DE102007021549A1 - Transdermal therapeutic system containing at least two opioids - Google Patents

Abstract

The invention relates to a transdermal therapeutic system (TTS) with two or more opioid drugs, the one covering layer, optionally a removable protective layer and a drug-containing layer or a drug-containing reservoir or multiple drug-containing layers or more active substance-containing reservoirs between the cover layer and the optional removable protective layer is / are included.

Description

The Invention relates to a transdermal therapeutic system (TTS), containing at least two opioid drugs.

TTS are active ingredient-containing patches that over the active ingredient the skin into the underlying tissue and blood vessels so that it can be systemically effective. TTS are suitable in particular for the administration of active substances with short biological Half-life, since the duration of action by the over a longer Periodic delivery of the active substance via a TTS can be extended.

Out From a historical point of view, the TTS is divided into two big classes one, namely in matrix systems and membrane-controlled Reservoir systems. The latter have a polymer membrane permitting the permeation of a Control and draw drug from a reservoir into the skin characterized by a relatively constant liberation. A disadvantage: In membrane-controlled reservoir systems, the drug may be used in mechanical violation of the control membrane released abruptly be "dose-dumping"; this increases the risk of unwanted Drug reactions.

Matrix Diffusion Controlled Systems are simpler because they are not a separate control element to have. Drug release is by a lipophilic or hydrophilic Controlled polymer matrix in which the active ingredient dissolved or homogeneously dispersed. Matrix TTS put the active ingredients not always time constant free. A "dose-dumping" is not possible so that this drug form with highly active drugs as safe applies.

Transdermal therapeutic systems containing an opioid drug have been used for years. For example, TTS are used with the drug fentanyl for years to treat severe chronic pain, such as the membrane-controlled reservoir system Durogesic ^®. Furthermore TTS are available with the opioid drug buprenorphine to Basisanalgesie in severe pain, for example, the matrix TTS TRANSTEC ^®.

By The transcutaneous administration of the opioid agents will be the gastrointestinal Bypassed passage and associated first-pass metabolism, resulting in a higher bioavailability than under oral medication. The plasma levels achievable with TTS are usually proportional to the respective patch size. Similar In a continuous intravenous infusion, the plasma levels remain above the Time in which the TTS is in contact with the skin, almost constant. To maintain constant drug levels over a longer period of time To ensure the TTS in regular Intervals are changed, for example, after each about 72 hours.

at chronic use of opioid drugs are becoming common adverse drug reactions observed. Especially it often comes with chronic use to the training of Tolerance, d. H. to a weakening effect due to habituation to the active ingredient. When training a tolerance must always higher drug dose administered to the same Effect to achieve. Due to the strong respiratory depressive effect of Most opioid agents can increase tolerance training lead that a drug dose is required, the is lethal when administered by respiratory paralysis. In addition, in a long-term use mental and physical dependencies are formed. When weaning of the drug can then trigger withdrawal symptoms such as arousal, nervousness, Insomnia and hyperkinesia occur. For chronic use of opioid drugs it is because of intolerance, Side effects and too short or weak effect therefore often necessary to change the active ingredient.

The Formation of the above-mentioned adverse drug reactions how tolerance and dependence can be slowed down or prevent by administering different opioid drugs become. Without training tolerance can also be the drug dose proportion of each opioid drug kept low, allowing increased drug concentrations be avoided in the blood, which increases the risk of unwanted Drug effects decreased, especially of lethal Respiratory paralysis. Also, the risk of addiction can through the relatively low-dose Administration of different opioid drugs can be reduced. Different opioid drugs bind to different opioid receptors, whereby one necessary for the education of dependency Habituation of a receptor to the presence of a certain Opioid drug can be avoided.

All previously used TTS with opioid drugs are formulated exclusively as single-agent, ie the TTS contains only a single opioid drug. This is due to the fact that opioid drugs can bind to different opioid receptors, namely μ-, κ- and δ-receptors, and can have both agonistic and antagonistic properties. For example, buprenorphine binds to μ-, κ- and δ-receptors and has partial agonistic properties at the central μ-opiate receptors and at the same time shows antagonistic effects at the κ and δ receptors. In combination with μ-agonists buprenorphine acts antagonistically, ie buprenorphine can reduce the effect of pure μ-agonists such as fentanyl reduce or inhibit and even lead to an opposite effect. With a time-overlapping administration of two or more opioid drugs thus unpredictable effects could occur with adverse effects. For example, the analgesic effect of the opioid drugs could be absent. In particular, respiratory depressions could occur, which can lead to death; a dreaded characteristic side effect in the treatment with opioid drugs. Therefore, a time-overlapping transdermal administration of two or more opioid drugs has hitherto been considered excluded.

task the invention is to provide a transdermal therapeutic system, the time-overlapping administration of two or three allows more opioid drugs and development prevented by tolerance or at least delayed.

According to one Embodiment, this object is achieved by a transdermal therapeutic system with two or more opioid drugs, a covering layer, an active substance-containing layer or an active substance-containing Reservoir or more active ingredient-containing layers or more active substance-containing Reservoirs and optionally a removable protective layer, e.g. Legs Peel-off film. The active substance-containing layer (s) or Reservoir (s) is / are between the covering layer and the optional one Protective layer arranged.

According to the invention the two or more opioid drugs in the / a drug-containing Layer / reservoir or the active substance-containing layers / reservoirs in solution or as a dispersion.

According to the invention TTS is a matrix, drug-in-adhesive monolayer, or drug-in-adhesive multilayer system be.

According to the invention the two or more opioid drugs in one or more drug-containing Layers, in particular matrix layers, be contained.

According to the invention the system comprises several active ingredient-containing layers, in particular matrix layers, and each of the two or more opioid drugs can be separated be contained in each one layer.

According to the invention at least one of the opioid active ingredients molecule-dispersed in one active ingredient-containing layer or the active substance-containing layers.

According to the invention the TTS will be a reservoir system.

According to the invention at least one of the two or more opioid drugs contained in a reservoir be.

According to the invention the two or more opioid drugs are contained in a reservoir.

According to the invention in a reservoir system, at least one of the two or more opioid drugs be contained in a matrix layer.

According to the invention the TTS have an adhesive layer on the skin side.

According to the invention the adhesive layer is a self-adhesive polymer matrix layer.

According to the invention the self-adhesive polymer matrix layer as a drug-containing layer be formed and at least one of the two or more opioid drugs contain.

According to the invention the adhesive layer comprise or consist of at least one component, which is selected from the group consisting of natural Rubber, synthetic rubber, acrylic adhesive, polyvinyl acetate, Polyisobutylene, silicone, especially polydimethylsiloxane, and hydrogels, in particular high molecular weight polyvinylpyrrolidone, polyvinyl alcohol and oligomeric polyethylene oxide.

According to the invention the adhesive layer comprise or consist of a polyacrylate.

According to the invention the polyacrylate comprises monomers selected from the group consisting of from n- or iso-butyl acrylate, propyl acrylate, methyl acrylate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate consists.

According to the invention the synthetic rubber is a styrene-butadiene-styrene block copolymer or a styrene-butadiene block copolymer.

According to the invention the one or more active ingredient-containing layers and / or the adhesive layer contain a crosslinking agent.

According to the invention the TTS as a further layer additionally a control membrane contain.

According to the invention, a control membrane may be arranged on the skin-remote side of an adhesive layer, wherein the adhesive layer is pure Adhesive layer, ie adhesive layer without active ingredient, or may be formed as a drug-containing layer.

According to the invention, the C _{max of} one of the two or more opioid active substances can be achieved after 4 to 30 hours, in particular after 10 to 24 hours.

According to the invention, the C _{max of} a second of the two or more opioid active substances can be achieved after 30 to 60 hours, in particular after 36 to 50 hours.

According to the invention the two or more opioid drugs are selected the group comprising hydromorphone, buprenorphine, nalbuphine, levomethadone, Dextromoramide, oxycodone, fentanyl, sufentanil, alfentanil and remifentanil or their pharmaceutically acceptable salts.

According to the invention the opioid agents buprenorphine and fentanyl used in the TTS or their pharmaceutically acceptable salts.

According to the invention, the C _max of fentanyl can be achieved after 4 to 30 hours, in particular after 10 to 24 hours, and the C _max of buprenorphine can be reached after 30 to 60 hours, in particular after 36 to 50 hours.

According to the invention the TTS additionally one or more penetration aids contain.

According to the invention the TTS additionally contain one or more preservatives.

According to the invention the TTS additionally contain one or more supersaturation stabilizers.

According to the invention the TTS additionally contain one or more antioxidants.

According to the invention the TTS additionally contain one or more thickening agents.

According to the invention the TTS additionally one or more substances from the group moisturizers, skin protectants and buffering agents.

One TTS according to the invention can via a In addition, the tolerances can be applied treatment with a single opioid drug.

According to another embodiment, the TTS may be a system having one or more near-skin electrodes and having one or more counterelectrodes near the capping layer, as shown in FIG EP 03 005 664.2 is described.

In a further embodiment, the TTS may be an iontophoretic system, as described, for example, in US Pat DE 37 03 321 . WO 87/04936 . WO 91/16077 . WO 92/04938 . WO 00/53256 . US 3,991,755 . US 4 141 359 . US 5,415,629 and US 5,944,685 is described.

Out the previous description follows that it has been found that by the temporally overlapping delivery of two or more opioid drugs by means of a TTS tolerance development and the risk of developing mental and physical dependence is reduced.

In In one embodiment, the invention relates to a method for administration of the two or more opioid drugs. The procedure includes the application of an inventive TTS containing the opioid drugs in a therapeutically effective amount contains, on the skin of a living thing that needs it.

In In another embodiment, the invention comprises a TTS according to the invention with a therapeutic effective amount of the two or more opioid drugs or pharmaceutically compatible salts thereof, together with instructions packed, which relates to the application of the patch on the skin.

In In another embodiment, the invention relates to a TTS, which includes a cover layer and a drug-containing polymer matrix adhesive layer which comprises a therapeutically effective amount of the two or more Contains opioid drugs.

In Yet another embodiment relates to the invention a TTS that has a cover layer, a reservoir with at least one the two or more opioid drugs in a therapeutically effective Amount, for example fentanyl and / or buprenorphine, a control membrane, in particular a control membrane of poly (ethylene vinyl acetate) copolymer, and an active ingredient-containing polymer matrix adhesive layer having at least one of two or more opioid drugs in a therapeutic effective amount, for example fentanyl.

Furthermore, a TTS according to the invention can be used beyond the period in which tolerances usually occur in the treatment with a single opioid active substance. This means that the development of tolerance to at least two opioid drugs used in combination, if any, is greatly delayed in time compared to the ent Tolerance when using only a single opioid drug. An inventive TTS can therefore be used, for example, for a longer period of time for the treatment of pain, as a TTS with only one opioid drug.

These and further features of the invention, details and advantages will become apparent from the following description of examples of the invention and the claims explained in more detail.

Here, the term "C _max " means the maximum active substance concentration in the plasma, which value can be easily determined by standard methods known to the person skilled in the art for determining plasma concentrations of active substance.

As used herein, the term "therapeutically effective amount" means the amount of opioid drug required to achieve the desired effect, for example, analgesic. Therapeutically effective amounts are described for most opioid drugs in textbooks (cf. eg. General and Special Pharmacology and Toxicology, Klaus Aktories, Urban & Fischer Verlag, Munich, 9th ed. (2005) ).

The The term "living being" herein means any Animal, preferably a mammal, and more preferred a person.

The term "pharmaceutically-acceptable salt (s)" as used herein means a salt of the particular active ingredient which retains the biological activity and properties of the neutral active ingredient and is suitable for pharmaceutical use Pharmaceutically acceptable salts include Salts of acidic or basic groups which may be present in the opioid drugs The pharmaceutically acceptable addition of salts of basic opioid drugs used in the present invention are those which form non-toxic salts, ie salts, the pharmacologically acceptable anions such as hydrochloride , Hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, panthotenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate , Methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and Pamoa t included. Opioid drugs according to the invention which contain a basic group, for example an amino moiety, can form pharmaceutically acceptable salts with amino acids. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, magnesium, zinc, and ammonium. An overview of pharmaceutically acceptable salts is found, for. In Berge et al., J. Pharm. Sci., 66, 1-19 (1977) which is hereby incorporated by reference.

Suitable penetration aids for use in the invention include, for example, ethyl alcohol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, N-methylpyrrolidone and fatty acid esters such as e.g. Isopropyl myristate, methyl laurate, glycerol monooleate and propylene glycol monooleate. In particular, the penetration aid may be an aloe composition as described in U.S. Pat DE 103 40 428 A1 is disclosed.

suitable Preservatives include, for example, alcohols, quaternary Amines, organic acids, parabens and phenols. According to the invention preferred are alcohols and especially ethanol.

Suitable supersaturation stabilizers include, for example, polyvinylpyrrolidone, cellulose derivatives, especially cyclodextrins, and substances with amphiphilic groups, such as lecithin, quaternary ammonium compounds and polysorbate. Polyvinylpyrrolidone is preferred according to the invention.

suitable Humectants include, for example, urea and alcohols, for example, glycerol, sorbitol, polyethylene glycols and propylene glycol. According to the invention, preferred are alcohols and in particular Propylene glycol.

suitable Buffering agents include, for example, citric, hydrochloric and lactic acid buffers. Salt buffers and are preferred according to the invention in particular phosphate buffer.

suitable Antioxidants include, for example, ascorbic acid and their esters, sodium bisulfite, butylated hydroxytoluene, butylated Hydroxyanisole, tocopherols and chelating agents such as EDTA and Citric acid. According to the invention preferred are tocopherols and especially α-tocopherol.

suitable Skin protection agents include, for example, vitamin E oil, Allantoin, dimethicone, glycerin, petrolatum, linoleic acid and zinc oxide.

The reservoir contains the opioid drug (s) as a solution or as a dispersion. In a dispersion, the opioid (s) may be present in molecular dispersion, colloidally disperse or coarsely dispersed. The solution may be undersaturated, saturated or supersaturated. Suitable solvents include, for example, organic solvents such as ethanol, benzyl benzoate, vegetable oils, paraffin oil, lecithin, polysorbates and quaternary ammonium chlorides. Ethanol is preferably used according to the invention used.

the Reservoir may additionally contain suitable thickening agents be added. These include, for example, silicon dioxide, Bentonite, cellulose derivatives or polyvinylpyrrolidone. According to the invention preferably used silica.

In In a preferred embodiment, the TTS is designed to fentanyl delivery is rapid and effective fentanyl plasma levels after a short time, z. B. after 4 to 10 hours, can be achieved and the release of buprenorphine with a delay, z. B. only after 36 hours. This different levy can be achieved by using suitable matrices with the desired properties are selected.

Preferably The properties of the TTS components correspond to the viscoelastic Properties of the skin and adapt to them during movements, to avoid unwanted shearing and detachment of the TTS to avoid and the highest possible comfort to achieve.

Preferably can TTS according to the invention for 72 to 196 hours, d. H. 3, 4, 5, 6 or 7 days or longer, adhere to the skin and the transcutaneous absorption of opioid agents enable.

Preferred TTS include (1) matrix TTS, (2) drug-in-adhesive monolayer TTS, (3) drug-in-adhesive multilayer TTS, and (4) reservoir TTS. An overview of such systems can be found in Ghosh TK et al., Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc., pp. 249-297 , which is hereby incorporated by reference. Such systems are also known in the art and are generally available commercially.

The matrix system comprises a drug-containing matrix layer, a cover layer supporting the adhesive layer, and optionally a removable protective layer. In some cases, it may be necessary to incorporate an impermeable layer to minimize drug migration into the carrier sheet, such as in U.S. Pat US 4,336,243 is described. The active substance-containing matrix is held by an adhesive layer on the skin. Examples of suitable matrix materials for opioid drugs include lipophilic polymers such as polyvinyl chloride, polyvinyl acetate, silicone, especially polydimethylsiloxane, acrylates, polyisobutylene, rubber and hydrophilic polymers such as polyvinylpyrrolidone and polyvinyl alcohol, gelatin-based hydrogels or polyvinylpyrrolidone / polyethylene oxide blends.

The design of the reservoir plaster is characterized by a cover layer which is coated with an adhesive layer, and a drug-containing reservoir which contains the active substance preferably in the form of a solution, suspension or dispersion and which is separated from the skin by a semi-permeable membrane. Optionally, another adhesive layer is located on the skin-facing side of the membrane. Such a system is for example in US Pat. No. 4,615,699 described.

The design of a drug-in-adhesive monolayer system is characterized by the inclusion of the active agent in the skin-contacting adhesive layer, a cover layer, and preferably a removable protective layer. The adhesive layer also acts as a matrix layer, delivering the active ingredient to the skin and holding the system on the skin. The drug-in-adhesive system does not require an adherent topcoat. Also, drug-in-adhesive systems are thin and comfortable to wear. Such a system is for example in US 4,751,087 described. The layer thickness of the active ingredient-containing adhesive layer is preferably from 20 to 500 μm, more preferably from 25 to 150 μm, and most preferably from 35 to 70 μm.

The design of a drug-in-adhesive multilayer system can, in addition to several active substance-containing layers, additionally comprise one or more semi-permeable membranes, which can be arranged between two different drug-in-adhesive layers or several drug-in-adhesive layers, have on a carrier layer. Such a system is for example in Peterson, TA and Dreyer, SJ, Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 21: 477-478 described. The layer thickness of an active substance-containing layer is preferably from 20 to 500 μm, more preferably from 25 to 150 μm, and most preferably from 35 to 70 μm.

Semipermeable Membranes useful in the multilayer or reservoir patch include non-porous thin ethylene-vinyl acetate films or microporous thin polyethylene films that are microlaminated in Patches are used with a fixed reservoir.

Adhesives for use in drug-in-adhesive systems are known in the art and are readily selectable by one of ordinary skill in the art. Three commonly used basic types are polyisobutylenes, silicones and acrylic resins. Adhesives useful in the present invention can function within a wide range of conditions, such as high and low humidity, bathing and sweating. The adhesive may be a composition based on a natural or synthetic rubber, a polyacrylate such as polybutyl acrylate, polymethyl acrylate and poly-2-ethylhexyl acrylate, polyvinyl acetate, polydimethylsiloxane and / or hydrogels such as high molecular weight polyvinylpyrrolidone and oligomeric polyethylene oxide. Acrylic resin adhesives are most preferred in the invention.

According to the invention the adhesive is a filler such as a silica filler, For example, Aerosil (Degussa, Ridgefield Park, N.J.) or a Crosslinking agents such as aluminum acetylacetonate or polybutyltitanate contain.

suitable Protective layers include, for example, final opaque or clear polyester films with a thin coating from a pressure-sensitive protective film, for example silicone fluorosilicone and perfluorocarbon-based polymers.

suitable Cover layers can be impermeable or permeable and are of synthetic polymers such as polyolefins, polyesters, polyethylene, Polyvinylidene chloride and polyurethane or natural Derived materials such as cotton and wool. impervious Cover layers such as synthetic polyesters lead to a Hydration of the outer layers of the stratum corneum, while permeable backing sheets allow the skin area to breathe, d. H. the water vapor release from the skin surface. According to the invention the cover layer is preferably an impermeable polyolefin film (Alevo, Dreieich, Germany). The thickness of the polyolefin film is preferably about 0.6 to 1 mm.

For The practice of the invention are drug-in adhesives and Reservoir TTS is particularly preferred. Most preferred is a monolayer-type drug-in-adhesion TTS.

The Amount of opioid active ingredient in the invention TTS is generally about 0.5 to 100 mg, preferably 1 to 40 mg, and most preferably 2 to 20 mg.

Even though the invention in particular with reference to certain preferred Embodiments have been described are alternative embodiments possible. Preferred embodiments or combinations however, preferred embodiments are particular prefers.

The subsequent embodiments serve the closer Explanation of the invention.

EXAMPLES

Example 1: Drug-in-Adhesive TTS

5% by weight (based on the total weight of the active substance-containing acrylate adhesive layer) of fentanyl (free base) and of buprenorphine, dissolved in ethanol, are added to a 42% strength solution of an acrylate adhesive. By stirring for one hour, the active substance-containing adhesive composition is homogenized and then spread with a doctor blade on a siliconized, 100 micron thick polyester film in a wet film thickness of about 310 microns. After drying (1 hour at 60 ° C), the clear and homogeneous laminate is laminated with a polyester film. A 10 cm ² patch contains 3.0 mg of fentanyl and buprnorphine each at a matrix weight of 60.0 g / m ² .

Example 2: Reservoir TTS

One Fentanyl / buprenorphine reservoir that releases fentanyl and buprenorphine in an ethanolic solution is prepared, by dispersing 3 g of colloidal silica in 20 g of isopropyl myristate become. In a separate vessel becomes a drug solution prepared by adding 5 g of buprenorphine and 0.5 g of fentanyl in 40 g of ethanol (absolutely) to be solved. The drug solution is added with stirring to Isopropylmyristatmischung and supplemented with water to 100 g, creating a fentanyl / buprenorphine mixture is obtained. Made of a protective layer (polyester film), adhesive layer (Silicone adhesive) and control membrane (ethylene vinyl acetate or polyethylene) a laminate is produced. This laminate comes with an impermeable Covering layer (polyethylene / aluminized polyester / ethylene vinyl acetate Multilaminat) welded to an empty TTS, which in the weld a filling opening for filling the TTS with active ingredient. The fentanyl / buprenorphine mixture is carried out by means of a filling-sealing machine the filling opening, which is between the impermeable Covering layer and the laminate of protective layer, adhesive layer and Control diaphragm is placed in the empty TTS. Subsequently the filling opening is by thermal fusion sealed.

Example 3: Reservoir TTS with active substance-containing adhesive layer

One TTS according to Example 2 is prepared using instead the silicone adhesive layer comprises a fentanyl-containing polyacrylate matrix layer is used.

Example 4: Reservoir TTS with active substance-containing adhesive layer

One TTS according to Example 2 is produced, wherein the Reservoir contains only buprenorphine and instead of the silicone adhesive layer a fentanyl-containing polyacrylate matrix layer is used.

QUOTES INCLUDE IN THE DESCRIPTION

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

Cited patent literature

• - EP 03005664 [0043]
• - DE 3703321 [0044]
• WO 87/04936 [0044]
• WO 91/16077 [0044]
• WO 92/04938 [0044]
• WO 00/53256 [0044]
• US 3991755 [0044]
• US 4141359 [0044]
• US 5415629 [0044]
• US 5944685 [0044]
• DE 10340428 A1 [0056]
• US 4336243 [0069]
• US 4615699 [0070]
• US 4751087 [0071]

Cited non-patent literature

• - General and Special Pharmacology and Toxicology, Klaus Aktories, Urban & Fischer Verlag, Munich, 9th ed. (2005) [0053]
• Berge et al., J. Pharm. Sci., 66, 1-19 (1977) [0055]
• Ghosh TK et al., Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc., pp. 249-297 [0068]
• TA and Dreyer, SJ, Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 21: 477-478 [0072]

Claims (29)

Transdermal therapeutic system (TTS) with two or more opioid drugs comprising: (i) a cover layer; (Ii) optionally a removable protective layer; and (iii) an active ingredient Layer or a drug-containing reservoir or more active ingredient Layers or several active substance reservoirs, between the cover layer and the optional removable protective layer is / are arranged. TTS according to claim 1, wherein the two or more opioid drugs in the / m a drug-containing Layer / reservoir or in the active substance-containing layers / reservoirs in solution or as a dispersion. TTS according to claim 1 or 2, wherein the system is a matrix, a drug-in-adhesive monolayer, or a Is drug-in-adhesive multilayer system. TTS according to claim 3, wherein the two or more opioid drugs in one or more active ingredients Layers are included. TTS according to claim 3 or 4, wherein the system has several active ingredient-containing layers and each the two or more opioid drugs separated in each case one layer is included. TTS according to at least one of Claims 3 to 5, wherein at least one of the opioid drugs molecular disperse in an active substance-containing layer or the active substance-containing layers is present. TTS according to claim 1 or 2, wherein the system is a reservoir system. TTS according to claim 7, wherein at least one of the two or more opioid drugs contained in a reservoir is. TTS according to claim 7 or 8, wherein containing two or more opioid drugs in a reservoir are. TTS according to at least one of Claims 7 to 9, wherein at least one of the two or more Opioid agents are contained in a matrix layer. TTS according to at least one of previous claims, wherein the system skin side a Has adhesive layer. TTS according to claim 11, wherein the Adhesive layer is a self-adhesive polymer matrix layer. TTS according to claim 12, wherein the self-adhesive polymer matrix layer an active substance-containing layer and contains at least one of the two or more opioid drugs. TTS according to at least one of Claims 11 to 13, wherein the adhesive layer at least one component includes or consists of those selected from the group is made of natural rubber, synthetic rubber, Acrylic adhesive, polyvinyl acetate, polyisobutylene, silicone, in particular Polydimethylsiloxane, and hydrogels, especially high molecular weight Polyvinylpyrrolidone, polyvinyl alcohols and oligomeric polyethylene oxide, consists. TTS according to claim 14, wherein the Adhesive layer comprises or consists of a polyacrylate. TTS according to claim 15, wherein said Polyacrylate includes monomers selected from the group from n- or iso-butyl acrylate, propyl acrylate, methyl acrylate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate consists. TTS according to claim 14, wherein it the synthetic rubber is a styrene-butadiene-styrene block copolymer or a styrene-butadiene block copolymer. TTS according to at least one of preceding claims, wherein the at least one or more active ingredient-containing layers and / or the adhesive layer, a crosslinking agent contain. TTS according to at least one of preceding claims, wherein the system as a further layer additionally contains a control membrane. TTS according to at least one of preceding claims, in particular of the claims 11 to 18, wherein on the skin-facing side of an adhesive layer a control diaphragm is arranged. TTS according to any one of the preceding claims, wherein the C _{max of} one of the two or more opioid drugs is reached after 4 to 30 hours, especially after 10 to 24 hours. TTS according to claim 20, wherein the C _{max of} a second of the two or more opioid drugs is reached after 30 to 60 hours, especially after 36 to 50 hours. TTS according to any one of the preceding claims, wherein the two or more opioid drugs are selected from the group comprising hydromorphone, buprenorphine, nalbuphine, levomethadone, dextromoramide, oxycodone, fenta nyl, sufentanil, alfentanil and remifentanil or their pharmaceutically acceptable salts. TTS according to claim 22, wherein the Opioid agents buprenorphine and fentanyl or their pharmaceutical are compatible salts. TTS according to claim 23, wherein the C _max of fentanyl is reached after 4 to 30 hours and the C _max of buprenorphine is reached after 30 to 60 hours, especially after 36 to 50 hours. TTS according to at least one of previous claims, wherein the system additionally contains one or more penetration aids. TTS according to at least one of previous claims, wherein the system additionally contains one or more preservatives. TTS according to at least one of previous claims, wherein the system additionally contains one or more supersaturation stabilizers. Use of a TTS according to at least one of the preceding claims, wherein the TTS via a period beyond which tolerances can be applied occur during treatment with a single opioid drug.