EP1740161A2 - Transdermal system secured against misuse - Google Patents

Transdermal system secured against misuse

Info

Publication number
EP1740161A2
EP1740161A2 EP05735106A EP05735106A EP1740161A2 EP 1740161 A2 EP1740161 A2 EP 1740161A2 EP 05735106 A EP05735106 A EP 05735106A EP 05735106 A EP05735106 A EP 05735106A EP 1740161 A2 EP1740161 A2 EP 1740161A2
Authority
EP
European Patent Office
Prior art keywords
transdermal system
abuse
gel
emetic
forming agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05735106A
Other languages
German (de)
French (fr)
Inventor
Heinrich Kugelmann
Johannes BARTHOLOMÄUS.
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP1740161A2 publication Critical patent/EP1740161A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates

Definitions

  • the present invention relates to a transdermal system which is secured against abuse and which, in addition to one or more active substances with abuse potential, contains at least one gel-forming agent in such amounts that it forms a gel with a minimum amount of an aqueous liquid, and as further abuse-aggravating or - preventing agent has at least one emetic (c) and / or at least one dye (d) as an aversive agent and possibly at least one irritant (a) and / or at least one antagonist (b) for the active substance or substances with abuse potential.
  • opioids which show excellent effectiveness in combating severe to very severe pain, are often used by abusers to induce intoxicating, euphoric conditions.
  • oral dosage forms such as tablets or capsules
  • the active ingredient is extracted from the powder thus obtained with the aid of a preferably aqueous liquid, and the resulting solution, if appropriate after filtration through cotton wool or cellulose, parenterally, especially intravenously.
  • a swellable agent to the oral or rectal dosage form. This swells when water is added to extract the active ingredient and has the effect that the filtrate separated from the gel contains only a small amount of active ingredient.
  • Transdermal systems such as plasters, which are used to deliver an active ingredient to a human or animal organism, are also cut into small pieces by an abuser, extracted with the aid of a preferably aqueous liquid and the resulting solution, if necessary after filtration through cotton wool or cellulose, parenterally, especially intravenously.
  • the transdermal system has an opioid antagonist and another abuse-aggravating agent, such as. B. add a gel-forming compound with an aqueous liquid.
  • transdermal system protected against abuse which, in addition to one or more active substances with potential for abuse, contains at least one gel-forming agent in amounts such that it is mixed with a minimum amount of an aqueous Liquid forms a gel and is another abuse-aggravating or preventing agent
  • Active substances with abuse potential preferably pharmaceutical active substances with abuse potential
  • the transdermal system according to the invention is also suitable for the administration of several active substances with potential for abuse.
  • the transdermal system preferably has only one active substance with potential for abuse for transdermal administration.
  • the transdermal system according to the invention is preferably suitable for preventing the abuse of at least one transdermally administrable pharmaceutical active substance with abuse potential, which is selected from the group comprising narcotics, opioids, tranquillizers, preferably benzodiazepines, stimulants and other narcotics.
  • the transdermal system according to the invention is very particularly preferably suitable for preventing the abuse of at least one transdermally administrable opioid, tranquillizer or another anesthetic which is selected from the group comprising N- ⁇ 1- [2- (4-ethyl-5-oxo-2 -tetrazolin-1-yl) ethyl] -4- methoxymethyl-4-piperidyl ⁇ propionanilide (alfentanil), 5,5-diallyl barbituric acid (allobarbital), allylprodine, alphaprodine, 8-chloro-1-methyl-6-phenyl-4H- [1, 2.4] triazolo [4.3 -a] [1, 4] -benzodiazepine (alprazolam), 2-diethylaminopropiophenone (amfepramon), ( ⁇ ) - ⁇ - methylphenethylamine (amfetamine), 2- ( ⁇ -methylphenethylamino) -2-phenylacet
  • the transdermal system according to the invention is particularly suitable for preventing the abuse of an opioid active substance selected from the group comprising (1 R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (2R, 3R ) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, (1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane -1, 3-diol, (1 R, 2R) - 3- (2-dimethylaminonethyl-cyclohexyl) -phenol, their physiologically compatible salts, preferably hydrochlorides, physiologically compatible enantiomers, stereoisomers, diastereomers, racemates and their physiologically compatible derivatives, preferably Ethers, esters or amides.
  • the transdermal system according to the invention is very particularly preferably suitable for preventing the misuse of opioids, preferably analgesic opioids, particularly preferably of at least one opioid selected from the group comprising morphine, oxicodone, buprenorphine, sulfentanil, hydromorphone, carfentanil, lofentanyl and fentanyl Buprenorphine, its derivatives, such as esters, ethers or amides, or their respective physiologically compatible compounds, preferably their salts, such as hydrochlorides or sulfates, or solvates, their respective stereoisomeric compounds, enantiomers, diastereomers and / or racemates.
  • opioids preferably analgesic opioids, particularly preferably of at least one opioid selected from the group comprising morphine, oxicodone, buprenorphine, sulfentanil, hydromorphone, carfentanil, lofentanyl and fentanyl Buprenor
  • an abuser of any kind of abuse i. H. is not only prevented from parenteral, in particular intravenous abuse, but also from oral or nasal abuse, or if the active ingredient is misused, the active ingredient does not remain in the abuser 's body long enough to have its effects caused by the abuse, especially the kick to evoke.
  • the transdermal system according to the invention not only has at least one gel-forming agent in such amounts that it forms a gel with a minimum amount of an aqueous liquid, but also, as a further abuse-aggravating or preventing compound, at least one physiologically soluble in an aqueous solution compatible dye (d) and / or at least one emetic (c).
  • an abuser For misuse, preferably for intravenous administration of an active substance with potential for abuse, an abuser usually tries to extract it from the transdermal system with the aid of an aqueous liquid, preferably water.
  • an aqueous liquid preferably water.
  • the equipment of the transdermal system according to the invention can already be form a gel in the transdermal system from which no significant amount of active ingredient can be extracted, or the aqueous extract from the transdermal system is converted by the viscosity-increasing agent, ie the gel-forming agent, into a gel which can no longer be filtered or applied.
  • the transdermal system according to the invention furthermore contains a dye which is soluble in aqueous liquid, preferably water, as a further abuse-preventing agent, an intensive coloring of the gel or the extract will result in an attempt at aqueous extraction of the active ingredient for misuse reached.
  • This coloring additionally leads to a deterrent to the potential abuser, so that not only parenteral, preferably intravenous administration is dispensed with because of the health risks associated with the administration of highly viscous liquids, but also recourse to oral and / or nasal administration.
  • Suitable dyes and the amounts required for this can be found in WO 03/015531, the corresponding disclosure being considered part of the present disclosure and hereby introduced as a reference.
  • the gelling agent i.e. H. the viscosity-increasing agent is added to the transdermal system in such amounts that, with the aid of a necessary minimum amount of an aqueous liquid, preferably in the case of the aqueous extract obtained from the transdermal system, a gel is formed which cannot be applied safely and preferably when introduced in a further amount of an aqueous liquid also remains visually distinguishable.
  • Visual distinguishability in the sense of the present invention means that the gel containing active substance formed with the aid of a necessary minimum amount of aqueous liquid, when introduced, preferably with the aid of an injection needle, remains essentially insoluble and coherent in a further amount of aqueous liquid of 37 ° C. and cannot be easily dispersed in such a way that parenteral, in particular intravenous, safe application is possible.
  • the duration of the visual differentiation is preferably at least one minute, preferably at least 10 minutes.
  • the increase in viscosity of the extract makes it difficult or even impossible for it to pass or spray. If the gel remains visually distinguishable, this means that the gel obtained when introduced into a further amount of aqueous liquid, e.g. by injection into blood, initially in the form of a largely coherent thread, which can be broken down into smaller fragments by mechanical action, but cannot be dispersed or even dissolved in such a way that parenteral, in particular intravenous, application is possible without risk.
  • the active ingredient is mixed with the viscosity-increasing agent and suspended in 10 ml of water at a temperature of 25 ° C. If a gel is formed which satisfies the conditions mentioned above, the corresponding viscosity-increasing agent is suitable for preventing or preventing abuse in the transdermal system according to the invention.
  • the transdermal system may be added one or more viscosity-increasing agents, which are selected from the group comprising microcrystalline cellulose with 11 wt .-% carboxymethylcellulose sodium (Avicel ® RC 591), carboxymethylcellulose sodium (Blanose ®, CMC-Na C300P ® Frimulsion BLC-5 ® , Tylose C300 P ® ), polyacrylic acid, acrylate copolymers that are preferably cross-linked (Carbopol ® 980 NF, Carbopol ® 981), locust bean gum (Cesagum ® LA-200, Cesagum ® LID / 150, Cesagum ® LN- 1), pectins, preferably from citrus fruits or apples (Cesapectin ® HM Medium Rapid Set), sucrose acetate isobutyrate, waxy maize starch (C * Gel 04201 ® ), sodium alginate (Frimulsion ALG (E401
  • a compound selected from the group comprising crosslinked homo- or copolymers of acrylic acid, gellan gum, propylene glycol alginate, pectin, preferably apple pectin, sodium hyaluronate, xanthan gum, particularly preferably xanthan or a homo- or copolymer of is particularly preferred as the gel-forming agent
  • Acrylic acid preferably crosslinked with allylpentaeritrol, is used.
  • those agents are used which form gel in aqueous liquid and which, in addition to the conditions mentioned above, also form a gel with the necessary minimum amount of aqueous liquid during extraction from the transdermal system, which includes air bubbles.
  • the gel obtained in this way is distinguished by a cloudy appearance, through which the potential abuser is additionally optically warned and prevented from being parenterally administered.
  • an amount of 0.01 to 25% by weight, preferably 0.05 to 15% by weight, particularly preferably 1 to 10% by weight, based on the total weight of the transdermal system, of the gel-forming agent mentioned is sufficient, to prevent abuse.
  • the gel-forming agent is present in the transdermal system according to the invention preferably in amounts of> 5 mg, particularly preferably in amounts> 10 mg.
  • the transdermal system ensures in a preferred embodiment that the abusive application active substance ingested does not remain in the abuser 's body long enough to produce the effects associated with the abuse.
  • transdermal system in addition to the viscosity-increasing, ie. H. gelling agent and optionally the aversive dye (d), an emetic (c) is also added.
  • viscosity-increasing ie. H. gelling agent and optionally the aversive dye (d), an emetic (c) is also added.
  • This emetic is present in a spatially separate arrangement from the other components of the transdermal system according to the invention in order not to have any effect in the body when used as intended. This is achieved by arranging the emetic in a layer which is separated from the layers which contain the other components of the transdermal system according to the invention with the aid of a separating layer impermeable to the emetic or the emetic in microcapsules made of materials which are suitable for the emetic are impermeable, arranges. Only when there is mechanical interference from the potential abuser, e.g. B.
  • the separation arrangements described above are damaged or canceled, so that there is a mixing of the emetic with the other components of the transdermal system according to the invention at the latest during the extraction. If an abuser ingests such a mixture as an extract, this triggers the abuse-preventing nausea before the effects associated with the abuse are caused in the body.
  • Suitable emetics to prevent misuse of an opioid are known to the person skilled in the art and can be in the transdermal system according to the invention as such or in the form of corresponding derivatives, in particular esters or ethers, or in the form of corresponding physiologically tolerable compounds, in particular in the form of their salts or solvates.
  • an emetic based on one or more ingredients of Radix Ipecacuanhae comes into consideration, as described, for. B. in "Pharmaceutical Biology - Drugs and their Ingredients" by Prof. Dr. Hildebert Wagner, 2nd, edited edition, Gustav Fischer Verlag, Stuttgart, New York 1982. The corresponding literature description is hereby introduced as a reference and is considered part of revelation.
  • the transdermal system according to the invention can preferably have the emetic emetin as component (c), preferably in an amount of> 10 mg, particularly preferably> 20 mg and very particularly preferably in an amount of> 40 mg per transdermal system.
  • Apomorphine can also preferably be used as an emetic as anti-abuse protection according to the invention, preferably in an amount of preferably> 3 mg, particularly preferably> 5 mg and very particularly preferably> 7 mg per transdermal system.
  • a potential abuser is not prevented from improper use due to the gel formation and coloring by the aversive dye, it is also possible to use at least one antagonist for the active substance with abuse potential to prevent abusive effects as an additional abuse-preventing agent for the inventive transdermal system add to the abuser.
  • the antagonist is to be arranged spatially separated from the other constituents of the transdermal system according to the invention, so that when the transdermal system according to the invention is used as intended System the antagonist can have no effect.
  • this can be achieved in that the antagonist is separated from the other components of the transdermal system according to the invention by a separating layer impermeable to the antagonist, or is encapsulated in microcapsules, the material of which is used for is impenetrable to the antagonists. It is only when the transdermal system according to the invention is handled mechanically and not as intended that the antagonist is mixed with the other components, so that the antagonist prevents the effects usually caused by misuse in the event of improper use.
  • Suitable antagonists for preventing abuse of the active compounds are known to the person skilled in the art and can be present in the transdermal system according to the invention as such or in the form of corresponding derivatives, in particular esters or ethers, or in the form of corresponding physiologically tolerable compounds, in particular in the form of their salts or solvates ,
  • the antagonist is preferably an antagonist selected from the group comprising naloxone, naltrexone, nalmefene, nalid, nalmexone, naiorphin and nalbuphin, in each case, if appropriate, in the form of a corresponding physiologically tolerable compound, in particular in In the form of a base, salt or solvate.
  • the corresponding antagonists are preferably used in an amount of> 10 mg, particularly preferably in an amount of 10 to 100 mg, very particularly preferably in an amount of 10 to 50 mg, based on the amount of active ingredient.
  • the transdermal system according to the invention has a stimulant as the active ingredient, a neuroleptic, preferably at least one compound selected from the group comprising haloperidol, promethacin, fluophenozin, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chloroprosteaxin, sugar-lopantexol, flupentexyl, prith is preferably used as the antagonist , Zotepin, Penperidol, Piparmeron, Melperol and Bromperidol, used.
  • the transdermal system according to the invention preferably has these antagonists in a customary therapeutic dosage known to the person skilled in the art, particularly preferably in a quantity which is doubled or tripled compared to the usual dosage.
  • the equipment of the transdermal system according to the invention with a gel-forming agent, an aversive dye and an antagonist to prevent abuse can also be supplemented by the transdermal system according to the invention additionally containing an emetic (c), which together with the antagonist (b) prevents the abusive effects on the abuser and may also be used instead of the aversive dye.
  • an emetic c
  • the antagonist b
  • transdermal system in addition to the components already listed, such as an emetic and optionally an antagonist, or at least one in addition to an antagonist Add irritant.
  • Substances that can cause inflammation, fever, a burning sensation and / or an itchiness are suitable as irritants.
  • Lipopolysaccharides and / or microorganisms such as lactobacilli or Saccharomyces species are suitable as fever and / or inflammation-causing irritants, which can act in particular against repetition of the abuse.
  • These substances act not only against parenteral, preferably intravenous abuse, since they can preferably cause inflammation already at the injection site, but also against oral and / or nasal abuse. The latter also applies to irritants that cause a burning sensation and / or itching.
  • Corresponding substances and their customary amounts are known to the person skilled in the art and can be determined by simple preliminary tests.
  • the irritants that cause a burning sensation or itchiness are preferably based on one or more ingredients or one or more plant parts, at least one hot substance drug.
  • the transdermal system according to the invention can preferably contain, as component (a), one or more ingredients of at least one hot substance drug, selected from the group comprising Allii sativi Bulbus, Asari Rhizoma c. Herba, Calami Rhizoma, Capsici Fructus (bell pepper), Capsici Fructus acer (Cayenne pepper), Curcumae longae Rhizoma, Curcumae xanthorrhizae Rhizoma, Galangae Rhizoma, Myristicae Semen, Piperis nigri Fructus (pepper), Sinapis albaig (Semucen nba, Semucen Zedoariae Rhizoma and Zingiberis Rhizoma, particularly preferably from the group comprising Capsici Fructus (paprika), Capsici Fructus acer (Cayenne pepper) and Piperis nigri Fructus (pepper).
  • the ingredients of the hot substance drugs are preferably o-methoxy (methyl) phenol compounds, acid amide compounds, mustard oils or sulfide compounds or compounds derived therefrom.
  • At least one ingredient of the hot substance drugs is particularly preferably selected from the group comprising myristicin, elemicin, isoeugenol, ⁇ - asarone, safrole, gingerols, xanthorrhizole, capsaicinoids, preferably capsaicin, capsaicin derivatives, such as N-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydinicin , Homocapsaicin, norcapsaicin, and nomorcapsaicin, piperine, preferably trans-piperine, glucosinolates, preferably based on non-volatile mustard oils, particularly preferably based on p-hydroxybenzyl mustard oil, methyl mercaptose oil or methylsulfonyl mustard oil .
  • the transdermal system according to the invention can preferably contain the plant parts of the corresponding hot substance drugs in an amount of 0.01 to 30% by weight, particularly preferably 0.1 to 0.5% by weight, in each case based on the total weight of the transdermal system according to the invention , If one or more ingredients of corresponding hot substance drugs are used, the amount in a transdermal system according to the invention is preferably 0.001 to 0.005% by weight, based on the total weight of the transdermal system according to the invention.
  • the layer of the transdermal system containing irritants is provided with a separating layer which is impermeable to the irritant and causes separation from the other components of the transdermal system according to the invention.
  • the irritant encapsulated in microcapsules the microcapsules having to be impermeable to the irritant.
  • the spatial arrangement for separating the anti-abuse components (a) to (d) not only means that the release agents must be impermeable to the respective anti-abuse agents, but also that the therapeutic effect is not influenced when the transdermal system according to the invention is used as intended.
  • the transdermal system according to the invention is preferably in the form of a plaster. It can then be constructed according to the reservoir or matrix system (Bauer KH, Frömming K.-H., 5.3 C, Pharmaceutical Technology, pages 381-383; Müller R. H., Hildebrand GE, Pharmaceutical Technology: Modern Dosage Forms, Chapter 8).
  • the inventive selection of the gel-forming agent in aqueous liquid makes it possible to combine the active substance with potential for abuse and the gel-forming agent in the plaster without spatial separation from one another, without the release of the active substance being impaired when the plaster is used as intended.
  • the gel-forming agent is preferably either dissolved or dispersed in the plaster according to the invention. This also applies to the other components for further prevention of abuse, provided that they are encapsulated in microcapsules, which can possibly dissolve in at least aqueous liquids.
  • the agent which forms a gel in aqueous liquid is preferably present in or adjacent to the active substance-containing matrix layer or in the active substance-containing reservoir of the plaster, in particular if it thickens on the plaster on contact with an aqueous liquid to form a gel from which practically no active substance can be extracted is.
  • the gel-forming agent can, however, also be present in one of the active substance segment layers of the patch, in particular when the gel-forming agent and the active agent are extractable on contact with the aqueous liquid and the gel is formed in the extract.
  • the plaster according to the invention can preferably have a carrier layer, an active ingredient-containing layer and an adhesive layer, wherein the active ingredient-containing layer can simultaneously be the adhesive layer in which the active ingredient and preferably the gel-forming agent are dissolved and / or dispersed in a matrix together with the adhesive is present.
  • the further abuse-preventing components (a) to (d) can be present in encapsulated form in the active ingredient-containing or active ingredient-containing and adhesive-containing layer or in a separate layer which, with the aid of a separating layer impermeable to these abuse-preventing components (a) to (d) the active ingredient Layer is delimited.
  • the plaster according to the invention additionally has a protective layer.
  • Pressure-sensitive adhesives are preferably used as adhesives for the adhesive layer of the plaster according to the invention.
  • polymers such as polyacrylates, polyvinyl ethers, polyisobutylenes (PIB), styrene / isoprene or butadiene / styrene copolymers or polyisoprene rubbers are suitable for this purpose
  • silicone adhesives such as, for example, crosslinked polydimethylsiloxanes, plastics based on esters of glycines, glycerol or polytaerythrol, or hydrocarbons such as polyterpenes
  • acrylate-based adhesives are obtained by polymerizing acrylates, methacrylates, alkyl acrylates and / or alkyl methacrylates, optionally with further ⁇ , ⁇ -unsaturated monomers, such as acrylamide, dimethylacrylamide, dimethylaminoethyl acrylate, hydroxyethyl acrylate,
  • the adhesive layer of the patch according to the invention can also contain skin penetration enhancers, fillers (such as zinc oxide or silica), crosslinking agents, antioxidants and / or solvents.
  • the thickness of the adhesive layer is preferably 3 to 100 ⁇ m .
  • the backing layer or cover layer of the plaster according to the invention is preferably impermeable and inert to the active ingredient, adhesive and the components (a) to (d) which prevent abuse.
  • the layer of polymers such as polyester, e.g. B.
  • polyethylene terephthalate polyolefins, such as polyethylenes, polypropylenes or polybutylenes, polycarbonates, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidene chlorides and / or copolymers such as acrylonitrile / butadiene / styrenic copolymers, or textile fibers and fibers thereof, optionally containing paper fibers Mixtures built up, which can be metallized or pigmented if necessary.
  • the backing layer or cover layer of the plaster can also consist of a combination of metal foil and polymer layer.
  • the thickness of the carrier layer is preferably 3 to 100 ⁇ m.
  • the active substance-containing matrix layer of the patch according to the invention can contain matrix-forming polymers, skin penetration enhancers, solubilizers, crosslinking agents, stabilizers, emulsifiers, preservatives, thickeners and / or other customary auxiliaries.
  • At least one film-forming polymer is preferably selected from the group comprising hydroxypropyl cellulose, carboxymethyl cellulose, polyethylenes, chlorinated polyethylenes, polypropylenes, polyurethanes, polycarbonates, polyacrylic acid esters, polyacrylates, polymethacrylates, polyvinyl alcohols, polyvinyl chlorides, polyvinylidene chlorides, polyvinyl pyrrolidones, polyethylene terefluoroethylene, polyethylene terephthalate, polyethylene terephthalate Copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, ethylene / vinyl alcohol copolymers, ethylene / vinyloxyethanol copolymers, vinyl chloride / vinyl acetate copolymers, vinylpyrrolidone / ethylene / vinyl acetate copolymers, rubbers, rubber-like, synthetic homo-, co- or block polymers, silicone
  • N-methyl-2-pyrrolidone, laurylpyrrolidone, triethanolamine, triacetin, diethylene glycol monoethyl ether, derivatives of fatty acids or fatty alcohols can be used as compounds to improve the solubility of the active ingredient.
  • the reservoir membrane can be made of inert polymers such as. B. polyethylenes, polypropylenes, polyvinyl acetates, polyamides, ethylene / vinyl acetate copolymers and / or silicones.
  • the active substance and preferably the gel-forming agent can be dissolved or dispersed in the reservoir.
  • the other anti-abuse components can, as stated above, be arranged spatially separated therefrom.
  • Antioxidants such as vitamin E, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, ascorbyl palmitate, and / or chelating agents, such as, for example, may be used as stabilizers for the active substance-containing matrix or the active substance-containing reservoir.
  • the active substance-containing matrix or the active substance-containing reservoir can also contain conventional skin pressure penetration enhancers.
  • the plaster according to the invention can also be in one or more layers at least one plasticizer selected from the group comprising long-chain alcohols, such as dodecanol, undecanol, octanol, esters of carboxylic acids with polyethoxylated alcohols, diesters of aliphatic dicarboxylic acids, such as adipic acid, and medium-chain triglycerides of caprylic acid and / or capric acid, coconut fat, polyhydric alcohols, such as 1, 2-propanediol, esters of polyhydric alcohols, such as glycerol with levulinic acid or caprylic acid, and etherified polyhydric alcohols.
  • long-chain alcohols such as dodecanol, undecanol, octanol
  • esters of carboxylic acids with polyethoxylated alcohols diesters of aliphatic dicarboxylic acids, such as adipic acid, and medium-chain triglycerides of cap
  • the peelable protective layer of the plaster according to the invention can be made of polyethylene, polyester, polyethylene terephthalate, polypropylene, polysiloxane, polyvinyl chloride or polyurethane and optionally from treated paper fibers, such as, for. B. cellophane, and optionally have a silicone, fluorosilicone or fluorocarbon coating.
  • the transdermal system according to the invention preferably the plaster
  • a 420 mm wide, transparent polyester film is coated with the mixture described above in such a way that the weight per unit area of the dried adhesive layer is 80 g / m 2 .
  • a polyester film that can be removed again with a silicone coating serves as a protective layer.
  • a yellow dye (FD&C yellow No. 6), which is soluble in water, was added to the mixture and physiologically harmless, and was homogeneously distributed.
  • a siliconized polyester film (Hostaphan films RNT 36) were each 20 g of Carbopol listed above and dye-containing adhesive mixture using 509 / MC-1 is applied a 120 ⁇ m squeegee using the Erichsen Coatmaster film puller. The application speed was 5 mm / sec. After at least 2 hours of drying time, a siliconized polyester film was laminated as a protective layer on the uncoated side of the adhesive layer. Then 7x7 cm squares were cut from the double-sided laminated, abuse-aggravating adhesive layers.
  • each of the adhesive layers provided with a different concentration of Carbopol and with dye was bonded to the exposed adhesive layer of the buprenorphine-containing patch obtained according to 1 a).
  • Xanthan as a gel-forming compound was glazed over a 50 ⁇ m sieve and the fine fraction was used again.
  • the uncoated side of the adhesive layer was also laminated with a siliconized polyester film as a protective film. From this 7x7 cm squares were cut. Each of the adhesive layers finished with different concentrations of xanthan and with dye was bonded to the likewise exposed adhesive layer of the buprenorphine-containing plaster obtained according to 1 a) after removal of the protective film.
  • the plasters obtained in accordance with b.1 or b.2 and provided with an abuse-aggravating adhesive layer were brought into contact with 5 ml of water after removal of the protective layer on the abuse-aggravating adhesive layer.

Abstract

The invention relates to a transdermal system which is secured against misuse. Said system contains, in addition to one or several active substances having misuse potential, at least one gel-forming agent in such an amount that it forms a gel having a minimum amount of an aqueous liquid. It also contains, as additional misuse aggravating and/or preventing agents, at least one emetic and/or at least one colorant as aversive agents.

Description

Gegen Missbrauch gesichertes transdermaies System Transdermaies system secured against abuse
Die vorliegende Erfindung betrifft ein gegen Missbrauch gesichertes, transdermales System, das neben einem oder mehreren Wirkstoffen mit Missbrauchspotential wenigstens ein gelbildendes Mittel in solchen Mengen enthält, dass es mit einer Mindestmenge einer wässrigen Flüssigkeit ein Gel bildet, und als weitere missbrauchs-erschwerende bzw. -verhindernde Mittel wenigstens ein Emetikum (c) und/oder wenigstens einen Farbstoff (d) als aversives Mittel und ggf. wenigstens einen Reizstoff (a) und/oder ggf. wenigstens einen Antagonisten (b) für den bzw. die Wirkstoffe mit Missbrauchspotential aufweist.The present invention relates to a transdermal system which is secured against abuse and which, in addition to one or more active substances with abuse potential, contains at least one gel-forming agent in such amounts that it forms a gel with a minimum amount of an aqueous liquid, and as further abuse-aggravating or - preventing agent has at least one emetic (c) and / or at least one dye (d) as an aversive agent and possibly at least one irritant (a) and / or at least one antagonist (b) for the active substance or substances with abuse potential.
Eine Vielzahl von pharmazeutischen Wirkstoffen weist neben einer ausgezeichneten Wirksamkeit auf ihrem therapeutischen Anwendungsgebiet auch ein Missbrauchspotential auf, d. h. sie können von einem Missbraucher eingesetzt werden, um Wirkungen herbeizuführen, die nicht ihrem Bestimmungszweck entsprechen.In addition to excellent effectiveness in their therapeutic field of application, a large number of active pharmaceutical ingredients also have a potential for abuse, i. H. they can be used by an abuser to produce effects that do not meet their intended purpose.
So werden beispielsweise Opioide, die eine exzellente Wirksamkeit bei der Bekämpfung von starken bis sehr starken Schmerzen zeigen, von Missbrauchern häufig zum Einleiten rauschartiger, euphorisierender Zustände verwendet.For example, opioids, which show excellent effectiveness in combating severe to very severe pain, are often used by abusers to induce intoxicating, euphoric conditions.
Um Missbrauch zu ermöglichen, werden beispielsweise orale Darreichungsformen, wie Tabletten oder Kapseln, vom Missbraucher u. a. durch Mörsern zerkleinert, der Wirkstoff aus dem so erhaltenen Pulver mit Hilfe einer vorzugsweise wässrigen Flüssigkeit extrahiert und die resultierende Lösung, ggf. nach Filtration durch Watte oder Zellstoff, parenteral, insbesondere intravenös, appliziert. Bei dieser Art der Verabreichung kommt es zu einem gegenüber einer oralen missbräuchlichen Applikation noch zusätzlich beschleunigten Anfluten des Wirkstoffes mit dem vom Missbraucher gewünschten Ergebnis, nämlich den Kick. Zur Verhinderung des Missbrauchs wurde in dem US-A- 4,070,494 vorgeschlagen, der oralen oder rektalen Darreichungsform ein quellbares Mittel zuzusetzen. Dieses quillt bei der Zugabe von Wasser zur Extraktion des Wirkstoffes auf und bewirkt, dass das vom Gel separierte Filtrat nur eine geringe Menge an Wirkstoff enthält.To enable abuse, for example, oral dosage forms, such as tablets or capsules, are crushed by the abuser, inter alia, using mortars, the active ingredient is extracted from the powder thus obtained with the aid of a preferably aqueous liquid, and the resulting solution, if appropriate after filtration through cotton wool or cellulose, parenterally, especially intravenously. With this type of administration, there is an additionally accelerated flooding of the active substance compared to an oral improper application with the result desired by the abuser, namely the kick. In order to prevent abuse, it has been proposed in US-A-4,070,494 to add a swellable agent to the oral or rectal dosage form. This swells when water is added to extract the active ingredient and has the effect that the filtrate separated from the gel contains only a small amount of active ingredient.
Aber nicht nur orale oder rektale Darreichungsformen mit Wirkstoffen, die missbräuchlich verwendet werden können, werden für das Erreichen rauschähnlicher Zustände verwendet. Auch transdermale Systeme, wie Pflaster, die zur Abgabe eines Wirkstoffes an einen menschlichen oder tierischen Organismus verwendet werden, werden von einem Missbraucher kleingeschnitten, mit Hilfe einer vorzugsweise wässrigen Flüssigkeit extrahiert und die resultierende Lösung, ggf. nach Filtration durch Watte oder Zellstoff, parenteral, insbesondere intravenös, appliziert.But not only oral or rectal dosage forms with active ingredients that can be misused are used to achieve intoxication-like states. Transdermal systems, such as plasters, which are used to deliver an active ingredient to a human or animal organism, are also cut into small pieces by an abuser, extracted with the aid of a preferably aqueous liquid and the resulting solution, if necessary after filtration through cotton wool or cellulose, parenterally, especially intravenously.
Um auch diesen Missbrauch zu erschweren, wird in der internationalen Veröffentlichung WO 03/013479 offenbart, dem transdermalen System einen Opioidantagonisten und ein weiteres missbrauchserschwerendes Mittel, wie z. B. eine mit einer wässrigen Flüssigkeit gelbildende Verbindung, zuzusetzen.In order to make this abuse more difficult, it is disclosed in international publication WO 03/013479 that the transdermal system has an opioid antagonist and another abuse-aggravating agent, such as. B. add a gel-forming compound with an aqueous liquid.
Trotz dieser Maßnahme zur Erschwerung des parenteralen, insbesondere intravenösen, Missbrauchs von Wirkstoffen mit Missbrauchspotential besteht darüber hinaus eine erhöhter Bedarf, jegliche Art von missbräuchlicher Anwendung so zu verhindern, dass der Missbraucher entweder bereits schon von einer missbräuchlichen Einverleibung des Wirkstoffes mit Missbrauchspotential soweit wie möglich abgehalten wird oder nach einer missbräuchlichen Einverleibung des Wirkstoffes mit Missbrauchspotential dieser nicht lange genug im Körper des Missbrauchers verbleibt, um dort die mit einer missbräuchlichen Einnahme eines Wirkstoffes mit Missbrauchspotential verbundenen Zustände hervorzurufen.Despite this measure to aggravate the parenteral, in particular intravenous, abuse of active substances with abuse potential, there is an increased need to prevent any type of misuse in such a way that the abuser either already discourages the abuse of the active substance with abuse potential as far as possible or after an improper incorporation of the active substance with potential for abuse, it does not remain in the abuser 's body long enough to cause the conditions associated with the improper use of an active substance with potential for abuse.
Diese Aufgabe wird durch die Bereitstellung des erfindungsgemäßen, gegen Missbrauch gesicherten transdermalen Systems gelöst, das neben einem oder mehreren Wirkstoffen mit Missbrauchspotential wenigstens ein gelbildendes Mittel in solchen Mengen enthält, dass es mit einer Mindestmenge einer wässrigen Flüssigkeit ein Gel bildet und als weiteres missbrauchs-erschwerendes bzw. - verhinderndes MittelThis object is achieved by the provision of the transdermal system protected against abuse according to the invention which, in addition to one or more active substances with potential for abuse, contains at least one gel-forming agent in amounts such that it is mixed with a minimum amount of an aqueous Liquid forms a gel and is another abuse-aggravating or preventing agent
. wenigstens ein Emetikum (c) und/oder . wenigstens einen Farbstoff (d) als aversives Mittel und . ggf. wenigstens einen Reizstoff (a) und/oder . ggf. wenigstens einen Antagonisten (b) für den bzw. die Wirkstoffe mit Missbrauchspotential, at least one emetic (c) and / or. at least one dye (d) as an aversive agent and. if necessary at least one irritant (a) and / or. optionally at least one antagonist (b) for the active substance or substances with potential for abuse
aufweist.having.
Wirkstoffe mit Missbrauchspotential, vorzugsweise pharmazeutische Wirkstoffe mit Missbrauchspotential, sind ebenso wie deren Dosierung bzw. deren Herstellungsverfahren dem Fachmann bekannt und können als solche, in Form ihrer Derivate, insbesondere Ester, Amide oder Ether, oder jeweils in Form ihrer transdermal verabreichbaren physiologisch verträglichen Verbindungen, vorzugsweise in Form ihrer Salze, ganz besonders bevorzugt als Hydrochloride, oder Solvate, in dem erfindungsgemäßen transdermalen System vorliegen.Active substances with abuse potential, preferably pharmaceutical active substances with abuse potential, are known to the person skilled in the art, just like their dosage and their production processes, and as such, in the form of their derivatives, in particular esters, amides or ethers, or in each case in the form of their transdermally administrable physiologically tolerable compounds, preferably in the form of their salts, very particularly preferably as hydrochlorides, or solvates, in the transdermal system according to the invention.
Das erfindungsgemäße transdermale System eignet sich auch für die Verabreichung von mehreren Wirkstoffen mit Missbrauchspotential. Vorzugsweise weist das transdermale System nur einen Wirkstoff mit Missbrauchspotential zur transdermalen Verabreichung auf.The transdermal system according to the invention is also suitable for the administration of several active substances with potential for abuse. The transdermal system preferably has only one active substance with potential for abuse for transdermal administration.
Das erfindungsgemäße transdermale System eignet sich vorzugsweise zur Verhinderung des Missbrauchs wenigstens eines transdermal verabreichbaren pharmazeutischen Wirkstoffs mit Missbrauchspotential, der ausgewählt ist aus der Gruppe umfassend Narkotika, Opioide, Tranquillantien, vorzugsweise Benzodiazepinde, Stimulantien und weitere Betäubungsmittel.The transdermal system according to the invention is preferably suitable for preventing the abuse of at least one transdermally administrable pharmaceutical active substance with abuse potential, which is selected from the group comprising narcotics, opioids, tranquillizers, preferably benzodiazepines, stimulants and other narcotics.
Ganz besonders bevorzugt eignet sich das erfindungsgemäße transdermale System zur Verhinderung des Missbrauchs wenigstens eines transdermal verabreichbaren Opioids, Tranquillanz oder eines anderen Betäubungsmittels, das ausgewählt ist aus der Gruppe umfassend N-{1-[2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4- methoxymethyl-4-piperidyl}propionanilid (Alfentanil), 5,5-Diallylbarbitursäure (Allobarbital), Allylprodin, Alphaprodin, 8-Chlor-1-methyl-6-phenyl-4H- [1 ,2,4]triazolo[4,3-a][1 ,4]-benzodiazepin (Alprazolam), 2-Diethylaminopropiophenon (Amfepramon), (±)-α-Methylphenethylamin (Amfetamin), 2-(α- Methylphenethylamino)-2-phenylacetonitril (Amfetaminil), 5-Ethyl-5- isopentylbarbitursäure (Amobarbital), Anileridin, Apocodein, 5,5-Diethylbarbitursäure (Barbital), Bemidon, Benzylmorphin, Bezitramid, 7-Brom-5-(2-pyridyl)-1/-/-1.4- benzodiazepin-2(3H)-on (Bromazepam), 2-Brom-4-(2-chlorphenyl)-9-mettϊNI-6/-/- thieno[3,2 ] [1 ,2,4]triazolo[4,3-a][1 ,4]diazepin (Brotizolam), 17-Cyclopropylmethyl-The transdermal system according to the invention is very particularly preferably suitable for preventing the abuse of at least one transdermally administrable opioid, tranquillizer or another anesthetic which is selected from the group comprising N- {1- [2- (4-ethyl-5-oxo-2 -tetrazolin-1-yl) ethyl] -4- methoxymethyl-4-piperidyl} propionanilide (alfentanil), 5,5-diallyl barbituric acid (allobarbital), allylprodine, alphaprodine, 8-chloro-1-methyl-6-phenyl-4H- [1, 2.4] triazolo [4.3 -a] [1, 4] -benzodiazepine (alprazolam), 2-diethylaminopropiophenone (amfepramon), (±) - α- methylphenethylamine (amfetamine), 2- ( α -methylphenethylamino) -2-phenylacetonitrile (amfetaminil), 5-ethyl -5- isopentylbarbituric acid (amobarbital), anileridine, apocodeine, 5,5-diethylbarbituric acid (barbital), bemidon, benzylmorphine, bezitramide, 7-bromo-5- (2-pyridyl) -1 / - / - 1.4-benzodiazepine-2 ( 3H) -one (bromazepam), 2-bromo-4- (2-chlorophenyl) -9-mettϊNI-6 / - / - thieno [3.2] [1, 2.4] triazolo [4,3-a] [1, 4] diazepine (Brotizolam), 17-cyclopropylmethyl
4,5α-epopxy-7α[(S)-1-hydroxy-1 ,2,2-trimethyl-propyl]-6-methoxy-6,14-e/ιc/o- ethanomorphinan-3-ol (Buprenorphin), 5-Butyl-5-ethylbarbitursäure (Butobarbital), Butorphanol, (7-Chlor-1 ,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1 ,4-benzodiazepin-3- yl)-dimethyl-carbamat (Camazepam), (1 s.2s)-2-Amino-1-phenyl-1-propanol (Cathin / D-Norpseudoephedrin), 7-Chlor-/v-methyl-5-phenyl-3 -1 ,4 — benzodiazepin-2-ylamin- 4-oxid (Chlordiazepoxid), 7-Clor-1-methyl-5-phenyl-lH-1 ,5-benzodiazepin- 2,4(3/-/,5/-y)-dion (Clobazam), 5-(2-Chlorphenyl)-7-nitro-1 -1 ,4-benzodiazepin-2(3/-/)- on (Clonazepam), Clonitazen, Carfentanil, Clofedanol, 7-ChIor-2,3-dihydro-2-oxo-5- phenyl-1f - ,4-benzodiazepin-3-carbonsäure (Clorazepat), 5-(2-ChIorphenyl)-7-ethyl- 1 -methyl-1 H-thieno[2,3-e][1 ,4]diazepin-2(3H)-on (Clotiazepam), 10-Chlor-11 b- (2chlorphenyl)-2,3,7,11 b-tetrahydrooxazolo[3,2-c/][1 ,4]benzodiazepin-6(5H)-on (Cloxazolam), (-)-Methyl-[3ß-benzoyloxy-2ß(1αH,5α/-/)-tropancarboxylat] (Cocain), 4,5α-Epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol (Codein), 5-(1 -Cyclohexenyl)-5- ethylbarbitursäure (Cyclobarbital), Cyclorphan, Cyprenorphin, 7-Chlor-5-(2- chlorphenyl)-1/-/-1 ,4-benzodiazepin-2(3H)-on (Delorazepam), Desomorphin, Dextromoramid, (+)-(1 -Benzyl-3-dimethylamino-2-methyl-1 -phenylpropyl)propionat (Dextropropoxyphen), Dextromethorphan, Dezocin, Diampromid, Diamorphon, 7- Chlor-1-methyl-5-phenyl-1 -/-1 ,4-benzodiatepin-2(3f/)-on (Diazepam), 4,5α-Epoxy-3- methoxy-17-methyl-6α-morphinanol (Dihydrocodein), 4,5α-Epoxy-17-methyl-3,6a- morphinandiol (Dihydromorphin), Dimenoxadol, Dimephetamol, Dimethylthiambuten, Dioxaphetylbutyrat, Dipipanon, (6a/ , 10aft)-6,6,9-Trimethyl-3-pentyl-6a, 7,8,10a~ tetrahydro-6/-/-benzo[c]chromen-1-ol (Dronabinol), Ephedrin, Pseudoephedrin, Eptazocin, 8-Chlor-6-phenyl-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin (Estazolam), Ethoheptazin, Ethylmethylthiambuten, Ethyl-[7-chlor-5-(2-fluorphenyl)-2,3-dihydro-2- oxo-1 -/-1.4 benzodiazepin-3-carboxylat] (Ethylloflazepat), 4,5α-Epoxy-3-ethoxy-17- methyl-7-morphinen-6α-ol (Ethylmorphin), Etonitazen, 4,5α-Epoxy-7α-(1-hydroxy-1- methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol (Etorphin), [\i- Ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamin (Fencamfamin), 7-[2-(α- Methylphenethylamino)ethyl]-theophyllin) (Fenetyllin), 3-(α- Methylphenethylamino)propionitril (Fenproporex), Fenpipramid, /\/-(1-Phenethyl-4- piperidyl)propionanilid (Fentanyl), 7-Chlor-5-(2-fluorphenyl)-1-methyl-1 -1 ,4- benzodiazepin-2(3H)-on (Fludiazepam), 5-(2-Fluorphenyl)-1 -methyl-7-nitro-1 /-/-1.4- benzodiazepin-2(3H)-on (Flunitrazepam), 7-Chlor-1 -(2-diethylaminoethyl)-5-(2- fluorphenyl)-1 -1 ,4-benzodiazepin-2(3/-/)-on (Flurazepam), 7-Chlor-5-phenyl-1- (2,2,2-trifluorethyl)-1 H-1 ,4-benzodiazepin-2(3H)-on (Halazepam), 10-Brom-11 b-(2- fluorphenyl)-2,3,7,11 b-tetrahydrθ[1 ,3]θxazolθ[3,2-d][1 ,4]benzodiazepin-6(5/- )-on (Haloxazolam), Heroin, 4,5α-Epoxy-3-methoxy-17-methyl-6-morphinanon (Hydrocodon), 4,5α-Epoxy-3-hydroxy-17-methyl-6-morphinanon (Hydromorphon), Hydroxypethidin, Isomethadon, Hydroxymethylmorphinan, 1 -Chlor-8,12b-dihydro- 2,8-dimethyl-12b-phenyl-4H-[1 ,3]θxazino[3,2-d][1 ,4]benzodiazepin-4,7(6H)-dion4.5 α- epopxy-7 α [(S) -1-hydroxy-1, 2,2-trimethyl-propyl] -6-methoxy-6,14-e / ιc / o-ethanomorphinan-3-ol (buprenorphine ), 5-butyl-5-ethylbarbituric acid (butobarbital), butorphanol, (7-chloro-1, 3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1, 4-benzodiazepin-3-yl) -dimethyl-carbamate (camazepam), (1 s . 2s) -2-amino-1-phenyl-1-propanol (cathine / D-norpseudoephedrine), 7-chloro- / v-methyl-5-phenyl-3 -1 , 4 - benzodiazepin-2-ylamine-4-oxide (chlorodiazepoxide), 7-chloro-1-methyl-5-phenyl-lH-1,5-benzodiazepine-2,4 (3 / - /, 5 / -y) -dione (clobazam), 5- (2-chlorophenyl) -7-nitro-1 -1, 4-benzodiazepin-2 (3 / - /) - one (clonazepam), clonitazene, carfentanil, clofedanol, 7-chloro-2 , 3-dihydro-2-oxo-5-phenyl-1f -, 4-benzodiazepine-3-carboxylic acid (clorazepate), 5- (2-chlorophenyl) -7-ethyl-1-methyl-1 H-thieno [2, 3-e] [1, 4] diazepin-2 (3H) -one (clotiazepam), 10-chloro-11 b- (2chlorophenyl) -2,3,7,11 b-tetrahydrooxazolo [3,2-c /] [1, 4] benzodiazepine-6 (5H) -one (cloxazolam), (-) - methyl- [3ß-benzoyloxy-2ß (1 α H, 5 α / - /) - tropane carboxylate] (cocaine) , 4,5 α- epoxy-3-methoxy-17-methyl-7-morphine-6 α -ol (codeine), 5- (1-cyclohexenyl) -5-ethylbarbituric acid (cyclobarbital), cyclorphan, cyprenorphin, 7-chlorine -5- (2-chlorophenyl) -1 / - / - 1,4-benzodiazepin-2 (3H) -one (delorazepam), desomorphine, dextromoramide, (+) - (1-benzyl-3-dimethylamino-2-methyl -1-phenylpropyl) propionate (dextropropoxyphen), dextromethorphan, decocin, diampromide, diamorphone, 7-chloro-1-methyl-5-phenyl-1 - / - 1, 4-benzodiatepin-2 (3f /) - on (diazepam) , 4,5 α- epoxy-3-methoxy-17-methyl-6 α -morphinanol (dihydrocodeine), 4,5 α- epoxy-17-methyl-3,6-morphinanediol (dihydromorphine), dimenoxadol, dimephetamol, dimethylthiambutene, Dioxaphetyl butyrate, dipipanone, (6a /, 10aft) -6,6,9-trimethyl-3-pentyl-6a, 7,8,10a ~ tetrahydro-6 / - / - benzo [c] chromen-1-ol (dronabinol) , Ephedrine, pseudoephedrine, eptazocine, 8-chloro-6-phenyl-4H- [1, 2.4] triazolo [4,3-a] [1, 4] benzodiazepine (estazolam), ethoheptazine, ethylmethylthiambutene, ethyl [7 -chloro-5- (2-fluorophenyl) -2,3-dihydro-2-oxo-1 - / - 1.4 benzodiaz epin-3-carboxylate] (ethyloflazepate), 4.5 α- epoxy-3-ethoxy-17- methyl-7-morphine-6 α -ol (ethylmorphine), etonitazene, 4.5 α -epoxy-7 α - (1-hydroxy-1-methylbutyl) -6-methoxy-17-methyl-6,14-endo- etheno-morphinan-3-ol (etorphin), [\ i-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (fencamfamine), 7- [2- ( α -methylphenethylamino) ethyl] theophylline ) (Fenetylline), 3- ( α - methylphenethylamino) propionitrile (fenproporex), fenpipramide, / \ / - (1-phenethyl-4-piperidyl) propionanilide (fentanyl), 7-chloro-5- (2-fluorophenyl) -1 -methyl-1 -1, 4-benzodiazepine-2 (3H) -one (fludiazepam), 5- (2-fluorophenyl) -1 -methyl-7-nitro-1 /-/-1.4- benzodiazepine-2 (3H) -one (flunitrazepam), 7-chloro-1 - (2-diethylaminoethyl) -5- (2-fluorophenyl) -1 -1, 4-benzodiazepin-2 (3 / - /) - one (flurazepam), 7-chloro -5-phenyl-1- (2,2,2-trifluoroethyl) -1 H-1,4-benzodiazepin-2 (3H) -one (halazepam), 10-bromo-11 b- (2-fluorophenyl) -2 , 3,7,11 b-tetrahydrθ [1, 3] θxazolθ [3,2-d] [1, 4] benzodiazepin-6 (5 / -) -one (haloxazolam), heroin, 4,5 α- epoxy- 3-methoxy-17-methyl-6-morphinanone (hydrocodone), 4.5 α- epoxy-3-hydroxy-17-met hyl-6-morphinanone (hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan, 1-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H- [1, 3] θxazino [3,2-d] [1, 4] benzodiazepine-4,7 (6H) dione
(Ketazolam), 1 -[4-(3-Hydroxyphenyl)-1 -methyl-4-piperidyl]-1 -propanon (Ketobemidon), (3s,6s)-6-Dimethylamino-4,4-diphenylheptan-3-ylacetat (Levacetylmethadol (LAAM)), (-)-6-Dimethylamino-4,4-diphenyl-3-heptanon (Levomethadon), (-)-17-Methyl-3-morphinanol (Levorphanol), Levophenacylmorphan, Lofentanil, 6-(2-Chlorphenyl)-2-(4-methyl-1-piperazinylmethylen)-8-nitro-2H- imidazo[1 ,2-a][1 ,4] benzodiazepin-1 (4/-/)-on (Loprazolam), 7-Chlor-5-(2-chlorphenyl)- 3-hydroxy- 1/^-1 ,4-benzodiazepin-2(3H)-on (Lorazepam), 7-Chlor-5-(2-chlorphenyl)-3- hydroxy-1-methyl-1/γ-1 ,4-benzodiazepin-2(3 )~on (Lormetazepa ), 5-(4- Chlorphenyl)-2,5-dihydro-3/-/-imidazo[2,1-a]isoindol-5-ol (Mazindol), 7-Chlor-2,3- dihydro-1-methyl-5-phenyl-1 H-1 ,4-benzodiazepin (Medazepam), /v-(3-Chlorpropyl)-α- methylphenethylamin (Mefenorex), Meperidin, 2-Methyl-2- propyltrimethylendicarbamat (Meprobamat), Meptazinol, Metazocin, Methylmorphin, N,α-Dimethylphenethylamin (Metamfetamin), (+)-6-Dimethylamino-4,4-diphenyl-3- heptanon (Methadon), 2-Methyl-3-0-tolyl-4(3/-/)-chinazolinon (Methaqualon), Methyl- [2-phenyl-2-(2-piperidyl)acetat] (Methylphenidat), 5-Ethyl-1 -methyl-5- phenylbarbitursäure (Methylphenobarbital), 3,3-Diethyl-5-methyl-2,4-piperidindion (Methyprylon), Metopon, 8-Chlor-6-(2-fluorphenyl)-1-methyl-4 v_imidazo[1 ,5-a] [1 ,4]benzodiazepin (Midazolam), 2-(Benzhydrylsulfinyl)acetamid (Modafinil), 4,5α- Epoxy-17-methyl-7-morphinen-3,6α-diol (Morphin), Myrophin, (±Hrans-3-( 1.1- Dimethylheptyl)-7,8, 10, 10α-tetrahydro-1 -hydroxy-6,6-dimethyl-6H-dibenzo [b, d\ pyran-9(6αH)-on (Nabilon), Naibuphen, Naiorphin, Narcein, Nicomorphin, 1-Methyl-7- nitro-5-phenyl-lH- ,4-benzodiazepin-2(3/-/)-on (Nimetazepam), 7-Nitro-5-phenyl-1^/- 1 ,4-benzodiazepin-2(3/-/)-on (Nitrazepam), 7-Chlor-5-phenyl-lH-1 ,4-benzodiazepin- 2(3π)-on (Nordazepam), Norlevorphanol, 6-Dimethylamino-4,4-diphenyl-3-hexanon (Normethadon), Normorphin, Norpipanon, der geronnene Saft der zur Art Papaver somniferum gehörenden Pflanzen (Opium), 7-Chlor-3-hydroxy-5-phenyl-1/-/-1.4- benzodiazepin-2(3 -/)-on (Oxazepam), (cis-transY IO-Chlor-2,3,7,11b-tetrahydro-2- methyl-11b-phenyloxazolo[3,2-c][1 ,4] benzodiazepin-6-(5H)-on (Oxazolam), 4,5α- Epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanon (Oxycodon), Oxymorphon, Pflanzen und Pflanzenteile der zur Art Papaver somniferum (einschließlich der Unterart setigerum) gehörenden Pflanzen (Papaver somniferum), Papaveretum, 2- lmino-5-phenyl-4-oxazolidinon (Pernolin), 1 ,2,3,4,5,6-Hexahydro-6,11-dimethyl-3-(3- methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol (Pentazocin), 5-Ethyl-5-(1 - methylbutyl)-barbitursäure (Pentobarbital), Ethyl-(1 -methyl-4-phenyl-4- piperidincarboxylat) (Pethidin), Phenadoxon, Phenomorphan, Phenazocin, Phenoperidin, Piminodin, Pholcodin, 3-Methyl-2-phenylmorpholin (Phenmetrazin), 5- Ethyl-5-phenylbarbitursäure (Phenobarbital), α,α-Dimethylphenethylamin (Phentermin), 7-Chlor-5-phenyl-1 -(2-propinyl)-1 /- -1 ,4-benzodiazepin-2(3H)-on (Pinazepam), -(2-Piperidyl)benzhydrylalkohol (Pipradrol), 1'-(3-Cyan-3,3- diphenylpropyl)[1 ,4'-bipiperidin]-4'-carboxamid (Piritramid), 7-Chlor-1- (cyclopropylmethyl)-5-phenyl-lH-1 ,4-benzodiazepin-2(3/-/)-on (Prazepam), Profadol, Proheptazin, Promedol, Properidin, Propoxyphen, N-(1-Methyl-2-piperidinoethyl)-N- (2-pyridyl)propionamid , Methyl{3-[4-methoxycarbonyl-4-(/v- phenylpropanamido)piperidino]propanoat} (Remifentanil), 5-Sec~Butyl-5- ethylbarbitursäure (Secbutabarbital), 5-Aliyl-5-(1 -methylbutyl)-barbitursäure (Secobarbital), /\/-{4-Methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilid (Sufentanil), 7-Chlor-2-hydroxy-methyl-5-phenyl-1 H-1 ,4-benzodiazepin-2(3H)-on (Temazepam), 7-Chlor-5-(1 -cyclohexenyl)-1 -methyl-1 /-/-1 ,4-benzodiazepin-2(3/-/)-on (Tetrazepam), Ethyl-(2-dimethylamino-1 -phenyl-3-cyclohexen-1 -carboxylat) (Tilidin (eis und trans)), Tramadol, 8-Chlor-6-(2-chlorphenyl)-1-methyl-4H-[1 ,2,4]triazolo[4,3- a][1 ,4]benzodiazepin (Triazolam), 5-(1-Methylbutyl)-5-vinylbarbitursäure (Vinylbital), (1 R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1 R, 2R, 4S)-2- [Dimethylamino)methyl-4-(p-fluorbenzyloxy)-1 -(m-methoxyphenyl)cyclohexanol, (1 R, 2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol, (1 S, 2S)-3(3-Dimethylamino-1 - ethyl-2-methyl-propyl)-phenol, (2R, 3R)-1 -Dimethylamino-3(3-Methoxy-phenyl)-2- methyl-pentan-3-ol, (1RS, 3RS, 6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)- cyclohexan-1 ,3-diol, vorzugsweise als Racemat, 3-(2-Dimethylaminomethyl-1- hydroxy-cyclohexyl)-phenyl 2-(4-isobutyl-phenyl)-propionat, 3-(2- Dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)- propionat, 3-(2-Dimethylaminomethyl-cyclohex-1 -enyl)-phenyl 2-(4-isobutyl-phenyl)- propionat, 3-(2-Dimethylaminomethyl-cyclohex-1 -enyl)-phenyl 2-(6-methoxy- naphthalen-2-yl)-propionat, (RR-SS)-2-Acetoxy-4-trifluoromethyl-benzoesäure 3-(2- dimethylaminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-Hydroxy-4- trifluoromethyl-benzoesäure 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-4-Chloro-2-hydroxy-benzoesäure 3-(2-dimethylaminomethyl-1 - hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-Hydroxy-4-methyl-benzoesäure 3-(2- dimethylaminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-Hydroxy-4- methoxy-benzoesäure 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl-ester, (RR-SS)-2-Hydroxy-5-nitro-benzoesäure 3-(2-dimethylaminomethyl-1-hydroxy- cyclohexyl)-phenyl ester, (RR-SS)-2',4'-Difluoro-3-hydroxy-biphenyl-4-carbonsäure 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester sowie entsprechende stereoisomere Verbindungen, jeweils deren entsprechende Derivate, insbesondere Amide, Ester oder Ether, und jeweils deren physiologisch verträgliche Verbindungen, insbesondere deren Salze und Solvate, besonders bevorzugt Hydrochloride.(Ketazolam), 1 - [4- (3-hydroxyphenyl) -1-methyl-4-piperidyl] -1-propanone (ketobemidone), (3s, 6s) -6-dimethylamino-4,4-diphenylheptan-3-ylacetate (Levacetylmethadol (LAAM)), (-) - 6-dimethylamino-4,4-diphenyl-3-heptanone (levomethadone), (-) - 17-methyl-3-morphinanol (levorphanol), levophenacylmorphan, lofentanil, 6- ( 2-chlorophenyl) -2- (4-methyl-1-piperazinylmethylene) -8-nitro-2H-imidazo [1, 2-a] [1, 4] benzodiazepin-1 (4 / - /) - one (loprazolam) , 7-chloro-5- (2-chlorophenyl) -3-hydroxy-1 / ^ - 1, 4-benzodiazepin-2 (3H) -one (lorazepam), 7-chloro-5- (2-chlorophenyl) -3 - hydroxy-1-methyl-1 / γ-1, 4-benzodiazepin-2 (3) ~ on (Lormetazepa), 5- (4-chlorophenyl) -2,5-dihydro-3 / - / - imidazo [2, 1- a ] isoindol-5-ol (Mazindol), 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepine (medazepam), / v- (3-chloropropyl ) - α - methylphenethylamine (Mefenorex), meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate), meptazinol, metazocin, methylmorphine, N, α- dimethylphenethylamine (metamfetamine), (+) - 6-dimethylamino-4,4-dipheny l-3-heptanone (methadone), 2-methyl- 3-0- tolyl-4 (3 / - /) - quinazolinone (methaqualon), methyl- [2-phenyl-2- (2-piperidyl) acetate] (methylphenidate ), 5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital), 3,3-diethyl-5-methyl-2,4-piperidinedione (methyprylon), metopone, 8-chloro-6- (2-fluorophenyl) - 1-methyl-4 v_imidazo [1,5- a ] [1,4] benzodiazepine (midazolam), 2- (benzhydrylsulfinyl) acetamide (modafinil), 4,5 α - epoxy-17-methyl-7-morphinen-3, 6 α -diol (morphine), myrophin, (± Hrans-3- (1.1- Dimethylheptyl) -7.8, 10, 10 α -tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b, d \ pyran-9 (6 α H) -one (nabilone), naibuphen, Naiorphin, Narcein, nicomorphine, 1-methyl-7-nitro-5-phenyl-1H-, 4-benzodiazepin-2 (3 / - /) - one (nimetazepam), 7-nitro-5-phenyl-1 ^ / - 1, 4-benzodiazepin-2 (3 / - /) - one (nitrazepam), 7-chloro-5-phenyl-lH-1, 4-benzodiazepin-2 (3π) -one (nordazepam), norlevorphanol, 6-dimethylamino-4 , 4-diphenyl-3-hexanone (normethadone), normorphin, norpipanone, the coagulated sap of the plants belonging to the Papaver somniferum species (opium), 7-chloro-3-hydroxy-5-phenyl-1 / - / - 1.4-benzodiazepine -2 (3 - /) - one (oxazepam), (cis-transY IO-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo [3,2-c] [1, 4] benzodiazepin-6- (5H) -one (oxazolam), 4,5 α - epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone), oxymorphone, plants and parts of plants of the species Papaver somniferum ( including plants belonging to the subspecies setigerum) (Papaver somniferum), Papaveretum, 2- lmino-5-phenyl-4-oxazolidino n (pernoline), 1, 2,3,4,5,6-hexahydro-6,11-dimethyl-3- (3-methyl-2-butenyl) -2,6-methano-3-benzazocin-8-ol (Pentazocin), 5-ethyl-5- (1-methylbutyl) barbituric acid (pentobarbital), ethyl (1-methyl-4-phenyl-4-piperidinecarboxylate) (pethidine), phenadoxone, phenomorphan, phenazocin, phenoperidine, piminodine, Pholcodin, 3-methyl-2-phenylmorpholine (phenmetrazine), 5-ethyl-5-phenylbarbituric acid (phenobarbital), α , α- dimethylphenethylamine (phentermine), 7-chloro-5-phenyl-1 - (2-propynyl) -1 / - -1, 4-benzodiazepin-2 (3H) -one (pinazepam), - (2-piperidyl) benzhydryl alcohol (Pipradrol), 1 '- (3-cyan-3,3-diphenylpropyl) [1, 4'- bipiperidine] -4'-carboxamide (piritramide), 7-chloro-1- (cyclopropylmethyl) -5-phenyl-lH-1, 4-benzodiazepin-2 (3 / - /) - one (prazepam), profadol, proheptazin, Promedol, properidine, propoxyphene, N- (1-methyl-2-piperidinoethyl) -N- (2-pyridyl) propionamide, methyl {3- [4-methoxycarbonyl-4 - (/ v-phenylpropanamido) piperidino] propanoate} (remifentanil ), 5- S ec ~ butyl-5-ethylbarbituric acid (Secbutabarbit al), 5-aliyl-5- (1-methylbutyl) barbituric acid (secobarbital), / \ / - {4-methoxymethyl-1- [2- (2-thienyl) ethyl] -4-piperidyl} propionanilide (sufentanil) , 7-chloro-2-hydroxy-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2 (3H) -one (temazepam), 7-chloro-5- (1 -cyclohexenyl) -1-methyl- 1 / - / - 1, 4-benzodiazepin-2 (3 / - /) - one (tetrazepam), ethyl (2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine (ice and trans) ), Tramadol, 8-chloro-6- (2-chlorophenyl) -1-methyl-4H- [1, 2,4] triazolo [4,3- a] [1,4] benzodiazepine (triazolam), 5- ( 1-methylbutyl) -5-vinylbarbituric acid (vinylbital), (1 R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (1 R, 2R, 4S) -2- [Dimethylamino) methyl-4- (p-fluorobenzyloxy) -1 - (m-methoxyphenyl) cyclohexanol, (1 R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) phenol, (1 S, 2S) -3 (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol, (2R, 3R) -1 -dimethylamino -3 (3-methoxy-phenyl) -2-methyl-pentan-3-ol, (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) cyclohexan-1, 3-diol, preferably as a racemate, 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl 2- (4-isobutyl-phenyl) propionate, 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl 2- (6- methoxy-naphthalene-2-yl) propionate, 3- (2-dimethylaminomethyl-cyclohex-1-enyl) phenyl 2- (4-isobutyl-phenyl) propionate, 3- (2-dimethylaminomethyl-cyclohex-1-enyl ) -phenyl 2- (6-methoxy-naphthalene-2-yl) propionate, (RR-SS) -2-acetoxy-4-trifluoromethyl-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester , (RR-SS) -2-hydroxy-4-trifluoromethyl-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -4-chloro-2-hydroxy-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl ester, (RR-SS) -2-hydroxy-4-methy l-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl ester, (RR-SS) -2-hydroxy-4-methoxy-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl -ester, (RR-SS) -2-hydroxy-5-nitro-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ester, (RR-SS) -2 ', 4'-difluoro-3 -hydroxy-biphenyl-4-carboxylic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl ester and corresponding stereoisomeric compounds, in each case their corresponding derivatives, in particular amides, esters or ethers, and in each case their physiologically compatible compounds, in particular their Salts and solvates, particularly preferably hydrochloride.
Insbesondere eignet sich das erfindungsgemäße transdermale System zur Verhinderung des Missbrauchs eines opioiden Wirkstoffes ausgewählt aus der Gruppe umfassend (1 R, 2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (2R, 3R)-1-Dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol, (1 RS, 3RS, 6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1 ,3-diol, (1 R, 2R)- 3-(2-Dimethylaminonethyl-cyclohexyl)-phenol, deren physiologisch verträglichen Salze, vorzugsweise Hydrochloride, physiologisch verträgliche Enantiomere, Stereoisomere, Diastereomere, Racemate und deren physiologisch verträglichen Derivate, vorzugsweise Ether, Ester oder Amide. Diese Verbindungen bzw. deren Herstellungsverfahren sind in der EP-A-693475 bzw. EP-A-780369 beschrieben. Die entsprechenden Beschreibungen werden hiermit als Referenz eingeführt und gelten als Teil der Offenbarung.The transdermal system according to the invention is particularly suitable for preventing the abuse of an opioid active substance selected from the group comprising (1 R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (2R, 3R ) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, (1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane -1, 3-diol, (1 R, 2R) - 3- (2-dimethylaminonethyl-cyclohexyl) -phenol, their physiologically compatible salts, preferably hydrochlorides, physiologically compatible enantiomers, stereoisomers, diastereomers, racemates and their physiologically compatible derivatives, preferably Ethers, esters or amides. These compounds and their production processes are described in EP-A-693475 and EP-A-780369. The corresponding descriptions are hereby introduced as a reference and are considered part of the disclosure.
Ganz besonders bevorzugt eignet sich das erfindungsgemäße transdermale System zur Verhinderung des Missbrauchs von Opioiden, vorzugsweise analgetisch wirksamen Opioiden, besonders bevorzugt von wenigstens einem Opioid ausgewählt aus der Gruppe umfassend Morphin, Oxicodon, Buprenorphin, Sulfentanil, Hydromorphon, Carfentanil, Lofentanyl und Fentanyl, besonders bevorzugt Buprenorphin, deren Derivate, wie Ester, Ether oder Amide, oder deren jeweils physiologisch verträglichen Verbindungen, vorzugsweise deren Salze, wie Hydrochloride oder Sulfate, oder Solvate, deren jeweilige stereoisomere Verbindungen, Enantiomere, Diastereomere und/oder Racemate.The transdermal system according to the invention is very particularly preferably suitable for preventing the misuse of opioids, preferably analgesic opioids, particularly preferably of at least one opioid selected from the group comprising morphine, oxicodone, buprenorphine, sulfentanil, hydromorphone, carfentanil, lofentanyl and fentanyl Buprenorphine, its derivatives, such as esters, ethers or amides, or their respective physiologically compatible compounds, preferably their salts, such as hydrochlorides or sulfates, or solvates, their respective stereoisomeric compounds, enantiomers, diastereomers and / or racemates.
Durch das zur Verfügung stellen des erfindungsgemäßen transdermalen Systems wird erreicht, dass ein Missbraucher von jeglicher Art von Missbrauch, d. h. nicht nur von einem parenteralen, insbesondere intravenösen Missbrauch, sondern auch von einem oralen oder nasalen Missbrauch abgehalten wird, oder bei einer dennoch vorgenommenen missbräuchlichen Zuführung des Wirkstoffes der Wirkstoff nicht lange genug im Körper des Missbrauchers verbleibt, um dort seine durch den Missbrauch verursachten Wirkungen, insbesondere den Kick, hervorzurufen.By making the transdermal system according to the invention available, an abuser of any kind of abuse, i. H. is not only prevented from parenteral, in particular intravenous abuse, but also from oral or nasal abuse, or if the active ingredient is misused, the active ingredient does not remain in the abuser 's body long enough to have its effects caused by the abuse, especially the kick to evoke.
Dazu weist das erfindungsgemäße transdermale System nicht nur wenigstens ein gelbildendes Mittel in solchen Mengen auf, dass es mit einer Mindestmenge einer wässrigen Flüssigkeit ein Gel bildet, sondern auch als weitere missbrauchs- erschwerende bzw. -verhindernde Verbindung wenigstens einen in einer wässrigen Lösung löslichen, physiologisch verträglichen Farbstoff (d) und/oder wenigstens ein Emetikum (c) auf.For this purpose, the transdermal system according to the invention not only has at least one gel-forming agent in such amounts that it forms a gel with a minimum amount of an aqueous liquid, but also, as a further abuse-aggravating or preventing compound, at least one physiologically soluble in an aqueous solution compatible dye (d) and / or at least one emetic (c).
Üblicherweise versucht ein Missbraucher zur missbräuchlichen Anwendung, vorzugsweise zur intravenösen Verabreichung eines Wirkstoffes mit Missbrauchspotential, diesen aus dem transdermalen System mit Hilfe einer wässrigen Flüssigkeit, vorzugsweise Wasser, zu extrahieren. Gemäß der erfindungsgemäßen Ausrüstung des transdermalen Systems kann sich bereits auf dem transdermalen System ein Gel ausbilden, aus dem keine nennenswerte Wirkstoffmenge extrahiert werden kann, oder das wässrige Extrakt aus dem transdermalen System wird durch das Viskositätserhöhende Mittel, d. h. das gelbildende Mittel, in ein Gel umgewandelt, das nicht mehr filtrierbar bzw. applizierbar ist.For misuse, preferably for intravenous administration of an active substance with potential for abuse, an abuser usually tries to extract it from the transdermal system with the aid of an aqueous liquid, preferably water. According to the equipment of the transdermal system according to the invention, can already be form a gel in the transdermal system from which no significant amount of active ingredient can be extracted, or the aqueous extract from the transdermal system is converted by the viscosity-increasing agent, ie the gel-forming agent, into a gel which can no longer be filtered or applied.
Da das erfindungsgemäße transdermale System darüber hinaus als weiteres missbrauchsverhinderndes Mittel in einer ihrer bevorzugten Ausführungsformen einen in wässriger Flüssigkeit, vorzugsweise in Wasser, löslichen Farbstoff enthält, wird bei dem Versuch einer wässrigen Extraktion des Wirkstoffes zur missbräuchlichen Anwendung eine intensive Farbgebung des Gels bzw. des Extraktes erreicht. Diese Farbgebung führt zusätzlich zu einer Abschreckung beim potentiellen Missbraucher, so dass nicht nur von einer parenteralen, vorzugsweise intravenösen Applikation wegen den mit einer Verabreichung von hochviskosen Flüssigkeiten verbundenen gesundheitlichen Risiken abgesehen wird, sondern auch vor einer oralen und/oder nasalen Applikation zurückgeschreckt wird. Geeignete Farbstoffe sowie die dafür notwendigen Mengen sind der WO 03/015531 zu entnehmen, wobei die entsprechende Offenbarung als Teil der vorliegenden Offenbarung gelten soll und hiermit als Referenz eingeführt wird.Since, in one of its preferred embodiments, the transdermal system according to the invention furthermore contains a dye which is soluble in aqueous liquid, preferably water, as a further abuse-preventing agent, an intensive coloring of the gel or the extract will result in an attempt at aqueous extraction of the active ingredient for misuse reached. This coloring additionally leads to a deterrent to the potential abuser, so that not only parenteral, preferably intravenous administration is dispensed with because of the health risks associated with the administration of highly viscous liquids, but also recourse to oral and / or nasal administration. Suitable dyes and the amounts required for this can be found in WO 03/015531, the corresponding disclosure being considered part of the present disclosure and hereby introduced as a reference.
Wie vorstehend ausgeführt, wird das gelbildende Mittel, d. h. das Viskositätserhöhende Mittel dem transdermalen System in solchen Mengen zugesetzt, dass mit Hilfe einer notwendigen Mindestmenge einer wässrigen Flüssigkeit, vorzugsweise bei dem aus dem transdermalen System gewonnenen wässrigen Extrakt, ein Gel gebildet wird, das nicht gefahrlos applizierbar ist und vorzugsweise beim Einbringen in eine weitere Menge einer wässrigen Flüssigkeit auch visuell unterscheidbar bleibt.As stated above, the gelling agent, i.e. H. the viscosity-increasing agent is added to the transdermal system in such amounts that, with the aid of a necessary minimum amount of an aqueous liquid, preferably in the case of the aqueous extract obtained from the transdermal system, a gel is formed which cannot be applied safely and preferably when introduced in a further amount of an aqueous liquid also remains visually distinguishable.
Visuelle Unterscheidbarkeit im Sinne der vorliegenden Erfindung bedeutet, dass das mit Hilfe einer notwendigen Mindestmenge an wässriger Flüssigkeit gebildete, Wirkstoff-haltige Gel beim Einbringen vorzugsweise mit Hilfe einer Injektionsnadel, in eine weitere Menge wäßriger Flüssigkeit von 37°C im wesentlichen unlöslich und zusammenhängend bleibt und nicht auf einfache Weise so dispergiert werden kann, dass eine parenterale, insbesondere intravenöse, gefahrlose Applikation möglich ist. Vorzugsweise beträgt die Dauer der visuellen Unterscheidbarkeit wenigstens eine Minute, vorzugsweise mindestens 10 Minuten.Visual distinguishability in the sense of the present invention means that the gel containing active substance formed with the aid of a necessary minimum amount of aqueous liquid, when introduced, preferably with the aid of an injection needle, remains essentially insoluble and coherent in a further amount of aqueous liquid of 37 ° C. and cannot be easily dispersed in such a way that parenteral, in particular intravenous, safe application is possible. The duration of the visual differentiation is preferably at least one minute, preferably at least 10 minutes.
Die Viskositätserhöhung des Extrakts führt dazu, dass dessen Nadelgängigkeit bzw. Spritzbarkeit erschwert oder sogar unmöglich gemacht wird. Sofern das Gel visuell unterscheidbar bleibt, bedeutet dies, dass das erhaltene Gel beim Einbringen in eine weitere Menge wäßriger Flüssigkeit, z.B. durch Einspritzen in Blut, zunächst in Form eines weitgehend zusammenhängenden Fadens erhalten bleibt, der zwar durch mechanische Einwirkung in kleinere Bruchstücke zerteilt, nicht aber so dispergiert oder sogar gelöst werden kann, daß eine parenterale, insbesondere intravenöse, Applikation gefahrlos möglich ist.The increase in viscosity of the extract makes it difficult or even impossible for it to pass or spray. If the gel remains visually distinguishable, this means that the gel obtained when introduced into a further amount of aqueous liquid, e.g. by injection into blood, initially in the form of a largely coherent thread, which can be broken down into smaller fragments by mechanical action, but cannot be dispersed or even dissolved in such a way that parenteral, in particular intravenous, application is possible without risk.
Eine intravenöse Applikation eines entsprechenden Gels würde daher mit großer Wahrscheinlichkeit zur Verstopfung von Gefäßen, verbunden mit schweren gesundheitlichen Schäden des Missbrauchers führen.An intravenous application of a corresponding gel would therefore very likely lead to blockage of the vessels combined with serious damage to the health of the abuser.
Zur Überprüfung, ob ein Viskositätserhöhendes Mittel als gelbildendes Mittel zur Anwendung in dem transdermalen System geeignet ist, wird der Wirkstoff mit dem Viskositätserhöhenden Mittel gemischt und in 10 ml Wasser bei einer Temperatur von 25 °C suspendiert. Bildet sich hierbei ein Gel, welches den obenstehend genannten Bedingungen genügt, eignet sich das entsprechende, Viskositätserhöhende Mittel zur Missbrauchs-Vorbeugung bzw. - Verhinderung in dem erfindungsgemäßen transdermalen System.To check whether a viscosity-increasing agent is suitable as a gel-forming agent for use in the transdermal system, the active ingredient is mixed with the viscosity-increasing agent and suspended in 10 ml of water at a temperature of 25 ° C. If a gel is formed which satisfies the conditions mentioned above, the corresponding viscosity-increasing agent is suitable for preventing or preventing abuse in the transdermal system according to the invention.
Dem transdermalen System können ein oder mehrere Viskositätserhöhende Mittel hinzugefügt werden, die ausgewählt sind aus der Gruppe umfassend mikrokristalline Cellulose mit 11 Gew.-% Carboxymethylcellulose-Natrium (Avicel® RC 591), Carboxymethylcellulose-Natrium (Blanose®, CMC-Na C300P®, Frimulsion BLC-5®, Tylose C300 P®), Polyacrylsäure, Acrylatcopolymere, die vorzugsweise vernetzt sind, (Carbopol® 980 NF, Carbopol® 981 ), Johannisbrotkernmehl (Cesagum® LA-200, Cesagum® LID/150, Cesagum® LN-1), Pektine, vorzugsweise aus Citrusfrüchten oder Äpfeln (Cesapectin® HM Medium Rapid Set), Saccharoseacetatisobutyrat, Wachsmaisstärke (C*Gel 04201®), Natriumalginat (Frimulsion ALG (E401 )®), Guarkernmehl (Frimulsion BM®, Polygum 26/1-75®), lota-Carrageen (Frimulsion D021®), Karaya Gummi, Gellangummi (Kelcogel F®, Kelcogel LT100®), Galaktomannan (Meyprogat 150 ®), Tarakemmehl (Polygum 43/1®), Propylenglykoalginat (Protanal-Ester SD-LB®), ,The transdermal system may be added one or more viscosity-increasing agents, which are selected from the group comprising microcrystalline cellulose with 11 wt .-% carboxymethylcellulose sodium (Avicel ® RC 591), carboxymethylcellulose sodium (Blanose ®, CMC-Na C300P ® Frimulsion BLC-5 ® , Tylose C300 P ® ), polyacrylic acid, acrylate copolymers that are preferably cross-linked (Carbopol ® 980 NF, Carbopol ® 981), locust bean gum (Cesagum ® LA-200, Cesagum ® LID / 150, Cesagum ® LN- 1), pectins, preferably from citrus fruits or apples (Cesapectin ® HM Medium Rapid Set), sucrose acetate isobutyrate, waxy maize starch (C * Gel 04201 ® ), sodium alginate (Frimulsion ALG (E401) ® ), guar gum (Frimulsion BM ® , Polygum 26/1 -75 ® ), lota carrageenan (frimulsion D021 ® ), Karaya gum, gellan gum (Kelcogel F ® , Kelcogel LT100 ® ), galactomannan (Meyprogat 150 ® ), tarakem flour (Polygum 43/1 ® ), propylene glycoalginate (Protanal-Ester SD-LB ® ),,
Natrium-Hyaluronat, Tragant, Taragummi (Vidogum SP 200®), fermentiertes Polysaccharid- Welan Gum (K1A96), Xanthan-Gummi (Xantural 180®). Die in Klammern angegebenen Bezeichnungen sind die Handelsnamen, unter denen die jeweiligen Materialien am Markt geführt sind.Sodium hyaluronate, tragacanth, tara gum (Vidogum SP 200 ® ), fermented polysaccharide-welan gum (K1A96), xanthan gum (Xantural 180 ® ). The names given in brackets are the trade names under which the respective materials are listed on the market.
Besonders bevorzugt wird als gelbildendes Mittel eine Verbindung ausgewählt aus der Gruppe umfassend vernetzte Homo- oder Copolymere der Acrylsäure, Gellan- Gummi, Propylenglykolalginat, Pektin, vorzugsweise Apfelpektin, Natrium- Hyaluronat, Xanthan-Gummi, besonders bevorzugt Xanthan oder ein Homo- oder Copolymerisat der Acrylsäure, vorzugsweise vernetzt mit Allylpentaeritrol, eingesetzt.A compound selected from the group comprising crosslinked homo- or copolymers of acrylic acid, gellan gum, propylene glycol alginate, pectin, preferably apple pectin, sodium hyaluronate, xanthan gum, particularly preferably xanthan or a homo- or copolymer of is particularly preferred as the gel-forming agent Acrylic acid, preferably crosslinked with allylpentaeritrol, is used.
In einer besonders bevorzugten Ausführungsform der vorliegenden Erfindung kommen solche in wässriger Flüssigkeit gelbildende Mittel zum Einsatz, die neben den vorstehend genannten Bedinungen auch bei der Extraktion aus dem transdermalen System mit der notwendigen Mindestmenge an wässriger Flüssigkeit ein Gel bilden, das Luftblasen einschließt. Das so erhaltene Gel zeichnet sich durch ein trübes Erscheinungsbild aus, durch das der potentielle Missbraucher zusätzlich optisch gewarnt und vor dessen parenteraler Applikation abgehalten wird.In a particularly preferred embodiment of the present invention, those agents are used which form gel in aqueous liquid and which, in addition to the conditions mentioned above, also form a gel with the necessary minimum amount of aqueous liquid during extraction from the transdermal system, which includes air bubbles. The gel obtained in this way is distinguished by a cloudy appearance, through which the potential abuser is additionally optically warned and prevented from being parenterally administered.
Im allgemeinen ist eine Menge von 0,01 bis 25 Gew.%, bevorzugt 0,05 bis 15 Gew.%, besonders bevorzugt 1 bis 10 Gew.%, bezogen auf das Gesamtgewicht des transdermalen Systems, der/des genannten gelbildenden Mittels ausreichend, um den Missbrauch zu verhindern.In general, an amount of 0.01 to 25% by weight, preferably 0.05 to 15% by weight, particularly preferably 1 to 10% by weight, based on the total weight of the transdermal system, of the gel-forming agent mentioned is sufficient, to prevent abuse.
Das gelbildende Mittel liegt in dem erfindungsgemäßen transdermalen System bevorzugt in Mengen von > 5 mg, besonders bevorzugt in Mengen > 10 mg, vor.The gel-forming agent is present in the transdermal system according to the invention preferably in amounts of> 5 mg, particularly preferably in amounts> 10 mg.
Sofern sich ein potentieller Missbraucher durch die Gelbildung und gegebenenfalls zusätzliche Farbgebung mit der Komponente (d) nicht von einer missbräuchlichen Applikation abhalten lässt, so gewährleistet das erfindungsgemäße transdermale System in einer bevorzugten Ausführungsform, dass der missbräuchlich eingenommene Wirkstoff nicht ausreichend lange genug in dem Körper des Missbrauchers verbleibt, um dort die mit dem Missbrauch verbundenen Wirkungen hervorzurufen.If a potential abuser cannot be prevented from abusive application by the gel formation and possibly additional coloring with component (d), the transdermal system according to the invention ensures in a preferred embodiment that the abusive application active substance ingested does not remain in the abuser 's body long enough to produce the effects associated with the abuse.
Dies wird insbesondere dadurch erreicht, dass dem erfindungsgemäßen transdermalen System neben dem Viskositätserhöhenden, d. h. gelbildenden Mittel und gegebenenfalls dem aversiv wirkenden Farbstoff (d), auch noch ein Emetikum (c) hinzugefügt wird.This is achieved in particular in that the transdermal system according to the invention in addition to the viscosity-increasing, ie. H. gelling agent and optionally the aversive dye (d), an emetic (c) is also added.
Dieses Emetikum liegt in einer räumlich getrennten Anordnung von den übrigen Komponenten des erfindungsgemäßen transdermalen Systems vor, um bei der bestimmungsgemäßen Anwendung keine Wirkung im Körper entfalten zu können. Dies gelingt dadurch, dass man das Emetikum in einer Schicht anordnet, die mit Hilfe einer für das Emetikum undurchlässigen Trennschicht von den Schichten, die die übrigen Komponenten des erfindungsgemäßen transdermalen Systems enthalten, abgetrennt ist oder das Emetikum in Mikrokapseln aus Materialien, die für das Emetikum undurchlässig sind, anordnet. Erst u. a. bei einer mechanischen Einwirkung des potentiellen Missbrauchers, z. B. zum Zerschneiden des transdermalen Systems, das üblicherweise einer Extraktion mit einer wässrigen Flüssigkeit vorangeht, werden die vorstehend beschriebenen Trennungsanordnungen beschädigt bzw. aufgehoben, so dass es zu einem Vermischen des Emetikums mit den übrigen Komponenten des erfindungsgemäßen transdermalen Systems spätestens bei der Extraktion kommt. Sofern ein Missbraucher sich eine solche Mischung gegebenenfalls als Extrakt zuführt, löst dies den missbrauchsverhindernden Brechreiz aus, bevor die mit dem Missbrauch verbundenen Wirkungen in dem Körper hervorgerufen werden. This emetic is present in a spatially separate arrangement from the other components of the transdermal system according to the invention in order not to have any effect in the body when used as intended. This is achieved by arranging the emetic in a layer which is separated from the layers which contain the other components of the transdermal system according to the invention with the aid of a separating layer impermeable to the emetic or the emetic in microcapsules made of materials which are suitable for the emetic are impermeable, arranges. Only when there is mechanical interference from the potential abuser, e.g. B. for cutting the transdermal system, which usually precedes an extraction with an aqueous liquid, the separation arrangements described above are damaged or canceled, so that there is a mixing of the emetic with the other components of the transdermal system according to the invention at the latest during the extraction. If an abuser ingests such a mixture as an extract, this triggers the abuse-preventing nausea before the effects associated with the abuse are caused in the body.
Geeignete Emetika zur Verhinderung des Missbrauchs eines Opioids sind dem Fachmann bekannt und können als solche oder in Form entsprechender Derivate, insbesondere Ester oder Ether, oder jeweils in Form entsprechender physiologisch verträglicher Verbindungen, insbesondere in Form ihrer Salze oder Solvate in dem erfindungsgemäßen transdermalen System liegen.Suitable emetics to prevent misuse of an opioid are known to the person skilled in the art and can be in the transdermal system according to the invention as such or in the form of corresponding derivatives, in particular esters or ethers, or in the form of corresponding physiologically tolerable compounds, in particular in the form of their salts or solvates.
In dem erfindungsgemäßen transdermalen System kommt bevorzugt ein Emetikum auf Basis eines oder mehrerer Inhaltsstoffe von Radix Ipecacuanhae (Brechwurzel), vorzugsweise auf Basis des Inhaltsstoffes Emetin, in Betracht, wie sie z. B. in „Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe" von Prof. Dr. Hildebert Wagner, 2., bearbeitete Auflage, Gustav Fischer Verlag, Stuttgart, New York 1982 beschrieben werden. Die entsprechende Literaturbeschreibung wird hiermit als Referenz eingeführt und gilt als Teil der Offenbarung.In the transdermal system according to the invention, preferably an emetic based on one or more ingredients of Radix Ipecacuanhae (crow's root), preferably based on the ingredient emetin, comes into consideration, as described, for. B. in "Pharmaceutical Biology - Drugs and their Ingredients" by Prof. Dr. Hildebert Wagner, 2nd, edited edition, Gustav Fischer Verlag, Stuttgart, New York 1982. The corresponding literature description is hereby introduced as a reference and is considered part of revelation.
Vorzugsweise kann das erfindungsgemäße transdermale System als Komponente (c) das Emetikum Emetin aufweisen, bevorzugt in einer Menge von > 10 mg, besonders bevorzugt > 20 mg und ganz besonders bevorzugt in einer Menge von > 40 mg pro transdermales System.The transdermal system according to the invention can preferably have the emetic emetin as component (c), preferably in an amount of> 10 mg, particularly preferably> 20 mg and very particularly preferably in an amount of> 40 mg per transdermal system.
Ebenfalls bevorzugt kann als Emetikum Apomorphin als erfindungsgemäße Missbrauchssicherung zum Einsatz kommen, vorzugsweise in einer Menge von vorzugsweise > 3 mg, besonders bevorzugt > 5 mg und ganz besonders bevorzugt > 7 mg pro transdermales System.Apomorphine can also preferably be used as an emetic as anti-abuse protection according to the invention, preferably in an amount of preferably> 3 mg, particularly preferably> 5 mg and very particularly preferably> 7 mg per transdermal system.
Sofern ein potentieller Missbraucher durch die Gelbildung und Farbgebung durch den aversiv wirkenden Farbstoff dennoch nicht von einer missbräuchlichen Anwendung abgehalten wird, so ist es auch möglich, dem erfindungsgemäßen transdermalen System als zusätzliches missbrauchverhinderndes Mittel wenigstens einen Antagonisten für den Wirkstoff mit Missbrauchspotential zur Verhinderung von missbräuchlichen Wirkungen beim Missbraucher zuzusetzen.If a potential abuser is not prevented from improper use due to the gel formation and coloring by the aversive dye, it is also possible to use at least one antagonist for the active substance with abuse potential to prevent abusive effects as an additional abuse-preventing agent for the inventive transdermal system add to the abuser.
Auch in diesem Fall ist der Antagonist räumlich getrennt von den übrigen Bestandteilen des erfindungsgemäßen transdermalen Systems anzuordnen, so dass bei einer bestimmungsgemäßen Anwendung des erfindungsgemäßen transdermalen Systems der Antagonist keine Wirkung entfalten kann. Dies kann - wie bereits vorstehend im Zusammenhang mit der Emetikum-Komponente erwähnt - dadurch erreicht werden, dass der Antagonist durch eine für den Antagonisten undurchlässige Trennschicht von den übrigen Komponenten des erfindungsgemäßen transdermalen Systems getrennt angeordnet wird, oder in Mikrokapseln verkapselt wird, deren Material für den Antagonisten undurchlässig ist. Erst bei einer mechanischen, nicht bestimmungsgemäßen Handhabung des erfindungsgemäßen transdermalen Systems kommt es dann zu einem Vermischen des Antagonisten mit den übrigen Komponenten, so dass der Antagonist bei einer missbräuchlichen Anwendung die sonst üblicherweise durch den Missbrauch hervorgerufenen Wirkungen verhindert.In this case too, the antagonist is to be arranged spatially separated from the other constituents of the transdermal system according to the invention, so that when the transdermal system according to the invention is used as intended System the antagonist can have no effect. As already mentioned above in connection with the emetic component, this can be achieved in that the antagonist is separated from the other components of the transdermal system according to the invention by a separating layer impermeable to the antagonist, or is encapsulated in microcapsules, the material of which is used for is impenetrable to the antagonists. It is only when the transdermal system according to the invention is handled mechanically and not as intended that the antagonist is mixed with the other components, so that the antagonist prevents the effects usually caused by misuse in the event of improper use.
Geeignete Antagonisten zur Verhinderung des Mißbrauchs der Wirkstoffe sind dem Fachmann bekannt und können als solche oder in Form entsprechender Derivate, insbesondere Ester oder Ether, oder jeweils in Form entsprechender physiologisch verträglicher Verbindungen, insbesondere in Form ihrer Salze oder Solvate, in dem erfindungsgemäßen transdermalen System vorliegen.Suitable antagonists for preventing abuse of the active compounds are known to the person skilled in the art and can be present in the transdermal system according to the invention as such or in the form of corresponding derivatives, in particular esters or ethers, or in the form of corresponding physiologically tolerable compounds, in particular in the form of their salts or solvates ,
Sofern der in dem transdermalen System vorliegende Wirkstoff ein Opioid ist, kommt als Antagonist bevorzugt ein Antagonist ausgewählt aus der Gruppe umfassend Naloxon, Naltrexon, Nalmefen, Nalid, Nalmexon, Naiorphin und Nalbuphin, jeweils ggf. in Form einer entsprechenden physiologisch verträglichen Verbindung, insbesondere in Form einer Base, eines Salzes oder Solvates, zum Einsatz. Vorzugsweise werden die entsprechenden Antagonisten in einer Menge von > 10 mg, besonders bevorzugt in einer Menge von 10 bis 100 mg, ganz besonders bevorzugt in einer Menge von 10 bis 50 mg, bezogen auf die Wirkstoff menge, eingesetzt.If the active substance present in the transdermal system is an opioid, the antagonist is preferably an antagonist selected from the group comprising naloxone, naltrexone, nalmefene, nalid, nalmexone, naiorphin and nalbuphin, in each case, if appropriate, in the form of a corresponding physiologically tolerable compound, in particular in In the form of a base, salt or solvate. The corresponding antagonists are preferably used in an amount of> 10 mg, particularly preferably in an amount of 10 to 100 mg, very particularly preferably in an amount of 10 to 50 mg, based on the amount of active ingredient.
Weist das erfindungsgemäße transdermale System als Wirkstoff ein Stimulanz auf, wird als Antagonist bevorzugt ein Neuroleptikum, vorzugsweise wenigstens eine Verbindung ausgewählt aus der Gruppe umfassend Haloperidol, Promethacin, Fluophenozin, Perphenazin, Levomepromazin, Thioridazin, Perazin, Chlorpromazin, Chlorprotheaxin, Zucklopantexol, Flupentexol, Prithipendyl, Zotepin, Penperidol, Piparmeron, Melperol und Bromperidol, eingesetzt. Vorzugsweise weist das erfindungsgemäße transdermale System diese Antagonisten in einer üblichen, dem Fachmann bekannten therapeutischen Dosierung, besonders bevorzugt in einer gegenüber der üblichen Dosierung verdoppelten bis verdreifachten Menge auf.If the transdermal system according to the invention has a stimulant as the active ingredient, a neuroleptic, preferably at least one compound selected from the group comprising haloperidol, promethacin, fluophenozin, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chloroprosteaxin, sugar-lopantexol, flupentexyl, prith is preferably used as the antagonist , Zotepin, Penperidol, Piparmeron, Melperol and Bromperidol, used. The transdermal system according to the invention preferably has these antagonists in a customary therapeutic dosage known to the person skilled in the art, particularly preferably in a quantity which is doubled or tripled compared to the usual dosage.
Die Ausrüstung des erfindungsgemäßen transdermalen Systems mit einem gelbildenden Mittel, einem aversiven Farbstoff und einem Antagonisten zur Verhinderung von Missbrauch kann darüber hinaus noch ergänzt werden, indem das erfindungsgemäße transdermale System zusätzlich noch ein Emetikum (c) enthält, das zusammen mit dem Antagonisten (b) die missbräuchlichen Wirkungen beim Missbraucher verhindert und gegebenenfalls auch anstelle des aversiv wirkenden Farbstoffs zum Einsatz kommt.The equipment of the transdermal system according to the invention with a gel-forming agent, an aversive dye and an antagonist to prevent abuse can also be supplemented by the transdermal system according to the invention additionally containing an emetic (c), which together with the antagonist (b) prevents the abusive effects on the abuser and may also be used instead of the aversive dye.
Sofern ein potentieller Missbraucher trotz Gelbildung und gegebenenfalls aversiver Färbung nicht von einer missbräuchlichen Verabreichung abgehalten wird, kann es angebracht sein, dem erfindungsgemäßen transdermalen System neben den bereits aufgeführten Komponenten, wie einem Emetikum und gegebenenfalls einem Antagonisten, darüber hinaus noch oder anstelle eines Antagonisten wenigstens einen Reizstoff hinzuzufügen. Als Reizstoffe kommen solche Substanzen in Frage, die Entzündungen, Fieber, ein Brennen und/oder einen Juckreiz verursachen können.If a potential abuser is not prevented from misuse despite gel formation and possibly aversive staining, it may be appropriate to use the transdermal system according to the invention in addition to the components already listed, such as an emetic and optionally an antagonist, or at least one in addition to an antagonist Add irritant. Substances that can cause inflammation, fever, a burning sensation and / or an itchiness are suitable as irritants.
Als fieber- und/oder entzündungsverursachende Reizstoffe, die insbesondere gegen eine Wiederholung des Missbrauchs wirken können, eignen sich u. a. Lipopolysaccharide und/oder Mikroorganismen, wie Lactobazillen oder Saccharomyces-Arten. Diese Substanzen wirken nicht nur gegen einen parenteralen, vorzugsweise intravenösen Missbrauch, da sie vorzugsweise bereits an der Einstichstelle Entzündungen verursachen können, sondern darüber hinaus gegen einen oralen und/oder nasalen Missbrauch. Letzteres gilt auch für Reizstoffe, die ein Brennen und/oder einen Juckreiz verursachen. Entsprechende Stoffe und deren üblicherweise einzusetzenden Mengen sind dem Fachmann bekannt und können durch einfache Vorversuche ermittelt werden. Vorzugsweise basieren die Reizstoffe, die ein Brennen oder einen Juckreiz verursachen auf einem oder mehreren Inhaltsstoffen oder einem oder mehreren Pflanzenteilen, wenigstens einer Scharfstoffdroge.Lipopolysaccharides and / or microorganisms such as lactobacilli or Saccharomyces species are suitable as fever and / or inflammation-causing irritants, which can act in particular against repetition of the abuse. These substances act not only against parenteral, preferably intravenous abuse, since they can preferably cause inflammation already at the injection site, but also against oral and / or nasal abuse. The latter also applies to irritants that cause a burning sensation and / or itching. Corresponding substances and their customary amounts are known to the person skilled in the art and can be determined by simple preliminary tests. The irritants that cause a burning sensation or itchiness are preferably based on one or more ingredients or one or more plant parts, at least one hot substance drug.
Entsprechende Scharfstoffdrogen sind dem Fachmann bekannt und werden beispielsweise in "Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe" von Prof. Dr. Hildebert Wagner, 2., bearbeitete Auflage, Gustav Fischer Verlag, Stuttgart- New York, 1982, Seiten 82 ff., beschrieben. Die entsprechende Beschreibung wird hiermit als Referenz eingeführt und gilt als Teil der Offenbarung.Corresponding hot substance drugs are known to the person skilled in the art and are described, for example, in "Pharmaceutical Biology - Drugs and Their Ingredients" by Prof. Dr. Hildebert Wagner, 2nd, edited edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 ff. The corresponding description is hereby introduced as a reference and is considered part of the disclosure.
Vorzugsweise kann dem erfindungsgemäßen transdermalen System als Komponente (a) einer oder mehrere Inhaltsstoffe wenigstens einer Scharfstoffdroge, ausgewählt aus der Gruppe umfassend Allii sativi Bulbus, Asari Rhizoma c. Herba, Calami Rhizoma, Capsici Fructus (Paprika), Capsici Fructus acer (Cayennepfeffer), Curcumae longae Rhizoma, Curcumae xanthorrhizae Rhizoma, Galangae Rhizoma, Myristicae Semen, Piperis nigri Fructus (Pfeffer), Sinapis albae (Erucae) Semen, Sinapis nigri Semen, Zedoariae Rhizoma und Zingiberis Rhizoma, besonders bevorzugt aus der Gruppe umfassend Capsici Fructus (Paprika), Capsici Fructus acer (Cayennepfeffer) und Piperis nigri Fructus (Pfeffer), hinzugefügt werden.The transdermal system according to the invention can preferably contain, as component (a), one or more ingredients of at least one hot substance drug, selected from the group comprising Allii sativi Bulbus, Asari Rhizoma c. Herba, Calami Rhizoma, Capsici Fructus (bell pepper), Capsici Fructus acer (Cayenne pepper), Curcumae longae Rhizoma, Curcumae xanthorrhizae Rhizoma, Galangae Rhizoma, Myristicae Semen, Piperis nigri Fructus (pepper), Sinapis albaig (Semucen nba, Semucen Zedoariae Rhizoma and Zingiberis Rhizoma, particularly preferably from the group comprising Capsici Fructus (paprika), Capsici Fructus acer (Cayenne pepper) and Piperis nigri Fructus (pepper).
Bei den Inhaltsstoffen der Scharfstoffdrogen handelt es sich bevorzugt um o- Methoxy(Methyl)-phenol-Verbindungen, Säureamid-Verbindungen, Senföle oder Sulfidverbindungen oder um davon abgeleiteten Verbindungen.The ingredients of the hot substance drugs are preferably o-methoxy (methyl) phenol compounds, acid amide compounds, mustard oils or sulfide compounds or compounds derived therefrom.
Besonders bevorzugt ist wenigstens ein Inhaltsstoff der Scharfstoffdrogen ausgewählt aus der Gruppe umfassend Myristicin, Elemicin, Isoeugenol, α-Asaron, Safrol, Gingerolen, Xanthorrhizol, Capsaicinoiden, vorzugsweise Capsaicin, Capsaicin- Derivate, wie N-vanillyl -9E-octadecenamid, Dihydrocapsaicin, Nordihydrocapsaicin, Homocapsaicin, Norcapsaicin, und Nomorcapsaicin, Piperin, vorzugsweise trans-Piperin, Glucosinolaten, vorzugsweise auf Basis von nichtflüchtigen Senfölen, besonders bevorzugt auf Basis von p-Hydroxybenzylsenföl, Methylmercaptosenföl oder Methylsulfonylsenföl. und von diesen Inhaltsstoffen abgeleiteten Verbindungen als missbrauchsverhindernde weitere Komponente geeignet. Vorzugsweise kann das erfindungsgemäße transdermale System die Pflanzenteile der entsprechenden Scharfstoffdrogen in einer Menge von 0,01 bis 30 Gew.-%, besonders bevorzugt 0,1 bis 0,5 Gew.-%, jeweils bezogen auf das Gesamtgewicht des erfindungsgemäßen transdermalen Systems, enthalten. Kommen ein oder mehrere Inhaltsstoffe entsprechender Scharfstoffdrogen zum Einsatz, beträgt deren Menge in einem erfindungsgemäßen transdermalen System bevorzugt 0,001 bis 0,005 Gew.-%, bezogen auf das Gesamtgewicht des erfindungsgemäßen transdermalen Systems.At least one ingredient of the hot substance drugs is particularly preferably selected from the group comprising myristicin, elemicin, isoeugenol, α- asarone, safrole, gingerols, xanthorrhizole, capsaicinoids, preferably capsaicin, capsaicin derivatives, such as N-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydinicin , Homocapsaicin, norcapsaicin, and nomorcapsaicin, piperine, preferably trans-piperine, glucosinolates, preferably based on non-volatile mustard oils, particularly preferably based on p-hydroxybenzyl mustard oil, methyl mercaptose oil or methylsulfonyl mustard oil . and compounds derived from these ingredients are suitable as further components to prevent abuse. The transdermal system according to the invention can preferably contain the plant parts of the corresponding hot substance drugs in an amount of 0.01 to 30% by weight, particularly preferably 0.1 to 0.5% by weight, in each case based on the total weight of the transdermal system according to the invention , If one or more ingredients of corresponding hot substance drugs are used, the amount in a transdermal system according to the invention is preferably 0.001 to 0.005% by weight, based on the total weight of the transdermal system according to the invention.
Auch bei dem Einsatz von Reizstoffen ist es notwendig, dass diese in räumlich getrennter Anordnung von den übrigen Komponenten des transdermalen Systems in dem erfindungsgemäßen transdermalen System vorliegen. Dies kann - wie bereits vorstehend ausgeführt - dadurch erreicht werden, dass die Reizstoffe enthaltene Schicht des transdermalen Systems mit einer Trennschicht versehen ist, die für den Reizstoff undurchlässig ist und eine Abtrennung von den übrigen Komponenten des erfindungsgemäßen transdermalen Systems bewirkt. Es ist aber auch möglich, den Reizstoff in Mikrokapseln verkapselt hinzuzufügen, wobei die Mikrokapseln für den Reizstoff undurchlässig sein müssen. Erst u. a. bei einer mechanischen Einwirkung im Zuge einer Vorbereitung der missbräuchlichen Anwendung kommt es zum Vermischen des Reizstoffes mit den übrigen Komponenten des erfindungsgemäßen transdermalen Systems, so dass die Wirkungen des Reizstoffes entfaltet werden können.Also when using irritants, it is necessary that these are present in a spatially separate arrangement from the other components of the transdermal system in the transdermal system according to the invention. As already stated above, this can be achieved in that the layer of the transdermal system containing irritants is provided with a separating layer which is impermeable to the irritant and causes separation from the other components of the transdermal system according to the invention. However, it is also possible to add the irritant encapsulated in microcapsules, the microcapsules having to be impermeable to the irritant. First u. a. in the event of mechanical action in the course of preparing the misuse, the irritant is mixed with the other components of the transdermal system according to the invention, so that the effects of the irritant can be developed.
Die räumliche Anordnung zur Separierung der missbrauchsverhindemden Komponenten (a) bis (d) bedingt nicht nur, dass die Trennmittel undurchlässig für die jeweiligen missbrauchsverhindemden Mittel sein müssen, sondern dass darüber hinaus bei der bestimmungsgemäßen Anwendung des erfindungsgemäßen transdermalen Systems die therapeutische Wirkung nicht beeinflusst wird.The spatial arrangement for separating the anti-abuse components (a) to (d) not only means that the release agents must be impermeable to the respective anti-abuse agents, but also that the therapeutic effect is not influenced when the transdermal system according to the invention is used as intended.
Das erfindungsgemäße transdermale System liegt vorzugsweise als Pflaster vor. Es kann dann nach dem Reservoir- oder Matrix- System aufgebaut sein (Bauer K. H., Frömming K.-H., Führer C, Pharmazeutische Technologie, Seiten 381-383; Müller R. H., Hildebrand G. E., Pharmazeutische Technologie: Moderne Arzneiformen, Kapitel 8).The transdermal system according to the invention is preferably in the form of a plaster. It can then be constructed according to the reservoir or matrix system (Bauer KH, Frömming K.-H., Führer C, Pharmaceutical Technology, pages 381-383; Müller R. H., Hildebrand GE, Pharmaceutical Technology: Modern Dosage Forms, Chapter 8).
Durch die erfindungsgemäße Auswahl des in wässriger Flüssigkeit gelbildenden Mittel ist es möglich, den Wirkstoff mit Missbrauchspotential und das gelbildende Mittel ohne räumliche Trennung voneinander in dem Pflaster zu kombinieren, ohne dass die Freisetzung des Wirkstoffs bei bestimmungsgemäßer Applikation des Pflasters beeinträchtigt wird.The inventive selection of the gel-forming agent in aqueous liquid makes it possible to combine the active substance with potential for abuse and the gel-forming agent in the plaster without spatial separation from one another, without the release of the active substance being impaired when the plaster is used as intended.
Das gelbildende Mittel liegt vorzugsweise wie der Wirkstoff in dem erfindungsgemäßen Pflaster entweder gelöst oder dispergiert vor. Dies gilt auch für die übrigen Komponenten zur weiteren Missbrauchsverhinderung, sofern diese in Mikrokapseln verkapselt, die sich gegebenenfalls in zumindest wässrigen Flüssigkeiten auflösen können, vorliegen.Like the active ingredient, the gel-forming agent is preferably either dissolved or dispersed in the plaster according to the invention. This also applies to the other components for further prevention of abuse, provided that they are encapsulated in microcapsules, which can possibly dissolve in at least aqueous liquids.
Vorzugsweise liegt das in wässriger Flüssigkeit gelbildende Mittel in der wirkstoffhaltigen Matrix-Schicht bzw. in dem wirkstoffhaltigen Reservoir des Pflasters oder daran angrenzend vor, insbesondere wenn es auf dem Pflaster beim Kontakt mit einer wässrigen Flüssigkeit zu einem Gel verdickt, aus dem praktisch kein Wirkstoff extrahierbar ist. Das gelbildende Mittel kann aber auch in einer von wirkstoffsegmenten Schicht des Pflasters vorliegen, insbesondere dann, wenn beim Kontakt mit der wäßrigen Flüssigkeit das gelbildende Mittel und der Wirkstoff extrahierbar sind und im Extrakt die Gelbildung erfolgt.The agent which forms a gel in aqueous liquid is preferably present in or adjacent to the active substance-containing matrix layer or in the active substance-containing reservoir of the plaster, in particular if it thickens on the plaster on contact with an aqueous liquid to form a gel from which practically no active substance can be extracted is. The gel-forming agent can, however, also be present in one of the active substance segment layers of the patch, in particular when the gel-forming agent and the active agent are extractable on contact with the aqueous liquid and the gel is formed in the extract.
Entsprechend dem Matrix-System kann das erfindungsgemäße Pflaster vorzugsweise eine Trägerschicht, eine wirkstoffhaltige Schicht und eine Klebeschicht aufweisen, wobei die wirkstoffhaltige Schicht gleichzeitig die Klebeschicht sein kann, in dem der Wirkstoff und vorzugsweise das gelbildende Mittel gelöst und/oder dispergiert in einer Matrix zusammen mit dem Klebstoff vorliegt. Die weiteren missbrauchsverhindemden Komponenten (a) bis (d) können in verkapselter Form in der wirkstoffhaltigen bzw. Wirkstoff- und klebstoffhaltigen Schicht oder in einer separaten Schicht vorliegen, die mit Hilfe einer für diese missbrauchsverhindemden Komponenten (a) bis (d) undurchlässigen Trennschicht von der wirkstoffhaltigen Schicht abgegrenzt ist. Vorzugsweise, weist das erfindungsgemäße Pflaster zusätzlich noch eine Schutzschicht auf.According to the matrix system, the plaster according to the invention can preferably have a carrier layer, an active ingredient-containing layer and an adhesive layer, wherein the active ingredient-containing layer can simultaneously be the adhesive layer in which the active ingredient and preferably the gel-forming agent are dissolved and / or dispersed in a matrix together with the adhesive is present. The further abuse-preventing components (a) to (d) can be present in encapsulated form in the active ingredient-containing or active ingredient-containing and adhesive-containing layer or in a separate layer which, with the aid of a separating layer impermeable to these abuse-preventing components (a) to (d) the active ingredient Layer is delimited. Preferably, the plaster according to the invention additionally has a protective layer.
Als Klebstoffe für die Klebeschicht des erfindungsgemäßen Pflasters werden vorzugsweise druckempfindliche Klebemittel („pressure-sensitive adhesives") eingesetzt. Beispielsweise eignen sich dafür Polymere wie Polyacrylate, Polyvinylether, Polyisobutylene (PIB), Styrol/Isopren- oder Butadien-/Styrol Copolymere oder Polyisopren Kautschuke. Weiterhin eignen sich Silikon-Klebstoffe, wie z. B. gegebenenfalls vernetzte Polydimethylsiloxane. Ferner sind Kunststoffe auf Basis von Ester von Glycinen, Glycerin oder Polytaerythrol, oder Kohlenwasserstoffen, wie Polyterpene geeignet. Klebstoffe auf Acrylatbasis werden durch Polymerisation von Acrylaten, Methacrylaten, Alkylacrylaten und/oder Alkylmethacrylaten, mit gegebenenfalls weiteren α, ß- ungesättigten Monomeren, wie Acrylamid, Dimethylacrylamid, Dimethylaminoethylacrylat, Hydroxyethylacrylat, Hydroxypropylacrylat, Methoxyethylacrylat, Methoxyethylmethacrylat, Acrylnitril und/oder Vinylacetat, hergestellt.Pressure-sensitive adhesives are preferably used as adhesives for the adhesive layer of the plaster according to the invention. For example, polymers such as polyacrylates, polyvinyl ethers, polyisobutylenes (PIB), styrene / isoprene or butadiene / styrene copolymers or polyisoprene rubbers are suitable for this purpose Also suitable are silicone adhesives, such as, for example, crosslinked polydimethylsiloxanes, plastics based on esters of glycines, glycerol or polytaerythrol, or hydrocarbons such as polyterpenes, and acrylate-based adhesives are obtained by polymerizing acrylates, methacrylates, alkyl acrylates and / or alkyl methacrylates, optionally with further α , β-unsaturated monomers, such as acrylamide, dimethylacrylamide, dimethylaminoethyl acrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, methoxyethyl acrylate, methoxyethyl methacrylate, acrylonitrile and / or vinyl acetate.
Die Klebeschicht des erfindungsgemäßen Pflasters kann auch Hautdurchdringungsverstärker, Füllstoffe (wie Zinkoxid oder Silika), Vernetzer, Antioxidationsmittel und/oder Lösungsmittel enthalten. Die Dicke der Klebeschicht beträgt vorzugsweise 3 bis 100 μm.The adhesive layer of the patch according to the invention can also contain skin penetration enhancers, fillers (such as zinc oxide or silica), crosslinking agents, antioxidants and / or solvents. The thickness of the adhesive layer is preferably 3 to 100 μm .
Die Trägerschicht bzw. Deckschicht des erfindungsgemäßen Pflasters ist vorzugsweise für den Wirkstoff, Klebstoff und die missbrauchsverhindemden Komponenten (a) bis (d) undurchlässig und inert. Vorzugsweise ist die Schicht aus Polymeren, wie Polyester, z. B. Polyethylenterephthalat, Polyolefinen, wie Polyethylenen, Polypropylenen oder Polybutylenen, Polycarbonaten, Polyethylenoxiden, Polyurethanen, Polystyrrolen, Polyamiden, Polyimiden, Polyvinylacetaten, Polyvinylchloriden, Polyvinylidenchloriden und/oder Copolymeren wie Acrylnitril/Butadien/Styrrol Copolymeren gegebenenfalls enthaltend Papierfasern, Textilfasern und/oder deren Mischungen aufgebaut, die bei Bedarf metallisiert oder pigmentiert sein können. Die Trägerschicht bzw. Deckschicht des Pflasters kann auch aus einer Kombination aus Metallfolie und Polymerschicht bestehen. Die Dicke der Trägerschicht beträgt vorzugsweise 3 bis 100 μm. Die wirkstoffhaltige Matrix-Schicht des erfindungsgemäßen Pflasters kann matrixbildende Polymere, Hautdurchdringungsverstärker, Lösungsvermittler, Vernetzer, Stabilisatoren, Emulgatoren, Konservierungsmittel, Verdickungsmittel und/oder weitere übliche Hilfsmittel enthalten.The backing layer or cover layer of the plaster according to the invention is preferably impermeable and inert to the active ingredient, adhesive and the components (a) to (d) which prevent abuse. Preferably, the layer of polymers such as polyester, e.g. B. polyethylene terephthalate, polyolefins, such as polyethylenes, polypropylenes or polybutylenes, polycarbonates, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidene chlorides and / or copolymers such as acrylonitrile / butadiene / styrenic copolymers, or textile fibers and fibers thereof, optionally containing paper fibers Mixtures built up, which can be metallized or pigmented if necessary. The backing layer or cover layer of the plaster can also consist of a combination of metal foil and polymer layer. The thickness of the carrier layer is preferably 3 to 100 μm. The active substance-containing matrix layer of the patch according to the invention can contain matrix-forming polymers, skin penetration enhancers, solubilizers, crosslinking agents, stabilizers, emulsifiers, preservatives, thickeners and / or other customary auxiliaries.
Als matrixbildendes Polymeres wird vorzugsweise wenigstens ein filmbildendes Polymeres ausgewählt aus der Gruppe umfassend Hydroxypropylcellulose, Carboxymethylcellulose, Polyethylene, chlorierte Polyethylene, Polypropylene, Polyurethane, Polycarbonate, Polyacrylsäureester, Polyacrylate, Polymethacrylate, Polyvinylalkohole, Polyvinylchloride, Polyvinylidenchloride, Polyvinylpyrrolidone, Polyethylenterephthalate, Polytetrafluoroethylene, Ethylen/Propylen Copolymere, Ethylen/Ethylacrylat Copolymere, Ethylen/Vinylacetat Copolymere, Ethylen/Vinylalkohol Copolymere, Ethylen/Vinyloxyethanol Copolymere, Vinylchlorid/Vinylacetat Copolymere, Vinylpyrrolidon/Ethylen/Vinylacetat Copolymere, Kautschuke, gummiartige, synthetische Homo-, Co- oder Blockpolymere, Silikone, Silikon-Derivate, vorzugsweise Siloxan/Methacrylat Copolymere, Cellulose-Derivate, vorzugsweise Ethylcellulose oder Celluloseether und deren Mischungen eingesetzt. Wenn die wirkstoffhaltige Schicht gleichzeitig die Klebeschicht ist, enthält sie vorzugsweise neben wenigstens einem der aufgezählten Polymeren zumindest einen der vorstehend aufgeführten Klebstoffe.As the matrix-forming polymer, at least one film-forming polymer is preferably selected from the group comprising hydroxypropyl cellulose, carboxymethyl cellulose, polyethylenes, chlorinated polyethylenes, polypropylenes, polyurethanes, polycarbonates, polyacrylic acid esters, polyacrylates, polymethacrylates, polyvinyl alcohols, polyvinyl chlorides, polyvinylidene chlorides, polyvinyl pyrrolidones, polyethylene terefluoroethylene, polyethylene terephthalate, polyethylene terephthalate Copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, ethylene / vinyl alcohol copolymers, ethylene / vinyloxyethanol copolymers, vinyl chloride / vinyl acetate copolymers, vinylpyrrolidone / ethylene / vinyl acetate copolymers, rubbers, rubber-like, synthetic homo-, co- or block polymers, silicones, silicones Derivatives, preferably siloxane / methacrylate copolymers, cellulose derivatives, preferably ethyl cellulose or cellulose ethers and mixtures thereof. If the active substance-containing layer is at the same time the adhesive layer, it preferably contains at least one of the adhesives listed above in addition to at least one of the polymers listed.
Als Verbindungen zur Verbesserung der Löslichkeit des Wirkstoffes können N- methyl-2-pyrrolidon, Laurylpyrrolidon, Triethanolamin, Triacetin, Diethylenglykol- monoethylether, Derivate von Fettsäuren oder Fettalkoholen verwendet werden.N-methyl-2-pyrrolidone, laurylpyrrolidone, triethanolamine, triacetin, diethylene glycol monoethyl ether, derivatives of fatty acids or fatty alcohols can be used as compounds to improve the solubility of the active ingredient.
Wenn das erfindungsgemäße Pflaster nach dem Reservoir-System aufgebaut ist, kann die Reservoir-Membran aus inerten Polymeren wie z. B. Polyethylenen, Polypropylenen, Polyvinylacetaten, Polyamiden, Ethylen/Vinylacetat Copolymeren und/oder Silikonen bestehen. In dem Reservoir kann der Wirkstoff und vorzugsweise das gelbildende Mittel gelöst oder dispergiert vorliegen. Die übrigen missbrauchsverhindemden Komponenten können, wie vorstehend angegeben, davon räumlich getrennt angeordnet sein. Als Stabilisatoren für wirkstoffhaltige Matrix bzw. das wirkstoffhaltige Reservoir können Antioxidantien, wie Vitamin E, Butylhydroxytoluol, Butylhydroxyanisol, Ascorbinsäure, Ascorbylpalmitat, und/oder Chelatbildner, wie z. B. Dinatriumethylendiamintetraessigsäure, Kalium- oder Natriumeitrat verwendet werden.If the patch according to the invention is constructed according to the reservoir system, the reservoir membrane can be made of inert polymers such as. B. polyethylenes, polypropylenes, polyvinyl acetates, polyamides, ethylene / vinyl acetate copolymers and / or silicones. The active substance and preferably the gel-forming agent can be dissolved or dispersed in the reservoir. The other anti-abuse components can, as stated above, be arranged spatially separated therefrom. Antioxidants such as vitamin E, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, ascorbyl palmitate, and / or chelating agents, such as, for example, may be used as stabilizers for the active substance-containing matrix or the active substance-containing reservoir. B. disodium ethylenediaminetetraacetic acid, potassium or sodium citrate can be used.
Die wirkstoffhaltige Matrix bzw. das wirkstoffhaltige Reservoir kann auch übliche Hautdruckdringungsverstärker enthalten.The active substance-containing matrix or the active substance-containing reservoir can also contain conventional skin pressure penetration enhancers.
Das erfindungsgemäße Pflaster kann auch in einer oder mehreren Schichten wenigstens einen Weichmacher ausgewählt aus der Gruppe umfassend langkettige Alkohole, wie Dodecanol, Undecanol, Octanol, Ester von Carbonsäuren mit polyethoxylierten Alkoholen, Diester von aliphatischen Dicarbonsäuren, wie Adipinsäure, und mittelkettige Triglyceride von Caprylsäure und/oder Caprinsäure, Kokosfett, mehrwertige Alkohole, wie 1 ,2-Propandiol, Ester von mehrwertigen Alkoholen, wie Glycerin mit Lävulinsäure oder Caprylsäure, und veretherte mehrwertige Alkohole enthalten.The plaster according to the invention can also be in one or more layers at least one plasticizer selected from the group comprising long-chain alcohols, such as dodecanol, undecanol, octanol, esters of carboxylic acids with polyethoxylated alcohols, diesters of aliphatic dicarboxylic acids, such as adipic acid, and medium-chain triglycerides of caprylic acid and / or capric acid, coconut fat, polyhydric alcohols, such as 1, 2-propanediol, esters of polyhydric alcohols, such as glycerol with levulinic acid or caprylic acid, and etherified polyhydric alcohols.
Die abziehbare Schutzschicht des erfindungsgemäßen Pflasters kann aus Polyethylen, Polyester, Polyethylenterephthalat, Polypropylen, Polysiloxan, Polyvinylchlorid oder Polyurethan und gegebenenfalls aus behandelten Papierfasern, wie z. B. Zellophan, bestehen und gegebenenfalls eine Silikon-, Fluorsilikon- oder Fluorcarbonbeschichtung aufweisen.The peelable protective layer of the plaster according to the invention can be made of polyethylene, polyester, polyethylene terephthalate, polypropylene, polysiloxane, polyvinyl chloride or polyurethane and optionally from treated paper fibers, such as, for. B. cellophane, and optionally have a silicone, fluorosilicone or fluorocarbon coating.
Die Herstellung des erfindungsgemäßen transdermalen Systems, vorzugsweise Pflasters kann nach bekannten Herstellungsverfahren umfassend die Verfahrensschritte, wie Laminieren, Coextrudieren, Stanzen, Delaminieren, Abwickeln, Schneiden, Wiederaufwickeln, Montieren oder Dosieren (Verpackungs- Rundschau 4/2002, 83-84) erfolgen. BeispieleThe transdermal system according to the invention, preferably the plaster, can be produced by known production processes, including the process steps, such as laminating, coextruding, punching, delaminating, unwinding, cutting, rewinding, assembling or dosing (Verpackungs- Rundschau 4/2002, 83-84). Examples
Beispiel 1 a) Herstellung eines Buprenorphin-.haltigen PflastersExample 1 a) Preparation of a plaster containing buprenorphine
1139 g einer 48 Gew.%igen Polyacrylatlösung eines selbstvernetzenden Acrylatcopolymeren aus 2-Ethylhexylacrylat, Vinylacetat, Acrylsäure (Lösungsmittel: Ethylacetat:Heptan:lsopropanol:Toluol:Acetylacetonat im Verhältnis von 37:26:26:4:1), 100 g Lävulinsäure, 150 g Oleylacetat, 100 g Polyvinylpyrrolidon, 150 g Ethanol, 200 g Ethylacetat und 100 g Buprenorphinbase werden homogenisiert. Man rührt etwa zwei Stunden und kontrolliert visuell, ob alle Feststoffe gelöst sind. Mann kontrolliert den Verdunstungsverlust durch Zurückwiegen und ergänzt gegebenenfalls den Lösungsmittelverlust durch Zugabe von Ethylacetat.1139 g of a 48% by weight polyacrylate solution of a self-crosslinking acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (solvent: ethyl acetate: heptane: isopropanol: toluene: acetylacetonate in a ratio of 37: 26: 26: 4: 1), 100 g levulinic acid, 150 g of olefin acetate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate and 100 g of buprenorphine base are homogenized. The mixture is stirred for about two hours and checked visually whether all the solids have dissolved. Man controls the loss of evaporation by weighing it out and, if necessary, replenishes the loss of solvent by adding ethyl acetate.
Eine 420 mm breite, transparente Polyesterfolie wird mit der oben beschriebenen Mischung so beschichtet, dass das Flächengewicht der getrockneten Klebeschicht 80 g/m2 beträgt. Eine durch Silikonbeschichtung wieder ablösbare Polyesterfolie dient als Schutzschicht.A 420 mm wide, transparent polyester film is coated with the mixture described above in such a way that the weight per unit area of the dried adhesive layer is 80 g / m 2 . A polyester film that can be removed again with a silicone coating serves as a protective layer.
Man entfernt die Lösungsmittel durch Trocknen mit erwärmter Luft, die über die lösungsmittelhaltige Bahn geleitet wird. Durch die Wärmebehandlung verdunstet das Lösungsmittel. Abschließend deckt man die Klebstoffschicht mit der 15 μm dicken Polyesterfolie ab. Mit geeigneten Schneidewerkzeugen stanzt man eine der vorgesehenen Wirkstoffmenge entsprechende Fläche aus und entfernt die zwischen den einzelnen Systemen stehen gebliebenen Ränder. b) Herstellung von Missbrauch-verhindernden Klebstoffschichten b.1 Zur Herstellung einer Missbrauchs-verhindemden Klebstoffschicht wurden zunächst unter Rühren 2 g Carbopol 980 als gelbildendes Mittel in 100 g Ethanol (96%ϊg) gelöst und das verdunstete Ethanol ersetzt. Von dieser 2%igen Carbopol 980 / Ethanol-Lösung wurden jeweils 10 g, 5 g bzw. 2 g in 10 g, 15 g bzw. 18 g in die unter 1 a) beschriebenen Polyacrylatlösung zur Herstellung einer Klebstoffmischung eingerührt und dort homogen verteilt.The solvents are removed by drying with heated air which is passed over the solvent-containing web. The solvent evaporates due to the heat treatment. Finally, cover the adhesive layer with the 15 μm thick polyester film. Using suitable cutting tools, you punch out a surface corresponding to the intended amount of active ingredient and remove the edges that have remained between the individual systems. b) Production of anti-abuse adhesive layers b.1 To produce an anti-abuse adhesive layer, 2 g of Carbopol 980 as a gelling agent were first dissolved in 100 g of ethanol (96% 96g) with stirring and the evaporated ethanol was replaced. 10 g each of this 2% strength Carbopol 980 / ethanol solution, 5 g or 2 g in 10 g, 15 g or 18 g are stirred into the polyacrylate solution described under 1 a) to produce an adhesive mixture and homogeneously distributed there.
Darüber hinaus wurde der Mischung ein lebensmittelrechtlich und physiologisch unbedenklicher gelber Farbstoff (FD&C gelb No. 6), der in Wasser löslich ist, zugegeben und homogen verteilt.In addition, a yellow dye (FD&C yellow No. 6), which is soluble in water, was added to the mixture and physiologically harmless, and was homogeneously distributed.
Auf eine silikonisierte Polyesterfolie (Hostaphanfolien RNT 36) wurden jeweils 20 g der vorstehend aufgeführten Carbopol- und Farbstoff- haltigen Klebstoffmischung unter Verwendung eines 120 μm Rakel mit Hilfe des Erichsen Filmziehgeräts Coatmaster 509/MC-1 aufgetragen. Die Auftragsgeschwindigkeit betrug 5 mm/sek. Nach wenigstens 2 Stunden Trockenzeit wurde auf die unbeschichtete Seite der Klebstoffschicht eine silikonisierte Polyesterfolie als Schutzschicht laminiert. Anschließend wurden 7x7 cm große Quadrate aus den beidseitig laminierten, Missbrauchs-erschwerenden Klebstoffeschichten geschnitten.On a siliconized polyester film (Hostaphan films RNT 36) were each 20 g of Carbopol listed above and dye-containing adhesive mixture using 509 / MC-1 is applied a 120 μ m squeegee using the Erichsen Coatmaster film puller. The application speed was 5 mm / sec. After at least 2 hours of drying time, a siliconized polyester film was laminated as a protective layer on the uncoated side of the adhesive layer. Then 7x7 cm squares were cut from the double-sided laminated, abuse-aggravating adhesive layers.
Jede der mit einer unterschiedlichen Konzentration an Carbopol und mit Farbstoff ausgerüsteten Klebstoffschicht wurde nach Entfernung der silikonisierten Schutzschicht mit der freigelegten Klebstoffschicht des nach 1 a) erhaltenen Buprenorphin-haltigen Pflasters verbunden.After the siliconized protective layer had been removed, each of the adhesive layers provided with a different concentration of Carbopol and with dye was bonded to the exposed adhesive layer of the buprenorphine-containing patch obtained according to 1 a).
Herstellung weiterer Missbrauchs-verhindemder KlebeschichtenProduction of further anti-abuse adhesive layers
Xanthan als gelbildende Verbindung wurde über ein 50 μm Sieb glasiert und der Feinanteil weiterverwendet.Xanthan as a gel-forming compound was glazed over a 50 μm sieve and the fine fraction was used again.
Jeweils 1 g, 2 g bzw. 3 g Xanthan wurden in jeweils 3 g Ethanol (96%ig) suspendiert und die Suspension homogen in 19 g, 18 g bzw. 17 g der unter 1 a) beschriebenen Polyacrylatlösung zur Herstellung einer Klebstoffmischung homogen verteilt. Jeder Mischung wurde mit Hilfe eines Rotavapor 3 g Ethanol entzogen und in die Mischung wurde außerdem Beta-Carotin als Farbstoff komponente homogen eingetragen. Jede erhaltene Mischung wurde jeweils auf eine silikonisierte Polyesterfolie (Hostaphanfolie RNT 36) mit Hilfe eines 120 μm Rakel auf dem Erichsen Filmziehgerät Coatmaster 509/MC-1 als Klebstoffschicht aufgetragen. Die Auftragsgeschwindigkeit betrug 5 mm/sek. Nach wenigstens 2 Stunden Trockenzeit wurde auf die unbeschichtete Seite der Klebstoffschicht ebenfalls mit einer silikonisierten Polyesterfolie als Schutzfolie laminiert. Daraus wurden 7x7 cm große Quadrate geschnitten. Jeder der mit unterschiedlicher Konzentration an Xanthan und mit Farbstoff ausgerüsteten Klebstoffschicht wurde nach Entfernung der Schutzfolie mit der ebenfalls freigelegten Klebstoffschicht des nach 1 a) erhaltenen Buprenorphin-haltigen Pflasters jeweils verbunden.1 g, 2 g and 3 g of xanthan in each case were suspended in 3 g of ethanol (96% strength) and the suspension was homogeneously distributed in 19 g, 18 g and 17 g of the polyacrylate solution described under 1 a) to produce an adhesive mixture , 3 g of ethanol was removed from each mixture using a Rotavapor and was added to the mixture in addition, beta-carotene is homogeneously introduced as a dye component. Each mixture obtained was each applied to a siliconized polyester sheet (Hostaphan RNT 36) using a 120 μ m doctor blade onto the Erichsen Coatmaster film applicator 509 / MC-1 as an adhesive layer. The application speed was 5 mm / sec. After at least 2 hours of drying time, the uncoated side of the adhesive layer was also laminated with a siliconized polyester film as a protective film. From this 7x7 cm squares were cut. Each of the adhesive layers finished with different concentrations of xanthan and with dye was bonded to the likewise exposed adhesive layer of the buprenorphine-containing plaster obtained according to 1 a) after removal of the protective film.
Prüfung der Missbrauchserschwerung bzw. -VerhinderungExamining abuse prevention or prevention
Die nach b.1 bzw. b.2 erhaltenen, mit einer Missbrauchs- erschwerenden Klebstoffschicht versehenen Pflaster wurden nach Entfernung der Schutzschicht auf der Missbrauchs-erschwerenden Klebstoffschicht mit 5 ml Wasser in Kontakt gebracht. Es bildete sich eine rot bzw. gelbrötlich gefärbte Gelschicht auf dem jeweiligen Pflaster, wobei selbst nach einer Kontaktzeit von 5 Stunden in dem verbleibenden, von der Gelschicht nicht aufgenommenen Wasser kein Buprenorphin festgestellt werden konnte. The plasters obtained in accordance with b.1 or b.2 and provided with an abuse-aggravating adhesive layer were brought into contact with 5 ml of water after removal of the protective layer on the abuse-aggravating adhesive layer. A red or yellowish-red colored gel layer formed on the respective plaster, and even after a contact time of 5 hours, no buprenorphine could be found in the remaining water which was not absorbed by the gel layer.

Claims

Patentansprüche claims
1. Gegen Missbrauch gesichertes transdermales System, dadurch gekennzeichnet, dass es neben einem oder mehreren Wirkstoffen mit Missbrauchspotential wenigstens ein gelbildendes Mittel in solchen Mengen enthält, dass es mit einer Mindestmenge einer wässrigen Flüssigkeit ein Gel bildet, und als weitere missbrauchs-erschwerende bzw. -verhindernde Mittel wenigstens ein Emetikum (c) und/oder wenigstens einen Farbstoff (d) als aversives Mittel und ggf. wenigstens einen Reizstoff (a) und/oder ggf. wenigstens einen Antagonisten (b) für den bzw. die Wirkstoffe mit Missbrauchspotential aufweist.1. A transdermal system secured against abuse, characterized in that it contains, in addition to one or more active substances with potential for abuse, at least one gel-forming agent in such quantities that it forms a gel with a minimum amount of an aqueous liquid, and as further abuse-aggravating or - preventing agent has at least one emetic (c) and / or at least one dye (d) as an aversive agent and possibly at least one irritant (a) and / or at least one antagonist (b) for the active substance or substances with abuse potential.
2. Transdermales System gemäß Anspruch 1 , dadurch gekennzeichnet, dass das gelbildende Mittel mit einer Mindestmenge einer wässrigen Flüssigkeit extrahiert ein Gel bildet.2. Transdermal system according to claim 1, characterized in that the gel-forming agent extracted with a minimum amount of an aqueous liquid forms a gel.
3. Transdermales System gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass das Gel nicht parenteral verabreicht werden kann.3. Transdermal system according to claim 1 or 2, characterized in that the gel cannot be administered parenterally.
4. Transdermales System gemäß einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass das gelbildende Mittel in einer Menge von 0,01 bis 25 Gew.-%, bezogen auf das Gesamtgewicht des wirkstoffhaltigen Bereichs des transdermalen Systems, vorliegt.4. Transdermal system according to one of claims 1 to 3, characterized in that the gelling agent is present in an amount of 0.01 to 25 wt .-%, based on the total weight of the active ingredient-containing area of the transdermal system.
5. Transdermales System gemäß einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass das gelbildende Mittel wenigstens eine Substanz ausgewählt aus der Gruppe umfassend Carbomere (Carbopol® 980 NF, Carbopol® 981 ), Johannisbrotkernmehl (Cesagum® LA-200, Cesagum® LID/150, Cesagum® LN-1 ), Carboxymethylcellulose-Natrium (Blanose®, CMC-Na C300P®, Frimulsion BLC-5®, Tylose C300 P®), Natriumalginat (Frimulsion ALG (E401 )®), Guarkernmehl (Frimulsion BM®, Polygum 26/1- 75®), lota-Carrageen (Frimulsion D021®), Karaya Gummi, Gellangummi (Kelcogel F®, Kelcogel LT100®), Tarakernmehl (Polygum 43/1®), Propylenglykoalginat (Protanal-Ester SD-LB®), Pectine, vorzugsweise aus Äpfeln (Cesapectin® HM Medium Rapid Set), Saccharoseacetatisobutyrat, Natrium-Hyaluronat, fermentiertes Polysaccharid und Xanthane wie Xanthan- Gummi (Xantural 180®), ist.5. Transdermal system according to one of claims 1 to 4, characterized in that the gel-forming agent at least one substance selected from the group comprising carbomers (Carbopol® 980 NF, Carbopol® 981), locust bean gum (Cesagum® LA-200, Cesagum® LID / 150, Cesagum® LN-1), carboxymethyl cellulose sodium (Blanose®, CMC-Na C300P®, Frimulsion BLC-5®, Tylose C300 P®), sodium alginate (Frimulsion ALG (E401) ®), guar gum (Frimulsion BM®, Polygum 26 / 1- 75®), lota carrageenan (Frimulsion D021®), Karaya gum, gellan gum (Kelcogel F®, Kelcogel LT100®), tara gum (polygum 43 / 1®), propylene glycoalginate (Protanal-Ester SD-LB®), pectins, preferably from apples (Cesapectin® HM Medium Rapid Set), sucrose acetate butyrate, sodium hyaluronate, fermented polysaccharide and xanthans such as xanthan gum (Xantural 180®) , is.
6. Transdemales System gemäß einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass das in wässriger Flüssigkeit gelbildendes Mittel wenigstens eine Substanz ausgewählt aus der Gruppe umfassend vernetzte Homo- oder Copolymere der Acrylsäure, Gellangummi, Propylenglykolalginat, Apfelpektin, Natrium Hyaluronat, Xanthan Gummi, vorzugsweise ein Xanthan ist.6. Transdemales system according to any one of claims 1 to 5, characterized in that the agent forming a gel in aqueous liquid at least one substance selected from the group comprising cross-linked homo- or copolymers of acrylic acid, gellan gum, propylene glycol alginate, apple pectin, sodium hyaluronate, xanthan gum, is preferably a xanthan.
7. Transdermales System gemäß einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass als Wirkstoff mit Missbrauchspotential wenigstens ein Wirkstoff ausgewählt aus der Gruppe umfassend Opioide, Tranquillantien, Stimulantien und weitere Betäubungsmittel, vorzugsweise wenigstens ein Opioid, vorliegt.7. Transdermal system according to one of claims 1 to 6, characterized in that at least one active ingredient selected from the group comprising opioids, tranquillizers, stimulants and other anesthetics, preferably at least one opioid, is present as an active ingredient with potential for abuse.
8. Transdermales System gemäß Anspruch 7, dadurch gekennzeichnet, dass das Opioid Morphin, Oxycodon, Buprenorphin, Sulfentanil, Hydromorphon, Carfentanil, Lofentanil oder Fentanyl, bevorzugt Buprenorphin, ist.8. Transdermal system according to claim 7, characterized in that the opioid is morphine, oxycodone, buprenorphine, sulfentanil, hydromorphone, carfentanil, lofentanil or fentanyl, preferably buprenorphine.
9. Transdermales System nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass als Emetikum ein Emetikum auf Basis eines oder mehrerer Inhaltsstoffe von Radix Ipecacuanhae (Brechwurzel), vorzugsweise Emetin, und/oder Apomorph in enthält.9. Transdermal system according to one of claims 1 to 8, characterized in that contains as emetic an emetic based on one or more ingredients of Radix Ipecacuanhae (crow's root), preferably emetine, and / or apomorph in.
10. Transdermales System nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass es als weiteren missbrauchsverhindemden Hilfsstoff neben dem gelbildenden Mittel einen Farbstoff (d) enthält, der in wässriger Lösung eine intensive Farbgebung hervorruft. 10. The transdermal system according to one of claims 1 to 8, characterized in that it contains, as a further abuse-preventing auxiliary, in addition to the gel-forming agent, a dye (d) which causes an intensive coloring in aqueous solution.
11. Transdermales System nach einem der Ansprüche 1 bis 10, dadurch gekennzeichnet, dass es neben dem gelbildenden Mittel wenigstens ein Emetikum (c) und wenigstens einen aversiven Farbstoff (d) enthält.11. Transdermal system according to one of claims 1 to 10, characterized in that it contains at least one emetic (c) and at least one aversive dye (d) in addition to the gel-forming agent.
12. Transdermales System nach einem der Ansprüche 1 bis 11 , dadurch gekennzeichnet, dass es einen Antagonisten (b) für den Wirkstoff mit Missbrauchspotential enthält.12. Transdermal system according to one of claims 1 to 11, characterized in that it contains an antagonist (b) for the active substance with potential for abuse.
13. Transdermales System nach Anspruch 12, dadurch gekennzeichnet, dass es als Opioid-Antagonisten einen Antagonisten ausgewählt aus der Gruppe umfassend Naloxon, Naltrexon, Malmephin, Nalid, Nalmexon, Naiorphin und Nalbuphin, deren transdermal verabreichbaren physiologisch verträglichen Verbindungen, vorzugsweise deren Salze, Ester oder Ether enthält.13. The transdermal system according to claim 12, characterized in that it is an opioid antagonist, an antagonist selected from the group comprising naloxone, naltrexone, malmephine, nalid, nalmexone, naiorphine and nalbuphine, their transdermally administrable physiologically compatible compounds, preferably their salts, esters or contains ether.
14. Transdermales System nach einem der Ansprüche 1 bis 13, dadurch gekennzeichnet, dass es als Reizstoffe (a) entzündungsverursachende Substanzen und/oder fieberverursachende Substanzen aufweist.14. The transdermal system as claimed in one of claims 1 to 13, characterized in that it has, as irritants (a), inflammation-causing substances and / or fever-causing substances.
15. Transdermales System nach Anspruch 14, dadurch gekennzeichnet, dass es als fieberverursachende Substanzen wenigstens eine Substanz aus der Gruppe umfassend Lipopolysaccharide und Mikroorganismen, vorzugsweise Lactobazillen oder Saccharomyces aufweist.15. The transdermal system according to claim 14, characterized in that it has at least one substance from the group comprising lipopolysaccharides and microorganisms, preferably lactobacilli or saccharomyces, as fever-causing substances.
16. Transdermales System nach Anspruch 14, dadurch gekennzeichnet, dass es als Reizstoffe (a) wenigstens einen oder mehrere Inhaltsstoffe oder einen oder mehrere Pflanzenteile wenigstens einer Scharfstoffdroge, vorzugsweise aus Capsici Fructus, Capsici Fructus acer oder Piperis nigri Fructus enthält.16. The transdermal system according to claim 14, characterized in that it contains at least one or more ingredients or one or more plant parts of at least one hot substance drug, preferably from Capsici Fructus, Capsici Fructus acer or Piperis nigri Fructus, as irritants (a).
17. Transdermales System nach einem der Ansprüche 1 bis 11 , dadurch gekennzeichnet, dass der aversive Farbstoff (d) und/oder das Emetikum (c) von den übrigen Komponenten des transdermalen Systems in einer räumlich getrennten Anordnung vorliegen. 17. Transdermal system according to one of claims 1 to 11, characterized in that the aversive dye (d) and / or the emetic (c) of the other components of the transdermal system are present in a spatially separate arrangement.
18. Transdermales System nach Anspruch 18, dadurch gekennzeichnet, dass die räumlich getrennte Anordnung in einer Einkapselung des Emetikums (c) bzw. des aversiven Farbstoffes (d), vorzugsweise in Mikrokapseln aus einem für das Emetikum (c) bzw. den aversiven Farbstoff (d) undurchlässigen Material besteht.18. The transdermal system according to claim 18, characterized in that the spatially separate arrangement in an encapsulation of the emetic (c) or the aversive dye (d), preferably in microcapsules made of one for the emetic (c) or the aversive dye ( d) impermeable material.
19. Transdermales System nach einem der Ansprüche 1 bis 19, dadurch gekennzeichnet, dass auch der Antagonist (b) und/oder Reizstoff (a) jeweils in einer räumlich getrennten Anordnung von den übrigen Komponenten des transdermalen Systems vorliegt, vorzugsweise jeweils eingekapselt in Mikrokapseln aus einem für den Antagonisten bzw. für den Reizstoff undurchlässigen Material.19. Transdermal system according to one of claims 1 to 19, characterized in that the antagonist (b) and / or irritant (a) is in each case in a spatially separate arrangement from the other components of the transdermal system, preferably in each case encapsulated in microcapsules a material impermeable to the antagonist or the irritant.
20. Transdermales System nach einem der Ansprüche 1 bis 17, dadurch gekennzeichnet, dass die weiteren missbrauchsverhindemden Mittel (a) bis (d) durch eine für diese Mittel (a) bis (d) undurchlässige Trennschicht von den übrigen Komponenten des transdermalen Systems getrennt angeordnet sind.20. The transdermal system according to one of claims 1 to 17, characterized in that the further anti-abuse means (a) to (d) are arranged separately from the other components of the transdermal system by a separating layer impermeable to these means (a) to (d) are.
21. Transdermales System gemäß einem der Ansprüche 1 bis 20, dadurch gekennzeichnet, dass das in wässriger Flüssigkeit gelbildende Mittel gelöst oder dispergiert vorliegt.21. Transdermal system according to one of claims 1 to 20, characterized in that the gel-forming agent in aqueous liquid is dissolved or dispersed.
22. Transdermales System gemäß einem der Ansprüche 1 bis 21 , dadurch gekennzeichnet, dass das transdermale System ein Pflaster ist.22. Transdermal system according to one of claims 1 to 21, characterized in that the transdermal system is a plaster.
23. Pflaster gemäß Anspruch 21, dadurch gekennzeichnet, dass es ein Reservoir- Pflaster ist.23. Patch according to claim 21, characterized in that it is a reservoir patch.
24. Pflaster gemäß Anspruch 23, dadurch gekennzeichnet, dass das gelbildende Mittel in dem wirkstoffhaltigen Reservoir des Reservoir-Pflasters und jedes der vorhandenen weiteren missbrauchsverhindemden Mittel (a) bis (d) jeweils in für diese Mittel undurchlässigen Mikrokapseln eingeschlossen in dem Reservoir vorliegen. 24. Plaster according to claim 23, characterized in that the gel-forming agent in the active substance-containing reservoir of the reservoir plaster and each of the further anti-abuse agents (a) to (d) present are each enclosed in microcapsules impermeable to these agents in the reservoir.
25. Pflaster gemäß Anspruch 22, dadurch gekennzeichnet, dass das Pflaster ein Matrix-Pflaster ist.25. Patch according to claim 22, characterized in that the patch is a matrix patch.
26. Pflaster gemäß Anspruch 25, dadurch gekennzeichnet, dass das geilbildende Mittel in der wirkstoffhaltigen Matrix des Matrix-Pflasters gelöst oder dispergiert und jedes der vorhandenen weiteren missbrauchsverhindemden Mitteln (a) bis (d) jeweils in für diese Mittel undurchlässigen Mikrokapseln eingeschlossen in der Matrix dispergiert vorliegen. 26. A plaster according to claim 25, characterized in that the geil-forming agent is dissolved or dispersed in the active substance-containing matrix of the matrix plaster and each of the further anti-abuse agents (a) to (d) present is enclosed in microcapsules which are impermeable to these agents in the matrix are dispersed.
EP05735106A 2004-04-21 2005-04-21 Transdermal system secured against misuse Withdrawn EP1740161A2 (en)

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