Title of Invention	"A PROCESS FOR THE PRODUCTION OF AN ABUSE-PROOFED SOLID DOSAGE FORM"
Abstract	A process for the production of an abuse-proofed solid dosage form containing at least one active ingredient with potential for abuse (A) and at least one binder, which is present at least 20 wt. % relative to the total weight of the dosage form, and has a breaking strength of greater than or equal to 500 N characterized in that a mixture comprising the active ingredient of the kind such as hereinbefore described, the binder of the kind such as hereinbefore described and optionally an auxiliary substance which is conventional for formulation of solid dosage forms, is exposed to ultrasound and force wherein the said dosage form as such exhibits a breaking strength of at least 500N.

Title of Invention

"A PROCESS FOR THE PRODUCTION OF AN ABUSE-PROOFED SOLID DOSAGE FORM"

Abstract

A process for the production of an abuse-proofed solid dosage form containing at least one active ingredient with potential for abuse (A) and at least one binder, which is present at least 20 wt. % relative to the total weight of the dosage form, and has a breaking strength of greater than or equal to 500 N characterized in that a mixture comprising the active ingredient of the kind such as hereinbefore described, the binder of the kind such as hereinbefore described and optionally an auxiliary substance which is conventional for formulation of solid dosage forms, is exposed to ultrasound and force wherein the said dosage form as such exhibits a breaking strength of at least 500N.

Full Text	Process for the production of an abuse-proofed solid dosage form The present invention relates to a process for the production of an abuse-proofed solid dosage form containing at least one active ingredient with potential for abuse and at least one binder with a breaking strength of greater than or equal to 500 N, by exposing a mixture comprising the active ingredient and the binder to ultrasound and force. Many pharmaceutical active ingredients, in addition to having excellent activity in their appropriate application, also have potential for abuse, i.e. they can be used by an abuser to bring about effects other than those intended. Opiates, for example, which are highly active in combating severe to very severe pain, are frequently used by abusers to induce a state of narcosis or euphoria. In order to make abuse possible, the corresponding dosage forms, such as tablets or capsules are comminuted, for example ground in a mortar, by the abuser, the active ingredient is extracted from the resultant powder using a preferably aqueous liquid and the resultant solution, optionally after being filtered through cotton wool or cellulose wadding, is administered parenterally, in particular intravenously. An additional phenomenon of this kind of administration, in comparison with abusive oral administration, is a further accelerated increase in active ingredient levels giving the abuser the desired effect, namely the "kick" or "rush". This kick is also obtained if the powdered dosage form is administered nasally, i.e. is sniffed. Since delayed-release dosage forms containing active ingredients with potential for abuse do not give rise to the kick desired by the abuser when taken orally even in abusively high quantities, such dosage forms are also comminuted and extracted in order to be abused. US-A-4,070,494 proposed adding a swellable agent to the dosage form in order to prevent abuse. When water is added to extract the active ingredient, this agent swells and ensures that the filtrate separated from the gel contains only a small quantity of active ingredient. The multilayer tablet disclosed in WO 95/20947 is based on a similar approach to "^preventing parenteral abuse, said tablet containing the active ingredient with potential for abuse and at least one gel former, each in different layers. WO 03/015531 A2 discloses another approach to preventing parenteral abuse. A dosage form containing an analgesic opioid and a dye as an aversive agent is described therein. The colour released by tampering with the dosage form is intended to discourage the abuser from using the dosage form which has been tampered with. Another known option for complicating abuse involves adding antagonists to the active ingredients to the dosage form, for example naioxone or naltrexone in the case of opioids, or compounds which cause a physiological defence response, such as for example ipecacuanha (ipecac) root. Since, however, as in the past, it is in most cases necessary for the purposes of abuse to pulverise the dosage form, it was the object of the present invention to provide a process for the production of dosage forms comprising active ingredients with potential for abuse, with which process dosage forms are obtained which, when correctly administered, ensure the desired therapeutic action, but from which the active ingredients cannot be converted into a form suitable for abuse simply by pulverisation using means conventionally available to a potential abuser. This object has been achieved by the provision of the process according to the invention for the production of an abuse-proofed solid dosage form containing at least one active ingredient with potential for abuse and at least one binder with a breaking strength of greater than or equal to 500 N, by exposing a mixture comprising the active ingredient and the binder to ultrasound and force. Thanks to the process according to the invention using ultrasound and at least one binder with the stated breaking strength in quantities such that a dosage form also having a breaking strength of greater than or equal to 500 N is obtained, it is possible considerably to complicate or to prevent pulverisation of the dosage form using conventional means and hence any subsequent abuse. If comminution is inadequate, parenteral, in particular intravenous, administration cannot be performed safely or extraction of the active ingredient therefrom takes too long for the abuser or there is no "kick" when orally abused as release is not instantaneous. According to the invention, comminution is taken to mean pulverisation of the solid dosage form with conventional means which are available to an abuser, such as for example a pestle and mortar, a hammer, a mallet or other usual means for pulverisation by application offeree. The process according to the invention thus gives rise to dosage forms which are suitable for preventing parenteral, nasal and/or oral abuse of active ingredients, preferably of pharmaceutical active ingredients with potential for abuse. Active ingredients with potential for abuse, preferably pharmaceutical active ingredients with potential for abuse, are known to the person skilled in the art, as are the dosages thereof, and may be protected against abuse as such, in the form of the corresponding derivatives thereof, in particular esters, ethers or amides, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof, as racemates, enantiomers or stereoisomers by the process according to the invention. The dosage forms produced according to the invention may here contain one or more active ingredients, preferably only one active ingredient. The process according to the invention is in particular suitable for preventing the abuse of a pharmaceutical active ingredient, which is from the group comprising narcotic analgesics, opioids, tranquillisers, preferably benzodiazepines, barbiturates, stimulants and further narcotics. The process according to the invention is very particularly suitable for preventing abuse of at least one opioid, tranquilliser or at least one other narcotic 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-diallylbarbituric acid (allobarbital), ^llylprodine, alphaprodine, 8-chloro-1-methy!-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (alprazolam), 2-diethylaminopropiophenone (amfepramone), (±)-a-methylphenethylamine (amphetamine), 2-(a-methylphenethylamino)-2-phenylacetonitrile (amphetaminil), 5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine, apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine, bezitramide, 7-bromc~5-(2-pyridyl)-1 H-1,4-benzodiazepine-2(3H)-one (bromazepam), 2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-/I[1,2J4]triazolo[4,3-a][1,4]diazepine (brotizolam), 17-cyclopropylmethyl-4,5a-epoxy-7a[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-enc/o-ethanomorphinan-3-ol(buprenorphine), 5-butyl-5-ethylbarbtturic acid (butobarbital), butorphanol, (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl) dimethylcarbamate (camazepam), (1 S,2S)-2-amino-1-phenyl-1-propanol (cathine/D-norpseudoephedrine), 7-chloro-A/-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine 4-oxide (chlordiazepoxide), 7-chloro-1 -methyl-5-phenyi-1 H-1,5-benzodiazepine-2,4(3H,5H)-dione (clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one (clonazepam), clonitazene, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1 H-1,4-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-11b-(2-chlorophenyl)-2,3,7,11 b-tetrahydro-oxazolo[3,2-cG[1,4]benzodiazepin-6(5H)-one (cloxazolam), (->-IVIethyl-[3\|3-benzoyloxy-2p(1aH,5aH)-tropane carboxylate] (cocaine), 4,5a-epoxy-3-methoxy-17-methyl-7-morphinan-6a-ol (codeine), 5-(1-cyclohexenyi)-5-ethyl barbituric acid (cyclobarbital), cyclorphan, cyprenorphine, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one (delorazepam), desomorphine, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate (dextropropoxyphene), dezocine, diampromide, diamorphone, 7-chloro-1-methyi-5-phenyl-1 H-1,4-benzodiazepin-2(3H)-one (diazepam), 4,5a-epoxy-3-methoxy-17-methyl-6a-morphinanol (dihydrocodeine), 4,5a-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, (eaR.lOa/1?)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-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-chIoro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate] (ethyl loflazepate), 4,5a-epoxy-3-ethoxy-17-methyl-7-morphinen-6a-ol (ethylmorphine), etonitazene, 4,5a-epoxy-7a-(1 -hydroxy-1 -methylbutyI)-6-methoxy- 17-methyl-6,14-endo-etheno-morphinan-3-ol (etorphine), A/-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (fencamfamine), 7-[2-(a-methylphenethylamino)ethyfj-theophylline) (fenethylline), 3-(a-methylphenethylamino)propionitrile (fenproporex), /V-(1-phenethyl-4-piperidyl)propionanilide (fentanyl), 7-chloro-5-(2-fluorophenyl)-1 -methyl-1H-1,4-benzodiazepin-2(3/Y)-one (fludiazepam), 5-(2-fluorophenyl)-1-methyl-7-nitro-1 H-1,4-benzodiazepin-2(3H)-one (flunitrazepam}, 7-chloro-1 -(2-diethylamino-ethyl)-5-(2-fluorophenyl)-1 H-1,4-benzodiazepin-2(3/V)-one (flurazepam), 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one (halazepam), 10-bromo-11 b-(2-fluorophenyl)-2,3,7,11 b-tetrahydro[1,3]oxazolo[3,2-d][1,4]benzo-diazepin-6(5/-/)-one (haloxazolam), heroin, 4,5a-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone), 4,5a-epoxy-3-hydroxy-17-methyI-6-morphinanone (hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan, 11-chloro-S.^b-dihydro^.S-dimethyl-^b-phenyMH-II.SJoxazinoIS^-dJII^Jbenzo-diazepine-4,7(6H)-dione (ketazolam), 1 -[4-(3-hydroxyphenyl)-1 -methyl-4-piperidyl]-1 -propanone (ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate (levacetylmethadol (LAAM)), (-)-6-dimethylamino-4,4-diphenol-3-heptanone (levomethadone), (-)-17-methyl-3-morphinanol (levorphanol), levophenacyl-morphane, lofentanil, 6-(2-chlorophenyl)-2-(4-methyl-1 -piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepin-1 (4H)-one (loprazolam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one (lorazepam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1 -methyl-1 H-1,4-benzodiazepin-2(3H>one (lormetazepam), 5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1 -a]isoindol-5-ol (mazindol), 7-chloro-2,3-dihydro-1 -methyl-5-phenyl-1 H-\ ,4-benzodiazepine (medazepam), A/-(3-chloropropyl)-a-methylphenethylamine (mefenorex), meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate), meptazinol, metazocine, methylmorphine, N,a-dimethylphenethylamine (methamphetamine), (±)-6-dimethyl-amino-4,4-diphenol-3-heptanone(methadone),2-methyl-3-o-tolyl-4(3Ay)-quinazolin-one (methaqualone), 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), metopon, 8-ch(oro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5a][1,4]benzodiazepine (midazolam), 2-(benzhydrylsulfinyl)acetamide (modafinil), 4,5a-epoxy-17-methyl-7-morphinen-3,6a-diol (morphine), myrophine, (±)-trans-3-C\, 1 -dimethylheptyl)-7,8,10,1 Oa-tetrahydro-1 -hydroxy-6,6-dimethyI-6H-dibenzo-[jb,c(]pyran-9(6aH)-one (nabilone), nalbuphene, nalorphine, narceine, nicomorphine, 1 -methyl-7-nitro-5-phenyl-1 H-1,4-benzodiazepin-2(3H)-one (nimetazeparn), 7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam), 7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nordazepam), norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone(normethadone), normorphine, norpipanone, the exudation from plants belonging to the species Papaver somniferum (opium), 7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (oxazepam), (cis-trans)-! O-chloro-2,3,7,11 b-tetrahydro-2-methyl-11 b-phenyloxazolo-[3,2-c/][1,4jbenzodiazepin-6-(5H)-one (oxazolam), 4,5a-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone), oxymorphone, plants and parts of plants belonging to the species Papaver somniferum (including the subspecies setigerum) (Papaver somniferum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone (pernoline), 1,2,3,4,5,6-hexahydro-6, 11 -dirnethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol (pentazocine), 5-ethyl-5-(1-methylbutyl)-barbituric acid (pentobarbital), ethyl-(1 -methyl-4-phenyl-4-piperidinecarboxylate) (pethidine), phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine, pholcodine, 3-methyl-2-phenylmorpholine (phenmetrazine), 5-ethyl-5-phenylbarbituric acid (phenobarbital), a,a-dimethylphenethylamine (phentermine), 7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3H)-one (pinazepam), a-(2-piperidyl)-benzhydryl alcohol (pipradrol), 1'-(3-cyano-3,3-diphenylpropyl)[1,4'-bipiperidine]-4'-carboxamide (piritramide), 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1 H-1,4-benzodiazepin-2(3H)-one (prazepam), profadol, proheptazine, promedol, properidine, propoxyphene, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl {3-[4-methoxycarbonyl-4-(A/-phenylpropanamido)piperidino]propanoate}(remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbutabarbital), 5-allyl-5-(1-methylbutyl)-barbituric acid (secobarbital), A/-{4-methoxymethyl-1 -[2-(2-thienyl)ethy!]-4-piperidyl}propion-anilide (sufentanil), 7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (temazepam), 7-chloro-5-(1-cyclohexenyl)-1-methyl-1 W-1,4-benzodiazepin-2(3H)-one (tetrazepam), ethyl (2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine (cis and trans)), tramadol, 8-chloro-6-(2-chlorophenyl)-1-methyI-4H-[1,2,4]triazolo[4,3-a][;i ,4Jbenzodiazepine (triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital), (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (2R,3R)-1- dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, preferably as racemate, 3-(2-dimethylaminomethyl-1 -hydroxy-cyclohexyl)phenyi 2-(4-isobutoxy-phenyl)-propionate, 3-(2-dtmethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)-propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)-propionate, 3-(2-dimethylaminomethyl-cyclohex-1 -enyl)-pheny!2-(6-methoxy-naphthalen-2-yl)-propionate, (RR-SS)-2-acetoxy-4-trifluoro-methyl-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-methyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyc[ohexyl)-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-dimethyl-aminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2',4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-dimethylaminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester together with corresponding stereoisomeric compounds, in each case the corresponding derivatives thereof, in particular amides, esters or ethers, and in each case the physiologically acceptable compounds thereof, in particular the salts and solvates thereof, particularly preferably hydrochlorides. The dosage form according to the invention is particularly suitable for preventing abuse of an opioid active ingredient selected from among the group comprising oxycodone, hydromorphone, morphine, tramadol and the physiologically acceptable derivatives or compounds thereof, preferably the salts and solvates thereof, preferably the hydrochlorides or sulfates thereof or of methylphenidate or the salts, solvates or physiologically acceptable derivatives thereof. The dosage form according to the invention is furthermore in particular suitable for preventing abuse of an opioid active ingredient selected from among the group comprising (1 R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propy!)phenol, (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methy!-pentan-3-ol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, (1 R,2R}-3-(2-dimethylaminonethyl-cyclohexyl)phenoi, the physiologically acceptable salts thereof, preferably hydrochlorides, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, preferably ethers, esters or amides. These compounds and the process for the production thereof are described in EP-A-693475 and EP-A-780369 respectively. The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure. In order to achieve the necessary breaking strength of the dosage form according to the invention, at least one natural or synthetic polymer (C) with a breaking strength, measured using the method disclosed in the present application, of at least 500 N and optionally at least one wax (D) with a breaking strength of at least 500 N are used as the binder. At least one polymer selected from the group comprising polyalkylene oxides, preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers thereof, and mixtures of at least two of the stated polymers is preferably used as the polymer (C). High molecular weight, thermoplastic polyalkylene oxides are preferred. Particularly preferred are those high molecular weight polyethylene oxides with a molecular weight of at least 0.5 million, preferably of at least 1 million, particularly preferably of 1 to 15 million, very particularly preferably of at least 5 million, determined by rheological measurements. These polymers have a viscosity at 25°C of 4500 to 17600 cP, measured on a 5 wt.% aqueous solution using a model RVF Brookfield viscosimeter (spindle no. 2 / rotational speed 2 rpm), of 400 to 4000 cP, measured on a 2 wt.% aqueous solution using the stated viscosimeter (spindle no. 1 or 3 / rotational speed 10 rpm) or of 1650 to 10000 cP, measured on a 1 wt.% aqueous solution using the stated viscosimeter (spindle no. 2 / rotational speed 2 rpm). The polymers are preferably used as a powder. They may be soluble in water. In order to achieve the necessary breaking strength of the dosage form produced according to the invention, at least one natural, semi-synthetic or synthetic wax (D) with a breaking strength, measured using the method disclosed in the present application, of at least 500 N, may be used as an additional further binder. Waxes with a softening point of at least 60°C, preferably of at least 80°C, are preferred. Camauba wax and beeswax are particularly preferred. Carnauba wax is very particularly preferred. Carnauba wax is a natural wax which is obtained from the leaves of the carnauba palm and has a softening point of at least 80°C. When the wax component is additionally used, it is used together with at least one polymer (C) in quantities such that the dosage form produced according to the invention has a breaking strength of at least 500 N. The binder component(s) are preferably used in a quantity of at least 20 wt.%, preferably at least 35 wt.%, particularly preferably of 50 to 99.9 wt.%, very particularly preferably of at least 60 wt.%, relative to the total weight the dosage form. Auxiliary substances (B) may also be used in the process according to the invention. Auxiliary substances (B) which may be used are those known auxiliary substances which are conventional for the formulation of solid dosage forms. These are preferably plasticisers, such as polyethylene glycol, auxiliary substances which influence active ingredient release, preferably hydrophobic or hydrophilic, preferably hydrophilic polymers, very particularly preferably hydroxypropylmethylcellulose, and/or antioxidants. Suitable antioxidants are ascorbic acid, butylhydroxyanisole, butylhydroxytoluene, salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and the derivatives thereof, sodium bisulfite, particularly preferably butylhydroxytoluene (BHT) or butylhydroxyanisole (BHA) and ce-tocopherol. The antioxidant is preferably used in quantities of 0.01 to 10 wt.%, preferably of 0.03 to 5 wt.%, relative to the total weight of the dosage form. By using ultrasound in combination with the binder which has a breaking strength of £ 500 N, it is possible using the process according to the invention simply and reproducibly to achieve a breaking strength of the dosage from which is sufficiently high considerably to complicate or to prevent pulverisation of the dosage form with conventional means and hence any subsequent abuse. Using the process according to the invention, it is possible to obtain dosage forms in the form of tablets or in multiparticulate form, preferably as microtablets, micropellets, granules, microparticles, spheroids, beads or pellets, which are optionally press-moulded into tablets or packaged in capsules. The multiparticulate forms preferably have a size or size distribution in the range from 0.1 to 3 mm, particularly preferably in the range from 0.5 to 2 mm. Oral dosage forms are preferably produced using the process according to the invention. The method according to the invention is carried out by firstly producing a homogeneous mixture of at least one active ingredient with potential for abuse (A), at least one binder with the stated breaking strength and optionally at least one further abuse-preventing compound a) to f) listed below. Further auxiliary substances (B), such as for example fillers, plasticisers, agents to control release, antioxidants, slip agents or dyes may also be incorporated into this mixture. Mixing may be performed with the assistance of conventional mixers. Roll mixers, shaking mixers, shear mixers or compulsory mixers are, for example, suitable. The resultant powder mixture, after optional preforming, is exposed to ultrasound. During ultrasonication, it is preferred for there to be direct contact between the mixture, which is preferably in a shaping die, and the sonotrode of the ultrasound device, i.e. the sonotrode touches the mixture. An ultrasound device as shown in Figure 1 is preferably used in the process according to the invention. In this Figure 1, (1) denotes the press, with which the necessary force is applied, (2) the converter, (3) the booster, (4) the sonotrode, (5) the shaping die, (6) the bottom punch, (7) the base plate, (8) and (9) the ultrasound generator and device controller. The ultrasound device may comprise not only one shaping die and one bottom punch, but instead more than one of these units, the sonotrode being divided into a corresponding number of top punches. A frequency of 1 kHz to 2 MHz, preferably of 10 to 75 kHz, particularly preferably of 20 to 40 kHz, is maintained during ultrasonication. Ultrasonication should be performed until the binder has at least softened. This is preferably achieved within a few seconds, particularly preferably within at least 0.1 seconds, very particularly preferably within 0.1 to 5 seconds, in particular within 0.5 to 3 seconds. For the purpose of ultrasonication, the mixture is placed in the shaping die and the sonotrode is brought into contact with the mixture. The mixture is also subjected to shaping by application of force. The mixture is preferably shaped during or after ultrasonication. If shaping proceeds in the above-described ultrasound device, this is achieved with the assistance of the shaping die, the bottom punch and the sonotrode. To this end, the sonotrode, with the assistance of the press (1), exerts the necessary force onto the mixture. In this manner, compaction of the mixture results in shaping, preferably to obtain the final shape. For this shaping, the shaping die, the bottom punch and the sonotrode acting as top punch are preferably adapted to the shape to be achieved, preferably the final shape, wherein the punch format and sonotrode format, i.e. the opposing end faces thereof, are complementary in form. The mixture is consolidated and shaped by force applied onto the mixture by the sonotrode. The force exerted during shaping is preferably kept constant, while ultrasonication may also optionally be varied. This stepwise ultrasonication is preferably used when the highest possible energy input, e.g. for rapid plasticisation of the binder and to shorten the processing time, is desired at the beginning of ultrasonication, such that preferably as much as 30 to 60% of the total energy input is provided at the beginning, i.e. during the first stage of ultrasonication, by setting a higher ultrasound amplitude. Ultrasonication and the application offeree ensure uniform energy transfer, so bringing about rapid and homogeneous sintering of the mixture. In this manner, dosage forms are obtained which have a breaking strength of > 500 N and thus cannot be comminuted using conventional means. Before shaping is performed, the mixture may also be subjected to preforming by granulation and the resultant granules are shaped into the desired dosage form, such as tablets, by Ultrasonication and application offeree. Granulation may be performed in machinery and apparatus known to the person skilled in the art. If granulation is performed as wet granulation, water or aqueous solutions, such as for example ethanol/water or isopropanol/water, may be used as the granulation liquid. The mixture or the granules preformed therefrom may also be subjected to melt extrusion for shaping, wherein the mixture is converted into a melt by Ultrasonication and application offeree and then extruded through dies. The sonotrode here assumes the function of introducing ultrasound and of applying force as a piston, as in a piston injection moulding machine. The strands or strand obtained in this manner may be singulated to the desired length with the assistance of known apparatus and furthermore optionally converted into the final shape by application offeree with further Ultrasonication. The extrudates may also be shaped into the final shape by a calendering process between two contrarotating shaping rollers, preferably with application offeree. It is, however, also possible for the mixtures or granules also to be preformed into extrudates, preferably using suitable injection moulds, with the assistance of a piston injection moulding machine, and then to be subjected to Ultrasonication and application of force. As already mentioned, shaping into the final shape of the dosage form proceeds from a mixture, preferably in powder form, comprising at least the active ingredient with potential for abuse and at least one binder with a breaking strength of > 500 N, preferably by direct compression with application of force, wherein this mixture is exposed to ultrasound before or during the application offeree. The applied force may correspond to the force which is conventionally used for shaping, for example for moulding tablets or for press-moulding granules into the corresponding final shape. According to the invention, a force of at least 50 N, preferably of at least 200 N, very particularly preferably of at least 500 N should be applied during application of force. The necessary force may also be applied to the mixture with the assistance of rollers. However, shaping of the dosage forms preferably proceeds by direct press-moulding of a pulverulent mixture of the components of the dosage form or corresponding granules formed therefrom, wherein ultrasonication preferably proceeds during or before shaping. This ultrasonication proceeds until the binder is softened, which is conventionally achieved in less than 1 second to at most 5 seconds, and the mixture is compacted to such an extent that the dosage form has a breaking strength of at least 500 N. It is also possible, after ultrasonication and preforming by application of force to the mixture, to carry out final shaping in a conventional tablet press. The tablets produced according to the invention may also take the form of multilayer tablets. In multilayer tablets, at least the active ingredient-containing layer should be produced with ultrasonication and application of force. The dosage forms obtained by the production process according to the invention are distinguished in that, due to their hardness, they cannot be pulverised with the assistance of conventional comminution means available to an abuser. This virtually rules out oral, parenteral, in particular intravenous, or nasal abuse. However, in order to prevent any possible abuse of the dosage forms obtained by the production process according to the invention in the event of comminution and/or pulverisation which possibly occur nonetheless due to extraordinary force, in a preferred embodiment these dosage forms may contain further abuse-complicating or -preventing agents as auxiliary substances. The dosage forms obtained by the production process according to the invention may thus additionally comprise, apart from one or more active ingredients with potential for abuse and at least one binder, at least one the following components (a) to (f) as auxiliary substances: (a) at least one substance which irritates the nasal passages and/or pharynx, (b) at least one viscosity-increasing agent, which, with the assistance of a necessary minimum quantity of an aqueous liquid, forms a gel with the extract obtained from the dosage form, which gel preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid, (c) at least one antagonist for each of the active ingredients with potential for abuse, (d) at least one emetic, (e) at least one dye as an aversive agent, and/or (f) at least one bitter substance. Components (a) to (f) are additionally each individually suitable for abuse-proofing the dosage forms obtained by the production process according to the invention. Accordingly, component (a) is preferably suitable for proofing the dosage form against nasal, oral and/or parenteral, preferably intravenous, abuse, component (b) is preferably suitable for proofing against parenteral, particularly preferably intravenous and/or nasal abuse, component (c) is preferably suitable for proofing against nasal and/or parenteral, particularly preferably intravenous, abuse, component (d) is preferably suitable for proofing against parenteral, particularly preferably intravenous, and/or oral and/or nasal abuse, component (e) is suitable as a visual deterrent against oral or parenteral abuse and component (f) is suitable for proofing against oral or nasal abuse. Combined use according to the invention of at least one of the above-stated components makes it possible still more effectively to prevent abuse of dosage forms obtained by the production process according to the invention. For example, the dosage form obtained by the process according to the invention may also comprise two or more of components (a)-(f) in a combination, preferably (a), (b) and optionally (c) and/or (f) and/or (e) or (a), (b) and optionally (d) and/or (f) and/or (e). In another embodiment, the dosage form produced by the process according to the invention may comprise all of components (a)-(f). If the dosage form obtained by the process according to the invention comprises an abuse-preventing component (a), substances which irritate the nasal passages and/or pharynx which may be considered according to the invention are any substances which, when administered abusively via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the abuser that he/she does not wish to or cannot continue administration, for example burning, or physiologically counteracts taking of the corresponding active ingredient, for example due to increased nasal secretion or sneezing. These substances which conventionally irritate the nasal passages and/or pharynx may also bring about a very unpleasant sensation or even unbearable pain when administered parenterally, in particular intravenously, such that the abuser does not wish to or cannot continue taking the substance. Particularly suitable substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Appropriate substances and the quantities thereof which are conventionally to be used are known per se to the person skilled in the art or may be identified by simple preliminary testing. The substance which irritates the nasal passages and/or pharynx of component (a) is preferably based on one or more constituents or one or more plant parts of at least one hot substance drug. Corresponding hot substance drugs are known per se to the person skilled in the art and are described, for example, in "Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe" by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq.. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure. One or more constituents of at least one hot substance drug selected from the group comprising Allii sativi bulbus (garlic), Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma (calamus root), Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma (Javanese turmeric root), Galangae rhizoma (galangal root), Myristicae semen (nutmeg), Piperis nigri fructus (pepper), Sinapis albae semen (white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root), particularly preferably from the group comprising Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper) and Piperis nigri fructus (pepper) may preferably be added as component (a) to the dosage form obtained by the process according to the invention. The constituents of the hot substance drugs preferably comprise o-methoxy(methyl)-phenol compounds, acid amide compounds, mustard oils or sulfide compounds or compounds derived therefrom. Particularly preferably, at least one constituent of the hot substance drugs is selected from the group consisting of myristicin, elemicin, isoeugenol, cc-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids, preferably capsaicin, capsaicin derivatives, such as N-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, norcapsaicin and nomorcapsaicin, piperine, preferably trans-piperine, glucosinolates, preferably based on non-volatile mustard oils, particularly preferably based on p-hydroxybenzy! mustard oil, methylmercapto mustard oil or methylsulfonyl mustard oil, and compounds derived from these constituents. A dosage unit is taken to mean a separate or separable administration unit, such as for example a tablet or a capsule. The dosage form obtained by the process according to the invention may preferably contain the plant parts of the corresponding hot substance drugs in a quantity of 0.01 to 30 wt.%, particularly preferably of 0.1 to 0.5 wt.%, in each case relative to the total weight of the dosage unit. If one or more constituents of corresponding hot substance drugs are used, the quantity thereof in a dosage unit obtained by the process according to the invention preferably amounts to 0.001 to 0.005 wt.%, relative to the total weight of the dosage unit. Another option for preventing abuse of the dosage forms obtained by the process according to the invention consists in adding at least one viscosity-increasing agent as a further abuse-preventing component (b) to the dosage form, which, with the assistance of a necessary minimum quantity of an aqueous liquid, forms a gel with the extract obtained from the dosage form, which gel is virtually impossible to administer safely and preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid. For the purposes of the present invention, visually distinguishable means that the active ingredient-containing gel formed with the assistance of a necessary minimum quantity of aqueous liquid, when introduced, preferably with the assistance of a hypodermic needle, into a further quantity of aqueous liquid at 37°C, remains substantially insoluble and cohesive and cannot straightforwardly be dispersed in such a manner that it can safely be administered parenterally, in particular intravenously. The material preferably remains visually distinguishable for at least one minute, preferably for at least 10 minutes. The increased viscosity of the extract makes it more difficult or even impossible for it to be passed through a needle or injected. If the gel remains visually distinguishable, this means that the gel obtained on introduction into a further quantity of aqueous liquid, for example by injection into blood, initially remains in the form of a largely cohesive thread, which, while it may indeed be broken up mechanically into smaller fragments, cannot be dispersed or even dissolved in such a manner that it can safely be administered parenterally, in particular intravenously. In combination with at least one optionally present component (a) or (c) to (e), this additionally leads to unpleasant burning, vomiting, bad flavour and/or visual deterrence. Intravenous administration of such a gel would therefore most probably result in serious damage to the health of the abuser. In order to verify whether a viscosity-increasing agent is suitable as component (b) for use in the dosage form obtained by the production process according to the invention, the active ingredient is mixed with the viscosity-increasing agent and suspended in 10 ml of water at a temperature of 25°C. If this results in the formation of a gel which fulfils the above-stated conditions, the corresponding viscosity-increasing agent is suitable for preventing or averting abuse of the dosage forms obtained by the process according to the invention. If component (b) is added to the dosage form obtained by the process according to the invention, one or more viscosity-increasing agents are used which are selected from the group consisting of microcrystalline cellulose with 11 wt.% carboxymethylcellulose sodium (Avicel® RC 591), carboxymethylcellulose sodium (Blanose®, CMC-Na C300P®, Frimulsion BLC-5®, Tylose C300 P®), polyacrylic acid (Carbopol® 980 NF, Carbopol® 981), locust bean flour (Cesagum® LA-200, Cesagum® LID/150, Cesagum® LN-1), pectins, preferably from citrus fruit or apples (Cesapectin® HM Medium Rapid Set), waxy maize starch (C*Gel 04201®), sodium alginate (Frimulsion ALG (E401)®), guar flour (Frimulsion BM®, Polygum 26/1-75®), iota carrageenan (Frimulsion D021®), karaya gum, gellan gum (Kelcogel F®, Kelcogel LT100®), galactomannan (Meyprogat 150®), tara stone flour (Polygum 43/1®), propylene glycol alginate (Protanal-Ester SD-LB®), sodium hyaiuronate, tragacanth, tara gum (Vidogum SP 200®), fermented polysaccharide welan gum (K1A96), xanthans such as xanthan gum (Xantural 180®). Xanthans are particularly preferred. The names stated in brackets are the trade names by which the materials are known commercially. In general, a quantity of 0.1 to 20 wt.%, particularly preferably of 0.1 to 15 wt.%, relative to the total weight of the dosage forms, of the stated viscosity-increasing agent(s) is sufficient to fulfil the above-stated conditions. The component (b) viscosity-increasing agents, where provided, are preferably present in the dosage form obtained according to the invention in quantities of 1.5 mg per dosage unit, i.e. per administration unit. !n a particularly preferred embodiment of the present invention, the viscosity-increasing agents used as component (b) are those which, on extraction from the dosage form with the necessary minimum quantity of aqueous liquid, form a gel which encloses air bubbles. The resultant gels are distinguished by a turbid appearance, which provides the potential abuser with an additional optical warning and discourages him/her from administering the gel parenterally. The polymer (C) may optionally also serve as an additional viscosity-increasing agent which forms a gel with water. It is also possible to formulate the viscosity-increasing agent and the other constituents in the dosage form obtained by the production process according to the invention in a mutually spatially separated arrangement. In order to discourage and prevent abuse, the dosage form obtained by the process according to the invention may furthermore comprise component (c), namely one or more antagonists for the active ingredient or active ingredients with potential for abuse, wherein the antagonists are preferably spatially separated from the remaining constituents of the dosage form obtained by the process according to the invention and, when correctly used, do not exert any effect. Suitable antagonists for preventing abuse of the active ingredients are known to the person skilled in the art and may be present in the dosage form obtained by the production process according to the invention as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. If the active ingredient present in the dosage form is an opioid, the antagonist used is preferably an antagonist selected from the group comprising naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphine or naluphine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate. The corresponding antagonists, where component (c) is provided, are preferably used in a quantity of > 1 mg, particularly preferably in a quantity of 3 to 100 mg, very particularly preferably in a quantity of 5 to 50 mg per dosage form, i.e. per administration unit. If the dosage form obtained by the process according to the invention comprises a stimulant as active ingredient, the antagonist is preferably a neuroleptic, preferably at least one compound selected from the group comprising haloperidol, promethazine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopentixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, meiperone and bromperidol. The dosage form obtained by the process according to the invention preferably comprises these antagonists in a conventional therapeutic dose known to the person skilled in the art, particularly preferably in a quantity of twice to three times the conventional dose per administration unit. If, in order to discourage and prevent abuse of the dosage form obtained by the process according to the invention, component (d) is also used, at least one emetic is formulated such that it is present in a spatially separated arrangement from the other components and, when correctly used, cannot exert its effect in the body Suitable emetics for preventing abuse of an active ingredient are known to the person skilled in the art and may also be used in the production according to the invention of the dosage forms as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. An emetic based on one or more constituents of ipecacuanha (ipecac) root, preferably based on the constituent emetine may preferably be present in the dosage form obtained by the process according to the invention, as is, for example, described in "Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe" by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, New York, 1982. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure. The dosage form obtained by the process according to the invention may preferably comprise the emetic emetine as component (d), preferably in a quantity of > 3 mg , particularly preferably of > 10 mg and very particularly preferably in a quantity of > 20 mg per dosage form, i.e. administration unit. Apomorphine may likewise preferably be used as an emetic for additional abuse-proofing, preferably in a quantity of preferably > 3 mg , particularly preferably of > 5 mg and very particularly preferably of > 7 mg per administration unit. If the dosage form obtained by the process according to the invention contains component (e) as an additional abuse-preventing auxiliary substance, the use of such a dye brings about an intense coloration of a corresponding aqueous solution, in particular when the attempt is made to extract the active ingredient for parenteral, preferably intravenous administration, which coloration may act as a deterrent to the potential abuser. Oral abuse, which conventionally begins by means of aqueous extraction of the active ingredient, may also be prevented by this coloration. Suitable dyes and the quantities required for the necessary deterrence may be found in WO 03/015531, wherein the corresponding disclosure should be deemed to be part of the present disclosure and is hereby introduced as a reference. If the dosage form obtained by the process according to the invention contains component (f) as a further abuse-preventing auxiliary substance, this addition of at least one bitter substance and the consequent impairment of the flavour of the dosage form additionally prevents oral and/or nasal abuse. Suitable bitter substances and the quantities effective for use may be found in US-2003/0064099 A1, the corresponding disclosure of which should be deemed to be the disclosure of the present application and is hereby introduced as a reference. Suitable bitter substances are preferably aromatic oils, preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit aroma substances, preferably aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof, and/or denatonium benzoate (Bitrex®). Denatonium benzoate is particularly preferred. In a further preferred embodiment, the dosage form obtained according to the invention not only assumes the form of a tablet or a capsule but is also in the form of an oral osmotic therapeutic system (OROS), preferably if at least one further abuse-preventing component (a)-(f) is also present. If components (c) and/or (d) and/or (f) are present in the dosage form, care must be taken to ensure that they are formulated in such a manner or are present in such a low dose that, when correctly administered, the dosage form is able to bring about virtually no effect which impairs the patient or the efficacy of the active ingredient. If the dosage form obtained according to the invention contains component (d) and/or (f), the dosage must be selected such that, when correctly orally administered, no negative effect is caused. If, however, the intended dosage is exceeded in the event of abuse, nausea or an inclination to vomit or a bad flavour are produced The particular quantity of component (d) and/or (f) which can still be tolerated by the patient in the event of correct oral administration may be determined by the person skilled in the art by simple preliminary testing. If, however, irrespective of the fact that the further dosage form obtained according to the invention is virtually impossible to comminute, components (c) and/or (d) and/or (f) are used to protect the dosage form, these components should preferably be used at a dosage which is sufficiently high that, when abusively administered, they bring about an intense negative effect on the abuser. This is preferably achieved by spatial separation of at least the active ingredient or active ingredients from components (c) and/or (d) and/or (f), wherein the active ingredient or active ingredients is/are present in at least one subunit (X) and components (c) and/or (d) and/or (f) is/are present in at least one subunit (Y), and wherein, when the dosage form is correctly administered, components (c), (d) and (f) do not exert their effect on taking and/or in the body and the remaining components of the formulation, in particular component (C) and optionally (D), are identical. If the dosage form obtained according to the invention comprises at least 2 of components (c) and (d) or (f), these may each be present in the same or different subunits (Y). Preferably, when present, all the components (c) and (d) and (f) are present in one and the same subunit (Y). For the purposes of the present invention, subunits are solid formulations, which in each case, apart from conventional auxiliary substances known to the person skilled in the art, contain the active ingredients), at least one polymer (C) and the optionally present component (D) and optionally at least one of the optionally present components (a) and/or (b) and/or (e) or in each case at least one polymer (C) and optionally (D) and the antagonist(s) and/or emetic(s) and/or component (e) and/or component (f) and optionally at least one of the optionally present components (a) and/or (b). Care must here be taken to ensure that each of the stated subunits is formulated in accordance with the above-stated process. One substantial advantage of the separated formulation of active ingredients from components (c) or (d) or (f) in subunits (X) and (Y) of the dosage form obtained according to the invention is that, when correctly administered, components (c) and/or (d) and/or (f) are hardly released on taking and/or in the body or are only released in such small quantities that they exert no effect which impairs the patient or therapeutic success or, on passing through the patient's body, they are only liberated in locations where they cannot be sufficiently absorbed to be effective. When the dosage form is correctly administered, preferably hardly any of components (c) and/or (d) and/or (f) is released into the patient's body or they go unnoticed by the patient. The person skilled in the art will understand that the above-stated conditions may vary as a function of the particular components (c), (d) and/or (f) used and of the formulation of the subunits or the dosage form. The optimum formulation for the particular dosage form may be determined by simple preliminary testing. What is vital is that the particular subunits contain the binder component, i.e. the polymer (C) and optionally component (D), and have been formulated in the stated manner. Should, contrary to expectations, the abuser succeed in comminuting such a dosage form obtained according to the invention, which comprises components (c) and/or (e) and/or (d) and/or (f) in subunits (Y), for the purpose of abusing the active ingredient and obtain a powder which is extracted with a suitable extracting agent, not only the active ingredient but also the particular component (c) and/or (e) and/or (f) and/or (d) will be obtained in a form in which it cannot readily be separated from the active ingredient, such that when the dosage form which has been tampered with is administered, in particular by oral and/or parenteral administration, it will exert its effect on taking and/or in the body combined with an additional negative effect on the abuser corresponding to component (c) and/or (d) and/or (f) or, when the attempt is made to extract the active ingredient, the coloration will act as a deterrent and so prevent abuse of the dosage form. A dosage form, in which the active ingredient or active ingredients is/are spatially separated from components (c), (d) and/or (e), preferably by formulation in different subunits, may be formulated in many different ways, wherein the corresponding subunits may each be present in the dosage form according to the invention in any desired spatial arrangement relative to one another, provided that the above-stated conditions for the release of components (c) and/or (d) are fulfilled. The person skilled in the art will understand that component(s) (a) and/or (b) which are optionally also present may preferably be formulated in the dosage form obtained according to the invention both in the particular subunits (X) and (Y) and in the form of independent subunits corresponding to subunits (X) and (Y), provided that neither the abuse-proofing nor the active ingredient release in the event of correct administration is impaired by the nature of the formulation and the polymer (C) and optionally (D) is preferably included in the formulation and formulation is carried out in accordance with the above-stated process according to the invention in order to achieve the necessary hardness. In a preferred embodiment of the dosage form obtained according to the invention, subunits (X) and (Y) are present in rnultiparticulate form, wherein microtablets, microcapsules, micropellets, granules, spheroids, beads or pellets are preferred and the same form, i.e. shape, is selected for both subunit (X) and subunit (Y), such that it is not possible to separate subunits (X) from (Y), for example by mechanical selection. The rnultiparticulate forms are preferably of a size in the range from 0.1 to 3 mm, preferably of 0.5 to 2 mm. The subunits (X) and (Y) in rnultiparticulate form may also preferably be packaged in a capsule or be press-moulded into a tablet, wherein the final formulation in each case proceeds in such a manner that the subunits (X) and (Y) are also retained in the resultant dosage form. The rnultiparticulate subunits (X) and (Y) of identical shape should also not be visually distinguishable from one another so that the abuser cannot separate them from one another by simple sorting. This may, for example, be achieved by the application of identical coatings which, apart from this disguising function, may also incorporate further functions, such as, for example, delayed release of one or more active ingredients or provision of a finish resistant to gastric juices on the particular subunits. The rnultiparticulate subunits may also be formulated as an oral dosage form as a slurry or suspension in pharmaceutically safe suspending media. In a further preferred embodiment of the present invention, subunits (X) and (Y) are produced such that they are in each case arranged in layers relative to one another. The layered subunits (X) and (Y) are preferably arranged for this purpose vertically or horizontally relative to one another, wherein in each case one or more layered subunits (X) and one or more layered subunits (Y) may be present in the dosage form, such that, apart from the preferred layer sequences (X)-(Y) or (X)-(Y)-(X), any desired other layer sequences may be considered, optionally in combination with layers containing components (a) and/or (b). Another preferred dosage form produced by the process according to the invention is one in which subunit (Y) forms a core which is completely enclosed by subunit (X), wherein a separation layer (Z) may be present between said layers. Such a structure is preferably also suitable for the above-stated multiparticulate forms, wherein both subunits (X) and (Y) and an optionally present separation layer (Z) must satisfy the hardness requirement according to the invention and are formulated in one and the same multiparticulate form. In a further preferred embodiment of the process according to the invention, the subunit (X) forms a core, which is enclosed by subunit (Y), wherein the latter comprises at least one channel which leads from the core to the surface of the dosage form. The dosage form formulated according to the invention may comprise, between one layer of the subunit (X) and one layer of the subunit (Y), in each case one or more, preferably one, optionally swellable separation layer (Z) which serves to separate subunit (X) spatially from (Y). If the dosage form formulated according to the invention comprises the layered subunits (X) and (Y) and an optionally present separation layer (Z) in an at least partially vertical or horizontal arrangement, the dosage form preferably takes the form of a tablet or a laminate. In one particularly preferred embodiment, the entirety of the free surface of subunit (Y) and optionally at least part of the free surface of subunit(s) (X) and optionally at least part of the free surface of the optionally present separation layer(s) (Z) may be coated with at least one barrier layer (Z) which prevents release of component (c) and/or (e) and/or (d) and/or (f). The barrier layer (Z1) must also be formulated and produced in such a manner that it fulfils the hardness requirements according to the invention. Another particularly preferred embodiment of the dosage form produced according to the invention comprises a vertical or horizontal arrangement of the layers of subunits (X) and (Y) and at least one push layer (p) arranged therebetween, and optionally a separation layer (Z), in which dosage form the entirety of the free surface of the layer structure consisting of subunits (X) and (Y), the push layer and the optionally present separation layer (Z) is provided with a semtpermeable coating, which is permeable to a release medium, i.e. conventionally a physiological liquid, but substantially impermeable to the active ingredient and to component (c) and/or (d) and/or (f), and wherein this coating comprises at least one opening for release of the active ingredient in the area of subunit (X). A corresponding dosage form is known to the person skilled in the art, for example under the name oral osmotic therapeutic system (OROS), as are suitable materials and processes for the production thereof, inter alia from US 4,612,008, US 4,765,989 and US 4,783,337. The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure. What is vital is that these systems are adapted according to the invention during the production thereof such that they give rise to a breaking strength of > 500 N. In a further preferred embodiment, the subunit (X) of the dosage form produced according to the invention is in the form of a tablet, the edge face and optionally one of the two main faces of which is covered with a barrier layer (Zf) containing component (c) and/or (d) and/or (f). The person skilled in the art will understand that the auxiliary substances of the subunit(s) (X) or (Y) and of the optionally present separation layer(s) (Z) and/or of the barrier layer(s) (Z1) used in formulating the dosage form according to the invention will vary as a function of the arrangement thereof in the dosage form according to the invention, the mode of administration and as a function of the particular active ingredient of the optionally present components (a) and/or (b) and/or (e) and of component (c) and/or (d) and/or (f). The materials which have the requisite properties are in each case known per se to the person skilled in the art. If release of component (c) and/or (d) and/or (f) from subunit (Y) of the dosage form according to the invention is prevented with the assistance of a cover, preferably a barrier layer, the subunit may consist of conventional materials known to the person skilled in the art, providing that it contains at least one polymer (C) and optionally (D) to achieve the necessary breaking strength of the dosage form produced according to the invention. If a corresponding barrier layer (Z1) is not provided to prevent release of component (c) and/or (d) and/or (f), the materials of the subunits should be selected such that re\|ease of the particular component (c) and/or (d) from subunit (Y) is virtually ruled out. The materials which are stated below to be suitable for production of the barrier layer may preferably be used for this purpose. Preferred materials are those which are selected from the group comprising alkylcelluloses, hydroxyalkylcelluloses, glucans, scleroglucans, mannans, xanthans, copolymers of poly[bis(p-carboxyphenoxy)propane and sebacic acid, preferably in a molar ratio of 20:80 (commercially available under the name Polifeprosan 20®), carboxymethylcelluloses, cellulose ethers, cellulose esters, nitrocelluloses, polymers based on (meth)acrylic acid and the esters thereof, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, halogenated polyvinyls, polyglycolides, polysiloxanes and polyurethanes and the copolymers thereof. Particularly suitable materials may be selected from the group comprising methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylceflulose, cellulose acetate, cellulose propionate (of low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethylcellulose, cellulose triacetate, sodium cellulose sulfate, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate, polyoctadecyl acrylate, polyethylene, low density polyethylene, high density polyethylene, polypropylene, polyethylene glycol, polyethylene oxide, polyethylene terephthalate, polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate and polyvinyl chloride. Particularly suitable copolymers may be selected from the group comprising copolymers of butyl methacrylate and isobutyl methacrylate, copolymers of methyl vinyl ether and maleic acid of high molecular weight, copolymers of methyl vinyl ether and maleic acid monoethyl ester, copolymers of methyl vinyl ether and maleic anhydride and copolymers of vinyl alcohol and vinyl acetate. Further materials which are particularly suitable for formulating the barrier layer are starch-filled polycaprolactone (WO98/20073), aliphatic polyesteramides (DE 19 753 534 A1, DE 19 800 698 A1, EP 0 820 698 A1), aliphatic and aromatic polyester urethanes (DE 19822979), polyhydroxyalkanoates, in particular polyhydroxybutyrates, polyhydroxyvalerates, casein (DE 4 309 528), polylactides and copolylactides (EP 0 980 894 A1). The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure. The above-stated materials may optionally be blended with further conventional auxiliary substances known to the person skilled in the art, preferably selected from the group comprising glyceryl monostearate, semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone, gelatine, magnesium stearate, stearic acid, sodium stearate, talcum, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols and the derivatives thereof. If the dosage form obtained according to the invention comprises a separation layer (Z1), said layer, like the uncovered subunit (Y), may preferably consist of the above-stated materials described for the barrier layer. The person skilled in the art will understand that release of the active ingredient or of component (c) and/or (d) from the particular subunit may be controlled by the thickness of the separation layer. The dosage form obtained according to the invention exhibits controlled release of the active ingredient. It is preferably suitable for twice daily administration to patients. The dosage form produced according to the invention may comprise one or more active ingredients with potential for abuse at least partially in a further delayed-release form, wherein delayed release may be achieved with the assistance of conventional materials and methods known to the person skilled in the art, for example by embedding the active ingredient in a delayed-release matrix or by the application of one or more delayed-release coatings. Active ingredient release must, however, be controlled such that the above-stated conditions are fulfilled in each case, for example that, in the event of correct administration of the dosage form, the active ingredient or active ingredients are virtually completely released before the optionally present component (c) and/or (d) can exert an impairing effect. Addition of materials effecting controlled release must moreover not impair the necessary breaking strength. Controlled release from the dosage form obtained according to the invention may preferably be achieved by embedding the active ingredient in a matrix. The auxiliary substances acting as matrix materials control active ingredient release. Matrix materials may, for example, be hydrophilic materials, from which active ingredient release proceeds mainly by diffusion, or hydrophobic materials, from which active ingredient release proceeds mainly by diffusion from the pores in the matrix. Physiologically acceptable, hydrophobic materials which are known to the person skilled in the art may be used as matrix materials. Hydrophilic polymers, particularly preferably cellulose ethers, cellulose esters and/or acrylic resins are preferably used as hydrophilic matrix materials. Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivatives thereof, such as the salts, amides or esters thereof are very particularly preferably used as matrix materials. Matrix materials prepared from hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof are also preferred. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof are particularly preferably used as hydrophobic materials. It is also possible to use mixtures of the above-stated hydrophilic and hydrophobic materials as matrix materials. The binder component, i.e. component (C) and the optionally present component (D), which serve to achieve the breaking strength of at least 500 N which is necessary according to the invention, may furthermore themselves serve as additional matrix materials. If the dosage form obtained according to the invention is intended for oral administration, it may also preferably comprise a coating which is resistant to gastric juices and dissolves as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the dosage form according to the invention passes through the stomach undissolved and the active ingredient is only released in the intestines. The coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5. Corresponding materials and methods for the controlled release of active ingredients and for the application of coatings which are resistant to gastric juices are known to the person skilled in the art, for example from "Coated Pharmaceutical Dosage Forms - Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials" by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure. Method for determining breaking strength In order to verify whether a polymer may be used as a binder, i.e. component (C) or (D), the polymer is pressed to form a tablet with a diameter of 10 mm and a height of 5 mm using a force of 150 N at a temperature which at least corresponds to the softening point of the polymer and is determined with the assistance of a DSC diagram of the material. Using tablets produced in this manner, breaking strength is determined with the apparatus described below in accordance with the method for determining the breaking strength of tablets published in the European Pharmacopoeia 1997, page 143,144, method no. 2.9.8. The apparatus used for the measurement is a "Zwick Z 2.5" materials tester, Fmax = 2.5 kN with a maximum draw of 1150 mm, which should be set up with one column and one spindle, a clearance behind of 100 mm and a test speed adjustable between 0.1 and 800 mm/min together with testControl software. Measurement is performed using a pressure piston with screw-in inserts and a cylinder (diam. 10 mm), a force transducer, Fmax. 1 kN, diameter = 8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M to DIN 55350-18 (Zwick gross force Fmax = 1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany) with order no. BTC-FR 2.5 TH. D09 for the tester, order no. BTC-LC 0050N. P01 for the force transducer, order no. BO 70000 S06 for the centring device. Figure 2 shows the measurement of the breaking strength of a tablet, in particular the tablet (4') adjustment device (61) used for this purpose before and during the measurement. To this end, the tablet (4') is held between the upper pressure plate (1') and the lower pressure plate (31) of the force application apparatus (not shown) with the assistance of two 2-part clamping devices (21), which are in each case firmly fastened (not shown) with the upper and lower pressure plate once the spacing (51) necessary for accommodating and centring the tablet to be measured has been established. The spacing (51) may be established by moving the 2-part clamping devices horizontally outwards or inwards in each case on the pressure plate on which they are mounted. The tablets deemed to be resistant to breaking under a specific load include not only those which have not broken but also those which may have suffered plastic deformation under the action of the force. The breaking strength of the dosage forms obtained according to the invention is determined by the stated measurement method, wherein dosage forms other than tablets are also tested. The invention is explained below with reference to Examples. These explanations are given merely by way of example and do not restrict the general concept of the invention. Example 1 (Table Remove) Tramadol hydrochloride and polyethylene oxide powder were mixed in a free-fall mixer. The mixture was then pressed into tablets with ultrasonication and application of the force stated below. The following machine was used for this purpose: Press: Branson WPS, 94-003-A, pneumatic (Branson Ultraschall, Dietzenbach, Germany) Generator (2000 W): Branson PG-220A, 94-001-A analogue (Branson Ultraschall) The diameter of the sonotrode was 12 mm. The press surface was flat. The mixture was placed in a shaping die with a diameter of 12 mm. The bottom of the shaping die forms a bottom punch with a planar press surface 12 mm in diameter. The following parameters were selected for plasticisation of the mixture: Frequency: 20 Hz Amplitude: 50% Force: 250 N Ultrasonication and application offeree lasted 0.5 seconds, with ultrasonication and application offeree proceeding simultaneously with the assistance of the sonotrode. The breaking strength of the tablets is determined with the stated apparatus in accordance with the stated method. No breakage occurred when a force of 500 N was applied. The tablet could not be comminuted using a hammer, nor with the assistance of a pestle and mortar. In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus with sinker in accordance with Pharm. Eur.. The temperature of the release medium was 37°C and the rotational speed of the stirrer 75 min"1. The release medium used was 600 ml of intestinal juice, pH 6.8. The quantity of active ingredient released in each case into the medium at any one time was determined by spectrophotometry. (Table Remove) Example 2 (Table Remove) Tramadol hydrochloride and polyethylene oxide powder were mixed as a powder in a free-fall mixer. Then, as described in Example 1, the mixture was press-moulded into tablets with ultrasonication and application offeree. The following machine was used for this purpose: Press: Branson 2000 aemc (Branson Ultraschal!, Dietzenbach, Germany) Generator (2000 W): Branson 2000 b, digital 20:2.2 (Branson Ultraschail) The diameter of the sonotrode was 10 mm with a concave radius of curvature of 8 mm. The following parameters were selected in order to plasticise and compact the mixture in 3 stages: 1st stage: Amplitude level 75% for 0.15 sec Frequency: 20 Hz Force: 970 N 2nd stage: Amplitude level 32.5% for 0.55 sec Frequency: 20 Hz Force: 970 N 3rd stage: Force: 970 N for 2.3 sec No ultrasonication The breaking strength of the tablets is determined with the stated apparatus in accordance with the stated method. No breakage occurred when a force of 500 N was applied. The tablet could not be comminuted using a hammer, nor with the assistance of a pestle and mortar. In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus with sinker in accordance with Pharm. Eur.. The temperature of the release medium was 37°C and the rotational speed of the stirrer 75 min"1. The release medium used was 600 ml of intestinal juice, pH 6.8. The quantity of active ingredient released in each case into the medium at any one time was determined by spectrophotometry. (Table Remove) WE CLAIM 1. A process for the production of an abuse-proofed solid dosage form containing at least one active ingredient with potential for abuse (A) and at least one binder, which is present at least 20 wt. % relative to the total weight of the dosage form, and has a breaking strength of greater than or equal to 500 N characterized in that a mixture comprising the active ingredient of the kind such as hereinbefore described, the binder of the kind such as hereinbefore described and optionally an auxiliary substance which is conventional for formulation of solid dosage forms, is exposed to ultrasound and force wherein the said dosage form as such exhibits a breaking strength of at least 500 N. 2. A process as claimed in claim 1, wherein the dosage form is an oral dosage form, preferably a tablet. 3. A process as claimed in claim 1, wherein the dosage form is produced in multiparticulate form, preferably as microtablets, micropellets, granules, microparticles, spheroids, beads or pellets, which are optionally press-moulded into tablets or packaged in capsules. 4. A process according to any one of claims 1 to 3, wherein the binder which is used is at least one synthetic or natural polymer (C) and optionally at least one wax (®), in each case with a breaking strength of at least 500 N. 5. A process according to any one of claims 1 to 4, wherein the polymer (C) used is at least one polymer selected from the group consisting of polyethylene oxide, polymethylene oxide, polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers thereof and mixtures thereof, preferably polyethylene oxide. 6. A process according to any one of claims 1 to 5, wherein the polyethylene oxide (C) has a molecular weight of at least 0.5 million. 7. A process as claimed in claim 6, wherein the molecular weight of the polyethylene oxide (C) is at least 1 million, preferably 1-15 million, particularly preferably at least 5 million. 8. A process according to any one of claims 4 to 7, wherein the wax (®) used is at least one natural, semi synthetic or synthetic wax with a softening point of at least 60°C, preferably of at least 80°C. 9. A process as claimed in claim 8, wherein the wax (®) used is carnauba wax or beeswax. 10. A process as claimed in claim 1, wherein the binder component(s) is/are used in a quantity of at least 20 wt.%, preferably of at least 35 wt.%, particularly preferably of 50 to 99.9% wt.%, relative to the total weight of the dosage form. 11. A process as claimed in claim 10, wherein the binder component(s) is/are used in a quantity of at least 60 wt.%, relative to the total weight of the dosage form. 12. A process as claimed in any one of claims 1 to 11, wherein the active ingredient (A) used is at least one active ingredient selectee from among the group comprising opioids, tranquillisers, stimulants, barbiturates, further narcotics and the physiologically acceptable derivatives thereof. 13. A process as claimed in claim 12, wherein the physiologically acceptable derivatives used are salts, solvates, esters, ethers or amides. 14. A process as claimed in claim 12 or claim 13, wherein the active ingredient with potential for abuse (A) which is used is oxycodone, morphine, hydromorphone, tramadol, methylphenidate or the physiologically acceptable7 salts thereof, preferably hydrochlorides. 15. A process as claimed in claim 1, wherein the auxiliary substances (B) which are also used are plasticisers, preferably a low molecular weight polyethylene glycol, antioxidants and/or hydrophilic polymers and/or hydrophobic polymers. 16. A process according to any one of claims 1 to 15, wherein the ultrasound is applied at a frequency of 1 kHz to 2 MHz, preferably of 10 to 75 kHz. 17. A process as claimed in claim 16, wherein the ultrasound is applied at a frequency of 20 to 40 kHz. 18. A process according to any one of claims 1 to 17, wherein there is direct contact between the mixture and the sonotrode of the ultrasound device during ultrasonication. 19. A process as claimed in claim 18, wherein the sonotrode touches the mixture. 20. A process according to any one of claims 1 to 19, wherein ultrasound is applied until the binder has at least softened. 21. A process according to any one of claims 1 to 20, wherein application of force pnto the mixture proceeds by compacting the mixture during Or after ultrasonication. 22. A process as claimed in claim 21, wherein, during compaction of the mixture, a force is applied until the dosage form exhibits a breaking strength of at least 500 N. 23. A process according to any one of claims 1 to 22, wherein the mixture is shaped by the compaction. 24. A process as claimed in claim 23, wherein shaping of the mixture proceeds with the assistance of a shaping die and punch, by extrusion and with the assistance of rollers and/or calendering. 25. A process according to any one of claims 1 to 24, wherein compaction is performed with the assistance of the sonotrode as the punch. 26. A process according to any one of claims 1 to 25, wherein the mixture optionally comprises at least one of the following components a) to f): (a) at least one substance which irritates the nasal passages and/or pharynx, (b) at least one viscosity-increasing agent, which, with the assistance of a necessary minimum quantity of an aqueous liquid, preferably as an aqueous extract obtained from the dosage form, forms a gel which preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid, (c) at least one antagonist for the active ingredient or active ingredients with potential for abuse, (d) at least one emetic, (e) at least one dye as an aversive agent, (f) at least one bitter substance.

Full Text

Process for the production of an abuse-proofed solid dosage form
The present invention relates to a process for the production of an abuse-proofed solid dosage form containing at least one active ingredient with potential for abuse and at least one binder with a breaking strength of greater than or equal to 500 N, by exposing a mixture comprising the active ingredient and the binder to ultrasound and force.
Many pharmaceutical active ingredients, in addition to having excellent activity in their appropriate application, also have potential for abuse, i.e. they can be used by an abuser to bring about effects other than those intended. Opiates, for example, which are highly active in combating severe to very severe pain, are frequently used by abusers to induce a state of narcosis or euphoria.
In order to make abuse possible, the corresponding dosage forms, such as tablets or capsules are comminuted, for example ground in a mortar, by the abuser, the active ingredient is extracted from the resultant powder using a preferably aqueous liquid and the resultant solution, optionally after being filtered through cotton wool or cellulose wadding, is administered parenterally, in particular intravenously. An additional phenomenon of this kind of administration, in comparison with abusive oral administration, is a further accelerated increase in active ingredient levels giving the abuser the desired effect, namely the "kick" or "rush". This kick is also obtained if the powdered dosage form is administered nasally, i.e. is sniffed. Since delayed-release dosage forms containing active ingredients with potential for abuse do not give rise to the kick desired by the abuser when taken orally even in abusively high quantities, such dosage forms are also comminuted and extracted in order to be abused.
US-A-4,070,494 proposed adding a swellable agent to the dosage form in order to prevent abuse. When water is added to extract the active ingredient, this agent swells and ensures that the filtrate separated from the gel contains only a small quantity of active ingredient.

The multilayer tablet disclosed in WO 95/20947 is based on a similar approach to "^preventing parenteral abuse, said tablet containing the active ingredient with potential for abuse and at least one gel former, each in different layers.
WO 03/015531 A2 discloses another approach to preventing parenteral abuse. A dosage form containing an analgesic opioid and a dye as an aversive agent is described therein. The colour released by tampering with the dosage form is intended to discourage the abuser from using the dosage form which has been tampered with.
Another known option for complicating abuse involves adding antagonists to the active ingredients to the dosage form, for example naioxone or naltrexone in the case of opioids, or compounds which cause a physiological defence response, such as for example ipecacuanha (ipecac) root.
Since, however, as in the past, it is in most cases necessary for the purposes of abuse to pulverise the dosage form, it was the object of the present invention to provide a process for the production of dosage forms comprising active ingredients with potential for abuse, with which process dosage forms are obtained which, when correctly administered, ensure the desired therapeutic action, but from which the active ingredients cannot be converted into a form suitable for abuse simply by pulverisation using means conventionally available to a potential abuser.
This object has been achieved by the provision of the process according to the invention for the production of an abuse-proofed solid dosage form containing at least one active ingredient with potential for abuse and at least one binder with a breaking strength of greater than or equal to 500 N, by exposing a mixture comprising the active ingredient and the binder to ultrasound and force.
Thanks to the process according to the invention using ultrasound and at least one binder with the stated breaking strength in quantities such that a dosage form also having a breaking strength of greater than or equal to 500 N is obtained, it is possible considerably to complicate or to prevent pulverisation of the dosage form using conventional means and hence any subsequent abuse.

If comminution is inadequate, parenteral, in particular intravenous, administration cannot be performed safely or extraction of the active ingredient therefrom takes too long for the abuser or there is no "kick" when orally abused as release is not instantaneous.
According to the invention, comminution is taken to mean pulverisation of the solid dosage form with conventional means which are available to an abuser, such as for example a pestle and mortar, a hammer, a mallet or other usual means for pulverisation by application offeree.
The process according to the invention thus gives rise to dosage forms which are suitable for preventing parenteral, nasal and/or oral abuse of active ingredients, preferably of pharmaceutical active ingredients with potential for abuse.
Active ingredients with potential for abuse, preferably pharmaceutical active ingredients with potential for abuse, are known to the person skilled in the art, as are the dosages thereof, and may be protected against abuse as such, in the form of the corresponding derivatives thereof, in particular esters, ethers or amides, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof, as racemates, enantiomers or stereoisomers by the process according to the invention. The dosage forms produced according to the invention may here contain one or more active ingredients, preferably only one active ingredient.
The process according to the invention is in particular suitable for preventing the abuse of a pharmaceutical active ingredient, which is from the group comprising narcotic analgesics, opioids, tranquillisers, preferably benzodiazepines, barbiturates, stimulants and further narcotics.
The process according to the invention is very particularly suitable for preventing abuse of at least one opioid, tranquilliser or at least one other narcotic 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-diallylbarbituric acid (allobarbital),

^llylprodine, alphaprodine, 8-chloro-1-methy!-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (alprazolam), 2-diethylaminopropiophenone (amfepramone), (±)-a-methylphenethylamine (amphetamine), 2-(a-methylphenethylamino)-2-phenylacetonitrile (amphetaminil), 5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine, apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine, bezitramide, 7-bromc~5-(2-pyridyl)-1 H-1,4-benzodiazepine-2(3H)-one (bromazepam), 2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-/I[1,2J4]triazolo[4,3-a][1,4]diazepine (brotizolam), 17-cyclopropylmethyl-4,5a-epoxy-7a[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-enc/o-ethanomorphinan-3-ol(buprenorphine), 5-butyl-5-ethylbarbtturic acid (butobarbital), butorphanol, (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl) dimethylcarbamate (camazepam), (1 S,2S)-2-amino-1-phenyl-1-propanol (cathine/D-norpseudoephedrine), 7-chloro-A/-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine 4-oxide (chlordiazepoxide), 7-chloro-1 -methyl-5-phenyi-1 H-1,5-benzodiazepine-2,4(3H,5H)-dione (clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one (clonazepam), clonitazene, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1 H-1,4-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-11b-(2-chlorophenyl)-2,3,7,11 b-tetrahydro-oxazolo[3,2-cG[1,4]benzodiazepin-6(5H)-one (cloxazolam), (->-IVIethyl-[3|3-benzoyloxy-2p(1aH,5aH)-tropane carboxylate] (cocaine), 4,5a-epoxy-3-methoxy-17-methyl-7-morphinan-6a-ol (codeine), 5-(1-cyclohexenyi)-5-ethyl barbituric acid (cyclobarbital), cyclorphan, cyprenorphine, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one (delorazepam), desomorphine, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate (dextropropoxyphene), dezocine, diampromide, diamorphone, 7-chloro-1-methyi-5-phenyl-1 H-1,4-benzodiazepin-2(3H)-one (diazepam), 4,5a-epoxy-3-methoxy-17-methyl-6a-morphinanol (dihydrocodeine), 4,5a-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, (eaR.lOa/1?)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-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-chIoro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate] (ethyl loflazepate), 4,5a-epoxy-3-ethoxy-17-methyl-7-morphinen-6a-ol (ethylmorphine), etonitazene, 4,5a-epoxy-7a-(1 -hydroxy-1 -methylbutyI)-6-methoxy-

17-methyl-6,14-endo-etheno-morphinan-3-ol (etorphine), A/-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (fencamfamine), 7-[2-(a-methylphenethylamino)ethyfj-theophylline) (fenethylline), 3-(a-methylphenethylamino)propionitrile (fenproporex), /V-(1-phenethyl-4-piperidyl)propionanilide (fentanyl), 7-chloro-5-(2-fluorophenyl)-1 -methyl-1H-1,4-benzodiazepin-2(3/Y)-one (fludiazepam), 5-(2-fluorophenyl)-1-methyl-7-nitro-1 H-1,4-benzodiazepin-2(3H)-one (flunitrazepam}, 7-chloro-1 -(2-diethylamino-ethyl)-5-(2-fluorophenyl)-1 H-1,4-benzodiazepin-2(3/V)-one (flurazepam), 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one (halazepam), 10-bromo-11 b-(2-fluorophenyl)-2,3,7,11 b-tetrahydro[1,3]oxazolo[3,2-d][1,4]benzo-diazepin-6(5/-/)-one (haloxazolam), heroin, 4,5a-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone), 4,5a-epoxy-3-hydroxy-17-methyI-6-morphinanone (hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan, 11-chloro-S.^b-dihydro^.S-dimethyl-^b-phenyMH-II.SJoxazinoIS^-dJII^Jbenzo-diazepine-4,7(6H)-dione (ketazolam), 1 -[4-(3-hydroxyphenyl)-1 -methyl-4-piperidyl]-1 -propanone (ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate (levacetylmethadol (LAAM)), (-)-6-dimethylamino-4,4-diphenol-3-heptanone (levomethadone), (-)-17-methyl-3-morphinanol (levorphanol), levophenacyl-morphane, lofentanil, 6-(2-chlorophenyl)-2-(4-methyl-1 -piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepin-1 (4H)-one (loprazolam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one (lorazepam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1 -methyl-1 H-1,4-benzodiazepin-2(3H>one (lormetazepam), 5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1 -a]isoindol-5-ol (mazindol), 7-chloro-2,3-dihydro-1 -methyl-5-phenyl-1 H-\ ,4-benzodiazepine (medazepam), A/-(3-chloropropyl)-a-methylphenethylamine (mefenorex), meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate), meptazinol, metazocine, methylmorphine, N,a-dimethylphenethylamine (methamphetamine), (±)-6-dimethyl-amino-4,4-diphenol-3-heptanone(methadone),2-methyl-3-o-tolyl-4(3Ay)-quinazolin-one (methaqualone), 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), metopon, 8-ch(oro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5a][1,4]benzodiazepine (midazolam), 2-(benzhydrylsulfinyl)acetamide (modafinil), 4,5a-epoxy-17-methyl-7-morphinen-3,6a-diol (morphine), myrophine, (±)-trans-3-C\, 1 -dimethylheptyl)-7,8,10,1 Oa-tetrahydro-1 -hydroxy-6,6-dimethyI-6H-dibenzo-[jb,c(]pyran-9(6aH)-one (nabilone), nalbuphene, nalorphine, narceine,

nicomorphine, 1 -methyl-7-nitro-5-phenyl-1 H-1,4-benzodiazepin-2(3H)-one (nimetazeparn), 7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam), 7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nordazepam), norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone(normethadone), normorphine, norpipanone, the exudation from plants belonging to the species Papaver somniferum (opium), 7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (oxazepam), (cis-trans)-! O-chloro-2,3,7,11 b-tetrahydro-2-methyl-11 b-phenyloxazolo-[3,2-c/][1,4jbenzodiazepin-6-(5H)-one (oxazolam), 4,5a-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone), oxymorphone, plants and parts of plants belonging to the species Papaver somniferum (including the subspecies setigerum) (Papaver somniferum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone (pernoline), 1,2,3,4,5,6-hexahydro-6, 11 -dirnethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol (pentazocine), 5-ethyl-5-(1-methylbutyl)-barbituric acid (pentobarbital), ethyl-(1 -methyl-4-phenyl-4-piperidinecarboxylate) (pethidine), phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine, pholcodine, 3-methyl-2-phenylmorpholine (phenmetrazine), 5-ethyl-5-phenylbarbituric acid (phenobarbital), a,a-dimethylphenethylamine (phentermine), 7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3H)-one (pinazepam), a-(2-piperidyl)-benzhydryl alcohol (pipradrol), 1'-(3-cyano-3,3-diphenylpropyl)[1,4'-bipiperidine]-4'-carboxamide (piritramide), 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1 H-1,4-benzodiazepin-2(3H)-one (prazepam), profadol, proheptazine, promedol, properidine, propoxyphene, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl {3-[4-methoxycarbonyl-4-(A/-phenylpropanamido)piperidino]propanoate}(remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbutabarbital), 5-allyl-5-(1-methylbutyl)-barbituric acid (secobarbital), A/-{4-methoxymethyl-1 -[2-(2-thienyl)ethy!]-4-piperidyl}propion-anilide (sufentanil), 7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (temazepam), 7-chloro-5-(1-cyclohexenyl)-1-methyl-1 W-1,4-benzodiazepin-2(3H)-one (tetrazepam), ethyl (2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine (cis and trans)), tramadol, 8-chloro-6-(2-chlorophenyl)-1-methyI-4H-[1,2,4]triazolo[4,3-a][;i ,4Jbenzodiazepine (triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital), (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (2R,3R)-1-

dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, preferably as racemate, 3-(2-dimethylaminomethyl-1 -hydroxy-cyclohexyl)phenyi 2-(4-isobutoxy-phenyl)-propionate, 3-(2-dtmethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)-propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)-propionate, 3-(2-dimethylaminomethyl-cyclohex-1 -enyl)-pheny!2-(6-methoxy-naphthalen-2-yl)-propionate, (RR-SS)-2-acetoxy-4-trifluoro-methyl-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-methyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyc[ohexyl)-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-dimethyl-aminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2',4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-dimethylaminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester together with corresponding stereoisomeric compounds, in each case the corresponding derivatives thereof, in particular amides, esters or ethers, and in each case the physiologically acceptable compounds thereof, in particular the salts and solvates thereof, particularly preferably hydrochlorides.
The dosage form according to the invention is particularly suitable for preventing abuse of an opioid active ingredient selected from among the group comprising oxycodone, hydromorphone, morphine, tramadol and the physiologically acceptable derivatives or compounds thereof, preferably the salts and solvates thereof, preferably the hydrochlorides or sulfates thereof or of methylphenidate or the salts, solvates or physiologically acceptable derivatives thereof.
The dosage form according to the invention is furthermore in particular suitable for preventing abuse of an opioid active ingredient selected from among the group comprising (1 R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propy!)phenol, (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methy!-pentan-3-ol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, (1 R,2R}-3-(2-dimethylaminonethyl-cyclohexyl)phenoi, the physiologically acceptable salts thereof,

preferably hydrochlorides, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, preferably ethers, esters or amides.
These compounds and the process for the production thereof are described in EP-A-693475 and EP-A-780369 respectively. The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure.
In order to achieve the necessary breaking strength of the dosage form according to the invention, at least one natural or synthetic polymer (C) with a breaking strength, measured using the method disclosed in the present application, of at least 500 N and optionally at least one wax (D) with a breaking strength of at least 500 N are used as the binder.
At least one polymer selected from the group comprising polyalkylene oxides, preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers thereof, and mixtures of at least two of the stated polymers is preferably used as the polymer (C).
High molecular weight, thermoplastic polyalkylene oxides are preferred. Particularly preferred are those high molecular weight polyethylene oxides with a molecular weight of at least 0.5 million, preferably of at least 1 million, particularly preferably of 1 to 15 million, very particularly preferably of at least 5 million, determined by rheological measurements. These polymers have a viscosity at 25°C of 4500 to 17600 cP, measured on a 5 wt.% aqueous solution using a model RVF Brookfield viscosimeter (spindle no. 2 / rotational speed 2 rpm), of 400 to 4000 cP, measured on a 2 wt.% aqueous solution using the stated viscosimeter (spindle no. 1 or 3 / rotational speed 10 rpm) or of 1650 to 10000 cP, measured on a 1 wt.% aqueous solution using the stated viscosimeter (spindle no. 2 / rotational speed 2 rpm).
The polymers are preferably used as a powder. They may be soluble in water.

In order to achieve the necessary breaking strength of the dosage form produced according to the invention, at least one natural, semi-synthetic or synthetic wax (D) with a breaking strength, measured using the method disclosed in the present application, of at least 500 N, may be used as an additional further binder. Waxes with a softening point of at least 60°C, preferably of at least 80°C, are preferred. Camauba wax and beeswax are particularly preferred. Carnauba wax is very particularly preferred. Carnauba wax is a natural wax which is obtained from the leaves of the carnauba palm and has a softening point of at least 80°C. When the wax component is additionally used, it is used together with at least one polymer (C) in quantities such that the dosage form produced according to the invention has a breaking strength of at least 500 N.
The binder component(s) are preferably used in a quantity of at least 20 wt.%, preferably at least 35 wt.%, particularly preferably of 50 to 99.9 wt.%, very particularly preferably of at least 60 wt.%, relative to the total weight the dosage form.
Auxiliary substances (B) may also be used in the process according to the invention. Auxiliary substances (B) which may be used are those known auxiliary substances which are conventional for the formulation of solid dosage forms. These are preferably plasticisers, such as polyethylene glycol, auxiliary substances which influence active ingredient release, preferably hydrophobic or hydrophilic, preferably hydrophilic polymers, very particularly preferably hydroxypropylmethylcellulose, and/or antioxidants. Suitable antioxidants are ascorbic acid, butylhydroxyanisole, butylhydroxytoluene, salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and the derivatives thereof, sodium bisulfite, particularly preferably butylhydroxytoluene (BHT) or butylhydroxyanisole (BHA) and ce-tocopherol.
The antioxidant is preferably used in quantities of 0.01 to 10 wt.%, preferably of 0.03 to 5 wt.%, relative to the total weight of the dosage form.
By using ultrasound in combination with the binder which has a breaking strength of £ 500 N, it is possible using the process according to the invention simply and reproducibly to achieve a breaking strength of the dosage from which is sufficiently

high considerably to complicate or to prevent pulverisation of the dosage form with conventional means and hence any subsequent abuse.
Using the process according to the invention, it is possible to obtain dosage forms in the form of tablets or in multiparticulate form, preferably as microtablets, micropellets, granules, microparticles, spheroids, beads or pellets, which are optionally press-moulded into tablets or packaged in capsules. The multiparticulate forms preferably have a size or size distribution in the range from 0.1 to 3 mm, particularly preferably in the range from 0.5 to 2 mm.
Oral dosage forms are preferably produced using the process according to the invention.
The method according to the invention is carried out by firstly producing a homogeneous mixture of at least one active ingredient with potential for abuse (A), at least one binder with the stated breaking strength and optionally at least one further abuse-preventing compound a) to f) listed below. Further auxiliary substances (B), such as for example fillers, plasticisers, agents to control release, antioxidants, slip agents or dyes may also be incorporated into this mixture.
Mixing may be performed with the assistance of conventional mixers. Roll mixers, shaking mixers, shear mixers or compulsory mixers are, for example, suitable.
The resultant powder mixture, after optional preforming, is exposed to ultrasound.
During ultrasonication, it is preferred for there to be direct contact between the mixture, which is preferably in a shaping die, and the sonotrode of the ultrasound device, i.e. the sonotrode touches the mixture. An ultrasound device as shown in Figure 1 is preferably used in the process according to the invention.
In this Figure 1, (1) denotes the press, with which the necessary force is applied, (2) the converter, (3) the booster, (4) the sonotrode, (5) the shaping die, (6) the bottom punch, (7) the base plate, (8) and (9) the ultrasound generator and device controller. The ultrasound device may comprise not only one shaping die and one bottom

punch, but instead more than one of these units, the sonotrode being divided into a corresponding number of top punches.
A frequency of 1 kHz to 2 MHz, preferably of 10 to 75 kHz, particularly preferably of 20 to 40 kHz, is maintained during ultrasonication. Ultrasonication should be performed until the binder has at least softened. This is preferably achieved within a few seconds, particularly preferably within at least 0.1 seconds, very particularly preferably within 0.1 to 5 seconds, in particular within 0.5 to 3 seconds.
For the purpose of ultrasonication, the mixture is placed in the shaping die and the sonotrode is brought into contact with the mixture.
The mixture is also subjected to shaping by application of force. The mixture is preferably shaped during or after ultrasonication.
If shaping proceeds in the above-described ultrasound device, this is achieved with the assistance of the shaping die, the bottom punch and the sonotrode. To this end, the sonotrode, with the assistance of the press (1), exerts the necessary force onto the mixture. In this manner, compaction of the mixture results in shaping, preferably to obtain the final shape. For this shaping, the shaping die, the bottom punch and the sonotrode acting as top punch are preferably adapted to the shape to be achieved, preferably the final shape, wherein the punch format and sonotrode format, i.e. the opposing end faces thereof, are complementary in form. The mixture is consolidated and shaped by force applied onto the mixture by the sonotrode.
The force exerted during shaping is preferably kept constant, while ultrasonication may also optionally be varied. This stepwise ultrasonication is preferably used when the highest possible energy input, e.g. for rapid plasticisation of the binder and to shorten the processing time, is desired at the beginning of ultrasonication, such that preferably as much as 30 to 60% of the total energy input is provided at the beginning, i.e. during the first stage of ultrasonication, by setting a higher ultrasound amplitude.

Ultrasonication and the application offeree ensure uniform energy transfer, so bringing about rapid and homogeneous sintering of the mixture. In this manner, dosage forms are obtained which have a breaking strength of > 500 N and thus cannot be comminuted using conventional means.
Before shaping is performed, the mixture may also be subjected to preforming by granulation and the resultant granules are shaped into the desired dosage form, such as tablets, by Ultrasonication and application offeree.
Granulation may be performed in machinery and apparatus known to the person skilled in the art.
If granulation is performed as wet granulation, water or aqueous solutions, such as for example ethanol/water or isopropanol/water, may be used as the granulation liquid.
The mixture or the granules preformed therefrom may also be subjected to melt extrusion for shaping, wherein the mixture is converted into a melt by Ultrasonication and application offeree and then extruded through dies. The sonotrode here assumes the function of introducing ultrasound and of applying force as a piston, as in a piston injection moulding machine. The strands or strand obtained in this manner may be singulated to the desired length with the assistance of known apparatus and furthermore optionally converted into the final shape by application offeree with further Ultrasonication.
The extrudates may also be shaped into the final shape by a calendering process between two contrarotating shaping rollers, preferably with application offeree.
It is, however, also possible for the mixtures or granules also to be preformed into extrudates, preferably using suitable injection moulds, with the assistance of a piston injection moulding machine, and then to be subjected to Ultrasonication and application of force.

As already mentioned, shaping into the final shape of the dosage form proceeds from a mixture, preferably in powder form, comprising at least the active ingredient with potential for abuse and at least one binder with a breaking strength of > 500 N, preferably by direct compression with application of force, wherein this mixture is exposed to ultrasound before or during the application offeree. The applied force may correspond to the force which is conventionally used for shaping, for example for moulding tablets or for press-moulding granules into the corresponding final shape.
According to the invention, a force of at least 50 N, preferably of at least 200 N, very particularly preferably of at least 500 N should be applied during application of force.
The necessary force may also be applied to the mixture with the assistance of rollers. However, shaping of the dosage forms preferably proceeds by direct press-moulding of a pulverulent mixture of the components of the dosage form or corresponding granules formed therefrom, wherein ultrasonication preferably proceeds during or before shaping. This ultrasonication proceeds until the binder is softened, which is conventionally achieved in less than 1 second to at most 5 seconds, and the mixture is compacted to such an extent that the dosage form has a breaking strength of at least 500 N.
It is also possible, after ultrasonication and preforming by application of force to the mixture, to carry out final shaping in a conventional tablet press. The tablets produced according to the invention may also take the form of multilayer tablets.
In multilayer tablets, at least the active ingredient-containing layer should be produced with ultrasonication and application of force.
The dosage forms obtained by the production process according to the invention are distinguished in that, due to their hardness, they cannot be pulverised with the assistance of conventional comminution means available to an abuser. This virtually rules out oral, parenteral, in particular intravenous, or nasal abuse. However, in order to prevent any possible abuse of the dosage forms obtained by the production process according to the invention in the event of comminution and/or pulverisation

which possibly occur nonetheless due to extraordinary force, in a preferred embodiment these dosage forms may contain further abuse-complicating or -preventing agents as auxiliary substances.
The dosage forms obtained by the production process according to the invention may thus additionally comprise, apart from one or more active ingredients with potential for abuse and at least one binder, at least one the following components (a) to (f) as auxiliary substances:
(a) at least one substance which irritates the nasal passages and/or pharynx,
(b) at least one viscosity-increasing agent, which, with the assistance of a
necessary minimum quantity of an aqueous liquid, forms a gel with the extract
obtained from the dosage form, which gel preferably remains visually
distinguishable when introduced into a further quantity of an aqueous liquid,
(c) at least one antagonist for each of the active ingredients with potential for
abuse,
(d) at least one emetic,
(e) at least one dye as an aversive agent,
and/or
(f) at least one bitter substance.
Components (a) to (f) are additionally each individually suitable for abuse-proofing the dosage forms obtained by the production process according to the invention. Accordingly, component (a) is preferably suitable for proofing the dosage form against nasal, oral and/or parenteral, preferably intravenous, abuse, component (b) is preferably suitable for proofing against parenteral, particularly preferably intravenous and/or nasal abuse, component (c) is preferably suitable for proofing against nasal and/or parenteral, particularly preferably intravenous, abuse, component (d) is

preferably suitable for proofing against parenteral, particularly preferably intravenous, and/or oral and/or nasal abuse, component (e) is suitable as a visual deterrent against oral or parenteral abuse and component (f) is suitable for proofing against oral or nasal abuse. Combined use according to the invention of at least one of the above-stated components makes it possible still more effectively to prevent abuse of dosage forms obtained by the production process according to the invention.
For example, the dosage form obtained by the process according to the invention may also comprise two or more of components (a)-(f) in a combination, preferably (a), (b) and optionally (c) and/or (f) and/or (e) or (a), (b) and optionally (d) and/or (f) and/or (e).
In another embodiment, the dosage form produced by the process according to the invention may comprise all of components (a)-(f).
If the dosage form obtained by the process according to the invention comprises an abuse-preventing component (a), substances which irritate the nasal passages and/or pharynx which may be considered according to the invention are any substances which, when administered abusively via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the abuser that he/she does not wish to or cannot continue administration, for example burning, or physiologically counteracts taking of the corresponding active ingredient, for example due to increased nasal secretion or sneezing. These substances which conventionally irritate the nasal passages and/or pharynx may also bring about a very unpleasant sensation or even unbearable pain when administered parenterally, in particular intravenously, such that the abuser does not wish to or cannot continue taking the substance.
Particularly suitable substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Appropriate substances and the quantities thereof which are conventionally to be used are known per se to the person skilled in the art or may be identified by simple preliminary testing.

The substance which irritates the nasal passages and/or pharynx of component (a) is preferably based on one or more constituents or one or more plant parts of at least one hot substance drug.
Corresponding hot substance drugs are known per se to the person skilled in the art and are described, for example, in "Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe" by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq.. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure.
One or more constituents of at least one hot substance drug selected from the group comprising Allii sativi bulbus (garlic), Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma (calamus root), Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma (Javanese turmeric root), Galangae rhizoma (galangal root), Myristicae semen (nutmeg), Piperis nigri fructus (pepper), Sinapis albae semen (white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root), particularly preferably from the group comprising Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper) and Piperis nigri fructus (pepper) may preferably be added as component (a) to the dosage form obtained by the process according to the invention.
The constituents of the hot substance drugs preferably comprise o-methoxy(methyl)-phenol compounds, acid amide compounds, mustard oils or sulfide compounds or compounds derived therefrom.
Particularly preferably, at least one constituent of the hot substance drugs is selected from the group consisting of myristicin, elemicin, isoeugenol, cc-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids, preferably capsaicin, capsaicin derivatives, such as N-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, norcapsaicin and nomorcapsaicin, piperine, preferably trans-piperine, glucosinolates, preferably based on non-volatile mustard oils, particularly preferably based on p-hydroxybenzy! mustard oil, methylmercapto mustard oil or methylsulfonyl mustard oil, and compounds derived from these constituents.

A dosage unit is taken to mean a separate or separable administration unit, such as for example a tablet or a capsule.
The dosage form obtained by the process according to the invention may preferably contain the plant parts of the corresponding hot substance drugs in a quantity of 0.01 to 30 wt.%, particularly preferably of 0.1 to 0.5 wt.%, in each case relative to the total weight of the dosage unit.
If one or more constituents of corresponding hot substance drugs are used, the quantity thereof in a dosage unit obtained by the process according to the invention preferably amounts to 0.001 to 0.005 wt.%, relative to the total weight of the dosage unit.
Another option for preventing abuse of the dosage forms obtained by the process according to the invention consists in adding at least one viscosity-increasing agent as a further abuse-preventing component (b) to the dosage form, which, with the assistance of a necessary minimum quantity of an aqueous liquid, forms a gel with the extract obtained from the dosage form, which gel is virtually impossible to administer safely and preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid.
For the purposes of the present invention, visually distinguishable means that the active ingredient-containing gel formed with the assistance of a necessary minimum quantity of aqueous liquid, when introduced, preferably with the assistance of a hypodermic needle, into a further quantity of aqueous liquid at 37°C, remains substantially insoluble and cohesive and cannot straightforwardly be dispersed in such a manner that it can safely be administered parenterally, in particular intravenously. The material preferably remains visually distinguishable for at least one minute, preferably for at least 10 minutes.
The increased viscosity of the extract makes it more difficult or even impossible for it to be passed through a needle or injected. If the gel remains visually distinguishable, this means that the gel obtained on introduction into a further quantity of aqueous

liquid, for example by injection into blood, initially remains in the form of a largely cohesive thread, which, while it may indeed be broken up mechanically into smaller fragments, cannot be dispersed or even dissolved in such a manner that it can safely be administered parenterally, in particular intravenously. In combination with at least one optionally present component (a) or (c) to (e), this additionally leads to unpleasant burning, vomiting, bad flavour and/or visual deterrence.
Intravenous administration of such a gel would therefore most probably result in serious damage to the health of the abuser.
In order to verify whether a viscosity-increasing agent is suitable as component (b) for use in the dosage form obtained by the production process according to the invention, the active ingredient is mixed with the viscosity-increasing agent and suspended in 10 ml of water at a temperature of 25°C. If this results in the formation of a gel which fulfils the above-stated conditions, the corresponding viscosity-increasing agent is suitable for preventing or averting abuse of the dosage forms obtained by the process according to the invention.
If component (b) is added to the dosage form obtained by the process according to the invention, one or more viscosity-increasing agents are used which are selected from the group consisting of microcrystalline cellulose with 11 wt.% carboxymethylcellulose sodium (Avicel® RC 591), carboxymethylcellulose sodium (Blanose®, CMC-Na C300P®, Frimulsion BLC-5®, Tylose C300 P®), polyacrylic acid (Carbopol® 980 NF, Carbopol® 981), locust bean flour (Cesagum® LA-200, Cesagum® LID/150, Cesagum® LN-1), pectins, preferably from citrus fruit or apples (Cesapectin® HM Medium Rapid Set), waxy maize starch (C*Gel 04201®), sodium alginate (Frimulsion ALG (E401)®), guar flour (Frimulsion BM®, Polygum 26/1-75®), iota carrageenan (Frimulsion D021®), karaya gum, gellan gum (Kelcogel F®, Kelcogel LT100®), galactomannan (Meyprogat 150®), tara stone flour (Polygum 43/1®), propylene glycol alginate (Protanal-Ester SD-LB®), sodium hyaiuronate, tragacanth, tara gum (Vidogum SP 200®), fermented polysaccharide welan gum (K1A96), xanthans such as xanthan gum (Xantural 180®). Xanthans are particularly preferred. The names stated in brackets are the trade names by which the materials are known commercially. In general, a quantity of 0.1 to 20 wt.%, particularly preferably of 0.1 to

15 wt.%, relative to the total weight of the dosage forms, of the stated viscosity-increasing agent(s) is sufficient to fulfil the above-stated conditions.
The component (b) viscosity-increasing agents, where provided, are preferably present in the dosage form obtained according to the invention in quantities of 1.5 mg per dosage unit, i.e. per administration unit.
!n a particularly preferred embodiment of the present invention, the viscosity-increasing agents used as component (b) are those which, on extraction from the dosage form with the necessary minimum quantity of aqueous liquid, form a gel which encloses air bubbles. The resultant gels are distinguished by a turbid appearance, which provides the potential abuser with an additional optical warning and discourages him/her from administering the gel parenterally.
The polymer (C) may optionally also serve as an additional viscosity-increasing agent which forms a gel with water.
It is also possible to formulate the viscosity-increasing agent and the other constituents in the dosage form obtained by the production process according to the invention in a mutually spatially separated arrangement.
In order to discourage and prevent abuse, the dosage form obtained by the process according to the invention may furthermore comprise component (c), namely one or more antagonists for the active ingredient or active ingredients with potential for abuse, wherein the antagonists are preferably spatially separated from the remaining constituents of the dosage form obtained by the process according to the invention and, when correctly used, do not exert any effect.
Suitable antagonists for preventing abuse of the active ingredients are known to the person skilled in the art and may be present in the dosage form obtained by the production process according to the invention as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof.

If the active ingredient present in the dosage form is an opioid, the antagonist used is preferably an antagonist selected from the group comprising naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphine or naluphine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate. The corresponding antagonists, where component (c) is provided, are preferably used in a quantity of > 1 mg, particularly preferably in a quantity of 3 to 100 mg, very particularly preferably in a quantity of 5 to 50 mg per dosage form, i.e. per administration unit.
If the dosage form obtained by the process according to the invention comprises a stimulant as active ingredient, the antagonist is preferably a neuroleptic, preferably at least one compound selected from the group comprising haloperidol, promethazine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopentixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, meiperone and bromperidol.
The dosage form obtained by the process according to the invention preferably comprises these antagonists in a conventional therapeutic dose known to the person skilled in the art, particularly preferably in a quantity of twice to three times the conventional dose per administration unit.
If, in order to discourage and prevent abuse of the dosage form obtained by the process according to the invention, component (d) is also used, at least one emetic is formulated such that it is present in a spatially separated arrangement from the other components and, when correctly used, cannot exert its effect in the body
Suitable emetics for preventing abuse of an active ingredient are known to the person skilled in the art and may also be used in the production according to the invention of the dosage forms as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof.

An emetic based on one or more constituents of ipecacuanha (ipecac) root, preferably based on the constituent emetine may preferably be present in the dosage form obtained by the process according to the invention, as is, for example, described in "Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe" by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, New York, 1982. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure.
The dosage form obtained by the process according to the invention may preferably comprise the emetic emetine as component (d), preferably in a quantity of > 3 mg , particularly preferably of > 10 mg and very particularly preferably in a quantity of > 20 mg per dosage form, i.e. administration unit.
Apomorphine may likewise preferably be used as an emetic for additional abuse-proofing, preferably in a quantity of preferably > 3 mg , particularly preferably of > 5 mg and very particularly preferably of > 7 mg per administration unit.
If the dosage form obtained by the process according to the invention contains component (e) as an additional abuse-preventing auxiliary substance, the use of such a dye brings about an intense coloration of a corresponding aqueous solution, in particular when the attempt is made to extract the active ingredient for parenteral, preferably intravenous administration, which coloration may act as a deterrent to the potential abuser. Oral abuse, which conventionally begins by means of aqueous extraction of the active ingredient, may also be prevented by this coloration. Suitable dyes and the quantities required for the necessary deterrence may be found in WO 03/015531, wherein the corresponding disclosure should be deemed to be part of the present disclosure and is hereby introduced as a reference.
If the dosage form obtained by the process according to the invention contains component (f) as a further abuse-preventing auxiliary substance, this addition of at least one bitter substance and the consequent impairment of the flavour of the dosage form additionally prevents oral and/or nasal abuse.

Suitable bitter substances and the quantities effective for use may be found in US-2003/0064099 A1, the corresponding disclosure of which should be deemed to be the disclosure of the present application and is hereby introduced as a reference. Suitable bitter substances are preferably aromatic oils, preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit aroma substances, preferably aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof, and/or denatonium benzoate (Bitrex®). Denatonium benzoate is particularly preferred.
In a further preferred embodiment, the dosage form obtained according to the invention not only assumes the form of a tablet or a capsule but is also in the form of an oral osmotic therapeutic system (OROS), preferably if at least one further abuse-preventing component (a)-(f) is also present.
If components (c) and/or (d) and/or (f) are present in the dosage form, care must be taken to ensure that they are formulated in such a manner or are present in such a low dose that, when correctly administered, the dosage form is able to bring about virtually no effect which impairs the patient or the efficacy of the active ingredient.
If the dosage form obtained according to the invention contains component (d) and/or (f), the dosage must be selected such that, when correctly orally administered, no negative effect is caused. If, however, the intended dosage is exceeded in the event of abuse, nausea or an inclination to vomit or a bad flavour are produced The particular quantity of component (d) and/or (f) which can still be tolerated by the patient in the event of correct oral administration may be determined by the person skilled in the art by simple preliminary testing.
If, however, irrespective of the fact that the further dosage form obtained according to the invention is virtually impossible to comminute, components (c) and/or (d) and/or (f) are used to protect the dosage form, these components should preferably be used at a dosage which is sufficiently high that, when abusively administered, they bring about an intense negative effect on the abuser. This is preferably achieved by spatial separation of at least the active ingredient or active ingredients from components (c) and/or (d) and/or (f), wherein the active ingredient or active ingredients is/are present in at least one subunit (X) and components (c) and/or (d) and/or (f) is/are present in

at least one subunit (Y), and wherein, when the dosage form is correctly administered, components (c), (d) and (f) do not exert their effect on taking and/or in the body and the remaining components of the formulation, in particular component (C) and optionally (D), are identical.
If the dosage form obtained according to the invention comprises at least 2 of components (c) and (d) or (f), these may each be present in the same or different subunits (Y). Preferably, when present, all the components (c) and (d) and (f) are present in one and the same subunit (Y).
For the purposes of the present invention, subunits are solid formulations, which in each case, apart from conventional auxiliary substances known to the person skilled in the art, contain the active ingredients), at least one polymer (C) and the optionally present component (D) and optionally at least one of the optionally present components (a) and/or (b) and/or (e) or in each case at least one polymer (C) and optionally (D) and the antagonist(s) and/or emetic(s) and/or component (e) and/or component (f) and optionally at least one of the optionally present components (a) and/or (b). Care must here be taken to ensure that each of the stated subunits is formulated in accordance with the above-stated process.
One substantial advantage of the separated formulation of active ingredients from components (c) or (d) or (f) in subunits (X) and (Y) of the dosage form obtained according to the invention is that, when correctly administered, components (c) and/or (d) and/or (f) are hardly released on taking and/or in the body or are only released in such small quantities that they exert no effect which impairs the patient or therapeutic success or, on passing through the patient's body, they are only liberated in locations where they cannot be sufficiently absorbed to be effective. When the dosage form is correctly administered, preferably hardly any of components (c) and/or (d) and/or (f) is released into the patient's body or they go unnoticed by the patient.
The person skilled in the art will understand that the above-stated conditions may vary as a function of the particular components (c), (d) and/or (f) used and of the formulation of the subunits or the dosage form. The optimum formulation for the

particular dosage form may be determined by simple preliminary testing. What is vital is that the particular subunits contain the binder component, i.e. the polymer (C) and optionally component (D), and have been formulated in the stated manner.
Should, contrary to expectations, the abuser succeed in comminuting such a dosage form obtained according to the invention, which comprises components (c) and/or (e) and/or (d) and/or (f) in subunits (Y), for the purpose of abusing the active ingredient and obtain a powder which is extracted with a suitable extracting agent, not only the active ingredient but also the particular component (c) and/or (e) and/or (f) and/or (d) will be obtained in a form in which it cannot readily be separated from the active ingredient, such that when the dosage form which has been tampered with is administered, in particular by oral and/or parenteral administration, it will exert its effect on taking and/or in the body combined with an additional negative effect on the abuser corresponding to component (c) and/or (d) and/or (f) or, when the attempt is made to extract the active ingredient, the coloration will act as a deterrent and so prevent abuse of the dosage form.
A dosage form, in which the active ingredient or active ingredients is/are spatially separated from components (c), (d) and/or (e), preferably by formulation in different subunits, may be formulated in many different ways, wherein the corresponding subunits may each be present in the dosage form according to the invention in any desired spatial arrangement relative to one another, provided that the above-stated conditions for the release of components (c) and/or (d) are fulfilled.
The person skilled in the art will understand that component(s) (a) and/or (b) which are optionally also present may preferably be formulated in the dosage form obtained according to the invention both in the particular subunits (X) and (Y) and in the form of independent subunits corresponding to subunits (X) and (Y), provided that neither the abuse-proofing nor the active ingredient release in the event of correct administration is impaired by the nature of the formulation and the polymer (C) and optionally (D) is preferably included in the formulation and formulation is carried out in accordance with the above-stated process according to the invention in order to achieve the necessary hardness.

In a preferred embodiment of the dosage form obtained according to the invention, subunits (X) and (Y) are present in rnultiparticulate form, wherein microtablets, microcapsules, micropellets, granules, spheroids, beads or pellets are preferred and the same form, i.e. shape, is selected for both subunit (X) and subunit (Y), such that it is not possible to separate subunits (X) from (Y), for example by mechanical selection. The rnultiparticulate forms are preferably of a size in the range from 0.1 to 3 mm, preferably of 0.5 to 2 mm.
The subunits (X) and (Y) in rnultiparticulate form may also preferably be packaged in a capsule or be press-moulded into a tablet, wherein the final formulation in each case proceeds in such a manner that the subunits (X) and (Y) are also retained in the resultant dosage form.
The rnultiparticulate subunits (X) and (Y) of identical shape should also not be visually distinguishable from one another so that the abuser cannot separate them from one another by simple sorting. This may, for example, be achieved by the application of identical coatings which, apart from this disguising function, may also incorporate further functions, such as, for example, delayed release of one or more active ingredients or provision of a finish resistant to gastric juices on the particular subunits.
The rnultiparticulate subunits may also be formulated as an oral dosage form as a slurry or suspension in pharmaceutically safe suspending media.
In a further preferred embodiment of the present invention, subunits (X) and (Y) are produced such that they are in each case arranged in layers relative to one another.
The layered subunits (X) and (Y) are preferably arranged for this purpose vertically or horizontally relative to one another, wherein in each case one or more layered subunits (X) and one or more layered subunits (Y) may be present in the dosage form, such that, apart from the preferred layer sequences (X)-(Y) or (X)-(Y)-(X), any desired other layer sequences may be considered, optionally in combination with layers containing components (a) and/or (b).

Another preferred dosage form produced by the process according to the invention is one in which subunit (Y) forms a core which is completely enclosed by subunit (X), wherein a separation layer (Z) may be present between said layers. Such a structure is preferably also suitable for the above-stated multiparticulate forms, wherein both subunits (X) and (Y) and an optionally present separation layer (Z) must satisfy the hardness requirement according to the invention and are formulated in one and the same multiparticulate form. In a further preferred embodiment of the process according to the invention, the subunit (X) forms a core, which is enclosed by subunit (Y), wherein the latter comprises at least one channel which leads from the core to the surface of the dosage form.
The dosage form formulated according to the invention may comprise, between one layer of the subunit (X) and one layer of the subunit (Y), in each case one or more, preferably one, optionally swellable separation layer (Z) which serves to separate subunit (X) spatially from (Y).
If the dosage form formulated according to the invention comprises the layered subunits (X) and (Y) and an optionally present separation layer (Z) in an at least partially vertical or horizontal arrangement, the dosage form preferably takes the form of a tablet or a laminate.
In one particularly preferred embodiment, the entirety of the free surface of subunit (Y) and optionally at least part of the free surface of subunit(s) (X) and optionally at least part of the free surface of the optionally present separation layer(s) (Z) may be coated with at least one barrier layer (Z) which prevents release of component (c) and/or (e) and/or (d) and/or (f). The barrier layer (Z1) must also be formulated and produced in such a manner that it fulfils the hardness requirements according to the invention.
Another particularly preferred embodiment of the dosage form produced according to the invention comprises a vertical or horizontal arrangement of the layers of subunits (X) and (Y) and at least one push layer (p) arranged therebetween, and optionally a separation layer (Z), in which dosage form the entirety of the free surface of the layer structure consisting of subunits (X) and (Y), the push layer and the optionally present

separation layer (Z) is provided with a semtpermeable coating, which is permeable to a release medium, i.e. conventionally a physiological liquid, but substantially impermeable to the active ingredient and to component (c) and/or (d) and/or (f), and wherein this coating comprises at least one opening for release of the active ingredient in the area of subunit (X).
A corresponding dosage form is known to the person skilled in the art, for example under the name oral osmotic therapeutic system (OROS), as are suitable materials and processes for the production thereof, inter alia from US 4,612,008, US 4,765,989 and US 4,783,337. The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure. What is vital is that these systems are adapted according to the invention during the production thereof such that they give rise to a breaking strength of > 500 N.
In a further preferred embodiment, the subunit (X) of the dosage form produced according to the invention is in the form of a tablet, the edge face and optionally one of the two main faces of which is covered with a barrier layer (Zf) containing component (c) and/or (d) and/or (f).
The person skilled in the art will understand that the auxiliary substances of the subunit(s) (X) or (Y) and of the optionally present separation layer(s) (Z) and/or of the barrier layer(s) (Z1) used in formulating the dosage form according to the invention will vary as a function of the arrangement thereof in the dosage form according to the invention, the mode of administration and as a function of the particular active ingredient of the optionally present components (a) and/or (b) and/or (e) and of component (c) and/or (d) and/or (f). The materials which have the requisite properties are in each case known per se to the person skilled in the art.
If release of component (c) and/or (d) and/or (f) from subunit (Y) of the dosage form according to the invention is prevented with the assistance of a cover, preferably a barrier layer, the subunit may consist of conventional materials known to the person skilled in the art, providing that it contains at least one polymer (C) and optionally (D) to achieve the necessary breaking strength of the dosage form produced according to the invention.

If a corresponding barrier layer (Z1) is not provided to prevent release of component
(c) and/or (d) and/or (f), the materials of the subunits should be selected such that
re|ease of the particular component (c) and/or (d) from subunit (Y) is virtually ruled
out.
The materials which are stated below to be suitable for production of the barrier layer
may preferably be used for this purpose.
Preferred materials are those which are selected from the group comprising alkylcelluloses, hydroxyalkylcelluloses, glucans, scleroglucans, mannans, xanthans, copolymers of poly[bis(p-carboxyphenoxy)propane and sebacic acid, preferably in a molar ratio of 20:80 (commercially available under the name Polifeprosan 20®), carboxymethylcelluloses, cellulose ethers, cellulose esters, nitrocelluloses, polymers based on (meth)acrylic acid and the esters thereof, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, halogenated polyvinyls, polyglycolides, polysiloxanes and polyurethanes and the copolymers thereof.
Particularly suitable materials may be selected from the group comprising methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylceflulose, cellulose acetate, cellulose propionate (of low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethylcellulose, cellulose triacetate, sodium cellulose sulfate, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate, polyoctadecyl acrylate, polyethylene, low density polyethylene, high density polyethylene, polypropylene, polyethylene glycol, polyethylene oxide, polyethylene terephthalate, polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate and polyvinyl chloride.
Particularly suitable copolymers may be selected from the group comprising copolymers of butyl methacrylate and isobutyl methacrylate, copolymers of methyl

vinyl ether and maleic acid of high molecular weight, copolymers of methyl vinyl ether and maleic acid monoethyl ester, copolymers of methyl vinyl ether and maleic anhydride and copolymers of vinyl alcohol and vinyl acetate.
Further materials which are particularly suitable for formulating the barrier layer are starch-filled polycaprolactone (WO98/20073), aliphatic polyesteramides (DE 19 753 534 A1, DE 19 800 698 A1, EP 0 820 698 A1), aliphatic and aromatic polyester urethanes (DE 19822979), polyhydroxyalkanoates, in particular polyhydroxybutyrates, polyhydroxyvalerates, casein (DE 4 309 528), polylactides and copolylactides (EP 0 980 894 A1). The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure.
The above-stated materials may optionally be blended with further conventional auxiliary substances known to the person skilled in the art, preferably selected from the group comprising glyceryl monostearate, semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone, gelatine, magnesium stearate, stearic acid, sodium stearate, talcum, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols and the derivatives thereof.
If the dosage form obtained according to the invention comprises a separation layer (Z1), said layer, like the uncovered subunit (Y), may preferably consist of the above-stated materials described for the barrier layer. The person skilled in the art will understand that release of the active ingredient or of component (c) and/or (d) from the particular subunit may be controlled by the thickness of the separation layer.
The dosage form obtained according to the invention exhibits controlled release of the active ingredient. It is preferably suitable for twice daily administration to patients.
The dosage form produced according to the invention may comprise one or more active ingredients with potential for abuse at least partially in a further delayed-release form, wherein delayed release may be achieved with the assistance of conventional materials and methods known to the person skilled in the art, for

example by embedding the active ingredient in a delayed-release matrix or by the application of one or more delayed-release coatings. Active ingredient release must, however, be controlled such that the above-stated conditions are fulfilled in each case, for example that, in the event of correct administration of the dosage form, the active ingredient or active ingredients are virtually completely released before the optionally present component (c) and/or (d) can exert an impairing effect. Addition of materials effecting controlled release must moreover not impair the necessary breaking strength.
Controlled release from the dosage form obtained according to the invention may preferably be achieved by embedding the active ingredient in a matrix. The auxiliary substances acting as matrix materials control active ingredient release. Matrix materials may, for example, be hydrophilic materials, from which active ingredient release proceeds mainly by diffusion, or hydrophobic materials, from which active ingredient release proceeds mainly by diffusion from the pores in the matrix.
Physiologically acceptable, hydrophobic materials which are known to the person skilled in the art may be used as matrix materials. Hydrophilic polymers, particularly preferably cellulose ethers, cellulose esters and/or acrylic resins are preferably used as hydrophilic matrix materials. Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivatives thereof, such as the salts, amides or esters thereof are very particularly preferably used as matrix materials.
Matrix materials prepared from hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof are also preferred. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.
It is also possible to use mixtures of the above-stated hydrophilic and hydrophobic materials as matrix materials.

The binder component, i.e. component (C) and the optionally present component (D), which serve to achieve the breaking strength of at least 500 N which is necessary according to the invention, may furthermore themselves serve as additional matrix materials.
If the dosage form obtained according to the invention is intended for oral administration, it may also preferably comprise a coating which is resistant to gastric juices and dissolves as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the dosage form according to the invention passes through the stomach undissolved and the active ingredient is only released in the intestines. The coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5.
Corresponding materials and methods for the controlled release of active ingredients and for the application of coatings which are resistant to gastric juices are known to the person skilled in the art, for example from "Coated Pharmaceutical Dosage Forms - Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials" by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure.
Method for determining breaking strength
In order to verify whether a polymer may be used as a binder, i.e. component (C) or (D), the polymer is pressed to form a tablet with a diameter of 10 mm and a height of 5 mm using a force of 150 N at a temperature which at least corresponds to the softening point of the polymer and is determined with the assistance of a DSC diagram of the material. Using tablets produced in this manner, breaking strength is determined with the apparatus described below in accordance with the method for determining the breaking strength of tablets published in the European Pharmacopoeia 1997, page 143,144, method no. 2.9.8.

The apparatus used for the measurement is a "Zwick Z 2.5" materials tester, Fmax = 2.5 kN with a maximum draw of 1150 mm, which should be set up with one column and one spindle, a clearance behind of 100 mm and a test speed adjustable between 0.1 and 800 mm/min together with testControl software. Measurement is performed using a pressure piston with screw-in inserts and a cylinder (diam. 10 mm), a force transducer, Fmax. 1 kN, diameter = 8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M to DIN 55350-18 (Zwick gross force Fmax = 1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany) with order no. BTC-FR 2.5 TH. D09 for the tester, order no. BTC-LC 0050N. P01 for the force transducer, order no. BO 70000 S06 for the centring device.
Figure 2 shows the measurement of the breaking strength of a tablet, in particular the tablet (4') adjustment device (61) used for this purpose before and during the measurement. To this end, the tablet (4') is held between the upper pressure plate (1') and the lower pressure plate (31) of the force application apparatus (not shown) with the assistance of two 2-part clamping devices (21), which are in each case firmly fastened (not shown) with the upper and lower pressure plate once the spacing (51) necessary for accommodating and centring the tablet to be measured has been established. The spacing (51) may be established by moving the 2-part clamping devices horizontally outwards or inwards in each case on the pressure plate on which they are mounted.
The tablets deemed to be resistant to breaking under a specific load include not only those which have not broken but also those which may have suffered plastic deformation under the action of the force.
The breaking strength of the dosage forms obtained according to the invention is determined by the stated measurement method, wherein dosage forms other than tablets are also tested.
The invention is explained below with reference to Examples. These explanations are given merely by way of example and do not restrict the general concept of the invention.

Example 1

(Table Remove)

Tramadol hydrochloride and polyethylene oxide powder were mixed in a free-fall mixer. The mixture was then pressed into tablets with ultrasonication and application of the force stated below. The following machine was used for this purpose:
Press: Branson WPS, 94-003-A, pneumatic (Branson Ultraschall, Dietzenbach,
Germany)
Generator (2000 W): Branson PG-220A, 94-001-A analogue (Branson Ultraschall)
The diameter of the sonotrode was 12 mm. The press surface was flat.
The mixture was placed in a shaping die with a diameter of 12 mm. The bottom of the shaping die forms a bottom punch with a planar press surface 12 mm in diameter.
The following parameters were selected for plasticisation of the mixture:
Frequency: 20 Hz
Amplitude: 50%
Force: 250 N
Ultrasonication and application offeree lasted 0.5 seconds, with ultrasonication and
application offeree proceeding simultaneously with the assistance of the sonotrode.
The breaking strength of the tablets is determined with the stated apparatus in accordance with the stated method. No breakage occurred when a force of 500 N

was applied. The tablet could not be comminuted using a hammer, nor with the assistance of a pestle and mortar.
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus with sinker in accordance with Pharm. Eur.. The temperature of the release medium was 37°C and the rotational speed of the stirrer 75 min"1. The release medium used was 600 ml of intestinal juice, pH 6.8. The quantity of active ingredient released in each case into the medium at any one time was determined by spectrophotometry.

(Table Remove)
Example 2

(Table Remove)

Tramadol hydrochloride and polyethylene oxide powder were mixed as a powder in a free-fall mixer. Then, as described in Example 1, the mixture was press-moulded into tablets with ultrasonication and application offeree. The following machine was used for this purpose:

Press: Branson 2000 aemc (Branson Ultraschal!, Dietzenbach, Germany) Generator (2000 W): Branson 2000 b, digital 20:2.2 (Branson Ultraschail)
The diameter of the sonotrode was 10 mm with a concave radius of curvature of 8 mm.
The following parameters were selected in order to plasticise and compact the mixture in 3 stages:
1st stage:
Amplitude level 75% for 0.15 sec
Frequency: 20 Hz
Force: 970 N
2nd stage:
Amplitude level 32.5% for 0.55 sec
Frequency: 20 Hz
Force: 970 N
3rd stage:
Force: 970 N for 2.3 sec
No ultrasonication
The breaking strength of the tablets is determined with the stated apparatus in accordance with the stated method. No breakage occurred when a force of 500 N was applied. The tablet could not be comminuted using a hammer, nor with the assistance of a pestle and mortar.
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus with sinker in accordance with Pharm. Eur.. The temperature of the release medium was 37°C and the rotational speed of the stirrer 75 min"1. The release medium used was 600 ml of intestinal juice, pH 6.8. The quantity of active ingredient released in each case into the medium at any one time was determined by spectrophotometry.

(Table Remove)

WE CLAIM
1. A process for the production of an abuse-proofed solid dosage form containing at least one active ingredient with potential for abuse (A) and at least one binder, which is present at least 20 wt. % relative to the total weight of the dosage form, and has a breaking strength of greater than or equal to 500 N characterized in that a mixture comprising the active ingredient of the kind such as hereinbefore described, the binder of the kind such as hereinbefore described and optionally an auxiliary substance which is conventional for formulation of solid dosage forms, is exposed to ultrasound and force wherein the said dosage form as such exhibits a breaking strength of at least 500 N.
2. A process as claimed in claim 1, wherein the dosage form is an oral dosage form, preferably a tablet.
3. A process as claimed in claim 1, wherein the dosage form is produced in multiparticulate form, preferably as microtablets, micropellets, granules, microparticles, spheroids, beads or pellets, which are optionally press-moulded into tablets or packaged in capsules.
4. A process according to any one of claims 1 to 3, wherein the binder which is used is at least one synthetic or natural polymer (C) and optionally at least one wax (®), in each case with a breaking strength of at least 500 N.
5. A process according to any one of claims 1 to 4, wherein the polymer (C) used is at least one polymer selected from the group consisting of polyethylene oxide, polymethylene oxide, polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers thereof and mixtures thereof, preferably polyethylene oxide.
6. A process according to any one of claims 1 to 5, wherein the polyethylene oxide (C) has a molecular weight of at least 0.5 million.

7. A process as claimed in claim 6, wherein the molecular weight of the polyethylene oxide (C) is at least 1 million, preferably 1-15 million, particularly preferably at least 5 million.
8. A process according to any one of claims 4 to 7, wherein the wax (®) used is at least one natural, semi synthetic or synthetic wax with a softening point of at least 60°C, preferably of at least 80°C.
9. A process as claimed in claim 8, wherein the wax (®) used is carnauba wax or beeswax.
10. A process as claimed in claim 1, wherein the binder component(s) is/are used in a quantity of at least 20 wt.%, preferably of at least 35 wt.%, particularly preferably of 50 to 99.9% wt.%, relative to the total weight of the dosage form.
11. A process as claimed in claim 10, wherein the binder component(s) is/are used in a quantity of at least 60 wt.%, relative to the total weight of the dosage form.
12. A process as claimed in any one of claims 1 to 11, wherein the active ingredient (A) used is at least one active ingredient selectee from among the group comprising opioids, tranquillisers, stimulants, barbiturates, further narcotics and the physiologically acceptable derivatives thereof.
13. A process as claimed in claim 12, wherein the physiologically acceptable derivatives used are salts, solvates, esters, ethers or amides.
14. A process as claimed in claim 12 or claim 13, wherein the active ingredient with potential for abuse (A) which is used is oxycodone, morphine, hydromorphone, tramadol, methylphenidate or the physiologically acceptable7 salts thereof, preferably hydrochlorides.

15. A process as claimed in claim 1, wherein the auxiliary substances (B) which are also used are plasticisers, preferably a low molecular weight polyethylene glycol, antioxidants and/or hydrophilic polymers and/or hydrophobic polymers.
16. A process according to any one of claims 1 to 15, wherein the ultrasound is applied at a frequency of 1 kHz to 2 MHz, preferably of 10 to 75 kHz.
17. A process as claimed in claim 16, wherein the ultrasound is applied at a frequency of 20 to 40 kHz.
18. A process according to any one of claims 1 to 17, wherein there is direct contact between the mixture and the sonotrode of the ultrasound device during ultrasonication.
19. A process as claimed in claim 18, wherein the sonotrode touches the mixture.
20. A process according to any one of claims 1 to 19, wherein ultrasound is applied until the binder has at least softened.
21. A process according to any one of claims 1 to 20, wherein application of force pnto the mixture proceeds by compacting the mixture during Or after ultrasonication.
22. A process as claimed in claim 21, wherein, during compaction of the mixture, a force is applied until the dosage form exhibits a breaking strength of at least 500 N.
23. A process according to any one of claims 1 to 22, wherein the mixture is shaped by the compaction.
24. A process as claimed in claim 23, wherein shaping of the mixture proceeds with the assistance of a shaping die and punch, by extrusion and with the assistance of rollers and/or calendering.

25. A process according to any one of claims 1 to 24, wherein compaction is performed with the assistance of the sonotrode as the punch.
26. A process according to any one of claims 1 to 25, wherein the mixture optionally comprises at least one of the following components a) to f):

(a) at least one substance which irritates the nasal passages and/or pharynx,
(b) at least one viscosity-increasing agent, which, with the assistance of a necessary minimum quantity of an aqueous liquid, preferably as an aqueous extract obtained from the dosage form, forms a gel which preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid,
(c) at least one antagonist for the active ingredient or active ingredients with potential for abuse,
(d) at least one emetic,
(e) at least one dye as an aversive agent,
(f) at least one bitter substance.

Documents:

6286-delnp-2006- abstract.pdf

6286-delnp-2006- claims.pdf

6286-delnp-2006- description (complete).pdf

6286-delnp-2006- drawings.pdf

6286-delnp-2006- form-2.pdf

6286-delnp-2006- form-5.pdf

6286-delnp-2006- pct- search report.pdf

6286-DELNP-2006-Abstract-(20-06-2012).pdf

6286-delnp-2006-Assignment-(20-06-2013).pdf

6286-DELNP-2006-Claims-(20-06-2012).pdf

6286-DELNP-2006-Correspondence Others-(20-06-2012).pdf

6286-delnp-2006-Correspondence-Others-(20-06-2013).pdf

6286-delnp-2006-correspondence-others.pdf

6286-DELNP-2006-Form-1-(20-06-2012).pdf

6286-delnp-2006-Form-1-(20-06-2013).pdf

6286-delnp-2006-form-1.pdf

6286-DELNP-2006-Form-13 (19-06-2012).pdf

6286-delnp-2006-Form-13-(20-06-2013).pdf

6286-DELNP-2006-Form-2-(20-06-2012).pdf

6286-DELNP-2006-Form-3-(20-06-2012).pdf

6286-delnp-2006-form-3.pdf

6286-delnp-2006-Form-5-(20-06-2013).pdf

6286-DELNP-2006-GPA-(20-06-2012).pdf

6286-delnp-2006-gpa.pdf

6286-delnp-2006-pct-304.pdf

6286-DELNP-2006-Petition-137-(20-06-2012).pdf

6286-DELNP-2006Abstract221014.pdf

6286-DELNP-2006Claims221014.pdf

6286-delnp-2006correspondence-others (31-01-2008).pdf

6286-DELNP-2006Correspondence221014.pdf

6286-DELNP-2006Form 3221014.pdf

6286-delnp-2006form-18 (31-01-2008).pdf

6286-DELNP-2006OTHERS221014.pdf

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Patent Number

265327

Indian Patent Application Number

6286/DELNP/2006

PG Journal Number

08/2015

Publication Date

20-Feb-2015

Grant Date

19-Feb-2015

Date of Filing

26-Oct-2006

Name of Patentee

GRUNENTHAL GMBH

Applicant Address

ZIEGLERSTR 6,D-52078 AACHEN GERMANY

Inventors:

#	Inventor's Name	Inventor's Address
1	ELISABETH ARKENAU	STADTWALDGURTEL 50, D-50931 KOLIN, GERMANY,
2	JOHANNES BARTHOLOMAUS	OF BURGHOHENWEG 5,52080 AACHEN GERMANY

PCT International Classification Number

A61K 31/485

PCT International Application Number

PCT/EP2005/004225

PCT International Filing date

2005-04-20

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10/890,703	2004-04-14	Germany
2	10 2004 020 220.6	2004-04-22	Germany