DE102018110792A1 - Transdermal application system with safety adhesive layer - Google Patents

Abstract

The present invention relates to a transdermal delivery system (100, 100 ', 100 ", 100"') having at least one planar, active substance-containing storage layer arrangement (1), preferably a matrix arrangement (1), with an application side (2) and a back side (3). a back layer (5) having a front side (7) facing the rear side (3) of the storage layer arrangement (1), wherein the storage layer arrangement (1) has on its application side (2) in an outer edge region and / or the back layer (5) on its application side Front side (7) in a over the edge of the storage layer arrangement (1) projecting region a partial security adhesive layer (10, 20, 30, 40, 50). Furthermore, the present invention relates to a method and a device (200) for producing the transdermal application systems (100, 100 ', 100 ", 100'") according to the invention. Finally, the present invention relates to the use of such a transdermal delivery system (100, 100 ', 100 ", 100'").

Description

The present invention relates to a transdermal administration system with a security adhesive layer and to a method and a device for producing such a transdermal administration system. Furthermore, the present invention relates to the use of such a transdermal delivery system.

Transdermal delivery systems, commonly referred to as "TDS" (Transdermal Delivery System), are for administering drugs through the skin of a patient's bloodstream. They usually include a reservoir for the active ingredient, a drug-impermeable backing layer and a protective film which is removed prior to application of the system.

Transdermal administration systems usually contain the active substance or the active ingredient formulation in a two-dimensional storage layer or storage layer arrangement containing active ingredient, which is usually in the form of a matrix layer or matrix layer arrangement. Such a planar active substance-containing matrix layer can, for. B. be formed as a pressure-sensitive adhesive layer, with which this is attached to the skin. Also, a two-dimensional active substance-containing matrix layer can be formed as a solid, semi-solid or liquid active substance matrix which has no adhesive properties. In this case, a transdermal administration system may be provided with an additional, drug-containing or drug-free pressure-sensitive adhesive layer with which the TDS is fixed on the skin.

In transdermal administration systems, the active substance is introduced into the skin of a patient by diffusion of the active substance along the active ingredient concentration gradient, which exists between the active substance-containing storage layer arrangement or active substance-containing matrix of the TDS and the region of the skin penetrated by the blood vessel system. The active ingredient blood level achievable with a transdermal administration system is, apart from the contact surface of the storage layer arrangement or matrix on the skin of the patient, substantially determined via the concentration gradient of the active substance at the boundary layer skin to storage layer arrangement or matrix.

Drug-containing transdermal delivery systems are often worn for extended periods of one to seven days. The application sites are mainly on the upper body in the area of the back, the chest and the arms. In these applications, however, TDS are often exposed to heavy mechanical loads.

In particular, the shearing forces on the skin surface occurring during physical activity place high demands on the adhesive properties of a TDS and can frequently cause detachment from the skin and thus significantly shorten the adhesive duration of a TDS. In addition, external factors such as contact with shower water, increased sweat production, especially in connection with physical activities, or the use of skincare products may result in reduced TDS adhesion. Also, the adhesion of textile fibers may favor an unwanted detachment of the transdermal application system from the skin surface, usually starting from the edge regions and corners. Due to the lack of contact with the skin, the premature detachment of a TDS prevents an active ingredient permeation from the active substance-containing matrix into the skin, so that an effective blood-drug concentration is not reached and a desired therapeutic target is missed.

Due to the nature and composition of the adhesive used, both the bond strength and the shear strength of a TDS can be influenced. However, an increased shear strength of an adhesive can simultaneously lead to a reduced adhesive power on the skin. A combination of equally high bond strength and shear strength of a TDS is therefore important for the therapeutic efficacy of a transdermal delivery system. After all, not every adhesive with good adhesive properties is equally suitable as a storage layer for the active substance, so that in this respect a compromise between active substance storage or release and adhesive properties of the TDS often has to be found.

It is therefore an object of the present invention to provide a transdermal delivery system with a security adhesive layer and a method and apparatus for making such a TDS. It is also an object of the present invention to provide a corresponding TDS for medical, veterinary and cosmetic use.

This object is achieved by a TDS according to claim 1 and by a method for producing such a TDS according to claim 12 and an apparatus for producing a TDS according to claim 14. Furthermore, the object is achieved by an inventive TDS for medical, veterinary and cosmetic use according to claim 15.

A transdermal administration system according to the invention therefore comprises at least one planar active ingredient-containing storage layer arrangement with an application side and a back side. The two-dimensional active substance-containing storage layer arrangement in The sense of the present invention may be in the form of a solid to semi-solid matrix arrangement or in the form of a liquid reservoir arrangement and thus forms the active agent depot of the transdermal administration system. Also, a transdermal delivery system of the invention may comprise a matrix assembly and a reservoir assembly. However, the transdermal administration system according to the invention preferably comprises a matrix arrangement.

In this context, a flat active substance-containing matrix arrangement or reservoir arrangement is understood as meaning one or more active substance-containing matrix / ces or reservoirs which are arranged horizontally in the TDS, that is to say in a layer parallel to the surface. Since a matrix arrangement is preferred in most cases, the storage layer arrangement is also often referred to below as a matrix arrangement, wherein - unless otherwise stated - other storage layer arrangements should not be excluded.

The side of the TDS, generally intended for application to a skin or in contact with the skin, is referred to as the application side. As mentioned, the application side can be designed to be fully or partially pressure-sensitive adhesive-bonded, for example by the active substance-containing storage layer arrangement or the active substance-containing matrix arrangement itself being pressure-adhesive or partially adhesive-bonded to a self-adhesive.

According to the invention, the transdermal administration system, irrespective of the optionally existing pressure-sensitive adhesive properties of the storage layer arrangement, has at least one partial security adhesive layer. Also, a TDS according to the invention may comprise more than one partial security adhesive layer, so that areas of the security adhesive layers are applied such that they are interrupted by areas of the storage layer arrangement. In this case, the areas with one or more partial security adhesive layers can be interrupted by areas which have no coating or an alternative coating or they can run continuously.

According to a preferred embodiment, the application side of the storage layer arrangement has at least one partial securing adhesive layer located in an outer edge region of the application side.

In a further preferred embodiment, a transdermal application system according to the invention has at least one partial securing adhesive layer located in a front side of the back layer facing the rear side of the storage layer arrangement and protruding beyond the edge of the storage layer arrangement. According to the invention, such a security adhesive layer is located in a partial edge area, i. H. it does not cover the entire area of the edge area. This is advantageous in particular when it is intended to prevent or prevent a migration of active ingredient from the active substance-containing storage layer arrangement into the partial security adhesive layer.

On the side of the TDS facing away from the skin, the active substance-containing storage layer arrangement, for. As the active ingredient-containing matrix, provided with a backing layer, while on the intended use of the skin-facing side of the TDS preferably a removable protective film protects the storage layer assembly from contamination, thereby preventing uncontrolled leakage of active ingredient during storage of the TDS.

Insofar as a backing layer has a pressure-sensitive adhesive layer on the front side of the backing layer facing the rear side of the storage layer arrangement over the edge of the storage layer arrangement, this can advantageously be located over the entire surface of the backing layer or over the edge of the storage layer arrangement results in a simple and continuous coating step of the pressure-sensitive adhesive on the backing layer. This can advantageously be a pressure-sensitive adhesive with lower pressure-sensitive adhesive properties than the partial security adhesive layer. In this case, the areas which are exposed to particular shear forces can preferably be provided with a partial security adhesive layer, preferably with a partial security adhesive layer with strong pressure-sensitive adhesive properties. This ensures TDS adhesion to the skin, even under high mechanical stress, without, however, causing pain to the user when removing the TDS, as the areas that are highly adhesive to the skin can be kept to a minimum.

The at least one partial security adhesive layer is locally limited, possibly discontinuous, isolated or fragmentary, arranged in the outer edge region of the application side of the storage layer arrangement and / or in the outer edge region of the region of the backing layer front side projecting beyond the edge of the storage layer arrangement.

In this case, at least one region of the application side of the storage layer arrangement, preferably the central region in or around the center of the storage layer arrangement and / or a region of the region projecting beyond the storage layer arrangement, has Back layer front side, preferably the immediately adjacent to the storage layer arrangement inner edge region, no security adhesive layer on. A central region in or around the mid-point is to be understood as a region which is located approximately in the middle of the application side of the storage layer arrangement and comprises a region of approximately 1/5 to approximately 1/20 of the surface of the storage layer arrangement.

The arrangement of this at least one partial security adhesive layer in an outer edge region of the application side of the storage layer and / or in a region of the back layer front side projecting beyond the edge of the storage layer arrangement increases the adhesive force of a TDS and thus advantageously prevents its premature detachment from the skin, which, as mentioned above , often from the peripheral areas of the TDS.

Thus, in the TDS of the present invention, the wearing period can be extended to increase the effective drug delivery from the storage layer assembly. Advantageously, the residual active substance content within the storage layer arrangement can thus be reduced after the end of the wearing period of the TDS and / or the size of the TDS due to the efficient release of active ingredient and / or the active substance content of the TDS. This is of particular interest for TDS, which contain expensive active ingredients or which undergo cost-intensive production and thus can be used much more efficiently.

Advantageously, the duration of the TDS according to the invention can also be extended to up to seven days or more, which makes it even more straightforward for users who have problems re-applying a TDS, such as older people, for example. This is especially important for TDS, whose pressure-sensitive adhesive properties of the active ingredient-containing matrix are not sufficient for continuous contact of the matrix with the skin.

The transdermal administration systems according to the invention are suitable for the administration of basically all active ingredients or combinations of active substances. In the context of the present invention, an active substance means a pharmaceutically active substance or a cosmetic active ingredient and / or additive and / or nutrient or dietary supplement and / or essential oil.

The present invention thus also relates to the medical, veterinary and / or cosmetic use of the patch according to the invention for delivery of active ingredients to and optionally through the skin of a human or animal body and / or to an environment around the plaster.

1. (i) Bereitstellen einer flächigen wirkstoffhaltigen Speicherschichtanordnung, vorzugsweise einer Matrixanordnung, mit einer Applikationsseite und einer Rückseite,
2. (ii) Bereitstellen einer Rückschicht mit einer der Rückseite der wirkstoffhaltigen Speicherschichtanordnung zugewandten Vorderseite,

wobei eine partielle Sicherungsklebeschicht in einem äußeren Randbereich der Applikationsseite der Speicherschichtanordnung und/oder in einem äußeren Randbereich des über den Rand der Speicherschichtanordnung überstehenden Bereiches der Rückschichtvorderseite angeordnet wird.Furthermore, the present invention relates to a method for producing a TDS according to the invention, the method comprising the following steps:

1. (i) providing a laminar active substance-containing storage layer arrangement, preferably a matrix arrangement, with an application side and a back side,
2. (ii) providing a backing layer having a front side facing the rear side of the active substance-containing storage layer arrangement,

wherein a partial securing adhesive layer is arranged in an outer edge region of the application side of the storage layer arrangement and / or in an outer edge region of the region of the backing layer front side projecting beyond the edge of the storage layer arrangement.

• - eine erste Station zum Bereitstellen zumindest einer flächigen wirkstoffhaltigen Speicherschichtanordnung, vorzugsweise einer Matrixanordnung, mit einer Applikationsseite und einer Rückseite,
• - eine zweite Station zum Bereitstellen einer Rückschicht mit einer der Rückseite der Speicherschichtanordnung zugewandten Vorderseite,
• - eine Einrichtung zum Aufbringen zumindest einer partiellen Sicherungsklebeschicht, wobei die partielle Sicherungsklebeschicht in einem äußeren Randbereich der Applikationsseite der Speicherschichtanordnung und/oder in einem äußeren Randbereich des über den Rand der Speicherschichtanordnung überstehenden Bereiches der Rückschichtvorderseite angeordnet wird.

Finally, an object of the present invention comprises an apparatus for producing the transdermal therapeutic administration systems according to the invention, the apparatus having the following components:

• a first station for providing at least one laminar active ingredient-containing storage layer arrangement, preferably a matrix arrangement, with an application side and a back side,
• a second station for providing a backing layer with a front side facing the rear side of the storage layer arrangement,
• a device for applying at least one partial securing adhesive layer, the partial securing adhesive layer being arranged in an outer edge region of the application side of the storage layer arrangement and / or in an outer edge region of the region of the backing layer front side projecting beyond the edge of the storage layer arrangement.

The active substance-containing storage layer arrangement can be produced in one or more steps in a station, for example in the first station, or even by a separate device, for. B. at a supplier, manufactured and supplied in the station. Insofar as the storage layer arrangement is stored, for example, before its provision, this advantageously comprises the application side and the back covering films, such as process films or protective films, which in the course of the manufacturing process on the active substance-containing storage layer arrangement remain or be removed. If the active substance-containing storage layer arrangement has films on its application side and its rear side, then at least the film is removed which covers the application side or the region of the front side of the back layer projecting beyond the edge of the storage layer arrangement so as to apply the partial securing layer to the application side in the course of the production process to be able to

In a second station, the backing layer is provided with a back side and a front side, wherein the back layer is applied to the storage layer arrangement in this station itself or in another station with its front side.

In a further device, the at least one partial security adhesive layer is applied to an outer edge region of the application side of the storage layer arrangement and / or in an outer edge region of the region of the backing layer front side projecting beyond the edge of the storage layer arrangement.

Further particularly advantageous embodiments and developments of the invention will become apparent from the dependent claims and the preceding and following description, wherein the claims of a claim category can also be developed analogous to the claims and description parts to another claim category and in particular also individual features of different embodiments or variants can be combined to new embodiments or variants.

According to a preferred embodiment, the partial security adhesive layer is applied in or at a corner and / or along a side or an edge in a circumferential region of the transdermal application system. A corner of a TDS can in particular also comprise a rounded or bevelled corner. Particularly preferably, in each case a partial security adhesive layer can be arranged on at least each corner.

Most preferably, the transdermal delivery system may also have a partial security adhesive layer circulating annularly along an edge of the delivery system. Such a securing adhesive layer is therefore located all around in an edge region of an application side of the storage layer arrangement and / or the front side of the backing layer in a region projecting beyond the edge of the storage layer arrangement, wherein the security adhesive layer can be at least partially ring-like, preferably completely circumferential.

Further, the one or more partial adhesive adhesive layers may have a different form of configuration. For example, the partial adhesive bonding layer (s) may have a circular, oval or even an annular, rectangular or strip-shaped, triangular and / or star-shaped structure. However, the security adhesive layer (s) preferably has a circular, oval, annular or rectangular structure.

Depending on the size, the shape, the internal structures and the application of the transdermal application system, the area ratio of one or more on the application side of the storage layer assembly partial Sicherungsklebeschicht / s to the surface of the application side of the storage layer arrangement and / or the area ratio of in one of the Edge of the storage layer arrangement protruding portion of the backing layer front side partial security adhesive layer / s to the surface of the overlying the edge of the storage layer arrangement region of the backsheet front side in a wide range. The total area of application of the at least one active substance-containing storage layer arrangement is to be understood here as the area of the storage layer arrangement; By contrast, the surface area of the region of the backing layer front side projecting beyond the edge of the storage layer arrangement is understood to mean the surface which projects beyond the (total) application area of the at least one active substance-containing storage layer arrangement. Insofar as the transdermal administration system has more than one partial security adhesive layer, the area ratio always relates to the entirety of the partial security adhesive layers.

A preferred transdermal delivery system has an area ratio of a partial security adhesive layer located on the application side of the storage layer assembly to the entire surface of the application side of the storage layer assembly and / or the partial security adhesive layer located in a region of the backing layer front over the edge of the storage layer assembly to the entire surface of the over the edge the storage layer arrangement protruding portion of the back layer front side in a range of 1: 2 to 1: 100, more preferably in the range of about 1: 5 to about 1:50, in particular in the range of about 1:20 to about 1:25 on.

A particularly preferred transdermal administration system has at least one partial security adhesive layer on the application side of the storage layer arrangement in which the area ratio of the partial security adhesive layer increases the area of the storage layer arrangement preferably in the range of 1: 5 to 1:70, particularly preferably in the range of about 1:10 to about 1:50, in particular in the range of about 1:15 to about 1:40, particularly preferably in the range of about 1:20 to about 1:25.

Alternatively or additionally, a particularly preferred transdermal application system may have at least one partial security adhesive layer in a region of the backing layer front side projecting beyond the edge of the storage layer arrangement, in which the area ratio of the partial security adhesive layer to the area of the region of the backing layer front side projecting beyond the edge of the storage layer arrangement is in the range of approximately 1 0.1 to about 1:10, preferably in the range of about 1: 0.2 to about 1: 5, in particular in the range of about 1: 0.5 to about 1: 2.

As mentioned above, in an advantageous transdermal application system, the application side as well as the rear side of the storage layer arrangement facing away from the application side can be designed to be fully or partially adhesive-bonded. Preferably, both the application side and the application side facing away from the back of the storage layer arrangement are formed over the entire surface pressure-sensitive adhesive.

In one embodiment of an advantageous TDS with a partial security adhesive layer in a region of the backing layer front side projecting beyond the edge of the storage layer arrangement, a pressure-sensitive adhesive backing layer is preferably used. Advantageously, the application area of the active substance-containing storage layer arrangement and thus the active ingredient entry into the skin is not reduced by the arrangement or configuration of the partial security adhesive layer in a region of the backing layer projecting beyond the storage layer arrangement.

As mentioned above, the application side of the active substance-containing storage layer arrangement of a TDS is optionally supported by a peelable protective film in the form of a release liner. When storing the TDS, the storage layer arrangement or the partial security adhesive layer is thereby effectively protected from mechanical influences and / or undesired admission of air. Preventing unwanted entry of air prevents decomposition of active substances contained in the storage layer arrangement, in particular of the matrix, and in particular of oxygen-sensitive active substances, and thus improves the storage or long-term stability of the plaster (hereinafter the TDS is also referred to as plaster). To apply a TDS on the skin, the protective film of the plaster is then first removed. In order to facilitate the removal of the protective film, this protrudes beyond the edge of the remaining plaster on some plasters.

Suitable materials for a protective film are, for example, polyester, polypropylene, polyvinyl chloride, aluminum and paper, wherein at least one side of the process film has a silicone coating, polyethylene coating, fluorosilicone coating or polytetrafluoroethylene coating. The process film used is preferably a silicone-coated film, in particular a silicone-coated polyester film.

In a preferred development, a two-part protective film is used, the edges of which abut each other when the plaster is bent and thus can be gripped without touching the active substance-containing area of the plaster. In this case, a protective film may comprise a first protective film part and a second protective film part.

Embodiments may also expediently include the formation of the protective film parts made of different materials with which different adhesion properties can be achieved on a matrix system containing active ingredient. Such different adhesion properties can optionally be achieved by different coatings of the protective film, for example by silicone, fluoropolymer or fluorosilicone coating on the side facing the active ingredient-containing matrix. Particular embodiments have a first and a second protective film part, which may differ in their physical and / or optical properties and / or their size from the second protective film part.

In order to minimize the risk of contamination of the fingers when applying the patch to the skin, it is generally recommended to first remove only part of the divided protective film while at the same time keeping the patch on the area covered by the other part of the protective film, the exposed one Apply part of the patch on the skin and then remove the second part of the protective film. In order to further reduce the risk of contamination, the two parts of the protective film are arranged overlapping in advantageous embodiments.

Preferred embodiments of a transdermal administration system include, as mentioned as a storage layer arrangement, an active substance matrix and / or reservoir containing at least one active substance. Certain embodiments may also comprise more than one active substance-containing matrix or more than one active substance-containing reservoir, wherein the active ingredients used may be identical or different and in different Concentration may be present. Thus, for example, a storage layer may contain one hormone from the group of estrogens and a second or further storage layer may contain a hormone from the group of progestogens. Of course, active substances of different classes, such as, for example, an antiemetic in an active substance depot and an opioid in a second or further active substance depot of the TDS according to the invention can also be present.

Finally, not all layers of the transdermal application system according to the invention must contain an active ingredient, but the TDS or the active substance-containing storage layer arrangement can have one or more active substance-free layers in addition to the at least one active substance-containing storage layer arrangement, in particular a matrix layer containing active ingredient, wherein an active substance-free layer also belongs to the application side can. In this case, a partial security adhesive layer can be applied to a drug-free layer.

All materials usually suitable for transdermal therapeutic systems are suitable for the formation of an active substance-containing storage layer or an active substance-free layer of the transdermal administration system. Preferably, a matrix z. For example, tackifiers may be added to provide a self-adhesive (i.e., pressure-sensitive adhesive) matrix containing active ingredients in addition to the partial bond coat of this invention.

Also, the matrix may be constructed of a self-adhesive polymer. To mention here are especially polymers that are used in the production of transdermal systems and physiologically harmless, such. B. homo- and copolymers of (meth) acrylates, polyvinyl ethers, polyisobutylenes, polyisoprene rubbers, styrene-butadiene copolymers or styrene-butadiene-styrene copolymers and silicones. Among the (meth) acrylate copolymers, there can be mentioned, for example, the copolymers of alkyl acrylates and / or alkyl methacrylates and other unsaturated monomers, such as acrylic acid, methacrylic acid, acrylamide, dimethylacrylamide, dimethylaminoethylacrylamide, acrylonitrile and / or vinyl acetate.

In principle, the adhesive of the partial security adhesive layer may be identical to the adhesive of the active substance-containing storage layer arrangement and / or to an adhesive which is located on the backing layer. According to a preferred embodiment, however, the adhesive of the partial security adhesive layer is different from an adhesive of the active substance-containing storage layer arrangement and / or to an adhesive which is located on the backing layer.

A backing layer in the sense of the present invention may be composed of one or more layers, in particular also film layers. In this case, preferably at least one layer is occlusive, d. H. it can be designed as a barrier layer for, for example, the passage of active ingredients. As backing layers of a TDS according to the invention are usually so-called backing films of, for example, polyester with a thickness of up to 500 .mu.m, preferably from the range of 5 to 250 .mu.m, more preferably from the range of 10 to 100 .mu.m, in particular from the range of 20 to 50 microns, more preferably from the range of 30 to 40 microns used. Such backing layers are advantageously flexible, d. H. flexible and / or at least unidirectional, and may extend around the edges of the memory layer array, i. Lay around the laterally facing side surfaces of the storage layer arrangement and cover them. Preferably, the back layer front side of a TDS according to the invention overlaps the active substance-containing storage layer in lateral alignment on the application side of the storage layer arrangement.

Preferably, a backing layer is based on a polymer selected from the group consisting of polyolefins, olefin copolymers, polyesters, co-polyesters, polyamides, co-polyamides, polyurethanes, and the like. As examples of suitable materials can be mentioned polyesters and of these, in particular polyethylene terephthalates and polycarbonates, polyolefins such. As polyethylenes, polypropylenes or polybutylenes, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidene chlorides, co-polymers, such as acrylonitrile-butadiene-styrene terpolymers, or ethylene-vinyl acetate copolymers.

Furthermore, a transdermal application system or an active substance-containing storage layer arrangement between the storage layer arrangement and the back layer can have a so-called intermediate layer. Such an intermediate layer may comprise one or more pressure-sensitive adhesives and one or more films, so-called intermediate films. Preferably, an intermediate layer is occlusive, d. H. formed as a barrier layer for example, the passage of active ingredients.

It is also conceivable that the TDS or the active substance-containing storage layer arrangement has one or more intermediate layer (s) in the form of a porous membrane. It is conceivable that the porous membrane is provided on its side facing the skin with a further active substance-containing storage layer and / or drug-free layer. Insofar as the porous membrane is provided on the side facing the skin with a drug-free layer is, the partial security adhesive layer is applied to this layer.

In particular, an intermediate layer is based on a polymer selected from the group comprising polyolefins, olefin copolymers, polyesters, co-polyesters, polyamides, co-polyamides, polyurethanes and the like. As examples of suitable materials can be mentioned polyesters and of these, in particular polyethylene terephthalates and polycarbonates, polyolefins such. As polyethylenes, polypropylenes or polybutylenes, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidene chlorides, co-polymers, such as acrylonitrile-butadiene-styrene terpolymers, or ethylene-vinyl acetate copolymers.

The advantageous transdermal administration systems release the active substance from the planar storage layer arrangement, preferably the active substance-containing matrix, to the skin, it being possible for at least part of the active substance to be absorbed systemically. The transdermal administration system can therefore also be used for the dermal delivery of an active substance, for example for local anesthesia of the skin. Furthermore, an application system within the meaning of the present invention can also deliver a fragrance, such as, for example, an essential oil from a matrix. Advantageously, the perfume can be discharged into the environment essentially through a porous backing layer.

The active ingredients may be included in various forms in the composition, depending on which form gives the optimal release properties of the active ingredient from the TDS. In the case of pharmaceutically active substances, these may be in the form of the free base or acid or in the form of salts, esters or other pharmacologically acceptable derivatives or as components of molecular complexes.

The absolute amount of drug contained in the patch generally determines the length of time that continuous delivery into the organism is maintained. Therefore, the highest possible loading of the storage arrangement or the matrix with active ingredients is desirable when the application time of a patch is long, d. H. several days to a week.

The amount of the active ingredient to be included in the composition varies depending on the specific active ingredient, the desired therapeutic effect, and the period of time during which the TDS is to provide therapy. For most drugs, the passage of drugs through the skin is the rate-limiting step in their delivery. Thus, the amount of drug and rate of release are typically selected to provide transdermal delivery characterized by a substantially zero-order time dependence over a longer period of time.

Advantageously, therefore, the amount of active ingredient in the system may be at least about 0.5% by weight, preferably at least about 1.0% by weight, more preferably at least about 5% by weight, especially at least about 10% by weight .-% and / or up to about 50 wt .-%, preferably at most about 40 wt .-%, more preferably at most about 30 wt .-%, in particular to at most about 20 wt .-%, vary the amount of the active ingredient relates to the dried active substance-containing storage layer.

1. 1. Herzaktive Medikamente, zum Beispiel organische Nitrate, wie Nitroglycerin, Isosorbiddinitrat und Isosorbidmononitrat, Chinidinsulfat, Procainamid, Thiazide, wie Bendroflumethiazid, Chlorothiazid und Hydrochlorothiazid, Nifedipin, Nicardipin, adrenergische Blockiermittel, wie Timolol und Propranolol, Verapamil, Diltiazem, Captopril, Clonidin und Prazosin;
2. 2. Androgene Steroide, wie Testosteron, Methyltestosteron und Fluoxymesteron;
3. 3. Estrogene, wie konjugierte Estrogene, veresterte Estrogene, Estropipat, 17ß-Estradiol, 17ß-Estradiolvalerat, Equilin, Mestranol, Estron, Estriol, 17ß-Ethinylestradiol und Diethylstibestrol;
4. 4. Gestagene, wie Progesteron, 19-Norprogesteron, Norethindron, Norethindronacetat, Chlormadinon, Ethisteron, Etonogestrel, Medroxyprogesteronacetat, Hydroxyprogesteroncaproat, Norethynodrel, Norelgestromin, 17a-Hydroxyprogesteron, Dydrogesteron, Dimethisteron, Ethinylestrenol, Norgestrel, Demegeston, Promegeston und Megestrolacetat;
5. 5. Medikamente mit Wirkung auf das Zentralnervensystem, zum Beispiel Sedativa, Hypnotika, angstlösende Mittel, Analgetika und Anästhetika, wie Buprenorphin, Naloxon, Haloperidol, Fluphenazin, Pentobarbital, Phenabarbital, Secobarbital, Codein, Lidocain, Tetracain, Dibucain, Cocain, Procain, Mepivacain, Bupivacain, Etidocain, Prilocain, Benzocain, Fentanyl, Sufentanil, Alfentanil, Remifentanil, Tapentadol und Nicotin;
6. 6. Nährstoffe und Nahrungsergängzungsmittel, wie Vitamine, essentielle Aminosäuren und essentielle Fette;
7. 7. Entzündungshemmende Mittel, wie Hydrocortison, Cortison, Dexamethason, Fluocinolon, Triamcinolon, Prednisolon, Flurandrenolid, Methylprednisolon, Prednison, Methylprednisolon, Corticosteron, Paramethason, Betamethason, Ibuprofen, Naproxen, Fenoprofen, Fenbufen, Flurbiprofen, Ketoprofen, Suprofen, Indomethacin, Piroxicam, Aspirin, Salicylsäure, Diflunisal, Methylsalicylat, Phenylbutazon, Sulindac, Mefenaminsäure, Tolmetin und dergleichen;
8. 8. Antihistaminika, wie Diphenhydramin, Dimenhydrinat, Perphenazin, Triprolidin, Pyrilamin, Chlorcyclizin, Promethazin, Carbinoxamin, Tripelennamin, Brompheniramin, Clorprenalin, Terfenadin und Chlorpheniramin;
9. 9. Respiratorische Mittel, wie Theophillin und ß-adrenerge Agonisten, wie Albuterol, Terbutalin, Metaproterenol, Ritodrin, Carbuterol, Fenoterol, Chinterenol, Rimiterol, Solmefamol, Solerenal und Tetrochinol;
10. 10. Sympathomimetika und Parasympathomimetika, wie Dopamin, Norepinephrin, Phenylpropanolamin, Phenylephrin, Physostigmin, Pseudoephedrin, Amphetamin, Propylhexedrin und Epinephrin;
11. 11. Miotika, wie Pilocarpin und dergleichen;
12. 12. Cholinergische Agonisten, wie Cholin, Acetylcholin, Methacholin, Carbachol, Bethanechol, Pilocarpin, Muskarin und Arecolin;
13. 13. Antimuskarinische oder muskarinische cholinerge Gegenmittel, wie Atropin, Scopolamin, Methscopolamin, Homatropinmethylbromid, Methanthelin, Cyclopentolat, Tropicamid, Propanthelin, Dicyclomin und Eucatropin;
14. 14. Mydriatika, wie Atropin, Cydoperitolat und Hydroxyamphetamin;
15. 15. Psychoanaleptika, wie 3-(2-Aminopropyl)indol, 3-(2-Aminobutyl)indol und dergleichen;
16. 16. Antiinfektionsmittel, wie Antibiotika, einschließlich Penicillin, Tetracyclin, Chloramphenicol, Sulfacetamid, Sulfamethazin, Sulfadiazin, Sulfamerazin, Sulfamethizol und Sulfisoxazol; antivirale Mittel; antibakterielle Mittel, wie Erythromycin und Clarithromycin, und andere Antiinfektionsmittel einschließlich Nitrofurazon und dergleichen;
17. 17. Dermatologische Mittel, wie Vitamin A und Vitamin E;
18. 18. Humorale Mittel, wie natürliche und synthetische Prostaglandine, zum Beispiel PGE1, PGE2a und PGF2a und das PGEr Analogon Misoprostol;
19. 19. Antispasmodika, wie Atropin, Methanthelin, Papaverin und Methscapolamin;
20. 20. Antidepressiva, wie Isocarboxazid, Phenelzin, Tranylcypromin, Imipramin, Amitriptylin, Trimipramin, Doxepin, Desipramin, Nortriptylin, Protriptylin, Amoxapin, Maprotilin und Trazodon;
21. 21. Antidiabetika, wie Insulin, und Krebsmedikamente, wie Tamoxifen und Methotrexat;
22. 22. Anorektika, wie Dextroamphetamin, Methamphetamin, Phenylpropanolamin, Fenfluramin, Diethylpropion, Mazindol und Phentermin;
23. 23. Antiallergika, wie Antazolin, Methapyrilen, Chlorpheniramin, Mizolastin, Pyrilamin und Pheniramin;
24. 24. Beruhigungsmittel, wie Reserpin, Chlorpromazin und angstlösende Benzodiazepine, wie Alprazolam, Chlordiazepoxid, Clorazepat, Halazepam, Oxazepam, Prazepam, Flurazepam, Triazolam, Lorazepam und Diazepam;
25. 25. Antipsychotika, wie Thiopropazat, Chlorpromazin, Triflupromazin, Mesoridazin, Piperacetazin, Thiondazin, Acetophenazin, Fluphenazin, Perphenazin, Trifluoperazin, Chlorprathixen, Thiothixen, Haloperidol, Bromperidol, Loxapin und Molindon;
26. 26. Abschwellende Mittel, wie Phenylephrin, Ephedrin, Naphazolin, Tetrahydrozolin;
27. 27. Antipyretika, wie Aspirin, Salicylamid und dergleichen;
28. 28. Antimigränemittel, wie Dihydroergotamin und Pizotylin;
29. 29. Medikamente zur Behandlung von Übelkeit und Erbrechen, wie Chlorpromazin, Granisetron, Perphenazin, Prochlorperazin, Promethazin, Triethylperazin, Triflupromazin und Trimeprazin;
30. 30. Antimalariamittel, wie 4-Aminochinolin, a-Aminochinolin, Chlorochin und Pyrimethamin;
31. 31. Geschwürhemmende Mittel, wie Misoprostol, Omeprazol und Enprostil;
32. 32. Peptide, wie wachstumshormonfreisetzender Faktor;
33. 33. Medikamente für die Parkinson-Krankheit, Spastizität und akute Muskelspasmen, wie Rotigotin, Levodopa, Carbidopa, Amantadin, Apomorphin, Brorocripton, Selegilin (Deprenyl), Trihexyphenidylhydrochlorid, Benztropinmesylat, Procyclidinhydrochlorid, Baclofen, Diazepam und Dantrolen;
34. 34. Antiestrogen- oder -hormonmittel, wie Tamoxifen oder humanes Chorion-Gonadotropin;
35. 35. Aromatasehemmer, wie Anastrozol;
36. 36. Cholinesteraseinhibitoren, wie Rivastigmin, Physostigmin, Galantamin oder Pyridostigmin;
37. 37. Duftstoffe, wie ätherische Öle, wie Pfefferminzöl, Zitronenöl und dergleichen.

Exemplary active drugs that may be included in the patch of the present invention are:

1. 1. Cardioprotective drugs, for example organic nitrates such as nitroglycerin, isosorbide dinitrate and isosorbide mononitrate, quinidine sulfate, procainamide, thiazides such as bendroflumethiazide, chlorothiazide and hydrochlorothiazide, nifedipine, nicardipine, adrenergic blocking agents such as timolol and propranolol, verapamil, diltiazem, captopril, clonidine and prazosin;
2. 2. androgenic steroids, such as testosterone, methyltestosterone and fluoxymesterone;
3. 3. Estrogens such as conjugated estrogens, esterified estrogens, estropipate, 17β-estradiol, 17β-estradiol valerate, equilin, mestranol, estrone, estriol, 17β-ethinylestradiol and diethylstibestrol;
4. 4. progestins such as progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, chlormadinone, ethisterone, etonogestrel, medroxyprogesterone acetate, hydroxyprogesterone caproate, norethynodrel, norelgestromin, 17a-hydroxyprogesterone, dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, demegestone, promegestone and megestrol acetate;
5. 5. Central nervous system medications such as sedatives, hypnotics, anxiolytics, analgesics and anesthetics such as buprenorphine, naloxone, haloperidol, fluphenazine, pentobarbital, phenabarbital, secobarbital, codeine, lidocaine, tetracaine, dibucaine, cocaine, procaine, mepivacaine , Bupivacaine, etidocaine, prilocaine, benzocaine, fentanyl, sufentanil, alfentanil, remifentanil, tapentadol and nicotine;
6. 6. Nutrients and nutritional supplements, such as vitamins, essential amino acids and essential fats;
7. 7. Anti-inflammatory agents, such as hydrocortisone, cortisone, dexamethasone, Fluocinolone, triamcinolone, prednisolone, flurandrenolide, methylprednisolone, prednisone, methylprednisolone, corticosterone, paramethasone, betamethasone, ibuprofen, naproxen, fenoprofen, fenbufen, flurbiprofen, ketoprofen, suprofen, indomethacin, piroxicam, aspirin, salicylic acid, diflunisal, methylsalicylate, phenylbutazone, sulindac, Mefenamic acid, tolmetin and the like;
8. 8. Antihistamines such as diphenhydramine, dimenhydrinate, perphenazine, triprolidine, pyrilamine, chlorcyclizine, promethazine, carbinoxamine, tripelennamine, brompheniramine, clorprenaline, terfenadine and chlorpheniramine;
9. 9. Respiratory agents, such as theophillin and β-adrenergic agonists, such as albuterol, terbutaline, metaproterenol, ritodrine, carbuterol, fenoterol, chinterenol, rimiterol, solmefamol, solerenal and tetroquinol;
10. 10. sympathomimetics and parasympathomimetics such as dopamine, norepinephrine, phenylpropanolamine, phenylephrine, physostigmine, pseudoephedrine, amphetamine, propylhexedrine and epinephrine;
11. 11. Miotics, such as pilocarpine and the like;
12. 12. cholinergic agonists such as choline, acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, muscarine and arecoline;
13. 13. Antimuscarinic or muscarinic cholinergic antidotes, such as atropine, scopolamine, methscopolamine, homatropine methyl bromide, methantheline, cyclopentolate, tropicamide, propantheline, dicyclomine and eucatropine;
14. 14. mydriatics such as atropine, cydoperitolate and hydroxyamphetamine;
15. 15. psychoanaleptics such as 3- (2-aminopropyl) indole, 3- (2-aminobutyl) indole and the like;
16. 16. Anti-infective agents, such as antibiotics, including penicillin, tetracycline, chloramphenicol, sulfacetamide, sulfamethazine, sulfadiazine, sulfamerazine, sulfamethizole and sulfisoxazole; antiviral agents; antibacterial agents such as erythromycin and clarithromycin, and other anti-infective agents including nitrofurazone and the like;
17. 17. dermatological agents, such as vitamin A and vitamin E;
18. 18. Humoral agents, such as natural and synthetic prostaglandins, for example PGE1, PGE2a and PGF2a and the PGEr analogue misoprostol;
19. 19. antispasmodics, such as atropine, methantheline, papaverine and methscapolamine;
20. 20. Antidepressants such as isocarboxazid, phenelzine, tranylcypromine, imipramine, amitriptyline, trimipramine, doxepin, desipramine, nortriptyline, protriptyline, amoxapine, maprotiline and trazodone;
21. 21. Antidiabetics, such as insulin, and anticancer drugs, such as tamoxifen and methotrexate;
22. Anorexics such as dextroamphetamine, methamphetamine, phenylpropanolamine, fenfluramine, diethylpropion, mazindol and phentermine;
23. 23. Antiallergic agents, such as antazoline, methapyrilene, chlorpheniramine, mizolastine, pyrilamine and pheniramine;
24. (24) sedatives such as reserpine, chlorpromazine and anxiolytic benzodiazepines such as alprazolam, chlordiazepoxide, clorazepate, halazepam, oxazepam, prazepam, flurazepam, triazolam, lorazepam and diazepam;
25. 25. Antipsychotics such as thiopropazate, chlorpromazine, triflupromazine, mesoridazine, piperazineazine, thiondazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chlorprathixene, thiothixene, haloperidol, bromoperidol, loxapine and molindone;
26. 26. Decongestants, such as phenylephrine, ephedrine, naphazoline, tetrahydrozoline;
27. 27. antipyretics such as aspirin, salicylamide and the like;
28. 28. antimigraine agents, such as dihydroergotamine and pizotyline;
29. 29. medications for the treatment of nausea and vomiting, such as chlorpromazine, granisetron, perphenazine, prochlorperazine, promethazine, triethylperazine, triflupromazine and trimeprazine;
30. 30. Antimalarials, such as 4-aminoquinoline, α-aminoquinoline, chloroquine and pyrimethamine;
31. 31. Anti-ulcer agents such as misoprostol, omeprazole and enprostil;
32. 32. peptides, such as growth hormone releasing factor;
33. 33. drugs for Parkinson's disease, spasticity and acute muscle spasms, such as rotigotine, levodopa, carbidopa, amantadine, apomorphine, brorocriptone, selegiline (deprenyl), trihexyphenidyl hydrochloride, benztropine mesylate, procyclidine hydrochloride, baclofen, diazepam and dantrolene;
34. 34. Antiestrogen or hormone agents, such as tamoxifen or human chorionic gonadotropin;
35. 35. aromatase inhibitors, such as anastrozole;
36. 36. Cholinesterase inhibitors, such as rivastigmine, physostigmine, galantamine or pyridostigmine;
37. 37. fragrances such as essential oils such as peppermint oil, lemon oil and the like.

Continuous delivery of an active ingredient to the skin is essential especially for those conditions for which a controlled therapy for days with a continuous release of the active ingredient is a prerequisite. A preferred indication here is the therapy of pain, in particular of cancer pain and / or neuropathic and / or pain of the musculoskeletal system.

Another preferred indication is hormone treatment, in particular contraception and / or hormone replacement therapy.

Also preferred is the treatment of age-related diseases, especially dementias, such as primary and secondary forms of dementia and other neurodegenerative diseases such as Alzheimer's disease, idiopathic Parkinson's syndrome and vascular dementia.

Finally, the transdermal administration system according to the invention can be used in particular for use in the treatment of hypertension, motion sickness, in palliative medicine and in the supportive treatment of cancer, in particular of breast cancer.

Particularly preferred transdermal administration systems therefore contain an active substance from the group of analgesics, in particular buprenorphine and / or fentanyl and / or sufentanil and / or alfentanil and / or remifentanil and / or tapentadol, from the group of dopamine agonists, in particular rotigotine, from the group of Cholinesterase inhibitors, in particular rivastigmine, from the group of imidazolines, preferably the alpha2-adrenoceptor agonist, in particular clonidine, from the group of the tropane alkaloids, preferably the agonists of the muscarinic acetylcholine receptors, in particular scopolamine, from the group of aromatase inhibitors, in particular anastrozole, or from the group of hormones, in particular estrogen and / or estradiol and / or ethinylestradiol, norelgestromin and / or etonogestrel.

Further preferred active substances are selected from the group of essential oils, in particular eucalyptus oil, peppermint oil, citronella oil, chamomile oil, camphor, menthol, citrus oil, cinnamon oil, thyme oil, lavender oil, clove oil, tea tree oil, cajeput oil, niaouli oil, kanuka oil, manuka oil, mountain pine oil.

In an advantageous embodiment, a storage layer arrangement, in particular in the form of an active ingredient-containing planar matrix arrangement, contains at least 1% by weight, preferably at least 5% by weight, in particular at least 10% by weight, and / or at most up to 50% by weight. preferably at most up to 40% by weight, in particular at most up to 30% by weight, of an active ingredient (based on the dried matrix of the active substance-containing storage layer arrangement).

An advantageous TDS can also be designed as a so-called active transdermal application system. An active transdermal administration system is understood to be a system by means of which the active substance is not or not exclusively released via diffusion from the storage layer arrangement or drug-containing matrix, but for this purpose further technical means, as used for example in iontophoretic systems and / or electrophoretic systems , such as a power source, in particular a battery, are realized.

Also, a composition of the transdermal administration system according to the invention may contain agents which are known to accelerate the delivery of the active ingredient through the skin. These agents are referred to as skin penetration enhancers, accelerators or sorption promoters; they are collectively referred to as "amplifiers" here. Included in this class of agents are those having various mechanisms of action, including those which function to improve the solubility and diffusibility of the drug in the storage layer array, and those which enhance percutaneous absorption, for example, the ability of the stratum corneum for moisture retention, softening the skin, improving the permeability of the skin, acting as a penetration aid or hair follicle opener, or altering the condition of the skin including the boundary layer. Some of these agents may have more than one mechanism of action, but ultimately they serve to improve delivery of the active ingredient from the patch of the invention.

Some examples of penetration enhancers are polyhydric alcohols such as 4-oxo-pentanoic acid, dipropylene glycol, propylene glycol and polyethylene glycol, especially 4-oxo-pentanoic acid, which increase the solubility of the active ingredient, oils such as olive oil, squalene and lanolin, fatty ethers such as cetyl ether and oleyl ethers, fatty acid esters such as Isopropyl myristate which increase the diffusibility of the active ingredient, urea and urea derivatives such as allantoin which affect the ability of keratin to retain moisture, polar solvents such as dimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide and dimethylformamide that affect the permeability of keratin, salicylic acid that softens keratin, amino acids that are penetration aids; Benzyl nicotinate, which is a hair follicle opener; Higher molecular weight aliphatic surfactants, such as Lauryl sulfate salts that alter the surface condition of the skin and the administered drugs. Other agents include oleic and linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate and isopropyl palmitate.

For agents that have low solubility in the drug-containing matrix, preferably in the polymer system, co-solvent may be added for the drug and polymer. Co-solvents such as 4-oxo-pentanoic acid, lecithin, retinol derivatives, tocopherol, dipropylene glycol, triacetin, propylene glycol, saturated and unsaturated fatty acids, mineral oil, liquid silicone, alcohols, butyl benzyl phthalate and the like are depending on the solubility of the active ingredient in the TDS of the present invention suitable. Particularly suitable co-solvents are 4-oxo-pentanoic acid and tocopherol.

In certain embodiments of the invention, a plasticizer or tackifier may be included in the formulation to improve the adhesive properties of the dermal composition. A tackifier is particularly useful in those embodiments where the active agent does not soften the polymer. Suitable tackifiers are known in the art, including aliphatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons, aromatic hydrocarbons, substituted aromatic hydrocarbons, hydrogenated esters, polyterpenes, and hydrogenated tree resins. The tackifier used is preferably compatible with the mixture of polymers.

In preferred embodiments, the tackifier is a liquid silicone (e.g., 360 Medical Fluid, available from Dow Coming Corporation, Midland, MI) or mineral oil. A liquid silicone is suitable for mixtures comprising polysiloxane as the main component. For example, in other embodiments where a polyacrylate is an integral part of the TDS, 4-oxo-pentanoic acid and / or mineral oil, especially 4-oxo-pentanoic acid, is a preferred tackifier.

The composition of this invention may further be provided with various thickening agents, fillers and other additives suitable for use with dermal and transdermal compositions, respectively.

The configuration of the transdermal delivery system of the present invention may be of any shape or size that is necessary or desirable. For example, a beneficial dosage unit size of at least 1 cm ^2, preferably of at least 2.5 cm ^2, particularly preferably of at least 5 cm ^2, in particular of at least 10 cm ^2, and / or of at most 100 cm ^2, preferably of at most 60 cm ^{2 more} preferably of at most 40 cm ² , in particular of at most 25 cm ² , have.

In order to obtain the advantageous TDS, the application of the partial security adhesive layer to the application side of the storage layer arrangement and / or to a region of the backing layer front side projecting beyond the edge of the storage layer arrangement can take place in or between different process steps in the production process.

For example, a partial security adhesive layer may be applied after the provision of the two-dimensional storage layer arrangement containing active ingredient, for example after coating the active substance-containing storage layer arrangement on a film. Such a manufacturing step could be carried out, for example, by laminating a first laminate of active substance-containing storage layer and first film with a second laminate comprising the partial security adhesive layer and a second film, the second film remaining after the lamination process as a protective film or as a backing layer on the resulting total laminate or the second film is removed again as a so-called process film and the resulting laminate comprises the active substance-containing storage layer arrangement, the partial security adhesive layer and the first film.

Alternatively, however, the application of the partial securing adhesive layer can also be effected by means of a printing process on the storage layer arrangement and / or on a region of the backing layer front side projecting beyond the edge of the storage layer arrangement, wherein the storage layer arrangement applied with the aid of the printing method can optionally undergo a drying process.

Insofar as a partial securing adhesive layer is to be applied in a region of the backing layer front side projecting beyond the edge of the storage layer arrangement, the partial security adhesive layer can also be applied with the aid of a doctor blade or a knife pourer or the like. In this case, the application of the partial security adhesive layer can take place simultaneously with the application of the active substance-containing storage layer arrangement to the film or else in successive steps, thereby advantageously reducing the production time or the production costs. However, the method may also be modified by first applying the partial bond adhesive layer to the film is applied and then the active substance-containing storage layer assembly.

Also, an advantageous method can also be configured such that, for example, an active substance-containing storage layer arrangement and a first partial security adhesive layer are simultaneously applied to a film by means of a doctor blade or the like, wherein the partial security adhesive layer takes place in a lateral region of the backing layer front side projecting beyond the edge of the storage layer arrangement , In a next step, a second or further partial securing adhesive layer can be laminated or printed onto the active substance-containing storage layer arrangement and / or over a region of the storage layer arrangement, for example in an area which represents the corners of the finished TDS.

Finally, a further method can also provide for the application of an active substance-free layer to the rear side and / or the application side of the active substance-containing storage layer arrangement. Preferably, a drug-free layer is applied to the application side of the active substance-containing storage layer arrangement, so that the active substance-containing storage layer arrangement also comprises a drug-free layer.

To obtain the advantageous TDS, a manufacturing method may optionally provide for the application of a protective film directly or indirectly to the application side of the storage layer arrangement, wherein the direct application of the protective film to the storage layer arrangement is to be understood such that the protective film is in direct contact with the storage layer arrangement this is applied.

In a preferred embodiment of a transdermal application system, the active substance-containing storage layer is arranged in the form of a storage layer core in the TDS, wherein the back layer in this case projects beyond the storage layer arrangement.

1. (i) Bereitstellen der flächigen wirkstoffhaltigen Speicherschichtanordnung, vorzugsweise Stanzen von wirkstoffhaltigen Speicherschicht-Kernen aus der flächigen wirkstoffhaltigen Speicherschichtanordnung,
2. (ii) Aufbringen der wirkstoffhaltigen Speicherschichtanordnung, vorzugsweise der wirkstoffhaltigen Speicherschicht-Kerne, auf die Rückschicht,

und wobei ferner folgende Schritte enthalten sind:

• (iii) optional Stanzen der transdermalen Applikationssysteme aus dem Gesamtlaminat, wobei jedes transdermale Applikationssystem mindestens einen wirkstoffhaltigen Speicherschicht-Kern umfasst,
• (iv) optional Verpacken der transdermalen Applikationssysteme in Beutel und vorzugsweises anschließendes Versiegeln.

A preferred method for producing such a transdermal administration system comprises in particular the following steps:

1. (i) providing the laminar active substance-containing storage layer arrangement, preferably punching active ingredient-containing storage layer cores from the laminar active substance-containing storage layer arrangement,
2. (ii) applying the active ingredient-containing storage layer arrangement, preferably the active substance-containing storage layer cores, to the backing layer,

and further comprising the steps of:

• (iii) optionally stamping the transdermal delivery systems from the total laminate, each transdermal delivery system comprising at least one active substance-containing storage layer core,
• (iv) optionally packaging the transdermal delivery systems in pouches and preferably subsequent sealing.

By "providing" is meant both an on-site production and a delivery of a two-dimensional storage layer arrangement containing active ingredient. In this case, a storage layer arrangement, in particular a planar matrix arrangement, can already be provided with a protective film covering the application side of the storage layer arrangement, which remains on the latter during production or optionally can be replaced by a protective film in one or more manufacturing steps. Also, only a part of a protective film of the provided two-dimensional active substance-containing storage layer arrangement can be replaced by an alternative protective film.

In a further step, a back layer with a back side and a front side is provided in an analogous manner, wherein the front side of the back layer is applied to the active substance-containing storage layer arrangement. Such a backing layer can optionally be provided with an active substance-free pressure-sensitive adhesive layer preferably located on the front side thereof. Insofar as a backing layer is additionally provided with a protective film for protecting the pressure-sensitive adhesive layer, it is removed or removed before the backing layer is applied to the active substance-containing storage layer.

Of course, the inventive method can also be combined so that first the backing layer is provided and in a next step, the planar active substance-containing storage layer arrangement. Furthermore, an advantageous method can comprise further steps, such as a step for drying the active substance-containing matrix and / or the partial security adhesive layer and / or a step for separating the TDS, preferably for punching, and / or a packaging step and / or a step Printing the TDS and / or bagged TDS.

According to a further preferred method, the provision of storage layer cores from the active substance-containing storage layer arrangement is preferably carried out by punching. Preferably, the storage layer arrangement or are the punched Storage layer cores applied to a film, wherein the film remains after stamping on the storage layer and thus forms a preferably occlusive separation or intermediate layer. Alternatively, a release layer can also be applied to the storage layer in a separate step.

In a next step, the storage layer cores are applied with the release layer according to the above step (ii) on the backing layer. In this case, the backing layer is advantageously at least partially coated with a pressure-sensitive adhesive on its front side in order to ensure adhesion of the backing layer front side to the release layer. Preferably, the backing layer is coated over the entire surface with a pressure-sensitive adhesive. In this case, the backing layer preferably projects beyond the edge of the storage layer cores or the storage layer cores with the release film and forms a so-called overtape.

Finally, an advantageous method or an advantageous device may also have the different steps or stations in a different order, so that, for example, the back layer is provided in a first step or in a first station and the active substance-containing memory layer arrangement is provided in a second station. Instead of the backing layer, a process or protective film can also be provided.

Alternatively, an advantageous method or an advantageous device can have one or more steps or stations in which, for example, an active substance-containing storage layer is applied to a film, for example a backing layer or a process or protective film. In a next step or a next station, the active substance-containing storage layer arrangement can be dried and subsequently the active substance-containing storage layer arrangement can be provided with a backing layer or process or protective film.

Also, as a further step or station, for example, a take-up step or a take-up station may be included in which the active substance-containing storage layer arrangement provided with a backing layer and a process or protective film is wound up and temporarily stored, the intermediate storage also taking place outside the device can.

Of course, a station can also perform more than one function. Thus, for example, the application of the active substance-containing storage layer arrangement and the partial security adhesive layer in a station, at the same time or successively, take place.

Of course, a method or a device can be modified such that it comprises further steps or further devices or stations, such as a printer station, which serves, for example, to print the backsheet of the TDS on its side facing away from the storage layer arrangement.

Finally, the present invention comprises a transdermal delivery system obtainable by one of the methods as previously described.

• 1 eine Untersicht auf ein erstes Ausführungsbeispiel eines erfindungsgemäßen TDS (ohne Schutzfolie).
• 2 einen Längsschnitt durch ein erfindungsgemäßen TDS mit einer partiellen Sicherungsklebeschicht gemäß 1 (jedoch hier mit Schutzfolie).
• 3 eine Untersicht für ein zweites Ausführungsbeispiel eines erfindungsgemäßen TDS (ohne Schutzfolie).
• 4 einen Längsschnitt durch ein erfindungsgemäßes TDS gemäß 3 (jedoch hier mit Schutzfolie).
• 5 eine Untersicht eines dritten Ausführungsbeispiels eines erfindungsgemäßen TDS (ohne Schutzfolie).
• 6 eine Untersicht eines vierten Ausführungsbeispiels eines erfindungsgemäßen TDS (ohne Schutzfolie).
• 7 ein Ausführungsbeispiel für eine Vorrichtung zur Herstellung des erfindungsgemäßen transdermalen Applikationssystems.

Further features of the invention will become apparent from the following description of exemplary embodiments in conjunction with the claims and the figures. It should be noted that the invention is not limited to the embodiments of the described embodiments, but is determined by the scope of the appended claims. In particular, the individual features in embodiments according to the invention can be realized in a different number and combination than in the examples given below. In the following explanation of some embodiments of the invention, reference is made to the accompanying figures. Each show schematically:

• 1 a bottom view of a first embodiment of a TDS according to the invention (without protective film).
• 2 a longitudinal section through a TDS according to the invention with a partial security adhesive layer according to 1 (but here with protective film).
• 3 a bottom view of a second embodiment of a TDS according to the invention (without protective film).
• 4 a longitudinal section through an inventive TDS according to 3 (but here with protective film).
• 5 a bottom view of a third embodiment of a TDS according to the invention (without protective film).
• 6 a bottom view of a fourth embodiment of a TDS according to the invention (without protective film).
• 7 An embodiment of an apparatus for producing the transdermal application system according to the invention.

In the 1 and 2 schematically shows a first embodiment of a TDS according to the invention 100 shown, which by placing a partial adhesive bonding layer on the application side 2 the storage layer arrangement 1 has an improved bond strength. 1 shows a bottom view of the application side of the TDS 100 without protective film and 2 shows a longitudinal section ( along the section line AA in 1 ) through the TDS 100 with protective film.

The TDS 100 has as a storage layer arrangement 1 a drug-containing matrix 1 on the side intended for contact with the skin, the application side 2 , from a removable protective film 4 and on the other side, the back 3 , (indirectly) of a drug-impermeable backing layer 5 is covered. In the present case, the storage layer arrangement 1 on both sides, on the application side 2 and the back 3 , pressure-sensitive adhesive.

To remove the protective film 4 before application of the TDS 100 From its application side as possible to facilitate, is preferably an example silicone-coated protective film 4 used. Suitable materials for such a protective film 4 are, for example, polyester, polypropylene, polyvinyl chloride, aluminum and paper, wherein at least one side of the protective film 4 a silicone coating, polyethylene coating, fluorosilicone coating or polytetrafluoroethylene coating.

The matrix 1 a TDS 100 usually has a thickness of 10 to 500 microns. In the outer edge area of the application side 2 the matrix 1 are each partial adhesive bonding layers 10 arranged. In the present case, the partial circular bonding adhesive layer 10 in the respective corners of the TDS 100 located. The back 3 the matrix 1 is the front side 7 the backsheet 5 assigned.

In an alternative embodiment of the TDS 100 ' which in the 3 and 4 is shown, towers over the backing layer 5 the edges of the matrix 1 in the x and y directions by a distance d , This protruding area 6 may be constant at all regions of the matrix edges, but may also assume different values at different regions of the matrix edges. By the drug-impermeable in the present case and over the edge of the matrix 1 protruding backing layer 5 There is effective protection with regard to unwanted contact of the matrix edges by a person or by packaging material. 3 shows a bottom view of the application side of the TDS 100 ' without protective film and 4 shows a cross section (along the section line AA in 3 ) through the TDS 100 ' with protective film.

In the present case there are four partial security adhesive layers 20 in one over the edge of the matrix 1 projecting area 6 the pressure-sensitive backing layer front side 7 arranged. The partial security adhesive layers 20 are here advantageously rectangular in the respective corners along the Längsache L corresponding to the rectangular shape of the TDS 100 ' arranged so that the shear forces acting on the longitudinal axis L of the TDS effectively through the partial security adhesive layer 20 can be intercepted. It should be mentioned once again that alternative, for example triangular or star-shaped embodiments of the partial security adhesive layer 20 possible are. In the present case, the backing layer is coated on its front side on the area covering the active substance-containing storage layer with a pressure-sensitive adhesive (not shown). Alternatively, however, the backing layer may be only partially coated on a surface covering the active substance-containing storage layer, or it may be coated with a pressure-sensitive adhesive over the whole area, ie also in the entire area projecting beyond the active substance-containing storage layer.

In 5 is another particularly preferred embodiment of the TDS 100 ' shown, with a partial security adhesive layer 30 in one over the edge of the matrix 1 projecting area 6 the backsheet front 7 with a distance d is arranged annularly circumferentially. In this case, the backing layer is coated on its front side only partially on a surface covering the active substance-containing storage layer with a pressure-sensitive adhesive (not shown).

6 shows another (fourth) embodiment of a TDS 100 ' with two partial adhesive layers 50 in the form of a strip which is advantageous along the longitudinal axis L on the application page 2 the outer edge region of the active substance-containing storage layer 1 and four partial circular adhesive layers 40 in one over the edge of the storage layer assembly 1 projecting area 6 the backsheet front 7 are applied. In the present case, not only is the drug-containing storage matrix 1 overlapping area of the backsheet front 7 provided with a pressure-sensitive adhesive, but also the entire surface e of the over the edge of the matrix 1 projecting area 6 the backsheet front 7 , with the partial adhesive bonding layer on the pressure-sensitive adhesive of the over the edge of the matrix 1 projecting area 6 the backsheet front 7 is applied. Alternatively (not shown in a figure) may be a partial security adhesive layer 10 . 20 . 30 . 40 . 50 on the application area 2 the active substance-containing storage matrix 1 and / or on the over the edge of the matrix 1 projecting area 6 the backsheet front 7 be applied annularly circumferentially.

In 7 is a device 200 or plant or production line for the production of TDS invention 100 . 100 ' . 100 ' . 100 '" illustrated, wherein the device is a first station A for providing at least one laminar active substance-containing storage layer arrangement 1 , preferably a matrix arrangement 1 , with an application page 2 and a back 3 a second station B for providing a backing layer 5 with one of the back 3 the storage layer arrangement 1 facing front 7 , and a device C for applying the at least one partial security adhesive layer 10 . 20 . 30 . 40 . 50 having. Another station D allows the application of a protective film 4 on the active substance-containing storage layer arrangement 1 or the partial security adhesive layer 10 . 20 . 30 . 40 . 50 ,

The sequence of the stations also corresponds here to the manufacturing steps (I) . (Ii) . (Iii) and (iv) a preferred embodiment of the method according to the invention.

In a first step (I) become active-containing storage layer cores 1 in station A from the planar active substance-containing storage layer arrangement 1 , which is applied to a release layer, punched out.

In the further station B the production line will be in a next step (Ii) the active substance-containing storage layer cores 1 with the release layer on a pressure-sensitive backing layer 5 applied.

The following is the partial adhesive bonding layer 30 in a third step (Iii) or a third station C or device C by means of a printing process, annularly surrounding the over the edge of the storage layer arrangement 1 projecting area 6 the backsheet 5 applied. In the present case, it is over the edge of the storage layer arrangement 1 projecting area 6 the backsheet 5 coated over the entire surface with a pressure-sensitive adhesive, which is in the pressure-sensitive adhesive properties of the pressure-sensitive adhesive of the partial security adhesive layer 30 different.

Finally, in a further step (Iv) or another device or station D a protective film 4 applied to obtain a total laminate.

Optionally, in subsequent steps or stations (not shown) then transdermal application systems 100 ' are punched out of the total laminate, each transdermal delivery system 100 ' at least one active substance-containing storage layer core 1 includes. In another station or device (not shown), the punched TDS 100 ' packed in bags and then sealed. In principle, the total laminate from step (iv) may also be initially in or outside the device 200 stored and packaged as needed according to the optional steps mentioned above.

In the present case, the partial bonding adhesive layer is applied in a separate station. In principle, however, the application of the partial security adhesive layer (s) can also be distributed over one or more production steps, as explained above.

Examples

Example 1:

To prepare a transdermal system according to the invention with a partial security adhesive layer, a polyacrylate adhesive (DT 387-2054, Henkel, Germany) is diluted in ethyl acetate. In a separate vessel, the active ingredient buprenorphine is suspended in 2-propanol. Subsequently, the prepared mixtures are combined and optionally further diluted with 2-propanol until a solids content of 50% is reached. The mixture is then applied to an intermediate protective film ("Process Film I"), dried and laminated on the side facing away from the protective film with a backing layer, so that a laminate with a drug-containing, pressure-sensitive adhesive matrix is obtained. Suitable materials for a process film are, for example, polyester, polypropylene, polyvinyl chloride, aluminum and paper, wherein at least one side of the process film has a silicone coating, polyethylene coating, fluorosilicone coating or polytetrafluoroethylene coating.

In a separate approach, a drug-free laminate with a matrix consisting of polyacrylate adhesive (DT 387-2051, Henkel, Germany) is produced. For this, the adhesive is diluted with ethyl acetate to a solids content of 40%. The adhesive is then applied to an intermediate protective film ("Process Film II"), dried and laminated with a further intermediate protective film ("Process Film III") with a different from the process film II siliconization and thus different peel force. From this drug-free laminate adhesive dots of a defined size are then isolated in a punching operation (and / or cutting).

After removal of the intermediate protective film (process film I), the partial security adhesive layer in the form of adhesive dots is laminated on the application side of the dried active substance-containing laminate at predetermined intervals in such a way that they come to rest in the region of the corners of the subsequently punched TDS. The application side with the partial security adhesive layer is then provided with a protective film and TDS with a size of 50 cm ² punched.

Example 2:

In a further embodiment, a polyacrylate adhesive (DT 387-2054, Henkel, Germany) is first diluted in ethyl acetate to produce a transdermal system according to the invention with a partial security adhesive layer. In a separate vessel, buprenorphine is suspended in 2-propanol. Subsequently, the prepared mixtures are combined and optionally further diluted with 2-propanol until a desired solids content of 50% is reached. The mixture is then applied to a protective film (process film I), dried and laminated on the side facing away from the protective film with a release layer (Hostaphan MN15 DMF, Mitsubishi Polyester Film GmbH, Germany), so that a laminate with a drug-containing, pressure-sensitive adhesive matrix is obtained , This drug laminate is subsequently punched into cores of size 50 cm ² .

In a further approach, an active ingredient-free adhesive solution comprising a mixture of polyacrylate adhesives (DT 387-2051 and DT 387-2054, Henkel, Germany) is produced. For this, the adhesives are mixed and diluted with ethyl acetate to a solids content of 40%.

To produce the security adhesive layer, another active substance-free adhesive solution comprising a polyacrylate adhesive (DT 387-2051, Henkel, Germany) is produced in a separate batch. For this, the adhesive is diluted with ethyl acetate to a solids content of 40%.

Both drug-free adhesive solutions are used to produce a drug-free laminate ("overtape"). For this purpose, the adhesive solutions are applied to an intermediate protective film (process film II) by means of a doctor blade divided into at least three compartments, dried and laminated on the side facing away from the protective film with a backing layer. The outer compartments of the doctor blade are used for the application of the adhesive solution for the security adhesive layer, so that the resulting drug-free laminate has the securing adhesive layer on the longitudinal sides in strip-like form.

The active substance-free overtape laminate is applied to the application side opposite side of the active ingredient-containing cores so that it rests on the release layer. Subsequently, TDS are punched out with a size of 75 cm ² . The overtape projects beyond the active substance-containing surface of the cores by at least the width of the strips of the security adhesive layer.

It is finally pointed out once again that the examples described above are only exemplary embodiments which can be modified by the person skilled in many different ways without departing from the scope of the invention. Furthermore, the use of the indefinite article "on" or "one" does not exclude that the characteristics in question may also be present multiple times. Likewise, the term "station" and "device" or "plant" does not exclude that the components in question consist of several interacting sub-components, which may also be spatially distributed if necessary.

LIST OF REFERENCE NUMBERS

1

Active substance-containing storage layer arrangement (matrix layer arrangement)

2

Application side of the active substance-containing storage layer arrangement ( 1 )

3

Rear of the active substance-containing storage layer arrangement ( 1 )

4

protector

5

backing

6

projecting area of the backsheet front side ( 7 )

7

Front of the backsheet ( 5 )

10

Partial adhesive layer

20

Partial adhesive layer

30

Partial adhesive layer

40

Partial adhesive layer

50

Partial adhesive layer

d

Width of the protruding area of the backing layer ( 5 ) over the edge of the active substance-containing storage layer arrangement ( 1 )

e

Area of the protruding area of the backing layer ( 5 ) over the edge of the active substance-containing storage layer arrangement ( 1 )

Claims (15)

Transdermal application system (100, 100 ', 100 ", 100'") comprising - at least one planar, active substance-containing storage layer arrangement (1), preferably a matrix arrangement (1), with an application side (2) and a back side (3), - a backing layer (5) with a front side (7) facing the rear side (3) of the storage layer arrangement (1), wherein the storage layer arrangement (1) has a partial securing adhesive layer (10) on its application side (2) in an outer edge region and / or the backing layer (5) on its front side (7) in a region (6) projecting beyond the edge of the storage layer arrangement (1) , 20, 30, 40, 50). Transdermal delivery system according to Claim 1 wherein the partial securing adhesive layer (10, 20, 30, 40, 50) is arranged in a corner and / or along one side of an outer edge region. Transdermal delivery system according to one of the preceding claims, wherein at least each corner a respective partial security adhesive layer (10, 20, 30, 40, 50) is arranged. Transdermal application system according to one of the preceding claims, with a partial securing adhesive layer (30) circulating annularly along an outer edge region of the application system. Transdermal delivery system according to one of the preceding claims, wherein the partial security adhesive layer (10, 20, 30, 40, 50) is round, ring-like, rectangular, triangular or star-shaped. Transdermal delivery system according to one of the preceding claims, wherein the ratio of the area of the partial security adhesive layer (10, 50) located on the application side (2) of the storage layer arrangement (1) to the surface of the application side (2) of the storage layer arrangement (1) and / or the Ratio of the area of the partial securing adhesive layer (20, 30, 40, 50) located in a region (6) of the backing layer front side (7) over the edge of the storage layer arrangement (1) to the surface of the region projecting beyond the edge of the storage layer arrangement (1) (6) the backing layer front side (7) is at least 1: 100, preferably at least 1:50, in particular at least 1:20 and / or at most 1: 0.1, preferably at most 1: 0.5, in particular at most 1: 2 , Transdermal delivery system according to one of the preceding claims, wherein the partial security adhesive layer (10, 50) on the application side (2) of the storage layer assembly (1) is arranged and the area ratio of the partial security adhesive layer (10, 50) to the surface of the storage layer assembly (1) at least 1:70, preferably at least 1:50, more preferably at least 1:40, in particular at least 1:25, and / or at most 1: 5, preferably at most 1:10, particularly preferably at most 1: 15, in particular at most 1:20, is located. Transdermal delivery system according to one of the preceding claims, wherein the partial securing adhesive layer (20, 30, 40) is arranged in a region (6) of the backing layer front side (7) projecting beyond the edge of the storage layer arrangement (1) and the ratio of the area of the partial security adhesive layer ( 20, 30, 40) to the area of the area (6) of the backing layer front side (7) projecting beyond the edge of the storage layer arrangement (1) at at least 1:10, preferably at least 1: 5, in particular at least 1: 2, and / or at most 1: 0.1, preferably at most 1: 0.2, in particular at most 1: 0.5, is located. Transdermal delivery system according to one of the preceding claims, wherein the active substance-containing storage layer arrangement (1) is pressure-sensitive and / or the backing layer (5) on its front side (7) at least in the over the edge of the storage layer assembly (1) projecting area (6) pressure-sensitive wherein the adhesive of the partial securing adhesive layer (10, 20, 30, 40, 50) is preferably different from an adhesive of the active substance-containing storage layer arrangement (1) and / or different from an adhesive in a protruding region of the backing layer (5). Transdermal delivery system according to one of the preceding claims, wherein the partial security adhesive layer (10, 20, 30, 40, 50) contains one or more active ingredients and / or auxiliaries. Transdermal delivery system according to one of the preceding claims, wherein the backing layer (5) is formed occlusively. A method for producing a transdermal administration system, the method comprising the following steps: (i) providing a laminar-active storage layer arrangement (1), preferably a matrix arrangement (1), with an application side (2) and a back (3), (ii) providing a backsheet (5) having a front side (7) facing the rear side (3) of the active substance-containing storage layer arrangement (1), a partial securing adhesive layer (10, 20, 30, 40, 50) being located in an outer edge region of the application side (2) of the storage layer arrangement (1) and / or in an outer edge region of the overlying edge of the storage layer arrangement (1) projecting portion (6) of the back layer front side (7) is arranged. Process for the preparation of a transdermal administration system according to Claim 12 in which the method comprises the following steps: (i) provision of the active substance-containing storage layer arrangement (1), preferably stamping of active substance-containing storage layer cores (1) from the storage layer arrangement (1) containing active ingredient, (ii) applying the active substance-containing storage layer arrangement (1) preferably the active substance-containing storage layer cores (1) on the backing layer (5), and further comprising the following steps: (iii) optionally punching the transdermal delivery systems (100, 100 ', 100 ", 100" `), wherein each transdermal delivery system at least (iv) optionally packaging the transdermal delivery systems (100, 100 ', 100 ", 100'") into pouches and preferably subsequent sealing. Device for producing a transdermal delivery system comprising: a first station (A) for providing at least one laminar active substance-containing storage layer arrangement (1), preferably a matrix arrangement, with an application side (2) and a back side (3), a second station (B) for providing a backing layer (5) with a front side (7) facing the rear side (3) of the storage layer arrangement (1), - A device (C) for applying at least one partial security adhesive layer (10, 20, 30, 40, 50), wherein the partial security adhesive layer (10, 20, 30, 40, 50) in an outer edge region of the application side (2) of the storage layer arrangement (1) and / or in an outer edge region of the overlying edge of the storage layer arrangement (1) projecting portion (6) of the back layer front side (7) is arranged. Use of a transdermal administration system (100, 100 ', 100 ", 100"') according to one of the preceding claims for medical, veterinary or cosmetic use, wherein the active ingredients contained in the storage layer arrangement (1), in particular the matrix arrangement (1), are preferably selected are from the group of analgesics, in particular buprenorphine and / or fentanyl and / or sufentanil and / or alfentanil and / or tapethanol and / or tapentadol, from the group of dopamine agonists, in particular rotigotine, from the group of cholinesterase inhibitors, in particular rivastigmine, from Group of imidazolines, preferably the alpha2-adrenoceptor agonist, in particular clonidine, from the group of tropane alkaloids, preferably the agonists of the muscarinic acetylcholine receptors, in particular scopolamine, from the group of aromatase inhibitors, in particular anastrozole, and / or from the group of hormones , in particular estrogen, estradiol, ethinyl estradiol, norelgestro min and / or etonogestrel.

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