EP3697396A1

EP3697396A1 - Stabilized transdermal delivery system

Info

Publication number: EP3697396A1
Application number: EP18792910.4A
Authority: EP
Inventors: Verena SONNTAG; Martina KESSLER; Hubert Kaffl
Original assignee: AMW GmbH
Current assignee: AMW GmbH
Priority date: 2017-10-20
Filing date: 2018-10-19
Publication date: 2020-08-26
Also published as: WO2019077118A1; US20210154154A1; WO2019077117A1; DE102018120506A1; EP3697395A1; DE102018120505A1; US20200289479A1

Abstract

The invention relates to a process for manufacturing a transdermal delivery system (TDS) comprising at least one active ingredient, the process involving temperature control. The invention further relates to a TDS which can be manufactured using the process of the invention as well as to the use of the TDS of the invention.

Description

stabilized

transdermal delivery system

The present invention relates to a method for producing a transdermal delivery system (TDS) comprising at least one active substance, wherein the method comprises a temperature control. Furthermore, the present invention relates to a TDS which can be produced by the process according to the invention and to the use of the TDS according to the invention.

The transdermal administration of active pharmaceutical ingredients is particularly useful when after oral administration, a large proportion of active substance in the first passage through the mucous membranes of the gastrointestinal tract is metabolized or retained by the liver (first-pass effect) and / or when the drug has a low plasma half-life. The transdermal delivery system (syn. Transdermal therapeutic system, TTS) is adhered to the skin and releases the active ingredient, which is then absorbed through the skin. In this case, the transdermal administration requires that the dosage form used allows the most uniform and controlled release of the active ingredient over a longer period of time.

In order to ensure a sufficiently high plasma level or to bring about a desired therapeutic effect, as high as possible active substance release rates should be achieved on or through the skin in general. The drug release rate depends on the one hand on the permeability properties of the skin for a particular active ingredient and on the other hand on the concentration of the active ingredient in the matrix of the transdermal therapeutic system. The permeability properties of the skin can usually be improved by so-called permeation enhancers. Therefore, to improve the drug delivery rate, it is common to increase the drug concentration in the drug reservoir until the saturation concentration is reached or even exceeded, thereby increasing the thermodynamic activity of the drug.

However, such an increased saturation concentration has the consequence that during storage or during the application period, as a result of the at least temporary exceeding of the saturation concentration, recrystallization of the active ingredient in the active substance matrix can easily occur. Due to recrystallization, the thermodyna- l increases mixing activity of the drug strongly and as a consequence, the drug release rate.

Furthermore, a crystallization of the active ingredient in the active substance-containing matrix can be caused or initiated by introduction of energy, for example by pressure during rolling up of the laminates or during the punching process or by crystallization nuclei.

In the prior art, various systems have been proposed with which high drug concentrations can be achieved in the matrix of a patch and at the same time the recrystallization of the drug is to be prevented.

For example, from US 4,624,665 A transdermal systems are known which contain the drug in the reservoir in microencapsulated form. The construction and production of this system is very complicated, since the active ingredient must be microencapsulated and homogeneously distributed in a liquid phase, which is embedded in further working steps between the backing layer and the membrane of the TTS.

EP 0 186 019 A1 describes active substance patches in which swellable polymers are added to a rubber / adhesive resin mass in water, from which the active substance can be released. However, it has been shown that the release of the drug from these Wirkstoffpfla star is much too low and does not meet the therapeutic requirements.

DE 39 33 460 A1 describes active substance patches based on homopolymers and copolymers with at least one derivative of acrylic or methacrylic acid which are additionally intended to contain substances which swell in water.

DE 195 00 662 A1 describes a transdermal therapeutic system with an active ingredient reservoir based on ethyl cellulose with a high proportion of rosin esters as a tackifying-making resin, which is intended to counteract a recrystallization of the active ingredient and thus reduce its release rate.

Thus, a transdermal system is to be developed, the production of which on the one hand takes place gently for the active ingredient-containing matrix and in which crystallization nuclei and / or crystals gently brought into solution, while ensuring the best possible stability of the active ingredient and the matrix. It is therefore an object of the present invention to prevent the crystallization of active ingredients in the active ingredient-containing matrix, in particular in transdermal therapeutic systems, but to allow the best possible stability of the active ingredient and the matrix. Furthermore, it is an object of the present invention to provide a process for the preparation of TDS with a drug-containing matrix, preferably on a non-aqueous basis, in order to prevent the crystallization of the drug in the matrix without significantly affecting the stability of the drug and the matrix ,

This object is achieved by a method for producing a TDS with a drug-containing matrix, preferably on a non-aqueous basis, according to claim 1, and by a TDS according to claim 4. Furthermore, the object is achieved by an inventive TDS for use according to claim 12.

The present invention therefore relates to a method for producing a transdermal delivery system comprising the steps

(i) providing at least one active ingredient-containing matrix, preferably a non-aqueous based active ingredient-containing matrix,

(ii) applying the at least one active substance-containing matrix to a film in order to obtain a laminate with an active substance-containing matrix,

(iii) optionally drying the laminate comprising the active ingredient-containing matrix,

(iv) optionally punching transdermal therapeutic systems to obtain sheet drug cores,

(v) optionally packaging transdermal therapeutic systems,

(vi) tempering the drug-containing matrix and / or the laminate and / or the punched transdermal therapeutic systems and / or the packaged transdermal therapeutic systems,

wherein the tempering takes place directly, preferably within 7 days, preferably within 3 days, particularly preferably within 2 days, in particular within 24 hours, after the application of the at least one active substance-containing matrix to the film.

Provision is understood here to mean both an on-site production and a delivery of a matrix containing active ingredient, preferably a matrix containing active ingredient, on a non-aqueous basis. In this case, an active substance-containing matrix may already be provided with a protective film covering the application side of the active substance-containing matrix, which in the further course of the production remains on this or optionally can be replaced in one or more manufacturing steps by an alternative protective film.

Tempering is understood as meaning a heating of the active substance-containing matrix and / or the laminate and / or the punched transdermal therapeutic systems and / or the packaged transdermal therapeutic systems to a moderately warm, well-tuned temperature at which the active substance-containing matrix or the active substance itself does not change adversely, for example undergoes no significant physicochemical change and / or crystallization of the active ingredient is brought about. Preferably, a temperature of the punched transdermal therapeutic systems and / or the packaged transdermal therapeutic systems.

According to a preferred embodiment, surface drug cores, z. For example, drug-containing matrix cores are punched before or after application to a protective film of the laminate with a drug-containing matrix and subjected in the further course of the inventive production process. An active ingredient core here is a two-dimensional active substance-containing matrix which advantageously comprises a backing layer or a protective film on its back side and / or on its application side and which is cut, in particular punched, from the above-mentioned active substance-containing laminate with the aid of a cutting tool, in particular a punching tool. becomes. Particular preference is given to laminating active substance cores from a laminate which comprises the active substance-containing matrix, preferably on a non-aqueous basis, and a protective film.

Furthermore, the present invention relates to a transdermal therapeutic system obtainable by a method as described above.

Advantageously, the TDS preparable by the process according to the invention can be stored at a preferred temperature of at least about 5 ° C. Preferably, the temperature for storage of the TDS of the present invention is from about 5 ° C up to about 25 ° C or at a temperature from about 5 ° C up to about 30 ° C or at a temperature from about 5 ° C up to about 40 ° C without crystallizing out a substantial proportion of the active ingredient and / or the stability of the active ingredient and / or the matrix is substantially impaired. Thus, the composition according to the invention or the TDS according to the invention can advantageously be stored for example for several months or even years at room temperature, without a significant proportion of the active ingredient crystallizing out or the stability of the matrix being impaired, for example by a cold flow. In particular, it has been observed that the formation of impurities in the TDS, which is produced by the method according to the invention, can be significantly reduced or the stability of the active ingredient is significantly improved.

Due to the above-mentioned advantageous properties, the TDS according to the invention shows a reproducible and controlled release of the active ingredient on or through the skin even after storage for several months or years. This is particularly relevant for the use of the composition according to the invention in dosage forms such as transdermal therapeutic systems in which delivery of the active substance from a crystal form is substantially delayed or reduced or due to the degradation of the active ingredient a sufficient content of the active ingredient is not available, which is why effective therapy can not be guaranteed.

The transdermal therapeutic system according to the invention also has a reduced moisture content, in particular a reduced water content, which has an advantageous effect on the stability in terms of recrystallization of the active ingredient.

Advantageously, the TDS according to the invention therefore has a water content in the dried matrix of up to about 2 wt .-%, preferably of up to about 1 wt .-%, particularly preferably of up to about 0.75 wt .-%, in particular from to to about 0.5% by weight, more preferably up to about 0.2% by weight.

In their simplest embodiment, the transdermal therapeutic systems of the present invention comprise a backing layer, at least one active agent-containing, preferably non-aqueous, matrix layer disposed horizontally in the TDS and with which the TTS is applied to the skin, and an optional protective layer based on the TDS active ingredient-containing matrix is applied and removed before application of the TTS.

By a matrix on a non-aqueous basis or under a non-aqueous matrix is meant a matrix or several matrices whose constituents, in particular their polymers, consist on a non-aqueous basis. The active substance-containing matrix layer is preferably self-adhesive on a non-aqueous basis. In the following, the wording "non-aqueous based matrix" synonymous with the term "non-aqueous matrix".

However, the present invention also encompasses TTS with a more complex construction, such as with two or more matrix layers of different composition and adhesiveness.

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. For this purpose, the application side can be designed to have a pressure-sensitive adhesive over the whole area, for example by the active substance-containing non-aqueous matrix itself being coated over the entire surface with a pressure-sensitive adhesive or with a self-adhesive or only with pressure-sensitive adhesive over part of the area.

The transdermal therapeutic systems according to the invention are suitable for the administration of basically all active ingredients or combinations of active substances. An active substance in the context of the present invention is understood to be a pharmaceutically active substance or a cosmetic active ingredient and / or an additive and / or a nutrient or a dietary supplement.

The transdermal therapeutic system according to the invention releases the active ingredient from the preferably non-aqueous active ingredient-containing matrix to the skin, wherein at least a portion of the active ingredient can be absorbed systemically. The transdermal therapeutic system can therefore also be used for the dermal delivery of an active substance, for example for local anesthetics, for antibiotic treatment or for the treatment of benign or malignant skin phenomena.

The active substances may be present in various forms in the matrix, depending on which form gives the optimal release property of the active ingredient from the TDS or the matrix. 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, hydrates 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 in which continuous delivery of the drug to or into the organism is maintained. Therefore, the highest possible loading of the matrix with active substance It is desirable if the application time of a patch is long, ie several days to a week. However, a transdermal therapeutic system according to the invention is preferably used for an application period of two to seven days, in particular for an application period of three days.

Finally, the present invention thus also encompasses the medical, veterinary and / or cosmetic use of the plasters according to the invention for delivering active substances to and optionally through the skin of a human or animal body and / or to an environment around the plaster.

Further particularly advantageous refinements and developments of the invention will become apparent from the dependent claims and the following description, wherein the claims of a particular category can also be developed according to the dependent claims of another category and features of different embodiments can be combined to form new embodiments.

According to a preferred method for the preparation of the transdermal delivery system, the temperature control of the active ingredient-containing matrix and / or the laminate and / or the punched transdermal therapeutic systems and / or the packaged transdermal therapeutic systems at a temperature of at least about 50 ° C, preferably at a temperature of at least about 60 ° C, more preferably at a temperature of at least about 70 ° C. At most, this is a temperature at a temperature of up to about 120 ° C, preferably at a temperature of up to about 100 ° C, more preferably at a temperature of up to about 90 ° C, in particular at a temperature of up to about 80 ° C, particularly preferably at a temperature of about 75 ° C, takes place.

The temperature control is preferably carried out over a period of up to 12 hours, preferably over a period of up to 6 hours, more preferably over a period of up to 2.5 hours, in particular over a period of up to about 1 hour, particularly preferably over a period of up to about 30 minutes, most preferably over a period of up to about 15 minutes.

Such an approach advantageously allows a complete solution of the active ingredient and effectively prevents the formation of nuclei, whereby recrystallization of the active ingredient can be prevented or at least delayed. par- In addition, such a temperature control of the punched transdermal therapeutic systems and / or the packaged transdermal therapeutic systems.

In principle, a temperature control may take place in conjunction with or immediately after drying of the active ingredient-containing matrix or of a laminate comprising the active ingredient-containing matrix. However, a temperature control can also take place completely independently of drying or in more than one Temperierungsvorgang immediately after drying. Preferably, a temperature control is independent of the drying of the active ingredient-containing matrix, in particular the temperature is carried out after the drying of the drug-containing matrix comprising laminate, the punched drug cores and / or the packaged transdermal therapeutic systems, in particular the punched transdermal therapeutic systems and / or packed transdermal therapeutic systems.

According to a preferred embodiment, an advantageous transdermal delivery system, which can be produced by the method according to the invention, further comprises an additional active substance-free or active substance-containing, but particularly preferably an active substance-containing application layer. In this case, an active substance-containing application layer preferably comprises a matrix on a non-aqueous basis, which in particular has pressure-sensitive adhesive properties.

However, as noted above, not all layers of the transdermal therapeutic system of the present invention need to contain an active ingredient, but the TDS may have one or more drug-free layers in addition to the at least one or two drug-containing matrix layers, preferably non-aqueous, preferably pressure-sensitive are.

A matrix layer of an advantageous TDS, particularly preferably a second active substance-containing matrix, can be advantageously separated from the first matrix by a control membrane applied between the first and the second matrix. Preferably, the first and second matrix are a nonaqueous based matrix. Thus, for example, a first active ingredient-containing nonaqueous matrix facing the backing layer can be separated by a control membrane from a second active ingredient-containing application layer, which in turn is preferably designed to be self-adhesive. In a corresponding preferred production process, a control membrane is introduced between the matrix and an active substance-containing or drug-free application layer. Such a control membrane may be hydrophobic or hydrophilic. In particular, however, such a control membrane is made hydrophobic. A drug diffusion is made possible by pores in the control membrane, which has a pore diameter of preferably at least about 0.05 μηι, more preferably of at least about 0.075 μηι, in particular of at least about 0.1 μηι having. A preferred control membrane has pores with a pore diameter of up to about 0.5 μηι, more preferably of up to about 0.25 μηι, in particular of up to about 0.2 μηι on.

In particular, a preferred control membrane 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, Polyvi- nylacetate, polyvinyl chlorides, polyvinylidene chlorides, co-polymers, such as acrylonitrile-butadiene-styrene terpolymers, or ethylene-vinyl acetate copolymers. A particularly preferred control membrane comprises a polypropylene and can be purchased, for example, under the name Celgard from the company Azelis (Germany).

In a further preferred embodiment, at least one matrix, preferably a non-aqueous matrix, of a transdermal delivery system according to the invention comprises a mineral oil content, more preferably a second or further matrix preferably nonaqueous base comprises a mineral oil content, the Content of mineral oil in the first and the second or further matrix may be the same or different. Thus, a transdermal delivery system in a first matrix preferably has a mineral oil content of at least about 25% by weight and / or at most up to about 40% by weight and / or a second matrix preferably has a mineral oil content of at least about 35% by weight .-% and / or at most up to about 50 wt .-% have. A suitable mineral oil is commercially available, for example, under the name Klearol from Sonneborn (Netherlands). As a further component, a preferred advantageous TDS may comprise at least one preferably nonaqueous based matrix, preferably also a second preferably nonaqueous based matrix, containing silica. An advantageous content of silicon dioxide in the first matrix, preferably also in the second matrix, is preferably at least about 1% by weight, more preferably at least about 2.5% by weight. At most, a preferred content of silicon dioxide in the first matrix, preferably also in the second matrix, is up to about 10% by weight, more preferably up to about 7.5% by weight, in particular about 5% by weight. , In particular, the silica has hydrophilic properties. Such silicon dioxide, for example, under the name Aerosil ^® 200 Pharma from Evonik Degussa (Germany) commercially available.

Another preferred component of the matrix preferably non-aqueous-based environmentally summarizes a polyvinyl pyrrolidone, in particular a crospovidone (Ph.Eur. 7th Edition Supplement 7.4, Type B) or copovidone, which, for example, under the name Kollidon ^® CL-M or Kollidon ^® VA64 is manufactured by the company BASF (Germany) and can be obtained from the company BTC Europe (Germany).

The polymer or the polymer systems of the TDS according to the invention forming the at least one matrix on preferably non-aqueous basis can in principle be configured to be pressure-sensitive or adhesive-free. However, the polymer or the polymer systems preferably have pressure-sensitive adhesive properties.

As already explained at the outset, the TDS preparable by the process according to the invention comprises a polymer system which forms the matrix or a polymer mixture preferably on a non-aqueous basis, which contains a pharmaceutical active substance. The polymer forming the matrix or the polymer mixture on preferably non-aqueous basis is not fundamentally determinative of the present invention, however, some polymers are better than others. Examples of suitable matrix-forming polymers here include polybutenes or polyisobutylenes, polyacrylates, polysiloxanes, block copolymers such as, for example, styrene-butadiene-styrene block copolymers, silicones and mixtures thereof.

A preferred TDS comprises at least one active substance-containing matrix comprising at least one polybutylene or polyisobutylene and mixtures thereof, such as, for example, mixtures of polybutylenes or polyisobutylenes with different molecular weight. cular weight (MW). It is not excluded that such a mixture also comprises one or more polymers of polybutylene or polyisobutylene, which in particular may have a molecular weight in the range mentioned above. Finally, a first and / or second polyisobutylene polymer may be partially or completely replaced by a first and / or second polybutene or polybutylene. Thus, a preferred blend of polybutylene polymer or polyisobutylene polymers has a first polyisobutylene having a molecular weight of at least about 20,000 g / mol and / or at most about 100,000 g / mol and / or a second polyisobutylene having a molecular weight of at least about 500,000 g / mol and / or of at most about 3500,000 g / mol.

According to a particularly preferred embodiment, such a polymer mixture comprises at least two polybutylene polymers or polyisobutylene polymers, wherein a first of the at least two polybutylene or polyisobutylene polymers preferably has a molecular weight of at least about 30,000 g / mol, particularly preferably about 35,000 g / mol; at most, a first of the at least two polybutylene or polyisobutylene polymers has a molecular weight of up to about 45,000 g / mol.

A second polybutylene or polyisobutylene polymer preferably has a molecular weight of at least about 800,000 g / mol and / or at most about 1,200,000 g / mol. The ratio of a first polybutylene or polyisobutylene polymer and a second polybutylene or polyisobutylene polymer is preferably at least about 0.75 to about 1, more preferably at least about 1 to about 1, in particular about 1, 25 to about 1. At most, a preferred ratio is up to about 2 to about 1, more preferably up to about 1.5 to about 1, more preferably up to about 1.4 to about 1. In particular, a TDS with such a polymer blend comprises an active ingredient the class of antiemetics, more preferably from a tropane alkaloid, especially from scopolamine.

According to a further preferred embodiment, a polymer mixture preferably comprises at least two polybutylene or polyisobutylene polymers, wherein a first of the at least two polybutylene or polyisobutylene polymers preferably has a molecular weight of at least about 30,000 g / mol, particularly preferably about 35,000 g / mol. mol; at most, a first of the at least two polybutylene or polyisobutylene polymers has a molecular weight of up to about 45,000 g / mol. A second polybutylene or polyisobutylene preferably has a molecular weight of at least about 800,000 g / mol and / or at most about 1,200,000 g / mol, in particular of 1 million,000 g / mol, on. According to a further preferred embodiment, the ratio of a first polyisobutylene and / or polybutene polymer and a second polyisobutylene and / or polybutene polymer is up to about 9 to about 0.1, more preferably up to about 7 about 0.5, in particular up to about 6 to about 1. In particular, a TDS comprising such a polymer mixture comprises an active substance from the class of dopamine agonists, particularly preferably from the class of D ₂ agonists and ergot alkaloid derivatives, in particular from rotigotine, pramipexole, ropinirole, cabergoline and / or lisuride, particularly preferably from rotigotine.

In order to prevent a migration of active ingredient from the matrix on a non-aqueous basis, a preferred transdermal delivery system advantageously has an occlusive back layer. As backing layer of a TDS according to the invention, so-called backing films of, for example, polyester with a thickness, preferably of at least about 5 μm, particularly preferably of at least about 10 μm, in particular of at least about 20 μm, particularly preferably of at least about 30 μm are used. At most, a backing film of, for example, polyester has a thickness of preferably up to about 200 μm, particularly preferably up to about 150 μm, in particular of up to about 100 μm, particularly preferably of up to about 50 μm, most preferably of up to about 40 μηη, on. Such backing sheets are flexible and may optionally surround the edges of the matrix layer, i. around the side surfaces of the drug-containing matrix pointing in lateral directions and cover them.

Preferably, a backing layer, in particular an occlusive 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, polyesters and especially polyethylene terephthalates (PET) as well as polycarbonates may be mentioned, polyolefins such as e.g. As polyethylenes, polypropylenes or polybutylenes, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidenchloride, co-polymers, such as acrylonitrile-butadiene-styrene terpolymers, or ethylene-vinyl acetate copolymers. A preferred material of a backing layer is selected from a polyester, particularly preferably from a polyethylene terephthalate. Such a backing layer can be purchased, for example, under the name Scotchpak 1 109 from 3M (USA). A back layer of a TDS according to the invention may also comprise a cover layer or an overtape, which protrudes laterally beyond the edges of the at least one active substance-containing matrix on a non-aqueous basis and thus can facilitate an improved adhesion of the TDS according to the invention to the skin. A preferred cover layer or a preferred overtape is formed occlusively.

The overtape can be multilayered. In particular, an overtape comprises an active ingredient-free adhesive layer and an overtape film, wherein an overtape film preferably comprises a polymer selected from the group of polyolefins, olefin copolymers, polyesters, co-polyesters, polyamides, co-polyamides, polyurethanes and the like. As examples of suitable materials, polyesters and of these, in particular polyethylene terephthalates, as well as polycarbonates, polyolefins, such as. 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 are called. A preferred material of an overtape is selected from a polyester, more preferably from a polyethylene terephthalate.

Insofar as a transdermal application system does not comprise an overtape or an overtape merely serves to protect against a cold flow of the active ingredient-containing matrix, a preferred matrix of the TDS according to the invention is pressure-sensitive, at least on its application side. This ensures a continuous contact of the application side with the skin and thus gives off a continuous active substance to or through the skin of a user.

In one embodiment of the TTS according to the invention, as mentioned above, the active substance-containing matrix or an active ingredient-containing or drug-free application layer can be covered with a peelable protective film, which is also referred to in the jargon as a release liner. When the TTS is stored, this effectively protects the active substance-containing matrix or the application layer from mechanical influences and / or undesired admission of air. Preventing unwanted entry of air prevents decomposition of active substances contained in the matrix, in particular of oxygen-sensitive active substances, and thus improves the long-term stability of the plaster (in the following the TTS is also referred to as plaster). For application of the patch is then removed before attaching the system on the skin first, the protective film of the plaster. For better gripping and thereby a solve the protective film to facilitate, the protective film protrudes over advantageous patches over the edge of the remaining plaster out.

Embodiments of the invention of a transdermal therapeutic system comprise, as mentioned, an active ingredient-containing active substance matrix preferably on a non-aqueous basis. According to a preferred embodiment, the active ingredient is dispersed in the form of a solution in the dried matrix or in the matrix-forming polymer or the polymer mixture. According to a further preferred embodiment, the active ingredient is also present in a non-dried matrix, that is to say for example in a coating solution containing active ingredient, in the form of a solution.

For the purposes of the present invention, a solution is understood as meaning a mixture of a solvent and a solvate, wherein the solvate may be molecularly disperse, ie may have a particle size of less than 1 nm. Furthermore, a solution can also colloidally disperse dissolved particles having a size in the range of 1 nm to 1 μηη and / or coarsely disperse dissolved particles having a size of about 1 μηη.

According to a preferred method, therefore, the active ingredient used for the preparation of the active ingredient-containing matrix is used in the form of a solution. In particular, while a drug solution is used, which was previously dried, so as to reduce the water content of the drug solution. Such drying may preferably be carried out at a temperature of at least about 60 ° C and at most about 70 ° C, preferably over a period of at least about 1 hour and at most about 5 hours, so that the dried active ingredient solution advantageously has a water content in the range of less than about 0.5% by weight, more preferably less than about 0.2% by weight, more preferably less than about 0.1% by weight, most preferably less than about 0.05% by weight , Suitable methods for determining the water content are known to the person skilled in the art. For example, it is possible to determine the water content by means of the Karl Fischer titration.

With the aid of the method according to the invention, it is thus possible to produce a preferred active substance-containing matrix on preferably non-aqueous basis and / or a laminate and / or a transdermal therapeutic system, in particular a transdermal therapeutic system, which has a water content in the dried and tempered matrix of up to about 2% by weight, preferably of up to about 1% by weight, more preferably of up to about 0.75% by weight, in particular of up to about 0.5% by weight, in particular particularly preferably up to about 0.2% by weight (as measured by Karl Fischer titration).

Depending on the desired delivery rate, application time and / or application, a preferred TDS according to the invention, as mentioned above, can comprise more than one active substance-containing matrix, preferably non-aqueous, whereby the active ingredients used can be identical or different and can be present in different concentrations.

Thus, for example, a first matrix layer of a preferred TDS according to the invention contain one hormone from the group of estrogens and a second or further matrix layer a hormone from the group of progestins. Of course, it is also possible to include active substances of different classes, such as, for example, an antiemetic in a first matrix layer and an opioid in a second or further matrix layer of the TTS according to the invention. Alternatively, for example, an antiemetic such as scopolamine may be contained in a first matrix layer and a caffeine in a second matrix layer.

According to a particularly preferred embodiment, however, the TTS according to the invention contains only one active ingredient, which is preferably selected from an antiemetic, more preferably from a tropane alkaloid, especially from scopolamine.

A particularly preferred embodiment comprises a first scopolamine-containing matrix on a non-aqueous basis and a second scopolamine-containing matrix on a non-aqueous basis, wherein the first and the second matrix layer are particularly preferably separated from one another by a control membrane.

In particular, the present invention encompasses a transdermal therapeutic system for use in the treatment of motion sickness. The treatment of motion sickness preferably takes place over an application period of one day to seven days, particularly preferably of up to three days.

Further particularly suitable active substances are selected from the class of the dopamine gonists, more preferably from the class of the D ₂ agonists and the ergot alkaloid derivatives, in particular from rotigotine, pramipexole, ropinirole, cabergoline and / or leucium. rid. Such a transdermal therapeutic system is particularly useful in the treatment of Parkinson's disease, idiopathic restless leg syndrome, amenorrhea, acromegaly, and hyperprolactinemia.

Also particularly suitable active ingredients include anti-dementia drugs, such as Revivigmin, Donezepil, galantamine, memantine, in particular rivastigmine, such TDS is used for the treatment of dementia diseases, in particular for the treatment of brain disorders, such as memory impairment and the ability to concentrate and think , However, such TDSs can also be used in the onset of dementia with personality changes such as mistrust, anxiety, or depressive mood. In particular, TDS can be used to treat Alzheimer's disease.

Finally, particularly suitable active ingredients also include the class of analgesics and sedatives, more preferably opioids, such as buprenorphine, fentanyl, sufentanil, alfentanil and remifentanil, such TDS being preferred for the treatment of pain and / or analgesic sedation.

Other suitable active compounds which may be present in the TDS according to the invention are selected from:

1 . Cardiac active 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. androgenic steroids, such as testosterone, methyltestosterone and fluoxymesterone;

3. Estrogens such as conjugated estrogens, esterified estrogens, estropipate, 17β-estradiol, 17β-estradiol valerate, equilin, mestranol, estrone, estriol, 17β-ethinylestradiol and diethylstibestrol;

4. progestins, such as progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, chlormadinone, ethisterone, etonogestrel, medroxyprogesterone acetate, hydroxyprogeste- roncaproate, norethynodrel, norelgestromin, 17a-hydroxyprogesterone, dydrogesterone, dimethisterone, ethynylestrenol, norgestrel, demegestone, promegestone and megestroacetate;

5. Central nervous system medications, for example, sedatives, hypnotics, anxiolytics, analgesics and anesthetics, such as naloxone, haloperidol, fluphenazine, pentobarbital, phenabarbital, secobarbital, codeine, lidocaine, tetracaine, dibucaine, cocaine, procaine, mepivacaine , Bupivacaine, etidocaine, prilocaine, benzocaine, tapentadol and nicotine;

6. Nutrients and nutritional supplements, such as vitamins, essential amino acids and essential fats;

7. Antiinflammatory agents such as hydrocortisone, cortisone, dexamethasone, flucincinol, triamcinolone, prednisolone, flurandrenolide, methylprednisolone, prednisone, methylprednisolone, corticosterone, paramethasone, betamethasone, ibuprofen, naproxen, fenoprofen, fenbufen, flurbiprofen, ketoprofen, suprofen, indomethacin, Piroxicam, aspirin, salicylic acid, diflunisal, methyl salicylate, phenylbutazone, sulindac, mefenamic acid, tolmetin and the like;

8. antihistamines such as diphenhydramine, dimenhydrinate, perphenazine, triprolidine, pyrroleine, chlorcyclizine, promethazine, carbinoxamine, tripelennamine, brompheniramine, clorprenaline, terfenadine and chlorpheniramine;

9. Respiratory agents such as theophylline and β-adrenergic agonists such as albuterol, terbutaline, metaproterenol, ritodrine, carbuterol, fenoterol, chinterenol, rimiterol, solmefamol, solerenal and tetroquinol;

10. sympathomimetics and parasympathomimetics such as dopamine, norepinephrine, phenylpropanolamine, phenylephrine, physostigmine, pseudoephedrine, amphetamine, propylhexedrine and epinephrine;

11. Miotics, such as pilocarpine and the like;

12. cholinergic agonists such as choline, acetylcholine, methacholine, carbachol, betainechol, pilocarpine, muscarine and arecoline; 13. Antimuscarinic or muscarinic cholinergic antidotes, such as atropine, methscopolamine, homatropine methyl bromide, methantheline, cyclopentolate, tropicamide, propyl heline, dicyclomine and eucatropine;

14. mydriatics such as atropine, cydoperitolate and hydroxyamphetamine;

15. psychoanaleptics such as 3- (2-aminopropyl) indole, 3- (2-aminobutyl) indole and the like;

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. dermatological agents, such as vitamin A and vitamin E;

18. Humoral agents, such as natural and synthetic prostaglandins, for example PGE1, PGE2a and PGF2a and the PGErAnalogon misoprostol;

19. antispasmodics, such as atropine, methantheline, papaverine and methscapolamine;

20. antidepressants such as isocarboxazid, phenelzine, tranylcypromine, imipramine, amitriptyline, trimipramine, doxepin, desipramine, nortriptyline, protriptyline, amoxapine, maprotiline and trazodone;

21. Antidiabetics, such as insulin, and anticancer drugs, such as tamoxifen and methotrexate;

22. Anorectics, such as dextroamphetamine, methamphetamine, phenylpropanolamine, fenfluramine, diethylpropion, mazindol and phentermine;

23. Antiallergic agents, such as antazoline, methapyrilene, chlorpheniramine, mizolastine, pyrilamine and pheniramine;

24. sedatives such as reserpine, chlorpromazine and anxiolytic benzodiazepines such as alprazolam, chlordiazepoxide, clorazepate, halazepam, oxazepam, prazepam, razepam, triazolam, lorazepam and diazepam;

25. Antipsychotics, such as thiopropazate, chlorpromazine, triflupromazine, mesoridazine, piperacetazine, thiondazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chlorprathixene, thiothixene, haloperidol, bromoperidol, loxapine and molindone;

26. Decongestants, such as phenylephrine, ephedrine, naphazoline, tetrahydrozoline;

27. antipyretics such as acetylsalicylic acid, salicylamide and the like;

28. antimigraine agents, such as dihydroergotamine and pizotyline;

29. medications for the treatment of nausea and vomiting, such as chlorpromazine, granisetron, perphenazine, prochlorperazine, promethazine, triethylperazine, triflupromazine and trimeprazine;

30. Antimalarials, such as 4-aminoquinoline, α-aminoquinoline, chloroquine and pyrimethamine;

31. Anti-ulcer agents, such as misoprostol, omeprazole and enprostil;

32. peptides, such as growth hormone releasing factor;

33. drugs for Parkinson's disease, spasticity and acute muscle spasms such as levodopa, carbidopa, amantadine, apomorphine, brorocriptone, selegiline (deprenyl), trihexyphenidyl hydrochloride, benztropine mesylate, procyclidine hydrochloride, baclofen, diazepam and dantrolene;

34. antiestrogen or hormone agents, such as tamoxifen or human chorionic gonadotropin;

35. aromatase inhibitors, such as anastrozole;

36. Cholinesterase inhibitors, such as physostigmine or pyridostigmine; 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, passage through the skin is the rate-limiting step for 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.

Thus, preferably, the amount of the active ingredient in the system may be at least about 0.3% by weight, preferably at least about 1% by weight, more preferably at least about 2.5% by weight, especially at least about 5% by weight % and / or of up to about 50% by weight, preferably of up to about 30% by weight, more preferably of up to about 20% by weight, in particular of up to about 10% by weight, vary.

To form a drug-containing matrix on preferably non-aqueous basis or drug-free layer of the TTS are all commonly suitable for transdermal therapeutic systems materials. Preferably, a matrix z. For example, tackifiers may be added to result in a self-adherent (i.e., pressure-sensitive adhesive) drug-containing matrix, as an alternative or in addition to the aforementioned skin-side pressure-sensitive adhesive layer. 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. As polyisobutylenes, homo- and copolymers of (meth) acrylates, polyvinyl ethers, polyisoprene rubbers, styrene-butadiene copolymers or styrene-butadiene-styrene copolymers and silicones. Of the (meth) acrylate copolymers, for example, the copolymers of alkyl acrylates and / or alkyl methacrylates and other unsaturated monomers may be mentioned, such as acrylic acid, methacrylic acid, acrylamide, dimethylacrylamide, dimethylaminoethylacrylamide, acrylonitrile and / or vinyl acetate.

It is also possible with preference to use so-called solubility promoters or cosolvents and / or permeation enhancers, for example from the group of alcohols, preferably from the group of aliphatic alcohols with a terminal OH group, in particular with a chain length between 10 and 14 carbon atoms, particularly preferably dodecanol. Further preferred cosolvents and / or permeation enhancers can be selected from lauryl lactate, vitamin E, aloe vera oil, propylene glycol monolaurate and / or from the group of the propyl esters, in particular from isopropyl myristate.

In particular, a content of one or more of the preferred cosolvents and / or permeation enhancers will result in a controlled and sustained release of the preferred transdermal therapeutic system, particularly a transdermal therapeutic system comprising an active agent of the class of dopamine agonists, most preferably of the class of D ₂ agonists and the parent coral alkaloid derivatives, in particular from rotigotine, pramipexole, ropinirole, cabergoline and / or lisuride, particularly preferably from rotigotine. Advantageously, a content of a cosolvent or a permeation enhancer in the active ingredient-containing matrix on a non-aqueous basis is at least about 1% by weight, in particular at least about 5% by weight, more preferably at least about 7% by weight and / or preferably at up to about 20 wt .-%, in particular up to about 10 wt .-%, particularly preferably up to about 8 wt .-%.

In principle, a suitable basis weight of the active substance-containing dried matrix is in a range which is usual for transdermal therapeutic systems. However, a preferred basis weight of at least one active substance-containing matrix preferably non-aqueous basis of at least about 10 mg / 10cm ^2, more preferably at least about 20 mg / 10 cm ^2, in particular at least about 30 mg / 10 cm ^2, particularly preferably at least about 35 mg / 10 cm ² and / or preferably up to about 100 mg / 10 cm ² , more preferably up to about 80 mg / 10 cm ² , in particular up to about 70 mg / 10 cm ² , in particular preferably up to about 65 mg / 10 cm ² .

Insofar as the TDS according to the invention has more than one matrix, the basis weight of a first or further matrix preferably moves at at least about 30 mg / 10 cm ² , more preferably at least about 35 mg / 10 cm ² , in particular at least about 40 mg / 10 cm ² . At most, the preferred basis weight of a first or a further matrix is up to about 70 mg / 10 cm ² , more preferably up to about 65 mg / 10 cm ² , in particular up to about 60 mg / 10 cm ² . However, in this case, a first or further matrix does not have to have the same basis weight, but rather a first matrix may have a basis weight of at least about 50 mg / 10 cm ² to about 65 mg / 10 cm ² and another matrix a basis weight of, for example, at least about 35 mg / 10 cm ² to about 55 mg / 10 cm ² . A matching of the basis weights to the total layer thickness or the total basis weight of the TDS according to the invention seems to make sense if a first initial release of an active substance from an application layer with an active substance content with a second longer lasting active substance should be coordinated from a matrix layer facing the back layer. Also, when selecting the basis weight, the influence on the wearing properties of the TDS must be considered.

In order to keep the moisture content, in particular the water content, as low as possible in the active substance-containing matrix of the TDS according to the invention, according to a preferred method in the production of the laminate, a backing layer and / or a protective film having moisture-absorbing material properties, such as, for example, materials comprising a silica Gel formulation, to be used.

Alternatively or additionally, a preferred method according to the invention may take into account the use of a pre-dried packaging material, in particular a bag, in which the TDSs are packaged, which may further be provided with moisture-absorbing materials.

Also, a moisture absorbent material, such as that available under the name Activ-Film ™ from CSP Technologies, may be incorporated into the bag in a packaging step, whereby the moisture content, in particular the water content, in the environment of the packaged TDS during the Storage can be additionally reduced. Of course, even a bag already provided with a moisture-absorbent material can be used directly for packaging the TDS.

In the course of drying and / or temperature control of the active ingredient-containing matrix, it can preferably be carried out under a nitrogen atmosphere in order to minimize the access of oxygen to or into the active substance-containing matrix and thus prevent possible oxidation and / or recrystallization of the active ingredient. Alternatively or additionally, it is also possible to use oxygen and / or carbon dioxide-absorbing materials.

Further features of the invention will become apparent from the following description of exemplary embodiments in conjunction with the claims. The individual features may be realized in one embodiment according to the invention, per se or in number, and do not limit the scope of the present invention. Examples

Examples 1 and 2 below show a preparation of inventive transdermal therapeutic systems and stability studies.

Example 1: Exemplary embodiment for the preparation and stability study of a scopolamine TDS according to the invention

A solution of 40.3% by weight of polyisobutylene (PIB) adhesive (Oppanol B80, BASF), 25.8% by weight of PIB adhesive (Oppanol B10, BASF), 20% by weight of mineral oil (paraffin Ph. Eur., Klearol, Fa. Sonneborn), 5 wt .-% silica (silica Ph.Eur., High purity and amorphous highly disperse silica, hydrophilic, Aerosil 200 Pharma, Evonik), 9 wt .-% scopolamine base ( Hyoscin, Fa. Alkaloids Private Limited) and an adequate amount of chloroform was on a one-side siliconized polyethylene terephthalate (PET) film (Primeliner PET 75μηι 1 S, Fa. Loparex) streaked so that after drying a matrix layer with a weight of about 56 g / m ² is formed. To remove the solvent was dried at 60 ° C for 15 min. The matrix layer was laminated with a one-side siliconized polyester protective film (Mitsubishi).

A solution of 33.8% by weight of PIB adhesive (Oppanol B80, BASF), 21, 6% by weight of PIB adhesive (Oppanol B10, BASF), 36.3% by weight of mineral oil (paraffin Ph Eur., Klearol, Fa. Sonneborn), 5 wt .-% silica (silica Ph.Eur., High purity and amorphous fumed silica, hydrophilic, Aerosil 200 Pharma, Evonik), 3.3 wt .-% scopolamine base (Hyoscine, Fa. Alkaloids Private Limited) and an adequate amount of chloroform was spread on a one-side siliconized polyethylene terephthalate (PET) film so that after drying an application layer (= adhesive layer) with a basis weight of about 45 g / m ² is formed , To remove the solvent was dried at 60 ° C for 15 min.

A microporous polypropylene membrane impregnated with mineral oil (paraffin Ph. Eur., Klearol, Fa. Sonneborn) (thickness 25 μm, microporous (porosity 41%), Celgard) was laminated onto the application layer. The PET film was peeled off the matrix layer and the matrix layer was applied to the application layer / membrane laminate. The determination of the water content of the active ingredient-containing matrix on a non-aqueous basis by means of Karl Fischer titration and gave a content of 0.24 wt .-% water.

The resulting TDSs were then treated as follows:

T1: the punched and bagged TDS were shipped within 24 hours of their

Preparation tempered for 24 h at 75 ° C;

T2: there was no tempering of the stamped and bagged TDS;

The transdermal therapeutic systems were each at room temperature (RT) and at 40 ° C / 75% r. F. (relative humidity) stored. The stability studies show that within the test period of six months in the TDS invention, which was tempered 24 hours after its preparation, no drug crystals had formed. In contrast, in TDSs which were not tempered, active-substance crystals can already be observed after 1.5 weeks (see Table 1).

Table 1: Stability studies for the crystallization of active ingredient in tempered (T1) and non-tempered (T2) TDS.

Example 2:

A solution of 26.7% by weight of polyisobutylene (PIB) adhesive (Oppanol N80, BASF), 33.3% by weight of PIB adhesive (Oppanol B10, BASF), 27% by weight of mineral oil (paraffin Ph.Eur., Klearol, Fa. Sonneborn), 5 wt .-% silica (silica Ph.Eur., High purity and amorphous highly disperse silica, hydrophilic, Aerosil 200 Pharma, Evonik), 8 wt .-% scopolamine base ( Hyoscin, Fa. Alkaloids Private Limited) and an adequate amount of 2-propanol and heptane was on a one-side siliconized polyethylene terephthalate (PET) film (Primeliner PET 75μηι 1 S, Fa. Loparex) streaked so that after drying a matrix layer with a Basis weight of about 56 g / m ² is formed. To remove the solvent was dried at 75 ° C for 30 min. The matrix layer was laminated with a one-side siliconized polyester protective film (polyester film from Mitsubishi).

A solution of 24.3% by weight of PIB adhesive (Oppanol N80, BASF), 30.4% by weight of PIB adhesive (Oppanol B10, BASF), 37% by weight of mineral oil (paraffin Ph.Eur , Klearol, Fa. Sonneborn), 5 wt .-% silica (silica Ph.Eur., High purity and amorphous fumed silica, hydrophilic, Aerosil 200 Pharma, Evonik), 3.3 wt .-% scopolamine base (hyoscine Alkaloids Private Limited) and an adequate amount of 2-propanol and heptane was coated on a one-side siliconized polyethylene terephthalate (PET) so that after drying an application layer (= adhesive layer) having a basis weight of about 45 g / m ² arises.

To remove the solvent was dried at 75 ° C for 30 min. A microporous polypropylene membrane (thickness 25 μm, microporous (porosity 41%), Celgard) impregnated with mineral oil (paraffin Ph. Eur., Klearol, Fa. Sonneborn) was laminated onto the application layer. The PET film was peeled off from the matrix layer and the matrix layer applied to the laminate of application layer and membrane. Subsequently, the laminate was punched to obtain transdermal therapeutic systems (TTS), which were subsequently bagged.

The determination of the water content of the active ingredient-containing matrix on a non-aqueous basis by means of Karl Fischer titration and gave a content of 0.24 wt .-% water. Investigations on the crystallization of the active ingredient scopolamine:

The bag-packed TTSs thus obtained were tempered for 24 hours at 75 ° C. in a drying oven for 24 hours and prepared for a period of 6 months at a temperature of 25 ° C./60% r. F. stored. Investigations on the crystallization of the active substance scopolamine showed that no crystals of the active ingredient had formed in any of the TDS according to the invention within the test period of 6 months.

Studies on the chemical stability of the active substance scopolamine:

In addition, studies were conducted on the chemical stability of the active substance. In a first step, it was investigated how the duration of the temperature control at an exemplary temperature of 75 ° C on the chemical stability of the active ingredient or the formation of impurities.

The bagged TDS were tempered for this purpose for one hour, 5.5 hours, 13.5 hours or 24 hours at a temperature of 75 ° C. Subsequently, the drug-containing matrix was examined for impurities resulting from drug degradation. The results of the tests are shown in Table 2.

From Table 2 it can be seen that a tempering period from about 13.5 hours causes an increase in the impurity profile, in this case the impurities "B" and "C". A tempering time of about 1 hour and about 5.5 hours, however, shows only a small effect on the drug degradation.

Table 2: Stability of the active substance in bagged TDS as a function of the duration of the Temperierungsdauer. VU = contamination; n.d. = not detected;

In a next step TDS, which were tempered for 30 minutes or for 5 hours at a temperature of 75 ° C, each for 6 months at a temperature of 25 ° C / 60% r. F. stored. The studies also show only a small amount of active ingredient degradation over the entire investigation period of 6 months when the TDS was tempered at a temperature for 30 minutes or for 5 hours at a temperature of 75 ° C. (see Tables 3A and 3B).

Table 3A: Stability of the active ingredient in tempered TDS after storage for 6 months at 25 ° C / 60% r. F. when heated to 75 ° C for 30 minutes. VU = contamination; RL = reporting level (0.1%); n.d. = not detected;

Table 3B: Stability of the active ingredient in tempered TDS after storage for 6 months at 25 ° C / 60% r. F. when heated to 75 ° C for 5 hours.

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.

Claims

claims

1 . A method of making a transdermal delivery system comprising the steps

(v) optionally packaging transdermal therapeutic systems,

(vi) tempering the non-aqueous based drug-containing matrix and / or the laminate and / or the punched transdermal therapeutic systems and / or the packaged transdermal therapeutic systems

wherein the tempering takes place directly, preferably within 7 days, preferably within three days, particularly preferably within two days, in particular within 24 hours, after the application of the at least one active substance-containing matrix to the film.

2. A method for producing a transdermal delivery system according to claim 1, wherein the temperature control at a temperature of at least about 50 ° C, preferably at a temperature of at least about 60 ° C, more preferably at a temperature of at least about 70 ° C and / or at a temperature of up to about 120 ° C, preferably at a temperature of up to about 100 ° C, more preferably at a temperature of up to about 90 ° C, especially at a temperature of up to about 80 ° C, most preferably at a temperature of about 75 ° C, takes place.

3. A method for producing a transdermal delivery system according to any one of claims 1 or 2, wherein the temperature over a period of up to 12 hours, preferably over a period of up to 6 hours, more preferably over a period of up to 2.5 hours , in particular over a period of up to about 1 hour, particularly preferably over a period of space of up to about 30 minutes, most preferably over a period of up to about 15 minutes.

4. transdermal delivery system, wherein the transdermal delivery system is obtainable by a method according to any one of claims 1 to 3.

5. Transdermal delivery system according to claim 4, wherein the transdermal delivery system further comprises an active ingredient-free or drug-containing pressure-sensitive adhesive application layer.

6. Transdermal delivery system according to claim 4 or 5, which has a control membrane between the matrix, preferably the non-aqueous Matirx, and the drug-free or drug-containing pressure-sensitive adhesive application layer.

7. Transdermal delivery system according to one of the preceding claims 4 to 6, wherein at least one non-aqueous based matrix comprises a mineral oil.

8. Transdermal delivery system according to one of the preceding claims 4 to 7, wherein at least one matrix, preferably the non-aqueous based matrix, comprises a silicon dioxide.

9. Transdermal delivery system according to one of the preceding claims 4 to 8, wherein the matrix, preferably the non-aqueous matrix, at least one polymer, preferably at least two polymers which are selected from the group of polybutylenes, especially the polyisobutylenes comprises.

10. Transdermal delivery system according to claim 9, wherein one of the at least two polybutylenes, especially the polyisobutylenes, a molecular weight of at least about 20,000 g / mol and / or of at most about 100,000 g / mol and / or a second polybutylene, in particular a polyisobutylene, a Molecular weight of at least about 500,000 g / mol and / or at most about 3,500,000 g / mol.

1 1. Transdermal delivery system according to one of the preceding claims 4 to 10, which has an occlusive backing layer.

12. Transdermal delivery system according to one of the preceding claims 4 to 11 for medical, veterinary or cosmetic use.

A transdermal delivery system according to any one of claims 4 to 12, comprising an antiemetic, a dopamine agonist, an analgesic, a sedative and / or an anti-dementive.

14. Transdermal delivery system according to claim 13, wherein the antiemetic agent is selected from a tropane alkaloid, in particular from scopolamine, and wherein the dopamine agonist is selected from a D ₂ agonist, in particular from rotigotine, and wherein the analgesic is selected from buprenorphine and / or fentanyl, and wherein the anti-dementive agent is selected from rivastigmine.

A transdermal delivery system according to any of the preceding claims 4 to 14 for use in the treatment of motion sickness, Parkinson's disease and / or restless leg syndrome, pain, especially cancer pain, and Alzheimer's disease.