111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20050031546Al
`
`(19) United States
`(12) Patent Application Publication
`Bartholomaus et al.
`
`(10) Pub. No.: US 2005/0031546 A1
`Feb. 10, 2005
`(43) Pub. Date:
`
`(54) ABUSE-PROFFED DOSAGE FORM
`
`(30)
`
`Foreign Application Priority Data
`
`(76)
`
`Inventors: Johannes Bartholomaus, Aachen (DE);
`Heinrich Kugelmann, Aachen (DE)
`
`Correspondence Address:
`PERMAN & GREEN
`425 POST ROAD
`FAIRFIELD, CT 06824 (US)
`
`(21)
`
`Appl. No.:
`
`10/718,112
`
`(22)
`
`Filed:
`
`Nov. 20, 2003
`
`Aug. 6, 2003
`
`(DE) ..................................... 103 36 400.5
`
`Publication Classification
`
`(51)
`Int. CI? ............................. A61K 49/00; A61K 9/14
`(52) U.S. Cl. ........................................... 424/10.1; 424/486
`
`ABSTRACT
`(57)
`The present invention relates to an abuse-proofed, thermo-
`formed dosage form containing, in addition to one or more
`active ingredients with abuse potential optionally together
`with physiologically acceptable auxiliary substances, at least
`one synthetic or natural polymer with a breaking strength of
`at least 500 N and to a process for the production thereof.
`
`KASHIV1024
`IPR of Patent No. 9,492,392
`
`

`

`US 2005/0031546 A1
`
`1
`
`Feb. 10,2005
`
`ABUSE-PROFFED DOSAGE FORM
`[0001] The present invention relates to an abuse-proofed,
`thermoformed dosage form containing, in addition to one or
`more active ingredients with abuse potential (A) optionally
`together with physiologically acceptable auxiliary sub-
`stances (B), at least one synthetic or natural polymer (C) and
`optionally at least one wax (D), wherein component (C)
`exhibits a breaking strength of at least 500 N, and to a
`process for the production of the dosage form according to
`the invention.
`[0002] Many pharmaceutical active ingredients, in addi-
`tion to having excellent activity in their appropriate appli-
`cation, also have abuse potential, 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
`[0003]
`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, option-
`ally after being filtered through cotton wool or cellulose
`wadding, is administered parenterally, in particular intrave-
`nously. An additional phenomenon of this kind of adminis-
`tration, 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 controlled-release
`dosage forms containing active ingredients with abuse
`potential 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.
`[0004] U.S. Pat. No. 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.
`[0005] 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 abuse poten-
`tial and at least one gel former, each in different layers.
`[0006] 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.
`[0007] Another known option for complicating abuse
`involves adding antagonists to the active ingredients to the
`dosage form, for example naloxone or naltexone in the case
`of opiates, or compounds which cause a physiological
`defence response, such as for example Radix ipecacuanha=
`ipecac root.
`[0008] However, since in most cases of abuse it is still
`necessary to pulverise the dosage form comprising an active
`ingredient suitable for abuse, it was the object of the present
`invention to complicate or prevent the pulverisation preced-
`
`ing abuse of the dosage form comprising the agents con-
`ventionally available for potential abuse and accordingly to
`provide a dosage form for active ingredients with abuse
`potential which ensures the desired therapeutic effect when
`correctly administered, but from which the active ingredi-
`ents cannot be converted into a form suitable for abuse
`simply by pulverisation.
`[0009] Said object has been achieved by the provision of
`the abuse-proofed, thermoformed dosage form according to
`the invention which contains, in addition to one or more
`active ingredients with abuse potential (A), at least one
`synthetic or natural polymer (C) and optionally at least one
`wax (D), wherein component (C) exhibits a breaking
`strength of at least 500 N.
`[0010] The use of polymers having the stated minimum
`breaking strength, preferably in quantities such that the
`dosage form also exhibits such a minimum breaking
`strength, means that pulverisation of the dosage form is
`considerably more difficult using conventional means, so
`considerably complicating or preventing the subsequent
`abuse.
`If comminution is inadequate, parenteral, in par-
`[0011]
`ticular 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 taken
`orally, as release is not spontaneous.
`[0012] According to the invention, comminution is taken
`to mean pulverisation of the dosage form with conventional
`means which are available to an abuser, such as for example
`a mortar and pestle, a hammer, a mallet or other usual means
`for pulverisation by application of force.
`[0013] The dosage form according to the invention is thus
`suitable for preventing parenteral, nasal and/or oral abuse of
`pharmaceutical active ingredients with abuse potential.
`ingredients with abuse
`[0014] Pharmaceutical active
`potential are known to the person skilled in the art, as are the
`quantities thereof to be used and processes for the produc-
`tion thereof, and may be present in the dosage form accord-
`ing to the invention as such, in the form of the corresponding
`derivatives thereof, 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, as racemates or stereoisomers. The dosage form
`according to the invention is also suitable for the adminis-
`tration of several active ingredients. It is preferably used to
`administer a specific active ingredient.
`[0015] The dosage form according to the invention is in
`particular suitable for preventing abuse of a pharmaceutical
`active ingredient selected from the group consisting of
`opiates, opioids, tranquillisers, preferably benzodiazepines,
`barbiturates, stimulants and other narcotics.
`[0016] The dosage form according to the invention is very
`particularly suitable for preventing abuse of an opiate,
`opioid, tranquilliser or another narcotic selected from the
`group consisting of N-{ 1-[2-( 4-ethyl-5-oxo-2-tetrazolin-1-
`y l)ethy 1 ]-4-methoxymethy 1-4-piperidy 1} propionanilide
`(alfentanil), 5,5-diallylbarbituric acid (allobarbital), allyl-
`prodine, alphaprodine, 8-chloro-1-methyl-6-phenyl-4H-[1,
`2,4 ]triazolo[ 4,3-a ][1,4 ]-benzodiazepine ( alprazolam), 2-di-
`ethylaminopropiophenone ( amfepramone ), (±)-a-methyl-
`
`KASHIV1024
`IPR of Patent No. 9,492,392
`
`

`

`US 2005/0031546 Al
`
`2
`
`Feb. 10,2005
`
`2-a-
`
`(amphetamine),
`phenethylamine
`methy lphenethylamino )-2-pheny lace to nitrile
`(amphetaminil), 5-ethyl-5-isopentylbarbituric acid (amobar-
`bital), anileridine, apocodeine, 5,5-diethylbarbituric acid
`(barbital), benzylmorphine, bezitramide, 7-bromo-5-(2-py-
`ridyl)-1H -1,4-benzodiazepine-2(3H)-one
`(bromazepam ),
`2-bromo-4-(2-chlorophenyl)-9-methyl-6H -thieno[3,2-f][ 1,
`2,4 ]triazolo-[ 4,3-a ][1,4 ]diazepine (brotizolam), 17-cyclo-
`propylmethyl-4,5a-epoxy-7a[ (S)-1-hydroxy-1,2,2-trim-
`ethy 1-propy 1 ]-6-methoxy -6, 14-endo-ethanomorphinane-3-
`ol
`(buprenorphine ),
`5-butyl-5-ethylbarbituric
`acid
`(butobarbital), butorphanol, (7 -chloro-1,3-dihydro-1-me-
`thy 1-2-oxo-5-pheny 1-2H -1 ,4-benzodiazepine-3-yl)-dimeth-
`ylcarbamate
`(camazepam),
`(1S,2S)-2-amino-1-phenyl-1-
`propanol
`( cathine/D-norpseudoephedrine ),
`7 -chloro-N-
`methyl-5-phenyl-3H-1,4-benzodiazepine-2-ylamine-4-
`oxide
`( chlorodiazepoxide ), 7-chloro-1-methyl-5-phenyl-
`1H-1,5-benzodiazepine-2,4(3H,5H)-dione ( clobazam), 5-(2-
`chlorophenyl)-7 -nitro-1H -1,4-benzodiazepine-2(3H)-one
`( clonazepam), clonitazene, 7 -chloro-2,3-dihydro-2-oxo-5-
`phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ( cloraze-
`pate ), 5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-
`e ][1,4]diazepine-2(3H)-one ( clotiazepam), 10-chloro-llb-
`(2-chloropheny 1)-2,3, 7 ,11b-tetrahydrooxazolo[3,2-d ][ 1,4]
`benzodiazepine-6(5H)-one ( cloxazolam), (-)-methyl-[3~­
`benzoyloxy-2~(1a(H,5aH)-tropancarboxylate] (cocaine),
`4,5a-epoxy-3-methoxy-17-methyl-7-morphinene-6a-ol
`(codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid ( cyclo-
`barbital), cyclorphan, cyprenorphine, 7-chloro-5-(2-chlo-
`rophenyl)-1H -1,4-benzodiazepine-2(3H)-one
`( delorazepam), desomorphine, dextromoramide, ( + )-(1-ben-
`zyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate
`( dextropropoxyphen), dezocine, diampromide, diamor-
`phone,
`7 -chloro-1-methyl-5-phenyl-1H -1,4-benzodiaz-
`epine-2(3H)-one (diazepam), 4,5a-epoxy-3-methoxy-17-
`methyl-6a-morphinanol (dihydrocodeine ), 4,5a-epoxy-17-
`methyl-3,6a-morphinandiol
`( dihydromorphine ),
`dimenoxadol, dimepheptanol, dimethylthiambutene, diox-
`aphetyl butyrate, dipipanone, ( 6aR,10aR)-6,6,9-trimethyl-3-
`pentyl-6a, 7,8,10a -tetrahydro-6H -benzo[ c ]chromene-1-ol
`( dronabinol), eptazocine, 8-chloro-6-phenyl-4H -[1,2,4 ]tria-
`zolo[ 4,3-a ][1,4 ]benzodiazepine ( estazolam ), ethoheptazine,
`ethylmethylthiambutene, ethyl
`[7-chloro-5-(2-fiuorophe-
`ny 1)-2,3-dihydro-2-oxo-1H -1 ,4-benzodiazepine-3-carboxy-
`late]( ethyl lofiazepate ), 4,5a-epoxy-3-ethoxy-17 -methyl-7-
`morphinene-6a-ol
`(ethylmorphine), etonitazene, 4,5a-
`epoxy-7a-(1-hydroxy-1-methylbutyl)-6-methoxy-17-
`methyl-6,14-endo-etheno-morphinan-3-ol
`( etorphine ),
`N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine(fencam-
`famine ), 7 -[2-(1-methyl-phenethylamino )ethyl]-theophyl-
`line) (fenethylline ), 3-( a-methylphenethylamino )propioni-
`trile
`(fenproporex),
`N-(1-phenethyl-4-
`piperidyl)propionanilide
`(fentanyl),
`7-chloro-5-(2-
`fiuorophenyl)-1-methyl-1H -1,4-benzodiazepine-2(3H)-one
`(fiudiazepam), 5-(2-fiuorophenyl)-1-methyl-7-nitro-1H-1,4-
`benzodiazepine-2(3H)-one (fiunitrazepam), 7-chloro-1-(2-
`diethylaminoethyl)-5-(2-fiuorophenyl)-1H -1,4-benzodiaz-
`epine-2(3H)-one (fiurazepam), 7-chloro-5-phenyl-1-(2,2,2-
`trifiuoroethyl)-1H -1,4-benzodiazepine-2(3H)-one
`(halazepam ), 10-bromo-llb-(2-fiuorophenyl)-2,3,7 ,llb-tet-
`rahydro[ 1,3 ]oxazoly 1[3,2-d][ 1,4 ]benzodiazepine-6( 5H)-one
`(haloxazolam), heroin, 4,5a-epoxy-3-methoxy-17-methyl-
`6-morphinanone (hydrocodone ), 4,5a-epoxy-3-hydroxy-17-
`methyl-6-morphinanone (hydromorphone ), hydroxypethi-
`
`dine, isomethadone, hydroxymethyl morphinane, 11-chloro-
`8,12b-dihydro-2,8-dimethyl-12b-phenyl-4 H -[ 1,3 ]oxazino
`[3,2-d][1,4 ]benzodiazepine-4, 7( 6H)-dione
`(ketazolam),
`1-[ 4-(3-hydroxyphenyl)-1-methyl-4-piperidyl ]-1-propanone
`(ketobemidone ),
`(3S,6S)-6-dimethy lamino-4,4-diphenyl-
`heptan-3-yl acetate(levacetylmethadol (LAAM)), (-)-6-
`dimethyl-amino-4,4-diphenol-3-heptanone
`(levometha-
`(-)-17-methyl-3-morphinanol
`(levorphanol),
`done ),
`levophenacylmorphane, lofentanil, 6-(2-chlorophenyl)-2-( 4-
`methyl-1-piperazinylmethylene )-8-nitro-2H -imidazo[1,2-a]
`[1,4 ]-benzodiazepine-1( 4H)-one (loprazolam), 7-chloro-5-
`(2-chlorophenyl)-3-hydroxy-1H -1,4-benzodiazepine-
`2(3H)-one
`(lorazepam), 7-chloro-5-(2-chlorophenyl)-3-
`hydroxy-1-methyl-1H -1,4-benzodiazepine-2(3H)-one
`(lormetazepam),
`5-( 4-chlorophenyl)-2,5-dihydro-3H-imi-
`dazo[2,1-a ]isoindol-5-ol (mazindol), 7-chloro-2,3-dihydro-
`1-methyl-5-phenyl-1H -1,4-benzodiazepine
`(medazepam),
`N-(3-chloropropyl)-a-methylphenethylamine (mefenorex),
`meperidine, 2-methyl-2-propyltrimethylene dicarbamate
`(meprobamate), meptazinol, metazocine, methylmorphine,
`N,a-dimethylphenethylamine (methamphetamine), (0)-6-
`dimethy lamino-4,4-dipheny 1-3-heptanone
`(methadone),
`2-methy 1-3-o-toly l-4(3H)-quinazolinone
`(methaqualone),
`methyl
`[2-phenyl-2-(2-piperidyl)acetate]
`(methylpheni-
`date), 5-ethyl-1-methyl-5-phenylbarbituric acid (methylphe-
`nobarbital), 3,3-diethyl-5 -methy 1-2,4-piperidinedione (met-
`hyprylon), metopon, 8-chloro-6-(2-fiuorophenyl)-1-methyl-
`4H -imidazo[1,5-a ][1,4 ]benzodiazepine
`(midazolam),
`2-(benzhydrylsulfinyl)-acetamide (modafinil), 4,5a-epoxy-
`17-methyl-7-morphinen-3,6a-diol (morphine), myrophine,
`(± )-trans-3-(1,1-dimethylheptyl)-7 ,8,10,10a-tetrahydro-1-
`hydroxy -6,6-dimethy l-6H -dibenzo[b,d ]pyrane-9 ( 6aH)-one
`(nabilone), nalbuphine, nalorphine, narceine, nicomorphine,
`1-methyl-7 -nitro-5-phenyl-1H -1,4-benzodiazepine-2(3H)-
`one
`(nimetazepam), 7-nitro-5-phenyl-1H-1,4-benzodiaz-
`epine-2(3H)-one (nitrazepam), 7-chloro-5-phenyl-1H-1,4-
`benzodiazepine-2(3H)-one (nordazepam), norlevorphanol,
`6-dimethylamino-4,4-diphenyl-3-hexanone
`(normetha-
`done ), normorphine, norpipanone, the exudation of plants
`belonging to the species Papaver somniferum (opium),
`7 -chloro-3-hydroxy-5-phenyl-1H -1,4-benzodiazepine-
`2(3H)-one (oxazepam), ( cis-trans)-10-chloro-2,3,7,11b-tet-
`rahydro-2-methyl-llb-phenyloxazolo[3,2-d][1,4 ]benzodi-
`azepine-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 seti-
`gerum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone
`(pemoline), 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-me-
`thyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol
`(pentazo-
`cine), 5-ethyl-5-(1-methylbutyl)-barbituric acid (pentobar-
`bital), ethyl-(1-methyl-4-phenyl-4-piperidine carboxylate)
`(pethidine), phenadoxone, phenomorphan, phenazocine,
`phenoperidine, piminodine, pholcodine, 3-methyl-2-phenyl-
`morpholine
`(phenmetrazine), 5-ethyl-5-phenylbarbituric
`acid (phenobarbital), a,a-dimethylphenethylamine(phen-
`termine ), 7 -chloro-5-phenyl-1-(2-propynyl)-1H -1,4-benzo-
`diazepine-2(3H)-one (pinazepam), a-(2-piperidyl)benzhy-
`dryl alcohol (pipradrol), 1'-(3-cyano-3,3-diphenylpropyl)[1,
`4'-bipiperidine ]-4'-carboxamide(piritramide ),
`7-chloro-1-
`( cyclopropylmethyl)-5-phenyl-1H -1,4-benzodiazepine-
`2(3H)-one (prazepam), profadol, proheptazine, promedol,
`properidine, propoxyphene, N -(1-methyl-2-piperidinoet-
`hyl)-N-(2-pyridyl)propionamide, methyl {3-[ 4-methoxycar-
`
`KASHIV1024
`IPR of Patent No. 9,492,392
`
`

`

`US 2005/0031546 Al
`
`3
`
`Feb. 10,2005
`
`bonyl-4-(N-phenylpropanamido )piperidino ]propanoate}
`(remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbut-
`abarbital), 5-allyl-5-(1-methylbutyl)-barbituric acid (seco-
`barbital), N -{ 4-methoxymethyl-1-[2-(2-thienyl)ethyl ]-4-pi-
`peridyl }-propionanilide (sufentanil), 7 -chloro-2-hydroxy-
`methyl-5-phenyl-1H -1,4-benzodiazepin-2(3H)-one
`( temazepam), 7 -chloro-5-(1-cyclohexenyl)-1-methyl-1H -1,
`4-benzodiazepine-2(3H)-one
`(tetrazepam), ethyl(2-dim-
`ethylamino-1-phenyl-3-cyclohexene-1-carboxylate)
`(tili-
`dine (cis and trans)), tramadol, 8-chloro-6-(2-chlorophenyl)-
`1-methyl-4H -[1,2,4 ]triazolo[ 4,3-a ][1,4 ]benzodiazepine
`(triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (vinyl-
`bital),
`(1R * ,2R *)-3-(3-dimethylamino-1-ethyl-2-methyl-
`propyl)-phenol, ( 1R,2R,4S)-2-( dime thy lamina )me thy 1-4-(p-
`fiuoro-benzyloxy)-1-(m-methoxyphenyl)cyclohexanol, (1R,
`(1S,
`2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,
`2S)-3-(3-dimethy lamino-1-ethy 1-2-methy 1-propy l)phenol,
`(2R,3R )-1-dimethy lamina-3( 3-methoxypheny 1)-2-me thy 1-
`pentan-3-ol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-
`methoxypheny 1)-cyclohexane-1 ,3-diol, 3-(2-dimethylami-
`nomethyl-1-hydroxy-cyclohexyl)phenyl
`2-( 4-isobutoxy-
`phenyl)-propionate, 3-(2-dimethylaminomethyl-1-hydroxy-
`cyclohexyl)phenyl
`2-( 6-methoxy-naphthalen-2-yl)-
`propionate, 3-(2-dimethylamino-methyl-cyclohex-1-enyl)-
`phenyl
`2-( 4-isobutyl-phenyl)-propionate,
`3-(2-
`dimethylaminomethyl-cyclohex-1-enyl)-phenyl
`2-( 6-
`methoxy-naphthalen-2-yl)-propionate,
`(RR-SS)-2-
`acetoxy-4-trifiuoromethyl-benzoic
`acid
`3-(2-
`dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
`(RR-SS)-2-hydroxy-4-trifiuoromethyl-benzoic acid 3-(2-
`dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
`(RR-SS)-4-chloro-2-hydroxy-benzoic acid 3-(2-dimethy-
`laminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-
`SS)-2-hydroxy-4-methyl-benzoic acid 3-(2-dimethylamino-
`methyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-
`hydroxy-4-methoxy-benzoic
`acid
`3-(2-
`dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
`(RR-SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethy-
`laminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-
`SS)-21,4'-difiuoro-3-hydroxy-biphenyl-4-carboxylic
`acid
`3-(2-dimethy laminomethy 1-1-hydroxy -cyclohexy 1)-pheny 1
`ester and for corresponding stereoisomeric compounds, the
`corresponding derivatives thereof in each case, in particular
`esters or ethers, and the physiologically acceptable com-
`pounds thereof in each case, in particular the salts and
`solvates thereof.
`[0017] The compounds (1R * ,2R *)-3-(3-dimethylamino-
`1-ethyl-2-methyl-propyl)-phenol,
`(1R,2R,4S)-2-( dime thy-
`lamina )methyl-4-(p-fiuorobenzyloxy)-1-(m-methoxyphe-
`nyl)cyclohexanol or the stereoisomeric compounds thereof
`or the physiologically acceptable compounds thereof, in
`particular
`the hydrochlorides
`thereof,
`the derivatives
`thereof, such as esters or ethers, and processes for the
`production thereof are known, for example, from EP-A-
`693475 or EP-A-780369. 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
`[0018]
`of the dosage form according to the invention, at least one
`synthetic or natural polymer (C) is used which has a break-
`ing strength, measured using the method disclosed in the
`present application, of at least 500 N. At least one polymer
`selected from the group consisting of polymethylene oxide,
`polyethylene oxide, polypropylene oxide, polyethylene,
`
`polypropylene, polyvinyl chloride, polycarbonate, polysty-
`rene, polyacrylate, copolymers thereof, and mixtures of at
`least two of the stated polymers is preferably used for this
`purpose. The polymers are distinguished by a molecular
`weight of at least 0.5 million, determined by rheological
`measurements. Thermoplastic polyalkylene oxides, such as
`polyethylene oxides, with a molecular weight of at least 0.5
`million, preferably of up to 15 million, determined by
`Theological measurements, are very particularly preferred.
`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).
`[0019] The polymers are used in powder form.
`In order to achieve the necessary breaking strength
`[0020]
`of the dosage form according to the invention, it is further-
`more possible additionally to use at least one natural or
`synthetic wax (D) with a breaking strength, measured using
`the method disclosed in the present application, of at least
`500 N. Waxes with a softening point of at least 60° C. are
`preferred. Carnauba wax and beeswax are particularly pre-
`ferred. Carnauba wax is very particularly preferred. Car-
`nauba wax is a natural wax which is obtained from the
`leaves of the carnauba palm and has a softening point of
`>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 has a breaking strength of at least
`500 N.
`[0021] The dosage forms according to the invention are
`distinguished in that, due their hardness, they cannot be
`pulverised, for example by grinding in a mortar. This vir-
`tually rules out oral or parenteral, in particular intravenous
`or nasal abuse. However, in order to prevent any possible
`abuse in the event of comminution and/or pulverisation of
`the dosage form according to the invention which has
`nevertheless been achieved by application of extreme force,
`the dosage forms according to the invention may, in a
`preferred embodiment, contain further agents which com-
`plicate or prevent abuse as auxiliary substances (B).
`[0022] The abuse-proofed dosage form according to the
`invention, which comprises, apart from one or more active
`ingredients with abuse potential, at least one hardening
`polymer (C) and optionally at least one wax (D), may
`accordingly also comprise at least one of the following
`components ( a)-(t) as auxiliary substances (B):
`(a) at least one substance which irritates the
`[0023]
`nasal passages and/or pharynx,
`(b) at
`least one viscosity-increasing agent,
`[0024]
`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 intro-
`duced into a further quantity of an aqueous liquid,
`(c) at least one antagonist for each of the active
`[0025]
`ingredients with abuse potential,
`(d) at least one emetic,
`[0026]
`
`KASHIV1024
`IPR of Patent No. 9,492,392
`
`

`

`US 2005/0031546 Al
`
`4
`
`Feb. 10,2005
`
`(f) at least one bitter substance.
`
`(e) at least one dye as an aversive agent,
`
`[0027]
`[0028]
`[0029] Components (a) to (f) are additionally each indi-
`vidually suitable for abuse-proofing the dosage form accord-
`ing to the invention. Accordingly, component (a) is prefer-
`ably 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, com-
`ponent (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. Com-
`bined use according to the invention of at least one of the
`above-stated components makes it possible still more effec-
`tively to prevent abuse of dosage forms according to the
`invention.
`
`In one embodiment, the dosage form according to
`[0030]
`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 according
`[0031]
`to the invention may comprise all of components (a)-(f).
`
`If the dosage form according to the invention
`[0032]
`comprises component (a) to counter abuse, substances
`which irritate the nasal passages and/or pharynx which may
`be considered according to the invention are any substances
`which, when administered 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 secre-
`tion 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.
`
`[0033] Particularly suitable substances which irritate the
`nasal passages and/or pharynx are those which cause burn-
`ing, 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 skilled
`person or may be identified by simple preliminary testing.
`
`[0034] 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.
`[0035] 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.
`[0036] The dosage form 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. %, particu-
`larly preferably of 0.1 to 0.5 wt. %, in each case relative to
`the total weight dosage unit.
`If one or more constituents of corresponding hot
`[0037]
`substance drugs are used, the quantity thereof in a dosage
`unit according to the invention preferably amounts to 0.001
`to 0.005 wt. %, relative to the total weight of the dosage unit.
`[0038] A dosage unit is taken to mean a separate or
`separable administration unit, such as for example a tablet or
`a capsule.
`[0039] One or more constituents of at least one hot sub-
`stance drug selected from the group consisting of Allii sativi
`bulbus (garlic), Asari rhizoma cum herba (Asarum root and
`leaves), Calami rhizoma (calamus root), Capsici fructus
`(capsicum), Capsici fructus acer (cayenne pepper), Curcu-
`mae longae rhizoma (turmeric root), Curcumae xanthor-
`rhizae 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 rhi-
`zoma (zedoary root) and Zingiberis rhizoma (ginger root),
`particularly preferably from the group consisting of Capsici
`fructus (capsicum), Capsici fructus acer (cayenne pepper)
`and Piperis nigri fructus (pepper) may preferably be added
`as component (a) to the dosage form according to the
`invention.
`[0040] The constituents of the hot substance drugs pref-
`erably comprise o-methoxy(methyl)phenol compounds, acid
`amide compounds, mustard oils or sulfide compounds or
`compounds derived therefrom.
`[0041] Particularly preferably, at least one constituent of
`the hot substance drugs is selected from the group consisting
`of myristicin, elemicin, isoeugenol, ~-asarone, safrole, gin-
`gerais, xanthorrhizol, capsaicinoids, preferably capsaicin,
`capsaicin derivatives, such as N-vanillyl-9E-octadecena-
`mide, dihydrocapsaicin, nordihydrocapsaicin, homocapsai-
`cin, norcapsaicin and nomorcapsaicin, piperine, preferably
`trans-piperine, glucosinolates, preferably based on non-
`volatile mustard oils, particularly preferably based on p-hy-
`droxybenzyl mustard oil, methylmercapto mustard oil or
`methylsulfonyl mustard oil, and compounds derived from
`these constituents.
`[0042] Another option for preventing abuse of the dosage
`form 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 assis-
`tance 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.
`[0043] 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
`
`KASHIV1024
`IPR of Patent No. 9,492,392
`
`

`

`US 2005/0031546 Al
`
`5
`
`Feb. 10,2005
`
`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.
`[0044] 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 distinguish-
`able, 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 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) to (e), this additionally
`leads to unpleasant burning, vomiting, bad flavour and/or
`visual deterrence.
`Intravenous administration of such a gel would
`[0045]
`most probably result in obstruction of blood vessels, asso-
`ciated with serious embolism or even death of the abuser.
`In order to verify whether a viscosity-increasing
`[0046]
`agent is suitable as component (b) for use in the dosage form
`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 according
`to the invention.
`If component (b) is added to the dosage form
`[0047]
`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. % carboxymethyl-
`cellulose sodium (Avicel® RC 591), carboxymethylcellu-
`lose 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
`such as citrus pectin (Cesapectin® HM Medium Rapid Set),
`apple pectin, pectin from lemon peel, waxy maize starch
`(Frimulsion ALG
`(C*Gel 04201®), sodium alginate
`(E401)®), guar flour (Frimulsion BM®, Polygum 26/1-
`75®), iota carrageen (Frimulsion D021®), karaya gum,
`gellan gum (Kelcogel F®, Kelcogel LTlOO®), galactoman-
`nan (Meyprogat 150®), tara bean flour (Polygum 43/1),
`propylene glycol alginate (Protanal-Ester SD-LB®), sodium
`hyaluronate, tragacanth, tara gum (Vidogum SP 200®),
`fermented polysaccharide welan gum (K1A96), 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 5 wt. % of the viscosity-increasing agent(s) is
`sufficient to fulfil the above-stated conditions.
`[0048] The component (b) viscosity-increasing agents,
`where provided, are preferably present in the dosage form
`according to the invention in quantities of >5 mg per dosage
`unit, i.e. per administration unit.
`In a particularly preferred embodiment of the
`[0049]
`present invention, the viscosity-increasing agents used as
`
`component (b) are those which, on extraction from the
`dosage form with the necessary minimum quantit