WO2008040512A2

WO2008040512A2 - Disposal system

Info

Publication number: WO2008040512A2
Application number: PCT/EP2007/008506
Authority: WO
Inventors: Heinrich Kugelmann; Johannes Bartholomäus
Original assignee: Grünenthal GmbH
Priority date: 2006-10-04
Filing date: 2007-10-01
Publication date: 2008-04-10
Also published as: DE102006047270A1; WO2008040512A3

Abstract

The invention relates to a disposal system for the controlled disposal of an active substance with potential for misuse. Said system comprises at least one active substance dispensing system comprising an active substance with potential for misuse and at least one multilayer disposal means (C) which is separate from the active substance dispensing system and is used for the controlled destruction of the active substance directly after the active substance dispensing system has come into contact with the disposal means (C).

Description

disposal system

The invention relates to a disposal system with controlled disposal comprising a drug delivery system to be disposed of containing an active substance with abuse potential and at least one of the disposable drug delivery system initially separated present, multi-layer disposal device for controlled destruction of the drug immediately after the first contact of the drug delivery system with the Entsorgungsmittei.

Used or expired, unused pharmaceutical drug delivery systems such as drug-containing patches are usually disposed of with household waste or hospital garbage. However, these drug delivery systems may still contain large amounts of a pharmacologically active ingredient.

This is a major problem, especially with pharmaceutical agents with abuse potential, especially those with psychotropic effect, such as opioids, stimulants, tranquilizers, etc. These drug delivery systems can be removed for misuse the garbage to the remaining amount of active ingredient z. B. by extraction and then to achieve the desired psychotropic effect, namely a so-called. "Kick", parenterally injected or taken orally.

Such inadequately disposed drug delivery systems therefore represent a non-negligible possibility for intravenous, oral and / or nasal abuse.

In the prior art, the prevention of such abuse by a proper, controlled disposal of a drug delivery system with a drug with abuse potential is not given.

For example, a system for disposing of transdermal patches is described in US Patent US-B-5804215. This disposal is in one tear-resistant, foldable, planar disposal means, which has a larger surface area than the plaster to be disposed and is designed on one side with a sticky surface, including the patch to be disposed of. In this case, the drug is not destroyed with abuse potential, but only included, so that an effective, final protection against misuse of the amount of active substance still contained in the patch is not guaranteed.

Furthermore, in WO02 / 085268 a disposal center! for transdermal systems. Also according to the teaching of this international application, the patch containing an active substance with potential for abuse is enclosed in a disposal means which has an impermeable deposit for a compound suitable for inactivating the active substance. Only in an opening attempt to allow drug abuse this depot is mechanically destroyed, so that the inactivating compound released and inactivated after mixing with the active ingredient.

This disposal system also has the disadvantage that the amount of active substance present in a transdermal system with abuse potential is not destroyed in a controlled manner after use or shelf life of the active substance delivery system, so that prevention of the abuse is not ensured.

It was therefore an object of the present invention to provide a simple disposal system for the controlled prevention of abuse of an amount of an active substance with abuse potential (still) present in a drug delivery system to be disposed of. In particular, the known abuse prevention should be improved, according to the drug delivery system to be disposed containing an active substance with abuse potential only included in a disposal and uncontrolled without destruction of the drug with drug potential with the waste disposed of to prevent misuse, preferably preclude.

The object of the present invention is encompassed by the provision of the disposal system according to the invention for the controlled abuse prevention of an active substance with abuse potential A) at least one to be disposed of, preferably sheet-like drug delivery system containing at least one drug with abuse potential

and

B) at least one of the disposable drug delivery system initially separated present, multi-layer, preferably sheet disposal means with an inactivation system for controlled, immediately after contacting the to be disposed drug delivery system with the disposal destructive destruction of existing in the drug delivery system to be disposed amount of the drug with abuse potential

solved.

Destruction according to the invention is the inactivation of the drug with abuse potential to at least one unsuitable for the abuser conversion, preferably the complete destruction or minimization of the concentration of the active ingredient, more preferably at least the chemical change of the drug to a stage in which no possibility of abuse more is, most preferably understood the complete destruction of the drug.

The disposal system according to the invention preferably comprises a disposal means which is planar, wherein the effective area of the disposal means, d. H. the area which the inactivation system delivers is preferably at least as large as the area of the active substance-containing area of the active substance delivery system.

The disposal means preferably has a layered structure comprising

a cover layer impermeable to the inactivation system as a surface layer, a layer, possibly adhesive, having the inactivation system and having a permeable layer, in which the inactivation system is distributed in a matrix material, taken up in a porous material or in a reservoir optionally having a membrane permeable to the inactivation system, is present,

optionally an adhesive layer permeable to the inactivation system,

- or optionally at least one adhesive edge, and

- A removable for the inactivation system, removable protective film.

Since the permeable layer containing the inactivation system is preferably bonded on one of its surfaces to a capping layer impermeable to the inactivation system, its delivery is controlled only in one direction.

The removable protective film preferably has release properties, so that a simple peeling is guaranteed.

In a preferred embodiment, the permeable layer comprising the inactivation system is provided with a full-area adhesive layer permeable to the inactivation system, especially when the inactivation system is distributed in a matrix, or at least one adhesive edge around the reservoir containing the inactivation system around the corresponding porous portion of the layer.

This reservoir is preferably chamber-shaped and may have at least two compartments separated from one another. The reservoir may be closed with a permeable membrane for the inactivation system or only with the removable protective film. Insofar as it is necessary for the destruction of the active ingredient by the inactivation system, by simple handling any separation between the compartments of the reservoir can be eliminated, so that the contents of the compartments can be brought together for mixing. The inactivation system can also be distributed in a matrix layer which is permeable to it, which may optionally also contain adhesives, so that the adhesive layer and this matrix layer produce a layer.

If the inactivating agent has an adhesive edge or an adhesive layer or is self-adhesive, it is preferably covered with a removable protective film before use.

Furthermore, the inactivation system can be accommodated in a section of the layer which is permeable to the inactivation system and which is made of a porous, preferably flexible material whose areal extent is at least as large as the area of the active substance-containing area of the active substance delivery system to be disposed of. Preferably, the porous material is an absorbent material, preferably having a sponge-like structure, from which the inactivation system, e.g. B. can already be released by light pressure

For the purposes of the present invention, "absorbent material" is understood as meaning materials which are capable of absorbing liquid or gel-like substances and, if appropriate, over a relatively long period of time, preferably 1-24 months, more preferably 1-12 months, even more preferably 1-8 months, most preferably 1-6 months, especially 1-4 months. As examples of absorbent materials, sponges or absorbent textiles that are physiologically harmless may preferably be used. It is obvious to a person skilled in the art that, depending on the inactivation system used, absorbent materials with the corresponding necessary absorption capacity are used. This can be determined by simple preliminary tests.

The inactivation system may be in solid, semi-solid or liquid form, preferably in solid or liquid form in the disposal means. In accordance with the invention, the inactivation system may be distributed in the form of crystals, granules, pellets, lozenges, in powder form, in microcapsules, as a solution or as a gel in a matrix material, in a porous material, preferably a sponge, or in a reservoir. According to the invention, the inactivation system can be present in undissolved or in dissolved form. If the inactivation system is in dissolved form, it may preferably be contained in a porous, flexible material.

If the inactivation system is in dissolved form, it may preferably be provided with a viscosifier.

It is also possible that the anti-drug efficacy of the inactivation system, especially if present in a reservoir, is physically, e.g. B. by dissolving in a suitable solvent, or chemically, for. B. by hydrolysis, to improve or only to produce. For this purpose, the inactivation system may preferably consist of at least two components which are mixed together only upon contact of the initially separately present inactivating agent with the drug delivery system.

Such components may, for. B. a salt with the destructive action and a suitable solvent, particularly preferably water, be present initially in separate compartments of the reservoir of the disposal agent. By bringing together these two components, one obtains the inactivation system which causes the destruction of the active ingredient, namely, by dissolving the salt in the solvent, whereby a rapid activity for destroying the active ingredient is achieved.

By simple pressure on the reservoir z. B. the departments of a reservoir connected and a destructive saline solution for diffusion through a permeable membrane of the reservoir are made.

According to the invention, the amounts or concentrations of the inactivation system are to be selected so that the destruction of the active substance begins immediately after contact of the disposal agent with the active substance delivery system and is completed within days, preferably within hours, without health risks if handled appropriately.

Preferably, the inactivation system comprises a compound which chemically destroys the active substance. Such a compound is preferably a compound selected from the group comprising inorganic or organic oxidizing agents, inorganic or organic reducing agents, the active substance with Abuse potential derivatizing compounds, acids, bases, organic salts and inorganic salts.

Accordingly, the destruction of the drug with abuse potential by oxidative, reductive, alkaline, acid or hydrolytic action takes place.

In a preferred embodiment, the inactivation system comprises an alkali salt, preferably a sodium or potassium salt, preferably an oxidative acid or H ₂ O ₂ .

More preferably, the inactivation system comprises at least one compound selected from the group comprising sodium perborate, potassium perborate, sodium peroxide, benzoyl peroxide, carbamide peroxide, sodium percarbonate, potassium percarbonate, sodium persulfate, potassium persulfate, sodium peroxodisulfate, potassium peroxodisulfate, sodium perphosphate, potassium perphosphate, H ₂ O ₂ , peracetic acid and potassium permanganate.

These compounds can be converted into an aqueous solution or are already present as such. In order to develop the full destructive effect at room temperature, said inactivation systems can also be an activator such. As TAED (tetraacetyl-ethylenediamine) include.

The drug delivery system of the disposal system according to the invention is preferably a sheet-like system for transdermal and / or topical drug delivery, preferably a patch. It is known to the person skilled in the art that active ingredient delivery systems, such as patches, may still contain up to 80% by weight of the original amount of active ingredient after their predetermined period of use, so that the disposal agent, as an element of the disposal system according to the invention, is particularly well suited for the destruction of (residual) Amounts of an active substance with abuse potential is suitable. In addition to a controlled abuse-preventive disposal of used drug delivery systems, such as patches, a controlled disposal of expired, unused patches is also possible. Preferably, the drug delivery system to be disposed of is a used drug delivery system which still has a residual content of drug with abuse potential. The drug delivery system may be constructed according to the reservoir or matrix system. In this connection, Bauer KH, Frömming K.-H., Führer C, Pharmazeutische Technologie, pp. 381-383; Müller RH, Hildebrand GE, Pharmaceutical Technology: Modern Dosage Forms, Chapter 8, are referenced. The corresponding description of the systems is considered part of the present disclosure.

According to the matrix system, the drug delivery system may preferably comprise a carrier layer, an active agent-containing layer and an adhesive layer, wherein the active substance-containing layer may simultaneously be the adhesive layer in which the active ingredient is dissolved and / or dispersed in a matrix optionally together with the adhesive is present.

Adhesives for the adhesive layer of the active substance delivery system are preferably pressure-sensitive adhesives, for example polymers such as polyacrylates, polyvinyl ethers, polyisobutylenes (PIB), styrene / isoprene or butadiene / styrene copolymers or polyisoprene rubbers. Also suitable are silicone adhesives, such as, for example, optionally crosslinked polydimethylsiloxanes.Also based on esters of glycines, glycerol or pentaerythrol, or hydrocarbons, such as polyterpenes are suitable.Acrylate-based adhesives are by polymerization of acrylates, methacrylates, alkylacrylates and or alkyl methacrylates, with optionally further α, β-unsaturated monomers, such as acrylamide, dimethylacrylamide, dimethylaminoethyl acrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, methoxyethyl acrylate, methoxyethyl methacrylate, acrylonitrile and / or vinyl acetate Fe can also be used for the production of the adhesive layer or an adhesive edge of the disposal agent described above.

The carrier layer or covering layer of the active substance delivery system is preferably impermeable and inert for the substances contained in the active substance-containing layer and in the adhesive layer, in particular for the active substance, and may be based on polymers, such as polyesters, preferably polyethylene terephthalate, polyolefins, such as polyethylenes, polypropylenes or polybutylenes , Polycarbonates, polyethylene oxides, polyurethanes, polystyrroles, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidene chlorides and / or copolymers such as acrylonitrile / butadiene / styrrole copolymers and / or mixtures thereof, optionally containing paper fibers or textile fibers, which may be metallized or pigmented if necessary.

The inactivation system impermeable cover layer of the above described disposal means may be identically constructed. The carrier layer or covering layer of the active substance delivery system or the inactivation system impermeable covering layer of the disposal agent may also consist of a combination of a metal foil and a polymer layer.

The active ingredient-containing matrix layer of the active substance delivery system may contain matrix-forming polymers, skin penetration enhancers, solubilizers, crosslinkers, stabilizers, emulsifiers, preservatives, thickeners and / or further customary auxiliaries.

The matrix-forming polymer used is preferably at least one film-forming polymer selected from the group comprising hydroxypropylcellulose, carboxymethylcellulose, polyethylenes, chlorinated polyethylenes, polypropylenes, polyurethanes, polycarbonates, polyacrylates, polyacrylates, polymethacrylates, polyvinyl alcohols, polyvinyl chlorides, polyvinylidene chlorides, polyvinylpyrrolidones, polyethylene terephthalates, polytetrafluoroethylenes, ethylene / propylene Copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, ethylene / vinyl alcohol copolymers, ethylene / vinyl oxanol copolymers, vinyl chloride / vinyl acetate copolymers, vinyl pyrrolidone / ethylene / vinyl acetate copolymers, rubbers, rubbery, synthetic homo-, co- or block polymers, silicones, silicone Derivatives, preferably siloxane / methacrylate copolymers, cellulose derivatives, preferably ethylcellulose or cellulose ethers and mixtures thereof. If the active substance-containing layer is at the same time the adhesive layer, it preferably contains, in addition to at least one of the enumerated polymers, at least one of the above-mentioned adhesives.

These matrix-forming polymers and optionally adhesives can also be used for the preparation of the inactivation system-containing matrix layer of the above described disposal means. Antioxidants such as vitamin E, butylhydroxytoluene, butylated hydroxyanisole, ascorbic acid, ascorbyl palmitate, and / or chelating agents, such as, for example, can be used as stabilizers for the active substance-containing matrix or the active substance-containing reservoir of the active substance delivery system. B. Dinatriurnethylendiamintetraessigsäure, potassium or sodium citrate can be used.

The active ingredient-containing matrix or the active substance-containing reservoir of the active substance delivery system may also contain conventional skin penetration enhancers.

The drug delivery system may also include, in one or more layers, at least one plasticizer or skin permeation enhancer selected from the group consisting of 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 caprylic acid medium chain triglycerides / or capric acid, coconut oil, polyhydric alcohols, such as 1, 2-propanediol, esters of polyhydric alcohols, such as glycerol with levulinic or caprylic, and etherified polyhydric alcohols.

The peelable protective film of the drug delivery system or the disposal agent described above can be selected from polyethylene, polyester, polyethylene terephthalate, polypropylene, polysiloxane, polyvinyl chloride or polyurethane and optionally from treated paper fibers such. As cellophane, and preferably have a silicone, fluorosilicone or fluorine-carbon coating as a release coating.

Substances with abuse potential, in particular those with a psychotropic effect, which are also suitable for transdermal and / or topical delivery, are known to the person skilled in the art. Many drugs with abuse potential, especially those with psychotropic effect, have the property of being able to influence mental processes, i. they have a specific effect on mental functions. Such agents can thus affect mood, either whitening or cushioning.

The active substances with potential for abuse, in particular those with a psychotropic effect, are preferably active substances which, especially in the case of non-intended type of application, are accelerated in comparison with the intended topical or transdermal application Influencing the drug with the result desired by an abuser, namely the kick. This kick can z. B. can be achieved when the drug is extracted from the drug delivery system and then z. B. administered parenterally or orally. For the purposes of the invention are to be understood by drugs with abuse potential, in particular those drugs with psychotropic effect, which influence the human mind and / or sensory perception in a manner that they are in principle suitable for abuse with appropriate dosage, dosage form and Darreichungsart.

The active substances with potential for abuse, in particular those with a psychotropic effect, are especially active substances which have an effect on or via the nervous system according to the ATC index. These agents preferably include transdermally and / or topically administrable anesthetics [N01], analgesics [N02], antielectics [N03], antiparkinson agents [N04], psycholeptics [N05], psychoanaleptics [N06] and / or other nervous system agents [N07] , and corresponding stereoisomeric compounds, in each case their corresponding derivatives, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and their physiologically acceptable derivatives, for example ethers, esters or amides, and in each case their physiologically acceptable compounds, in particular their salts and solvates, for example hydrochlorides. The designations in brackets correspond to the ATC index as used by the WHO for the classification of the drugs (preferred status: January 2005 or 2006). For further details on the ATC index, reference may be made, for example, to U. Fricke, Anatomisch-Therapischchemische Klassifikation with Tagesdosen: Official version of the ATC Index with DDD data for Germany in 2006, Scientific Institute of the AOK referenced.

For the purposes of the present invention, at least one active substance selected from the group consisting of opioids, stimulants, tranquilizers (barbiturates and benzodiazepines), further anesthetics, in each case corresponding stereoisomeric compounds, in each case corresponding to the abovementioned active substances with abuse potential, in particular those having a psychotropic effect Derivatives, in each case corresponding physiologically compatible enantiomers, stereoisomers, Diastereomers, racemates, in each case physiologically acceptable derivatives, such as ethers, esters or amides, and in each case physiologically acceptable compounds, in particular salts and solvates understood

In particular, the substance to be disposed of according to the invention with abuse potential or psychotropic effect is at least one transdermally and / or topically administrable active ingredient selected from the group comprising alfentanil, allobarbital, allylprodin, alphaprodine, alprazolam, amfepramone, amfetamine, amfetaminil, amobarbital, anileridine , Apocodein, barbital, bemidone, benzylmorphine, bezitramide, bromazepam, Brotizolam, buprenorphine, butobarbital, butorphanol, camazepam, carfentanil, cathin / D-norpseudoephedrine, chlordiazepoxide, clobazam, clofedanol, clonazepam, clonitazene, clorazepate, clotiazepam, cloxazolam, cocaine, codeine , Cyclazocine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, decocin, diamorphone, diampromide, diazepam, dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine, ethorphine , Ethyllaborate, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fencamfamine, fenetylline, fenpipramide, fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam, haloxazolam, heroin, hydrocodone, hydromorphone, hydroxymethylmorphinan, hydroxypethidine, isomethadone, ketazolam, ketobemidone, levacetylmethadol (LAAM), levallorphan, levomethadone, levophenacylmorphan, levorphanol, levoxemacin, lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, meptazinol, metamfetamine, metapon, metazocin, methadone, methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl, methylmorphine, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil, morphine, myrophin, N- (1-methyl-2-piperidinoethyl) -N- (2-pyridyl) -propionamide, nabilone, nalbuphene, nalbuphine, nalorphine , Narcein, nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam, oxycodone, O. xymorphone, papaver somniferum, papaveretum, pentazocine, pentobarbital, pernoline, pethidine, phenadoxone, phenazocine, phenmetrazine, phenobarbital, phenomorphan, phenoperidine, phentermine, pholcodein, piminodine, pinazepam, pipradrol, piritramide, prazepam, profadol, proheptazine, promedol, propperidine, propperidine , Propheptazine, Propiram, Propoxyphene, remifentanil, secbutabarbital, secobarbital, sufentanil, temazepam, tetrazepam, tilidine (eis and trans), tramadol, triazolam, vinylbital, (1R ₁ 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol, (1R, 2R, 4S) -2- (dimethylamino) methyl-4- (p-fluorobenzyloxy) -1- (m-methoxyphenyl) cyclohexanol, (1RS ₁ 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl ) -cyclohexane-1, (1S, 2S) -3 (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (2R, 3R) -1-dimethylamino-3 (3-methoxy-phenyl) - 2-methyl-pentan-3-ol, (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-2-propyl) -phenoxy, (RR-SS) -2 ', 4'-difluoro 3-hydroxy-bi-phenyl-4-carboxylic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl, (RR-SS) -2-acetoxy-4-trifluoromethyl-benzoic acid 3- (2-dimethylamino-methyl 1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-methoxybenzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl-ester, (RR-SS) - 2-hydroxy-4-methyl-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) -phenyl l ester, (RR-SS) -2-hydroxy-4-trifluoromethyl-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) -4-chloro-2-hydroxybenzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, 3 - (2-Dimethylamino-methyl-1-hydroxycyclohexyl) phenyl 2- (6-methoxynaphthalene-2-yl) propionate, 3- (2-dimethylaminomethylcyclohex-1-enyl) -phenyl 2- (4 -isobutyl-phenyl) propionate, 3- (2-dimethylaminomethyl-cyclohex-1-enyl) -phenyl 2- (6-methoxynaphthalene-2-yl) -propionate, 3-diol, preferably as racemate and 3- ( 2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl 2- (4-isobutyl-phenyl) -propionate, and corresponding stereoisomeric compounds, in each case their corresponding derivatives, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and their physiologically tolerated derivatives, for example Ethers, esters or amides, and each of their p physiologically compatible compounds, in particular their salts and solvates, for example hydrochlorides.

The active substance with abuse potential or psychotropic action to be disposed of according to the invention is particularly preferably at least one transdermally and / or topically administrable opioid selected from the group comprising allylprodin, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, Cyclazocine, desomorphine, dextromoramide, decocin, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, Eptazocine, ethoheptazine, ethorphine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophin, nalbuphine, Narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piriiramide, propheptazine, promedi, propranam, propoxyphene, sufentanil, tramadol and Tilidine, a corresponding stereoisomeric compound, a corresponding derivative, a physiologically acceptable enantiomer, stereoisomer, diastereomer, racemate, a physiologically acceptable derivative thereof, such as ether, ester or amide, and in each case a physiologically acceptable compound, in particular a salt and solvate.

Very particular preference is given to the active ingredient according to the invention with abuse potential to at least one transdermally and / or topically administrable opioid selected from the group comprising buprenorphine, fentanyl and sufentanil, a corresponding stereoisomeric compound, a corresponding derivative, a physiologically acceptable enantiomer, stereoisomer , Diastereomeres, racemate, a physiologically acceptable derivative thereof, such as an ether, ester or amide, and in each case a physiologically acceptable compound, in particular a salt and solvate, for example hydrochloride.

In a particularly preferred embodiment, the active ingredient to be disposed of according to the invention with abuse potential or psychotropic effect is buprenorphine.

Essential to the invention is that the controlled destruction of the drug with abuse potential is achieved only by applying the disposal agent on the drug-containing surface of the drug delivery system and begins immediately after the first contact of the drug delivery system with the disposal.

According to the invention, it is not necessary to include the drug delivery system to be disposed of in an inactivating agent, which still poses a risk of Abuse by the existing, not destroyed drug amount is given. The known inclusion of the drug delivery system to be disposed of without destruction of the active ingredient is avoided according to the invention, as by surface contact of the disposal agent with the active ingredient-containing region of the drug delivery system

a controlled destruction of the drug begins immediately after the application of the disposal agent.

Another object of the invention therefore also relates to a method for the controlled disposal and controlled abuse prevention of a present in a drug delivery system to be disposed amount of an active substance with abuse potential, which is characterized in that to destroy the located in the drug-containing portion of the drug delivery system amount of an active ingredient multi-layer, inventive disposal means is applied and immediately after the application of the inactivating agent on the active substance-containing area destruction of the active ingredient is continued at least up to a completely unsuitable for abuse concentration of the active ingredient, preferably until complete destruction of the remaining amount of active ingredient. The necessary duration of action of an inactivation system on the active ingredient or on the amount of active ingredient present can be determined by simple preliminary tests.

In order to ensure a proper controlled disposal of drug delivery systems and prevention of abuse, may be included for distribution of a drug delivery system already separately packaged thereon, disposal according to the invention, if necessary after use of the drug delivery system, if necessary under medical supervision for the proper disposal of the drug delivery system is used. characters

Figure 1 shows a cross-section of the disposal means (C) comprising an inactivation system impermeable cover layer (1) having an adhesive layer (6) pervious to the inactivation system with a reservoir (2) containing an inactivation system (7). The reservoir (2) is closed by a membrane (8) permeable to the inactivation system. A protective film (3) impermeable to the inactivation system covers the adhesive layer.

Figure 2 shows a cross section of the disposal means (C) with an inactivation system impermeable cover layer (1) and a matrix layer (5) containing and permeable to the inactivation system, covered with a protective film (3) impermeable to the inactivation system.

Figure 3 shows a cross-section of the disposal means (C) comprising a capping layer (1) impermeable to the inactivation system and a porous sub-layer (9) containing the inactivation system, in which the inactivation system is incorporated. The porous sublayer (9) is bordered by an adhesive edge (10). The porous sub-layer (9) and the adhesive edge (10) are covered with a protective film (3) impermeable to the inactivation system.

Figure 4 shows an embodiment of the disposal means (C) with a capping layer (1) impermeable to the inactivation system. The chamber-shaped reservoir (2) has two separate compartments (2a, 2b) and a membrane (8) permeable to the inactivation system. The compartments are separated by a wall (4) impermeable to the inactivation system, each containing one component (A or B) of the inactivation system. The membrane-shaped, permeable for the inactivation system layer is covered with a protective film (3).

By slight pressure, the partition (4) can be folded in the reservoir, whereby the two components A and B are mixed together, for. B. by dissolving a salt (A) in water (B) to an aqueous solution of the salt whereby the inactivation system is obtained. Examples

example 1

a) Preparation of a buprenorphine-containing patch

1139 g of a 48% strength by weight polyacrylate solution of a self-crosslinking acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (solvent: ethylacetafcHeptanMsopropanolToluohAcetyiacetonat in the ratio of 37: 26: 26: 4: 1), 100 g of levulinic acid, 150 g of oleyl acetate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate and 100 g of buprenorphine base are homogenized. Stir for about two hours and visually check to see if all solids are dissolved. It also controls the evaporation loss by weighing back and optionally adds the loss of solvent by adding ethyl acetate.

As a cover layer, a 420 mm wide, transparent polyester film is coated with the above-described mixture so that the weight per unit area of the dried adhesive layer is 80 g / m ² .

The solvents are removed by drying with heated air which is passed over the wet web. The heat treatment evaporates the solvents. Finally, the active ingredient-containing adhesive layer is covered with a 15 μm thick polyester film as a protective film, which can be removed again by silicone treatment. Using suitable cutting tools, a surface corresponding to the intended amount of active substance is punched out.

b) Preparation of the Disposal Agent

For the production of disposal according to the invention in each case a polyethylene terephthalate film with a thickness of 75 microns as a cover layer in an Ericsson film applicator (the company Ericsson GmbH & Co. KG, Hemertextilien, Germany) clamped. Subsequently, an approximately 300 .mu.m thick, made of textile material sub-layer, which is impregnated with an approximately 20% KMnO ₄ solution, applied to the cover layer. An adhesive edge made of acrylate / vinyl acetate copolymer is applied so that the edge comprises the textile material sub-layer (see Figure 3). A transparent protective film made of polyester is applied in such a way that its areal extent covers both the area of the textile layer containing the inactivation system and the surrounding adhesive edge.

In order to test the effectiveness of the disposal agent according to the invention, a buprenorphine plaster produced according to a) is prepared in each case with a disposal agent according to the invention prepared according to b) (after detachment of the peelable protective film) for 2, 6 or 24 hours at 25 ° C.

Thereafter, the residual content of buprenorphine in the patch is determined by conventional HPLC method.

The corresponding test results of these measurements are in the following

Table 1 is compiled.

Table 1 Remaining Buprenorphine (%) after Oh 2h 6h 24h

* 100% 2.8% * 100% - 1, 3%

* 100% - - 0.0%

* 100% active ingredient content

From Table 1 shows that after only two hours of contact of the disposal agent with the active substance-containing area of the patch at 25 ° C, the initial amount of drug with abuse potential has dropped drastically and is already so low that no more abuse is possible. After a 24-hour contact no active ingredient is analytically detectable.

Claims

claims

1. comprising a disposal system

A) at least one drug delivery system to be disposed of comprising at least one drug with abuse potential and

B) at least one separated from the drug delivery system to be disposed of present, multi-layer disposal system with an inactivation system for controlled onset of contacting the disposable drug delivery system with the disposable destruction of existing in the drug delivery system to be disposed amount of drug with abuse potential.

2. A disposal system according to claim 1, characterized in that the disposal means and the drug delivery system has a sheet-like extension.

3. A disposal system according to claim 1 or 2, characterized in that the effective area of the disposal means corresponds at least to the area of the active substance-containing area of the active substance delivery system.

4. A disposal system according to any one of claims 1 to 3, characterized in that the disposal means comprises a permeable for the inactivation system layer in which the inactivation system distributed in a matrix material, taken in a porous material or in a reservoir.

5. A disposal system according to claim 4, characterized in that the permeable to the inactivation system layer is connected on one of its surfaces with a non-impermeable for the inactivation topcoat.

6. A disposal system according to claim 4 or 5, characterized in that the reservoir is chamber-shaped and one for the inactivation system permeable membrane, which may correspond to the permeable for the inactivation system layer has.

7. A disposal system according to claim 6, characterized in that the chamber-shaped reservoir has at least two compartments separated by a partition.

8. A disposal system according to any one of claims 1 to 7, characterized in that the permeable for the inactivation system layer has an adhesive layer or an adhesive edge.

9. A disposal system according to any one of claims 1 to 8, characterized in that the disposal means comprises an adjacent to the permeable layer or the adhesive layer optionally removable protective film.

10. A disposal system according to any one of claims 1 to 9, characterized in that the inactivation system is present in solid, semi-solid or liquid form in the disposal means.

11. A disposal system according to claim 10, characterized in that the inactivation system in the form of crystals, granules, pellets, lozenges, powder, dispersed in microcapsules, as a solution or as a gel in a matrix material, in a porous material, preferably a sponge, or in a reservoir.

12. A disposal system according to claim 10 or 11, characterized in that the inactivation system comprises a compound chemically inactivating the active substance.

13. A disposal system according to claim 12, characterized in that the inactivating system destroys the active substance with abuse potential oxidative, reductive, alkaline, acidic or hydrolytic.

14. A disposal system according to any one of claims 10 to 13, characterized in that the inactivation system comprises at least one acid or base.

15. A disposal system according to any one of claims 10 to 13, characterized in that the inactivation system comprises at least one alkali metal salt, preferably a sodium or potassium salt of an oxidative acid.

16. A disposal system according to any one of claims 10 to 15, characterized in that the inactivation system comprises at least one compound selected from the group comprising sodium perborate, potassium perborate, potassium permanganate, benzoyl peroxide, sodium peroxide, carbamide peroxide, sodium percarbonate, potassium percarbonate, sodium persulfate, potassium persulfate, sodium peroxydisulfate, potassium peroxodisulfate, Sodium perphosphate, potassium perphosphate, H2O2 and peracetic acid.

17. A disposal system according to claim 16, characterized in that the inactivation system comprises an activator, preferably tetraacetyl-ethylenediamine.

18. A disposal system according to any one of claims 1-17, characterized in that the inactivation system is an aqueous potassium permanganate solution.

19. A disposal system according to any one of claims 1 to 18, characterized in that the drug delivery system to be disposed of is a transdermal and / or topical drug delivery system.

20. A disposal system according to any one of claims 1-19, characterized in that the drug delivery system to be disposed of is a plaster.

21. A disposal system according to any one of claims 1-20, characterized in that the drug delivery system to be disposed of is a used drug delivery system or an expired, unused drug delivery system.

22. A disposal system according to any one of claims 1 -21, characterized in that the active substance with Abuse potential at least one transdermally and / or topically administrable active ingredient from the group including anesthetics, analgesics, antielectics, antipakinson agents, psycholeptics, psychoanaleptics and other nervous system agents.

23. A disposal system according to any one of claims 1 to 22, characterized in that the active substance with Abuse potential at least one opioid, stimulant, tranquilizers (barbiturate and benzodiazepine), another anesthetic, a corresponding stereoisomeric compound, a corresponding derivative, a physiologically acceptable enantiomer , Stereoisomer, diastereomer, racemate, a physiologically acceptable derivative thereof, such as preferably an ether, ester or amide, and each is a physiologically acceptable compound, preferably a salt and solvate.

24. A disposal system according to claim 23, characterized in that the active substance with abuse potential comprises at least one transdermally and / or topically administrable opioid selected from the group comprising sulfentanil, allylprodin, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, Cyclazocine, desomorphine, dextromoramide, decocin, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethorphine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, Levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophin, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, Phenomorphan, phen azocine, phenoperidine, piminodin, piritramide, propheptazine, promedol, propperine, propiram, propoxyphene, sufentanil and tilidine, a corresponding stereoisomeric compound, a corresponding derivative, a physiologically acceptable enantiomer, stereoisomer, diastereomer, racemate, a physiologically acceptable derivative thereof, preferably one Ether, ester or amide, and each is a physiologically acceptable compound, preferably a salt and solvate, preferably buprenorphine.

5. A method for the controlled abuse prevention in one

Drug delivery system present active substance with abuse potential with the aid of a disposal agent according to one of claims 1 to 17, characterized in that for the controlled destruction of the active substance contained in the drug-containing portion of the drug delivery system, a multi-layer disposal means applied to the active substance-containing area and immediately after application of the Disposal must be initiated destruction of the active substance at least up to an unsuitable for abuse concentration, preferably up to a stage of complete destruction of the active ingredient, continued.