111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US0081143 83B2
`
`c12) United States Patent
`Bartholomaus et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,114,383 B2
`*Feb.14,2012
`
`(54) ABUSE-PROOFED DOSAGE FORM
`
`(75)
`
`Inventors: Johannes Bartholomiius, Aachen (DE);
`Heinrich Kugelmann, Aachen (DE);
`Elisabeth Arkenau-Maric, Kiiln (DE)
`
`(73) Assignee: Gruenenthal GmbH, Aachen (DE)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 325 days.
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 10/718,112
`
`(22) Filed:
`
`Nov. 20, 2003
`
`(65)
`
`(30)
`
`Prior Publication Data
`US 2005/0031546 AI
`Feb. 10, 2005
`
`Foreign Application Priority Data
`
`Aug. 6, 2003
`
`(DE) .................................. 103 36 400
`
`(51)
`
`Int. Cl.
`A61K 49100
`(2006.01)
`(52) U.S. Cl. ...................................... 424/10.1; 424/10.4
`(58) Field of Classification Search .................. 424/10.1
`See application file for complete search history.
`
`(56)
`
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`(Continued)
`
`AR
`
`FOREIGN PATENT DOCUMENTS
`46994
`1212004
`(Continued)
`
`OTHER PUBLICATIONS
`Zhang et al. (Pharm. Dev. Tech. 1999,4, 241-250).*
`(Continued)
`
`Primary Examiner- Michael G Hartley
`Assistant Examiner- Melissa Perreira
`(74) Attorney, Agent, or Firm- Norris McLaughlin &
`Marcus, P.A.
`
`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.
`
`9 Claims, No Drawings
`
`KASHIV1010
`IPR of Patent No. 9,492,392
`
`

`

`US 8,114,383 B2
`Page 2
`
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`
`KASHIV1010
`IPR of Patent No. 9,492,392
`
`

`

`CN
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`CN
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`DE
`DE
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`US 8,114,383 B2
`Page 3
`
`EP
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`KASHIV1010
`IPR of Patent No. 9,492,392
`
`

`

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`95/17174 Al
`95 22319 Al
`wo 95/20947
`95 30422
`96 00066
`96/03979 Al
`9614058 Al
`9733566
`9820073
`wo 98/20073
`98 28698 Al
`98/35655 A2
`99/12864 Al
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`99/48481 Al
`9944591 Al
`W0/00/33835
`W00033835
`0040205
`01112230 Al
`0108661 A2
`0115667 Al
`01152651 A2
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`02/26061 Al
`02/26262 A2
`02 26928
`02/088217 Al
`03 06723 Al
`03 013476 Al
`03/013479 AI
`wo 03/015531
`WO 03/015531 A2
`03 024430
`03/026624 Al
`03 026743 A2
`03/026743 A2
`03 028698 A2
`03/028990 Al
`03/031546 Al
`03 035029
`03/035177 A2
`03035029 Al
`03035053 Al
`03035054 Al
`03053417 A2
`03/068392 Al
`03/092648 Al
`03094812 Al
`03 105808
`2004/004693 Al
`2004/043967 Al
`2004 026263 A2
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`WO 2004026262 A2 *
`2004037230 Al
`2004037259 Al
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`2004/066910 A2
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`2005 016313
`2005 016314
`2005016314 AI
`2005/032524 A2
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`2005 041968
`2005/053656 Al
`2005/055981 A2
`2005 063214
`2005/066183 Al
`2005063214 Al
`2005 102286
`2005102286 AI
`2006 002883
`2006 002884
`2006002884
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`2/1996
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`

`

`US 8,114,383 B2
`
`1
`ABUSE-PROOFED DOSAGE FORM
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`The present invention relates to an abuse-proofed, thermo-
`formed 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 inven-
`tion.
`2. Brief Description of Related Developments
`Many pharmaceutical active ingredients, in addition to
`having excellent activity in their appropriate application, 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 20
`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 ingre- 25
`dient 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 30
`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 admin-
`istered nasally, i.e. is sniffed. Since controlled-release dosage 35
`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.
`U.S. Pat. No. 4,070,494 proposed adding a swellable agent 40
`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 45
`on a similar approach to preventing parenteral abuse, said
`tablet containing the active ingredient with abuse potential
`and at least one gel former, each in different layers.
`WO 03/015531 A2 discloses another approach to prevent-
`ing parenteral abuse. A dosage form containing an analgesic 50
`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 55
`adding antagonists to the active ingredients to the dosage
`form, for example naloxone or naltexone in the case of opi-
`ates, or compounds which cause a physiological defence
`response, such as for example Radix ipecacuanha=ipecac
`root.
`
`SUMMARY OF THE INVENTION
`
`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 preceding abuse of
`
`2
`the dosage form comprising the agents conventionally avail-
`able for potential abuse and accordingly to provide a dosage
`form for active ingredients with abuse potential which
`ensures the desired therapeutic effect when correctly admin-
`istered, but from which the active ingredients cannot be con-
`verted into a form suitable for abuse simply by pulverisation.
`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
`10 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.
`The use of polymers having the stated minimum breaking
`15 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 diffi-
`cult using conventional means, so considerably complicating
`or preventing the subsequent abuse.
`If comminution is inadequate, parenteral, in particular
`intravenous, administration carmot 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.
`According to the invention, comminution is take