SI8710679A - Flat therapeutic assembly - Google Patents

Abstract

The invention relates to a flat therapeutic assembly of one flexible carrier layer, one or more reservoirs for active substance, one or more adhesive layers, and in the given case one removable protective layer for the surface for contact with the skin of a flat therapeutic assembly, at making the skin contact surface therapeutic of a skin contact layer having one or more non-sticky layers for carrying the active substance and one or several sticky layers to connect to the skin that have in if any other active substance. This flat the therapeutic set is used locally or systemically application of the active substance through the skin in human medicine or veterinarians or cosmetics.

Description

Flat therapeutic assembly

FIELD OF THE INVENTION

The invention relates to the field of devices for introducing medicinal substances through the skin. Designation according to the International Classification of Inventions: A 61M 37/00.

A technical problem

The invention solves the problem of how to make a device for applying active substances to the skin, which, regardless of the required size of the surface of the transfer of the active substance, even at longer wearing times of the device, will ensure a lasting touch of the surface of the transfer of the active substance to the skin.

The state of the art

Kits for the application of active substances to the skin are precision instruments whose construction requires specific measures to be taken to ensure the continuous transfer of the active substance.

Therapeutic kits have been developed for a variety of uses, so that both local and systemic action can be achieved on the skin. The variety of active substances that can be used (applied) in this way, as well as their different chemical, physical and pharmacological properties make it impossible to solve all the problems posed by a single set.

A number of flat therapeutic kits are known for the application of medically active substances to the skin, and one overview of these kits can be found in Klaus Heilmann's book:

The Therapeutische Systeme (Edition): Ferdinand Enke Verlag, Stuttgart, 1977. The assemblies according to the present state of the art cannot give satisfactory results in all cases.

The usual construction of such a therapeutic assembly acting through the skin is a drug reservoir in which the active substance is in a solid, liquid or dusty state, as well as a pressure-bonding adhesive layer which firmly binds skin.

This principle is not applicable where the active substance cannot diffuse through the adhesive layer, or where a chemical reaction occurs between the active substance and the adhesive, or where the active substance is not soluble in the adhesive or only dissolves therein. In such cases, we attempt an adhesive reservoir containing the active substance or bring the active substance into direct contact with the skin, with that reservoir or active substance attached to the skin with additional measures. Special adhesive tapes or integration of the reservoir or active substance into the patch are suitable for this purpose, such that the reservoir or active substance is ringed along the entire circumference with the adhesive edge (see, e.g., DE-OS 29 02 183). If the surface of the contact exceeds a certain size, due to the inevitable movements of the body and muscles, we cannot maintain lasting contact with the skin, which is necessary for targeted therapy and which needs to be maintained for longer periods of days and weeks.

DE-OS 32 02 775 proposes to distribute the active substance mesh over the adhesive surface. The adhesive surface is generally large enough to attach the active substance to the skin and should theoretically allow a flat attachment of the active substance reservoir. However, since the active substance on the adhesive layer is not on par with this layer, it is constantly energized after being applied to the skin. Due to the inevitable movements of the body and muscles, the glued sites are very easily separated, which in the case of pressure changes adversely affects the permanent contact of the surface of the active substance with the skin, thus preventing any regulated transfer of the substance.

DE-OS 34 23 328 discloses a self-adhesive patch with separate segments of the active substance, in which the active substance segments and segments of the adhesive material are arranged on a non-sticky substrate in the form of a ball section. This results in the adhesive segments and the active substance segments having the same height. When using a patch, the size of skin contact segments and therefore the amount of active substance that will be transferred depends on the pressure on the patch. As a therapeutic assembly, this patch is useless.

DE-OS 33 19 469 proposes that the active substance be deposited in the pores of microporous foil, which may be partially or completely coated with a layer of adhesive to attach to the skin. Even in this embodiment, the contact of the active substance in the openings of the pores with the skin is threatened, since the openings of the pores do not lie on the same level with the areas where the adhesive is applied, and thus the contact between the active substance and the skin surface prevents the adhesive layer. Regular application of the active substance is also impossible with this system.

Description of solution to a technical problem

It is therefore an object of the invention to provide a flat therapeutic assembly for the application of the active substances to the skin, which, regardless of the required surface size, the transfer of the active substance will also ensure a permanent contact of the surface of the transfer of the active substance to the skin even at longer wearing times.

This objective is addressed by the flat therapeutic assembly of the type described above, in which the portions of the surface of contact that come in contact with the skin are at the same level. The assembly of the invention is particularly suitable for the application of active substances that either react badly with the adhesive or do not diffuse through the skin adhesive layer.

In one suitable development of the invention, portions of the surface for carrying the active substance are distributed evenly or unevenly over the skin contact surface. It may be advantageous for the portions of the surface to carry the active substance to be round or polygonal. Sections of the skin adhesive surface may be distributed evenly or unevenly over the skin contact surface. Portions of the surface for adhesion to the skin may be round or polygonal. For certain applications, it may be particularly advantageous for sections of the surfaces for adhesion to the skin and for the transfer of the active substance to be made in the form of alternately arranged strips. The skin contact surface may, in one suitable embodiment of the invention, have an adhesive skin-binding edge throughout the scope. The assembly of the invention may further have, on the side opposite to the skin, a flexible support layer, and optionally a removable protective layer. In addition, to enhance mechanical stability, a reinforcement layer may be provided with openings. The reinforcement layer may consist of paper, some flat textile material, metal or plastic foil, or laminates thereof. A layer of adhesive can be completely or partially applied between the reinforcement layer and the active substance reservoir. An active substance reservoir may contain one or more active substances with local or systemic action.

It is preferred that the active substance or substances be selected from cardiac glycosides from digitalis lanate-1S-acetyldigoxin, vasodilators, e.g. pentaerythrityltetranitrate, cinarizine or nitroglycerin, musculotropic spasmolytics such as moxaverine HCl, coronary therapists such as oxyphedrine HCl, coronary dilators such as N- (3,3-diphenylpropyl) -alpha-methylbenzylamine HCl (anti-phenylethaminin HCl) , analgesics such as caffeine, analgesics such as phenazone chloral hydrate, hypnotics such as chlorobutanol, musculotropic vasodilators such as nicotinic acid, vitamin B6 as pyridoxine, bronchodilators, cardiac, diuretics, soophylinetin compounds, theophylinetin, integrinophilinase compounds sodium glycinate, theophylline sodium salicylate, as well as theophylline derivatives, bromteophylline, chloroethophylline, ethaminphylline, diprophilin ethodylin and poxifylline, as well as rubefaciens, such as nicotinic acid / 3-butoxyethyl ester, ethyl ester, butyloxymethyl, butyl Suitable active substances are amphetaminyl, betahistine, beta-acetyldigoxin, bopindolol, boprenorphine, clemastine, dichlorophene, diltiazen, dimenhydrinate, diethylaminosalicylate, ethylene glycol monosalicylate, 5-fluorouracil, glibenclamide, hydromorbopropyl, hydrochromophenyl, hydrochloride, hydrochloride, hydrochloride, hydrochloride, hydrochromic acid -4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine-carboxylate, ketotifen, L-thyroxine, nicotine, nicotinic acid 3-butoxyethyl ester, vanillylamide nonylic acid, pinodol, salbutamol, tamoxifen , tizanidine, as well as their bases, salts and derivatives. The active substances can be combined into suitable combinations, with the following recommended:

A. Cardiac glycoside digitalis lanata- / 3-acetyldigoxin in combination with

-1. single vasodilators, such as pentaerythrityl tetranitrate or nitroglycerin

-2. a single musculotropic spasmolytic, such as moxaverine HCl

-3. to one coronary therapist such as oxyphedrine HCl, or

-4. to one coronary dilator such as N- (3,3-diphenylpropyl) -alpha.-methylbenzylamine HCl (fendilin)

B. Antihistamine, clemastine, in combination with a single glucocorticoid, such as dexamethasone or clocortolone-21-pivalate.

C. An antihistamine such as the anti-emetic dimenhydrinate combined with one

-1. vasodilators, antihistamines, such as cinarizin,

-2. analeptic, such as caffeine,

-3. analgesics, antipyretics, such as phenazone chloral hydrate,

-4. hypnotics, anesthetics, antiseptics, such as chlorobutanol,

-5. musculotropic vasodilators, lipid-lowering agents such as nicotinic acid, or

-6. vitamin B6, for example pyridoxine.

D. Bronchodilator, cardiac, diuretic, phosphodiesterase-theophylline inhibitor, in combination with other

-1. theophylline compounds such as choline-theophylline theophylline-ethylenediamine theophylline sodium glycinate theophylline sodium salicylate, or

-2. theophylline derivatives such as bromteophilin chloroethophylline ethaminphilin dipropphilin ethophilin proxyphilin.

E. Rubefaciens, such as nicotinic acid / 3-butoxyethyl ester and / or vanilylamide nonylic acid, in combination with a single antiflogistic agent, for example ethylene glycol monosalicylate or diethylamine salicylate.

A particular advantage that can be achieved with such combinations of active substances is that, ideally, more active substances, optionally at different rates of delivery, can be applied simultaneously, but which cannot be processed or stored in the form of a mixture, or due to the interaction, or due to different physical properties. The production phases, which will be explained later, make it possible to carry out a separate application of the active substances without difficulty.

Particularly suitable active substances for use in the assembly of the invention are the following:

anfetamilin, betahistine, / 3-acetyldigoxin, bopindolol, buprenorphine, clemastine, diltiazen, dimenhydrinate, diethylaminesalicylate, ethylene glycol-monosalicylate, 5-fluorouracil, glibenclamide, hydromorphone, ibuprofil, 4-benzophenol, 4- il) 1,4-dihydro-5-methoxy-carbonyl-2,6-dimethyl-3-pyridinecarboxylate, ketotifen, L-thyroxine, nicotine, nicotinic acid / 3-butoxyethyl ester, vanillylamide of nonyl acid, pindolol, salbutamol, tamoxinen, tizanidine , theophylline, as well as the bases, salts and derivatives of the aforementioned active substances.

Since, according to the invention, the therapeutically necessary surface for carrying the active substance alternately with the adhesive surfaces in one plane can be created, a sufficiently long tight contact of the reservoir for transferring the active substance to the surface of the host receiving the active substance is ensured, thus ensuring a continuous supply of the active substance, is therapeutically desirable.

Hereinafter, the invention will be explained with embodiments and with reference to the accompanying drawings, where:

- Figure 1 schematically shows a skin contact area of a section of a flat therapeutic assembly of the invention,

- Figure 2 shows, on an enlarged scale, the section along line I-I of Figure 1,

- Figure 3 shows one section of the skin contact surface of another embodiment of the invention,

- Figure 4 schematically shows, on an enlarged scale, the section along line II-II of Figure 3,

- Figure 5 shows a skin contact of one embodiment in the form of a patch of the present invention,

- Figure 6 shows the contact surface with the skin of another embodiment of the invention in the form of a patch,

- Figure 7 shows the in vitro release of ketotifen and bupindolol from the therapeutic assembly of the invention.

According to the invention, the skin contact layers are divided according to two basic principles;

Principle A

The active substance transfer surfaces are scattered or dispersed in the adhesive surface to the skin, which may also contain the active substance.

Principle B

The transfer surface of the active substance is interrupted by the adhesive surface to the skin, which may also contain the active substance.

Embodiments of the invention according to principle A are shown in Figures 1, 2 and 6, while Figures 3,4 and 5 show embodiments corresponding to principle B.

In Figures 1 and 2, circular surfaces 2 are arranged symmetrically on the adhesive surface 1 for carrying active substances. It is to be understood that this embodiment is taken by way of example only and is not intended to limit the object of the invention, since the arrangement of the surfaces for carrying the active substance, their size, geometric shape, as well as their mutual distances may vary and depend on the therapeutic and physical requirements and needs.

Figure 2 shows a cross-section along line I-I in Figure 1. An adhesive layer 4 is provided below the carrier layer 3 to provide a connection to the reservoir layer 5 for the active substance. The reservoir layer 5 is covered by a perforated protective layer 6 having a layer 1 for adhesion to the skin on the side facing the skin. The holes formed by the perforation are completely filled with the material of the reservoir 5 of the active substance, which here also forms sections 2 for the delivery of the active substance, so that on the surface of the skin contact they alternate at the same level of the surface 2 for carrying the active substance and the surface 1 for gluing to the skin.

Figure 6 shows one embodiment in the form of a patch of principle A, wherein the individual surfaces for carrying the active substance as a circular point are arranged symmetrically in the central part of one otherwise tacky patch-shaped section. A continuous adhesive edge 12 is provided in the edge region in scope, which, when used, provides a reliable adhesion of the patch to the skin along its edges.

3 and 4 show preferred embodiments of Principle B. In this case, the surface 8 of the active mass transfer is interrupted by symmetrically arranged hexagonal sections 7 for adhesion to the skin. Here, too, the layout of the adhesive areas, their distance, size and geometric shape are variable and can be changed depending on the production needs. The construction of the skin contact surface shown in Figure 3 for the assembly shown is derived from the section along line II-II of Figure 3, which is shown in large scale in Figure 4. An adhesive interlayer 10 is applied to the support layer 9, which is in contact with the reservoir layer 11. The adhesive points 7 on the skin are to a certain extent lowered into the reservoir layer 11 and in the same plane with the surface of the reservoir 8 they adhere to the skin. In this way, the adhesive points 7 are surrounded by a surface 8 for carrying the active substance.

Figure 5 shows another embodiment of principle B of the invention in the form of a section prepared in the form of a patch for use. In this case, the sections for adhesion to the skin are indicated by 12 and the surfaces for carrying the active substance by 13. In this embodiment, the surface of transfer of the active substance is symmetrically intersected with square points of adhesion to the skin and is surrounded on all sides by a circumferentially arranged adhesive edge at skin. It is particularly advantageous here to eliminate the problem of edge bonding in the patch-forming systems of the present invention.

The new flat therapeutic assemblies according to the invention have very different applications since, from the standpoint of particular embodiments, such as e.g. those shown in Figures 5 and 6 are made as a piece of fabric without a woven pattern and can therefore be divided into almost any shape. They can be used in the form of patches, ribbons and even bandages. By deliberately dividing the tape, edges that are not completely coated with adhesive may appear. For this reason, special care must be taken to ensure that the cutting lines always run through adhesive tapes, rings and the like.

The sections where there is no adhesive for attachment to the skin can be kept small by a special selection of geometric shapes of the assemblies so that even when wearing the patch for a long time, the edges are not peeled off. The surface area of the acceptable non-adhesive section depends on the selection of adhesive material for attachment to the skin. In this connection, a therapeutic assembly in which the surface of the transfer of the active substance is formed in the form of a strip on the surface of the adhesive for contact with the skin and / or skin, is emerging as a special example. is the surface of the adhesive for bonding to the skin in the form of a strip in the surface for transmitting the active substance. Here, the cutting edge should lie inside with the adhesive coated tape exclusively parallel to the direction of the tape, thereby expelling the edge completely without adhesive in this direction.

The new assembly is particularly suitable for the application of medical or cosmetic active substances to the skin, which cannot be used or difficult to use from adhesive-containing assemblies. It can also be used for any easily-used active substances that can penetrate the skin alone or with excipients.

It has already proved that the assembly is particularly suitable for the application of active substances such as e.g. ketotifen or bopindolol.

The reservoir layer for the active substance can be manufactured in a known manner, e.g. by dissolving the active substance in a matrix, dispersing the active substance in a matrix, or distributing the active substance in a microcapsulated matrix form, by introducing the active substance adsorbed onto an inert carrier into a matrix. In any case, the reservoir of the active substance may consist of pure active substance or substantially active pure substance. The matrix itself may consist of low or high molecular weight natural or synthetic materials, and its selection is determined by the properties of the active substance being applied and the therapeutic requirements known to those skilled in the art. Particularly good for ketotifen and bopindolol is the polyacrylate-based matrix which can swell in water.

The reservoir layer for the active substance may, in addition to the matrix components and the active substances, also contain other additives known to the person skilled in the art, such as e.g. dissolving agents, plasticizers, stabilizers, fillers and accelerators. The thickness of the reservoir layer, i.e. the distance between the reinforcing layer and the adhesive coated carrier layer is determined primarily according to the therapeutic requirements that are set for the assembly. Preferably, the total system thickness is between 40 μπι and 5 mm, preferably between 80 μπι and 1.2 mm. In special cases, the reservoir consists of only fully or partially filling the openings in the form of pores in the laminate formed by a reinforcement layer and a layer of adhesive that adheres to the skin so that the adhesive-coated carrier layer is directly connected to the reinforcement layer. Even in this embodiment, the surface of the transfer of the active substance is in the same plane with the surface of the adhesive for skin bonding, which is required by the present invention.

The carrier layer that covers the tank from the side opposite to where the skin is may be permeable or impermeable. It must be flexible and primarily serve to further mechanically stabilize the assembly. If the parts of the tank or the active substance being applied are volatile, the support layer for these materials must be impermeable. It can be multi-layered. Substances that can be used for its manufacture are polymeric materials such as polyethylene, polypropylene, polyethylene terephthalate and polyamide. Metal materials can be used as other materials, e.g. aluminum foil, alone or coated with a polymer base. Permeable carrier layers are flat textile products such as fabrics and nonwovens or porous polymeric materials. The required thickness of the support layer depends on the material selected, but should be in the range of 5 to 150 μπι, preferably between 10 and 60 μπι. If the inherent adhesiveness of the reservoir layer is not sufficient to permanently adhere to the carrier layer, the bonding is achieved by adhesive interlayer, with the adhesive force between the carrier layer and the interlayer being greater than that between the skin and skin contact surface. For this purpose, all physiologically neutral inert adhesives are suitable with respect to the active substance and other components of the tank, e.g. adhesives based on rubber, rubber-like homopolymers, copolymers or block copolymers, polyacrylic acid, esters and their copolymerizates, polyurethane and ioO silicone. The thickness of the adhesive layer 10 is between 10 and 100 gm, preferably between 20 and 40 μτη.

In carrying out the invention according to principle A, according to which the surfaces of the transfer of the active substance are arranged in a layer of adhesive for attachment to the skin, it has proved advantageous to apply a layer of adhesive to a reinforcement layer which is in contact with the reservoir of the active substance. In any case, structures without this reinforcement layer are possible and may be preferred to particularly persistent reservoir layers for the active substance. The reinforcement layer has openings, preferably open pores, which are filled, in whole or in part, with the mass of the transmitted active substance to the skin contact surface. As materials for this flexible reinforcement layer, paper, plastics and metal foils or flat textiles are appropriate. The layer thickness should be between 5 μτη and 2 mm, preferably between 10 μτη and 500 μτη. If a secure joint cannot be created between the active substance reservoir layer and the self-adhesive reservoir reinforcement layer, this joint can be made by applying up to one additional layer of adhesive between the reinforcing material and the active agent reservoir, with the adhesive force inside the whole assembly larger than that between the skin and skin surface only. The adhesive layer may cover the entire contact surface between the active substance reservoir layer and the reinforcement layer, but may be limited to the surfaces of the reinforcement layers parallel to the skin. Both the prepared adhesive and the adhesive between the layers between the reservoir and the support layer must create greater adhesion within the system than that between the skin and the skin contact surface. The thickness of this adhesive layer ranges between 10 and 100 / xm, preferably between 20 and 40 μτη.

In order to protect the skin-contacting surface and optionally prevent evaporation of the components of the active substance reservoir from the open surface for carrying the active substance, we cover the assembly of the invention on the skin-contacting surface with a layer that it can be removed before use, application, assembly. It can be made from the same material that is used to make the carrier layer, provided that it is designed to be removable, e.g. by applying a layer of silicone. Other removable layers are, as is well known to any person skilled in the art, e.g. polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride and others. For ease of decision, one can predict an otherwise known drag element on the protective layer. The thickness of the protective layer is irrelevant, since it is removed prior to application and does not affect the wearing comfort. It is acceptable that it is between 10 and 500 μτη, preferably between 20 and 150 μτη, but it can be very rough to avoid twisting the assembly prior to installation.

The process of the invention for the production of a new therapeutic assembly is a combination of known steps or stages. In order to produce the therapeutic assembly of the invention and according to the principle of A (single surface transfer of the active substance in the adhesive surface), the base, which is neutral, is first coated with a layer of skin adhesive and then, in the second stage, a reinforcement layer is applied thereto. The laminate thus obtained is then by some known process, e.g. by punching or by means of a perforation roller or a roller with a mesh surface, perforate, providing the desired geometric shape of the openings by selecting the tool. In this process of punching or. perforations, which can also be carried out at elevated temperatures if necessary, will in each case be reinforced and the adhesive layer perforated together and the neutral base will be either embossed or perforated. Later, in one of the following working operations, the liner is removed and replaced with one equally removable protective layer. Finally, a reservoir for the active substance is applied to the perforated side of the laminate, which has an adhesive layer for skin bonding.

When applied as a solution, the solvent must be evaporated before the next steps of the process. The consistency of the mass applied to the fabrication of the active substance reservoir must be adjusted to ensure that it is fully penetrated into the laminate openings. By adhering the carrier layer, which is optionally coated with a sticky layer (corresponding to the interlayer), the assembly will be completed. In this way, the fabricated material can be ready-made and packaged, as described above, in accordance with the therapeutic requirements.

A further development of this process consists in the fact that the reservoir layer for the active substance is carried out on a carrier layer, optionally coated with a layer of adhesive and then glued under pressure, or under pressure and by heating, to a laminate made of openings made of openings. reinforcement layers and adhesive layers for skin bonding.

If an additional layer of adhesive is required to bond the reservoir layer to the reinforcement layer, it should be applied to the reinforcement layer before perforating the laminate from the protective layer and the adhesive layer to bond to the skin. Perforations can be made directly on the laminate made in this way, or after being covered with another removable auxiliary layer (eg silicone paper).

Before applying or pasting the reservoir layer, the auxiliary layer will be removed.

When using reinforcement material, which is made with suitable openings before production, such as flat textile products (eg fabrics or nonwovens), the manufacturing process is modified in such a way that during the first stage the reinforcing material is coated or from one sides (eg by spraying) or double-sided (eg by dipping) with a sticky liner to which a removable protective layer is also fitted. The following steps of the process correspond to those described after perforation, and a neutral substrate can also be replaced.

The production of a flat therapeutic assembly according to principle A can be carried out without a layer of reinforcing material by producing the surface of the transfer of the active substance in the desired form, e.g. Using a screen printing process, on the protective layer, cover it with a layer of glue and cover it with a carrier layer.

Flat assemblies according to the invention and according to principle B (the transfer surface of the active substance is interrupted by sections of the adhesive surface on the skin) according to the invention can be made by a combination of the following steps:

Making the surface for adhesion to the skin of the desired shape by e.g. a screen-printing process on a neutral basis that serves primarily as a protective layer. Coating it with a reservoir containing the active substance. Adhesion of the carrier layer, optionally with adhesive layer and ready-to-wear. Here again, a previously described variant of manufacturing a reservoir layer on a carrier layer, optionally made with a layer of adhesive, may be selected.

In the embodiments of the assemblies according to the invention shown in Figures 5 and 6, they can be manufactured according to the procedures described, whereby in the patches according to Fig. 5 the adhesive application device for skin bonding (eg screen printing template) must be appropriately shaped while for the patch of Figure 6, the perforation tool must be properly structured. In both cases, we need to take into account the existing pattern of weaving.

The invention will be more specifically explained by the following examples.

Example 1:

Principle A therapeutic assembly:

In the manufacture is applied by means of the cylinder to the paper with a silicone layer of a neutral (area weight: 95 g / m ²⁾ a layer of an acrylate copolymer solution (280 DuroTak 2415, National Starch & Chemical BV, Netherlands) (solids content: 44%;

93.3 parts of acrylate copolymer + 6.7 parts of rosin methyl ester in ethyl acetate), the thickness of which is such that, after drying at 65 ° C, a layer of adhesive with a mass per unit area of 44 g / m ^{2 is} formed. Glue a polyamide non-woven fabric to the adhesive side with a mass per unit area of 33 g / m ² and then bring the laminate to a heated cylinder with a mesh surface of the embossing calender. The mesh surface cylinders are made as follows: inter-displaced rows of cropped pyramids at a distance of 2 mm, with the distance of cropped pyramids in a single row 2.5 mm, the rhomboid lower surface of the cropped pyramid has a surface of 2.7 mm ² , the rhomboidal upper the surface of the trimmed pyramid is 0.48 mm ² , the height of the trimmed pyramid is 0.85 mm. The perforation is carried out at 280 ° C to obtain a laminate in which the non-woven material and the adhesive layer have uniform perforations with a total proportion of about 9% of the total surface area. The silicone paper is removed and the siliconized polyester film (weight per unit area of 145 g / mm ² ) is glued.

32.5 parts of copolymerisate based on methacrylic acid ester and dimethylaminoethyl methacrylate (EUDRAGIT E, Rohm Pharma, Germany) are dissolved in 32.5 parts of methanol to make a reservoir mass and 30 parts of toluene are added

2-octyldodecanol (1: 1). Finally, 20 parts of the active substance 4- (1-methyl-4-piperidylindene) -4H-benzo 4,5 cycloheptane-1,2-b-thiophene-10 (9H) -one-hydrogen fumarate (ketotifen-HFU) are introduced and dissolved. The viscosity of the mass was adjusted with methylethyl ketone to 0.55 dPa.s. The application of the mass to the non-stick side of the perforated laminate described with non-woven material is carried out by means of a cylinder so that after drying at 65 ° C a reservoir layer of 44 g / m ^{2 is} obtained.

The adhesive layer-derived support layer is made by coating siliconized paper with an acrylate copolymer solution (DOROTAK 280-2416, National Starch & Chemical BV, The Netherlands) in ethyl acetate (dry matter content of 41%) and gluing the adhesive layer, which, after drying to 65 ° C Weight 30 g / m ² , on aluminised polyester film (weighing 20 g / m ² ). Finally, it is glued to the open side of the laminate from the reservoir layer, non-woven material and the adhesive layer.

In the ready-to-wear apparel, the patch pieces of the patch material obtained are cut out to suit the size of the therapeutic requirements. By cutting the protective layer over one corner, an element can be made to pull the protective layer.

The packaging can be done in suitable bags, which are closed by welding.

Example 2:

Production of Bopindolol-HMO patch:

Manufacturing of the therapeutic assembly is carried out prior to the manufacture and assembly of the reservoir mass of the active substance analogous to example 1. Here it is made by dissolving 30.6 parts by weight of the methacrylic acid ester (dimethylaminoethylmethacrylate copolymerizate) (EUDRAGIT E, Rohm Pharma, Germany) in 30.6 parts by weight tetrahydrofuran, 25 parts by weight of (±) -1- (tert-butylamino) -3 - [(2-methyl-1H-do-4-yl) oxy] -2-propanol-benzoate-hydrogenmalonate (Bopindolol-HMR) are added. 3.75 parts by weight of malonic acid as well as 10 parts by weight of 2-octyldodecanol and the viscosity was adjusted to 0.55 dPa.s. with methylethyl ketone.

Example 3:

In vitro release of the active substance from the therapeutic assembly:

One 16 m ² large section of piece goods made according to examples 1 and 2 is strengthened as a therapeutic assembly with one adhesive plastic film on one side and placed in a container and exposed to the receiving medium or environment (80 ml of physiological saline solution at 37 ° C). salt) in such a way that contact with the wall of the container is prevented and the release side is constantly completely wetted. After 2, 4, 8 and 24 hours after the start of the placement of the sections in saline, the receiving medium is restored. Quantitative determination of the released active substance is carried out photometrically. The ketotifen-HFU concentration was determined by measuring UV-absorption at 265 nm and at Bopindolol by measuring UV-absorption at 265 nm.

The results of this photometric survey are shown in Figure 7, with the amount of active substance released being applied as a percentage over time. Sessions have shown that the release kinetics of the active substance are the same for both active substances, although quantitatively different amounts of active substance are released over time depending on the different physical and chemical properties of Ketotifen-HFU and Bopindolol-HMO. Both curves undoubtedly indicate that the active substance is regulated within 24 hours.

Example 4:

Principle B of the invention comprising a ketotifen

One, on both sides, different siliconized polyester film with a surface area of 145 g / m ² , is coated with an aqueous dispersion process of an acrylic copolymer containing carboxyl groups (ACRONAL 80D, BASF, Ludvigshafen) (solids content: 55%), which, with some diurethane-based thickening agent, adjusts the viscosity to 8 Pa.s. The sieve drum has apertures of 1.5 mm in diameter with a mean median distance of 3.7 mm, reaching up to 16.7% of the open surface of the drum. On the foil, glue points are arranged in an analogous manner to the drum, which, after drying at 65 ° C, has a mass per unit area of 30 g / m ² . In the further coating of the product, the reservoir mass containing ketotifen described in Example 1 is applied using the cylinder in Example 1. The procedure is continued as in Example 1.

Example 5:

Production of the bopindolol assembly according to the principle of the invention

A therapeutic assembly according to the invention and as described in Example 3 is made, while applying the reservoir mass for the active substance described in Example 2.

Example 6:

Construction of therapeutic assembly with different active substances in sections for adhesion to the skin and sections for carrying the active substance

An assembly containing the active substances as described in Example 4 is made using lanate- / 3-acetyldigoxin in the acrylate system as a reservoir mass and nitroglycerin in the skin bonding section.

Claims (21)

Patent claims A flat therapeutic assembly for applying the active substances to the skin with the reservoir (s) of the active substance having the surfaces for carrying the active substances and the skin-mounted portions of the surfaces for adhesion to the skin, characterized in that the sections (2, 18, 13) of the surface for The skin adhesives that are brought into contact with the skin lie in the same level as the section (s) of the skin adhesive surface (1, 7,12) placed on the skin. Flat therapeutic assembly according to claim 1, characterized in that the portions (2, 8, 13) of the active substance transfer surface are evenly or unevenly distributed in the skin contact surface. Flat therapeutic assembly according to claim 1 or 2, characterized in that the section (2, 13) of the surface for carrying the active substance is round or polygonal. Flat therapeutic assembly according to claim 1, characterized in that sections (7, 12) of the adhesive surface of the skin are evenly or unevenly distributed in contact with the skin. A flat therapeutic assembly according to claim 1, characterized in that the sections (7, 12) of the adhesive surface are round or polygonal. A flat therapeutic assembly according to claim 1, characterized in that portions of the adhesive surface of the skin and portions of the surface for carrying the active substance are alternately arranged in the form of strips. A flat therapeutic assembly according to claims 1 to 5, characterized in that the skin contact surface has an edge for adhesion to the skin in circumference. Flat therapeutic assembly according to one of the preceding claims, characterized in that it further has one flexible support layer on the side opposite to the one against the skin and, optionally, a removable protective layer. Flat therapeutic assembly according to one of the preceding claims, characterized in that the adhesive interlayer (4, 10) is positioned between the carrier layer (9) and the reservoir (11, 5) of the active substance. Flat therapeutic assembly according to one of the preceding claims, characterized in that it contains a reinforcement layer (6) having openings and in contact with the active substance reservoir (5). Flat therapeutic assembly according to claim 10 or 11, characterized in that the reinforcement layer (6) consists essentially of paper, some textile flat product, metal or plastic foil or laminates thereof. Flat therapeutic assembly according to claim 10 or 11, characterized in that there is a complete or partial adhesive layer between the reinforcement layer (6) and the active substance reservoir. A flat therapeutic assembly according to one or more of the preceding claims, characterized in that the reservoir of the active substance contains one or more active substances with local or systemic action. A flat therapeutic assembly according to claim 12, characterized in that at least one active substance is selected from the group of cardiac glycosides, vasodilators, musculotropic spasmolytics, coronary therapists, coronary dilators, antihistamines, analeptics, analgesics, antipyretics, one hypnotics, one hypnotics, , one musculotropic vasodilator, lipid-lowering agent or one vitamin B6, bronchodilator, cardiac, diuretic, phosphodiesterase inhibitor, theophylline, its compounds and derivatives, and rubefaciens, also in the form of free bases, salts or derivatives thereof. A flat therapeutic unit according to claim 14, characterized in that the active substance or substances are selected from the group consisting of amphetaminyl, betahistine, beta-acetyldigoxin, bopindolol, buprenorphine, clemastine, diclofenac, diltiazen, dimenhydrinate, dimethylaminisalicylate, monosilenicilate, monosilicylate, monosilicylate, monosilicylate, monosilicic acid 5-fluorouracil, glibenclamide, hydromorphone, ibuprofen, isopropyl-4- (2, 1,3-benzoxidiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine-carboxylate, ketotifen L Thyroxine, nicotine, / 3-butoxyethyl ester of nicotinic acid, vanillylamide of nonyl acid, pindolol, salbutamol, tamoxifen, tizanidine, theophylline. A flat therapeutic assembly according to any one of claims 14 or 15, characterized in that it comprises one combination of one cardiac glycoside digitalis lanata- / 3-acetyldigoxin in combination with one vasodilator, one musculoskeletal spasmolytic, one coronary therapist or one coronary dilator. A flat therapeutic assembly according to claim 14 or 15, characterized in that it contains one combination of one antihistamine with one glucocorticoid, preferably clemastine with dexamethasone or clocortolone-21-pivalate, or one antihistamine, preferably antiemetic dimenhydrinate, with one vasodilator, one vasodilator analeptic, one analgesic, one hypnotic, one musculotropic vasodilator, or one vitamin B6. A flat therapeutic unit according to claim 14 or 15, characterized in that it contains one combination of one bronchodilator, cardiac, diuretic, phosphodiesterase inhibition as theophylline, with other theophylline compounds or theophylline derivatives. A flat therapeutic assembly according to claim 14 or 15, characterized in that it has one rubefaciens, such as nicotinic acid / 3-butoxyethyl ester and / or vanillylamide of nonyl acid in combination with one antiflogistic agent such as ethylene glycol monosalicylate or diethylaminosalicylate. A flat therapeutic assembly according to any one of the preceding claims, characterized in that it has at least one first active substance in the reservoir of active substance and one or more active substances in a section or sections of the surface for adhesion to the skin. A flat therapeutic assembly according to any one of claims 1 to 13, characterized in that the adhesive sections (1, 7,12) have skin as the active substance nitroglycerin.