUROTAK 280-2415, National Starch & Chemical 8.V., Netherlands) (solids content: 44%, 93% by weight) is applied by roll application to a paper finished by repellency (grammage: 95 g / m ² ) , 3 parts of acrylate Copoiymer + 6.7 parts of rosin methyl ester in ethyl acetate) was applied in a thickness such that after subsequent drying at 65 ⁰ C, a pressure-sensitive adhesive layer with a basis weight of 44g / m ² results. Pressure-sensitive adhesive side is then laminated a polyamide spunbonded nonwoven fabric with a basis weight of 33g / m ² and the laminate fed to a heated anilox roller of a stamping calender. The anilox roll is designed as follows: staggered rows voi. Truncated pyramids at a clear distance of 2 mm; clear distance of the stumps within a row: 2.5 mm; diamond-shaped base of the stumps: 2.7 mm ² ; diamond-shaped head surface of the stumps: 0.48mm ² ; Height of the stumps:

0.85 mm. The perforation is carried out at 280 ° C and provides a laminate in which the nonwoven fabric and pressure-sensitive adhesive layer in regular arrangements perforations with a total proportion of 9% of the total area. The silicone paper is peeled off and a siliconized polyester film (basis weight: 145 g / m ² ) is allowed to run in.

32.5 parts of a copolymer based on methacrylic acid esters and dimethylaminoethyl methacrylate (EUDRAGIT E, Fa. Röhm Pharma, FRG) are dissolved in 32.5 parts of methanol and 30 parts of a mixture of toluene 2-octyldodecanol (1: 1) added. Subsequently, 20 parts of the active ingredient 4- (1-methyl-4-piperidylindene) -4H-benzo 4,5 cyclohepta 1,2-b thiophene-10 (9H) -on-hydrogen fumarate (ketotifen-HFU) are added and dissolved.

The viscosity of the mass is adjusted to 0,!> 5dPa.s with methyl ethyl ketone. The mass application to the non-adhesive side of the above-prepared perforated nonwoven laminate erfo gt by means of a roller in a layer thickness that after subsequent drying at 65 ° C, a reservoir layer of 44g / m ^{2 is} obtained.

The pressure-sensitive adhesive backing layer is prepared by treating a siliconized paper with an acrylate copolymer solution (DUROTAK 280-2416, National Starch & Chemical BV, The Netherlands) in ethyl acetate (solids content: 41%) and laminating it after drying at 65 ° C obtained, 30 g / m ² pressure sensitive adhesive layer on an aluminized polyester film (basis weight: 20g / m ^? ) Made. Subsequently, it is laminated to the laminate of reservoir layer, nonwoven fabric and pressure-sensitive adhesive layer on the open side.

In the subsequent assembly, the patch sections are punched out of the obtained web material so that they correspond in size to the therapeutic requirements. By punching the protective layer over the corner, a removal aid for the protective layer can be created.

The packaging can be done for example in suitable sealed bags.

Example 2: Preparation of a Bopindolol HMO Patch:

The preparation of the therapeutic system is analogous Beispie! 1, except for the preparation and composition of the drug reservoir mass. It is obtained here by dissolving 30.6 parts by weight of a methacrylic ester / dimethylaminoethyl methacrylate copolymer (EUDRAGIT E, Röhm Pharma, Germany), dissolved in 30.6 parts by weight of tetrahydrofuran, adding 25 parts by weight of (±) -l- (tert. Butylamino) -3 - [(2-methyl-1H-in-dol-4-yl) oxy) -2-propanol-benzoate hydrogenmalonate (Bopindolol-HMO), 3.75 parts by weight of malonic acid and 10 parts by weight of 2-octyldou'ecanol and adjusting the viscosity by means of methyl ethyl ketone to 0.55dPa.s.

Example 3: In-vitro release of drugs from the therapeutic system:

Each 16m ² punched sheet of the product produced according to Example 1 and 2 is reinforced as a therapeutic system with a single-sided adhesive plastic film on the backing layer and exposed in each case at 37 "C an acceptor medium (80 ml of physiological saline), so that a The acceptor medium is renewed after 2,4,8 and 24 hours after the beginning of the insertion of the diecut into the physiological saline solution.The quantitative determination of d (released active ingredients is carried out photometrically, Di9 ketotifen -HFU concentration is determined by measuring the UV-abcrption at 265 nm and in bopindolol-HMU by measuring the UV-absorption at 265nm.

The results of this photometric study are shown in Figure 7, with the amount of drug released being plotted in% across the cell. It can be seen that the release kinetics are the same for both active ingredients, but due to the different physicochemical properties of ketotifen-HFU and bopindolol-HMO quantitatively different amounts of active ingredient are released as a function of time. However, both curves clearly show that there is controlled drug release over 24 hours.

Example 4: Ketotifen-containing system according to principle B of the invention:

A double-sided differently siliconized polyester film having a basis weight of 145 g / m ² is screen-printed with an aqueous dispersion of a carboxyl-containing acrylate copolymer (ACRONAL 80 D, BASF, Ludwigshafen) (solids content: 56%), with a thiurethane-based thickener on a viscosity of 8 Pa.s has been adjusted coated. The sieve drum is equipped with 1.5mm diameter holes with an average clearance of 3.7mm and an open area of 16.7%. On the film arise analogous to the screen drum arranged adhesive dots, which after drying at 65 ° C have a basis weight of 30g / m ² . In a further coating of the product by roll application, the keto-tifen-containing reserve composition described in Example 1 is applied. The process is continued as in Example 1.

Example 5: Preparation of a Bopindolol System According to Principle B of the Invention:

As described in Example 3, a therapeutic system according to the invention is prepared, wherein the drug reservoir mass described in Example 2 is applied.

Example 6: Production of a Therapeutic System with Different Active Agents in Skin Adhesion Sections and Drug delivery sections

A drug-containing system as described in Example 4 is prepared using lanata-β-acetyldigoxin in the acrylate system as a reservoir and nitroglycerin in the skin adhesion section.

Claims (23)

1. A surface-shaped therapeutic system for the administration of active substances to the skin, with active substance reservoir (s) having active substance delivery surfaces and skin adhesion surface sections arranged on the skin, characterized in that the active substance delivery surface sections (2, 8, 13) to be brought into contact with the skin the skin-side skin adhesion surface portion (s) (1,7,12) are at the same level. A sheet-like therapeutic system according to claim 1, characterized in that said drug delivery surface portions (2, 8, 13) are evenly or non-uniformly distributed in the skin contact surface. 3. A sheet-like therapeutic system according to claims 1 or 2, characterized in that the drug delivery surface sections (2, 13) are round or angular. 4. area-shaped therapeutic system according to claim 1, characterized in that in the skin-contact surface Hautadhäsionsflächenabschnitte (7,12) are regularly or irregularly distributed. 5. Area-shaped therapeutic system according to claim 1, characterized in that the Hautadhäsionsflächenabschnitte (7,12) are round or square. 6. A surface-shaped therapeutic system according to claim 1, characterized in that Hautadhäsions- and Wirkstoffabgabeflächenabschnitte are arranged in strips alternately. 7. The surface-shaped therapeutic system according to claims 1 to 5, characterized in that the skin-contact surface has a peripheral Hautadhäsionsrand. 8. A sheet-like therapeutic system according to one of the preceding claims, characterized in that it further comprises a skin-facing flexible backing layer (9) and optionally a removable protective layer. 9. The surface-shaped therapeutic system according to one of the preceding claims, characterized in that it has a pressure-sensitive adhesive interlayer (4; 10) between the backing layer (9) and the drug reservoir (11; 5). 10. A sheet-like therapeutic system according to one of the preceding claims, characterized in that it comprises an apertured support layer (6) in contact with the drug reservoir (5). A sheet-like therapeutic system according to claim 10 or 11, characterized in that the support layer (6) consists essentially of paper, a textile fabric, a metal or a plastic film or laminates thereof. 12. A planar therapeutic system according to claim 10 or 11, characterized in that between the support layer (6) and active reservoir is wholly or partially a pressure-sensitive adhesive layer. 13. A sheet-like therapeutic system according to one or more of the preceding claims, characterized in that it contains a drug reservoir for the absorption of one or more active substances with topical or systemic action contains. 14. A surface-shaped therapeutic system according to claim 12, characterized in that it comprises a drug reservoir for the uptake of at least one active substance selected from the group of cardiac glycosides, vasodilators, musculotropic spasmolytics, coronary therapeutic agents; coronary dilators, antihistamines, analeptics, analgesics, antipyretics, hypnotia, anesthetics, antiseptics a musculotropic vasodilator, lipid-lowering drugs or vitamin B 6; Broncholytica, Cardiaca, diuretica, Phosphordiesterasehemmer, theophylline, its compounds and derivatives and Rubefazientes, including in the form of free bases, salts or derivatives thereof. 15. The surface-shaped therapeutic system according to claim 14, characterized in that it comprises an active substance reservoir for the absorption of active ingredients selected from the group consisting of amphetaminil, betahistine, beta-acetyldigoxin, bopindolol, buprenorphine, clemastine, diclofenac, diltiazene, dimenhydrinate, diethylamine salicylate, Ethylene glycol monosalicylate, 5-fluorouracil, glibenclamide, hydromorphone, ibuprofen, isopropyl-4- (2,1,3-benzoxydiazol-4-yl) -1 adihydro-B-methoxycarbonyl ^ -dimethyl-S-pyridinecarboxylate, ketotifen, L Thyroxine, nicotine, nicotinic acid β-butoxyethyl ester, nonyl acid vanillylamide, pindolol, salbutamol, tamoxifen,) tizanidine, theophylline. 16. A sheet-like therapeutic system according to any one of claims 14 or 15, characterized in that it comprises an active substance reservoir for the inclusion of a combination of a cardiac glycoside from Digitalis lanata ß-acetyl digoxin in combination with: a vasodilator, a musculotropic spasmolytic, a Coronartherapeuticum or a coronary dilator. 7. A planar therapeutic system according to one of claims 14 or 15, characterized in that it comprises an active substance reservoir for administration a combination of: an antihistaminicum with a glucocorticoid, preferably of clemastine with dexamethasone or collocortolone-21-pivalate or an antihistaminicum, preferably comprises antiemetic dimenhydrinate with a vasodilator, an analpticun, a hypnotic, a musculotropic vasodilator or a vitamin B 6. A sheet-like therapeutic system according to any of claims 14 or 15, characterized in that it comprises a drug reservoir for receiving a combination of: a broncholytic, cardiac, diuretic, phosphodiserease inhibitor, such as theophylline, with other theophylline compounds or theophylline derivatives , 19. A sheet-like therapeutic system according to any one of claims 14 or 15, characterized in that it comprises a drug reservoir for the uptake of Rubefaziens, such as nicotinic ßbutoxyethylester and / or Nonylsäurevanillylamid in combination with an antiphlogistic, such as ethylene glycol monosalicylate or Diethylaminsalicylat having. 20. A sheet-like therapeutic system according to one of the preceding claims, characterized in that a drug reservoir for the reception of at least one first active substance and a Hautadhäsionsflächenabschnitt (s) for the inclusion of one or more further active ingredients. 21. A sheet-like therapeutic system according to any one of claims 1 to 13, characterized in that it has skin adhesion portion (1,7,12) for the uptake of nitroglycerin as an active ingredient. 22. A method for producing the sheet-like therapeutic system, characterized by: presenting a repellent pad, creating a skin adhesion layer on the pad; Laminating a support material; Perforation of the laminate thus formed; Replacement of the repellent backing with a removable protective layer; Coating of the protective layer-free surface with active substance-containing reservoir mass; Laminating the optionally pressure-sensitively coated backing layer and assembly. 23. The method according to claim 22, characterized in that after the perforation of the laminate, a coating with the active substance-containing Reservoirmasss is performed by lamination with a drug-containing reservoir layer produced on the backing layer under pressure or under pressure / heat. The method of claim 22, characterized by: applying skin adhesion layer portions to a protective layer pad; Boschichten der Hautadhäsionsschichtabschnitte and protective layer underlay with active substance-containing Reservoirmasse; Laminating the optionally pressure-sensitively adhesive backing layer; and packaging. For this 4 pages drawings