`
`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)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`3,806,603 A
`411974 Gaunt eta!.
`3,865,108 A
`211975 Hartop
`3,966,747 A
`611976 Monkovic
`911976 Shaw eta!.
`3,980,766 A
`4,002,173 A
`111977 Manning et a!.
`311977 Stube et al.
`4,014,965 A
`4,070,494 A
`111978 Hoffmeister et a!. ............. 42412
`4,070,497 A
`111978 Wismer
`4,175,119 A * 1111979 Porter ........................... 4241475
`4,207,893 A
`611980 Michaels
`4,262,017 A
`411981 Kuipers
`811982 Kawata eta!.
`4,343,789 A
`4,353,887 A
`1011982 Hess
`4,404,183 A
`911983 Kawata eta!.
`4,427,681 A
`111984 Manshi
`4,462,941 A
`711984 Lee
`4,603,143 A
`711986 Schmidt
`911986 Wong eta!. ................... 6041892
`4,612,008 A
`4,629,621 A
`1211986 Snipes
`911987 Uemura eta!.
`4,690,822 A
`4,713,243 A
`1211987 Schiraldi et a!.
`4,744,976 A
`511988 Snipes eta!.
`4,764,378 A
`811988 Keith eta!.
`4,765,989 A
`811988 Wong eta!. ................... 4241473
`4,774,074 A
`911988 Snipes
`1111988 Wong eta!. ................... 4241468
`4,783,337 A
`4,806,337 A
`211989 Snipes eta!.
`RE33,093 E
`1011989 Schiraldi et a!.
`4,880,585 A
`1111989 Klimesch
`111990 Theeuwes et al.
`4,892,778 A
`4,892,889 A
`111990 Kirk
`4,940,556 A
`711990 MacFarlane
`4,957,668 A
`911990 Plackard
`4,957,681 A
`911990 Klimesch
`4,960,814 A
`1011990 Wu
`
`4,992,278 A
`4,992,279 A
`5,004,601 A
`5,051,261 A
`5,169,645 A
`5,198,226 A
`5,200,197 A
`5,211,892 A
`5,273,758 A
`5,350,741 A
`5,378,462 A
`5,427,798 A
`RE34,990 E
`5,458,887 A
`5,460,826 A
`5,556,640 A
`5,562,920 A
`5,601,842 A
`5,620,697 A
`5,681,517 A
`5,792,474 A
`5,801,201 A
`5,811,126 A
`5,849,240 A *
`5,866,164 A *
`5,916,584 A
`5,928,739 A
`5,945,125 A
`5,948,787 A
`5,968,925 A
`6,009,390 A
`6,009,690 A
`6,077,538 A
`6,096,339 A
`6,117,453 A
`6,133,241 A
`6,228,863 B1
`6,235,825 B1
`6,238,697 B1 *
`6,245,357 B1
`6,248,737 B1
`6,261,599 B1
`6,306,438 B1
`
`211991 Khanna
`211991 Palmer
`411991 Snipes
`911991 McGinity eta!.
`1211992 Shukla
`311993 MacFarlane
`411993 Wright eta!.
`511993 Gueret et a!.
`1211993 Royce
`911994 Takada
`111995 Boedecker
`611995 Ludwig
`711995 Khanna
`1011995 Chen
`1011995 Merrill eta!.
`911996 Ito et al.
`1011996 Demmer eta!.
`211997 Bartholomaeus
`411997 Tormala et al.
`1011997 Metzger
`811998 Rauchfuss
`911998 Graudums eta!.
`911998 Krishnamurthy
`1211998 Miller eta!. .................. 2641460
`211999 Kuczynski eta!. ........... 4241472
`611999 O'Donoghue
`7 I 1999 Pophusen
`811999 Kim
`911999 Merrill eta!.
`1011999 Knidlberger
`1211999 Gupta eta!.
`112000 Rosenberg
`612000 Merrill
`812000 Ayer et a!.
`912000 Seth et al.
`1012000 Bok
`512001 Palermo et a!.
`512001 Yoshida
`512001 Kumar eta!. ................. 4241464
`612001 Edgren et al.
`612001 Buschmann et al.
`712001 Oshlack
`1012001 Oshlack et al.
`(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
`
`............... 424/473
`
`U.S. PATENT DOCUMENTS
`6,309,668 B1
`10/2001 Bastin eta!. .................. 424/472
`112002 Shell eta!.
`6,340,475 B2
`6,344,535 B1
`212002 Timmermann
`6,348,469 B1
`212002 Seth
`6,375,963 B1
`4/2002 Repka et al.
`6,399,100 B1
`6/2002 Clancy eta!.
`6,419,954 B1
`7/2002 Chu
`6,436,441 B1
`8/2002 Sako eta!.
`6,461,644 B1
`10/2002 Jackson
`6,488,962 B1
`12/2002 Berner eta!.
`6,488,963 B1
`12/2002 McGinity eta!.
`6,534,089 B1
`3/2003 Ayer eta!.
`6,547,997 B1
`4/2003 Breitenbach et a!.
`6,562,375 B1
`5/2003 Sako eta!.
`6,592,901 B2
`7/2003 Durig
`6,635,280 B2
`10/2003 Shell eta!.
`6,699,503 B1
`3/2004 Sako eta!.
`4/2004 Gusler eta!.
`6,723,340 B2
`6,733,783 B2 * 5/2004 Oshlack et a!.
`6/2004 Luber eta!.
`6,753,009 B2
`1112004 Hanuner
`6,821,588 B1
`7,141,250 B2
`1112006 Oshlack et a!.
`7,176,251 B1
`2/2007 Bastioli
`7,776,314 B2
`8/2010 Bartholomiius eta!.
`200110038852 A1
`1112001 Kolter
`2002/0012701 A1
`112002 Kolter
`2002/0015730 A1
`212002 Hoffmann
`2002/0051820 A1
`5/2002 Shell eta!.
`2002/0114838 A1
`8/2002 Ayer eta!.
`2002/0132359 A1
`9/2002 Waterman
`2002/0187192 A1
`12/2002 Joshi
`2003/0015814 A1
`112003 Krull
`2003/0017532 A1
`112003 Biswas
`2003/0021546 A1
`112003 Sato
`2003/0031546 A1
`2/2003 Araki
`2003/0044458 A1
`3/2003 Wright, IV
`2003/0044464 A1
`3/2003 Ziegler eta!.
`............... 424/465
`2003/0064099 A1
`4/2003 Oshlack et a!.
`2003/0068392 A1
`4/2003 Sackler ......................... 424/760
`2003/0091630 A1
`5/2003 Louie-Helmet a!.
`2003/0104052 A1
`6/2003 Berner eta!.
`2003/0118641 A1
`6/2003 Maloney eta!. .............. 424/465
`2003/0124185 A1
`7/2003 Oshlack et a!.
`............... 424/465
`2003/0125347 A1
`7/2003 Anderson et a!.
`2003/0133985 A1
`7/2003 Louie-Helmet a!.
`2003/0152622 A1
`8/2003 Louie-Helmet a!.
`2003/0158242 A1
`8/2003 Kugelmann
`2003/0175326 A1
`9/2003 Thombre
`2003/0232895 A1
`12/2003 Omidian
`2004/0010000 A1
`112004 Ayer eta!.
`2004/0011806 A1
`112004 Luciano
`2004/0052844 A1
`3/2004 Hsiao eta!.
`2004/0081694 A1
`4/2004 Oshlack
`2004/0091528 A1
`5/2004 Rogers
`2004/0131671 A1
`7/2004 Zhang
`2004/0156899 A1
`8/2004 Louie-Helmet a!.
`2004/0170567 A1 * 9/2004 Sackler ........................ 424/10.1
`9/2004 Berner eta!.
`2004/0185105 A1
`2004/0213848 A1
`10/2004 Li eta!.
`2005/0015730 A1
`112005 Gunturi et a!.
`2005/0031546 A1
`2/2005 Bartholornaus eta!.
`2005/0058706 A1
`3/2005 Bartholornaus
`2005/0063214 A1
`3/2005 Takashima
`2005/0089475 A1
`4/2005 Gruber
`2005/0095291 A1
`5/2005 Oshlack et a!.
`2005/0106249 A1
`5/2005 Hwang eta!.
`2005/0112067 A1
`5/2005 Kumar et al.
`2005/0127555 A1
`6/2005 Gusik
`2005/0152843 A1
`7/2005 Bartholornaus
`2005/0186139 A1
`8/2005 Bartholornaus
`2005/0191244 A1
`9/2005 Bartholornaus
`2005/0214223 A1
`9/2005 Bartholornaeus
`2005/0236741 A1
`10/2005 Arkenau
`2005/0266084 A1
`12/2005 Li eta!.
`2006/0002859 A1
`112006 Arkenau
`2006/0002860 A1
`112006 Bartholornaus
`2006/0039864 A1
`2/2006 Bartholornaus
`2006/0099250 A1
`5/2006 Tian
`
`8/2006 Arkenau-Maric
`2006/0188447 A1
`8/2006 Bartholomaus
`2006/0193782 A1
`8/2006 Ashworth
`2006/0193914 A1
`10/2006 Kiick eta!.
`2006/0240110 A1
`112007 Arkenau-Maric
`2007/0003616 A1
`112007 Sackler
`2007/0020188 A1
`2007/0020335 A1
`112007 Chen eta!.
`3/2007 Arkenau-Maric
`2007/0048228 A1
`2007/0065365 A1
`3/2007 Kugelmann
`4/2007 Joshi eta!.
`2007/0092573 A1
`2007/0183979 A1
`8/2007 Arkenau-Maric
`8/2007 Arkenau-Maric
`2007/0183980 A1
`8/2007 Breitenbach
`2007/0190142 A1
`8/2007 Pilgaonkar et al.
`2007/0196396 A1
`8/2007 Amidon
`2007/0196481 A1
`1112007 Kumar eta!.
`2007/0264327 A1
`2007/0269505 A1
`1112007 Flath eta!.
`4/2008 Wada
`2008/0081290 A1
`10/2008 Bartholomaus
`2008/0247959 A1
`10/2008 Bartholomaus
`2008/0248113 A1
`2008/0311049 A1
`12/2008 Arkenau-Maric
`12/2008 Ashworth
`2008/0311187 A1
`2008/0311197 A1
`12/2008 Arkenau-Maric
`12/2008 Arkenau-Maric
`2008/0312264 A1
`12/2008 Arkenau
`2008/0317854 A1
`112009 Arkenau-Maric
`2009/0004267 A1
`112009 Arkenau-Maric
`2009/0005408 A1
`3/2009 McKenna
`2009/0081290 A1
`8/2009 Jans
`2009/0202634 A1
`112010 Cailly-Dufestel
`2010/0015223 A1
`4/2010 Bartholomaus eta!.
`2010/0098758 A1
`2010/0151028 A1
`6/2010 Ashworth et a!.
`9/2010 Bartholomaus eta!.
`2010/0221322 A1
`2010/0260833 A1
`10/2010 Bartholomaus eta!.
`112011 Bartholomaus eta!.
`201110020451 A1
`201110038930 A1
`212011 Barnscheid et a!.
`201110082214 A1
`4/2011 Faure eta!.
`FOREIGN PATENT DOCUMENTS
`045353
`10/2005
`049562
`8/2006
`053304
`5/2007
`054222
`6/2007
`054328
`6/2007
`2003237944
`12/2003
`2003274071
`5/2004
`2003278133
`5/2004
`2003279317
`5/2004
`2004264666
`2/2005
`2004264667
`2/2005
`2004308653
`4/2005
`2005259476
`112006
`2005259478
`112006
`2006210145
`8/2006
`2009207796
`7/2009
`2009243681
`1112009
`P10413318
`10/2006
`P10413361
`10/2006
`P10513300
`5/2008
`P10606145
`212009
`2317747 A1
`7/1999
`2352874 A1
`6/2000
`250 2965 A1
`5/2004
`2534925
`2/2005
`2534932
`2/2005
`2551231
`7/2005
`2572352
`112006
`2572352 A1
`112006
`2572491
`112006
`2595954
`7/2006
`2595979
`8/2006
`2713128
`7/2009
`2723438
`1112009
`689109 A5
`10/1998
`1980643
`4/2005
`101010071
`6/2005
`101022787
`112006
`001863513
`1112006
`001863514
`1112006
`
`AR
`AR
`AR
`AR
`AR
`AU
`AU
`AU
`AU
`AU
`AU
`AU
`AU
`AU
`AU
`AU
`AU
`BR
`BR
`BR
`BR
`CA
`CA
`CA
`CA
`CA
`CA
`CA
`CA
`CA
`CA
`CA
`CA
`CA
`CH
`CN
`CN
`CN
`CN
`CN
`
`KASHIV1010
`IPR of Patent No. 9,492,392
`
`
`
`CN
`CN
`CN
`CN
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DE
`DK
`DK
`DK
`EC
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`
`01917862
`101027044
`101111232
`101175482
`2530 563
`2808505 A1
`4309528
`43 09 528
`69400215 T2
`19522899 C1
`19753534
`19800698
`19822979
`19753534 A1
`19800689 C1
`19800698 A1
`19822979 A1
`69229881 T2
`0980894
`19856147 A1
`19940740 A1
`19960494 A1
`10036400 A1
`19855440 A1
`69429710 T2
`10250083 A1
`10250084 A1
`10250087 A1
`10250088
`10336400 A1
`102004019916
`102004020220
`10 2004 032049 A1
`10 2004 032051 A1
`10 2004 032103 A1
`10 2005 005446 A1
`10 2005 005449 A1
`102007011485
`1658055
`1658054
`1515702
`SP066345
`0 008 131
`0043254 A1
`0177893 A2
`0 216 453
`0 226 061
`0228417
`0229652 A2
`0 232 877
`0240906 A2
`0261616 A2
`0270954 A1
`0 277 289
`0 293 066
`0 328 775
`0477135 A1
`0544144 A1
`0 583 726
`0 598 606
`0636370 A1
`0641195 A1
`0647448 A1
`0682945 A2
`0 661 045
`0661045 A1
`0675710 A1
`0693475
`0693475 A1
`0820693 A1
`0 696 598
`0756480 A1
`0760654 A1
`0780369
`0780369 A1
`0785775 A1
`0809488 A1
`0820698
`0820698 A1
`
`2/2007
`8/2007
`112008
`2/2008
`111977
`9/1978
`3/1993
`9/1994
`10/1996
`12/1996
`12/1997
`111998
`5/1998
`6/1999
`7/1999
`7/1999
`12/1999
`12/1999
`212000
`6/2000
`3/2001
`6/2001
`6/2002
`6/2002
`8/2002
`12/2003
`5/2004
`5/2004
`5/2004
`3/2005
`1112005
`1112005
`112006
`112006
`112006
`8/2006
`8/2006
`9/2008
`7/2007
`10/2007
`112009
`8/2006
`2/1980
`111982
`4/1986
`4/1987
`6/1987
`7/1987
`7/1987
`8/1987
`10/1987
`3/1988
`6/1988
`8/1988
`1111988
`8/1989
`3/1992
`6/1993
`2/1994
`5/1994
`2/1995
`3/1995
`4/1995
`5/1995
`7/1995
`7/1995
`10/1995
`111996
`111996
`111996
`2/1996
`2/1997
`3/1997
`6/1997
`6/1997
`7/1997
`12/1997
`111998
`111998
`
`US 8,114,383 B2
`Page 3
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`ES
`ES
`ES
`ES
`ES
`ES
`GB
`GB
`HR
`HR
`JP
`JP
`JP
`JP
`JP
`KR
`KR
`KR
`KR
`KR
`MX
`MX
`MX
`MX
`MX
`NO
`NO
`NO
`PT
`PT
`PT
`PT
`RU
`RU
`RU
`RU
`RU
`SI
`SI
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`0857062 A2
`0864324 A1
`0864326 A2
`0 980 894 A1
`0988106 A1
`1014941 A1
`1070504 A1
`1127871 A1
`1138321 A2
`1166776 A2
`1251120 A1
`1293127 A2
`1293196 A2
`1250045 B1
`1658055
`1515702
`1527775 A1
`1558221 A1
`1558257
`1560585
`1658054
`1740161
`1765303
`1786403
`1558221 B1
`1845955
`1845956
`1 859 789
`1897545 A1
`2131830
`2249811
`2273983
`2336571
`2260042 T3
`2285497
`2288621
`2289542
`2315505
`1147210 A
`2057878 A
`P20070272
`20070456
`3-0501737 A
`8 505076
`8-505076 A
`2002-275175 A
`2005534664
`1020060069832
`20070039041
`20070111510
`20100111303
`20110016921
`2007000008
`2007000009
`2007009393
`2010008138
`2010012039
`20061054
`20070578
`20074412
`1699440
`1658054
`1658055
`1515702
`2131244 C1
`2354357
`2007103712
`2007103707
`2007132975
`1515702
`1699440
`89/05624 A1
`90 03776
`9003776 A1
`93 06723
`93 10758 A1
`93 11749
`94 06414
`94 08567 A1
`
`8/1998
`9/1998
`9/1998
`9/1999
`3/2000
`7/2000
`112001
`8/2001
`10/2001
`112002
`10/2002
`3/2003
`3/2003
`9/2003
`2/2005
`3/2005
`4/2005
`8/2005
`8/2005
`8/2005
`5/2006
`112007
`3/2007
`5/2007
`6/2007
`10/2007
`10/2007
`1112007
`12/2008
`12/2009
`1112010
`112011
`12/2004
`1112006
`1112007
`112008
`2/2008
`4/2009
`4/1969
`4/1981
`6/2007
`1112007
`4/1991
`6/1996
`6/1996
`9/2002
`1112005
`6/2006
`4/2007
`1112007
`10/2010
`2/2011
`3/2007
`3/2007
`8/2007
`8/2010
`1112010
`3/2006
`112007
`1112007
`12/2004
`5/2006
`7/2007
`12/2008
`6/1999
`12/2007
`9/2008
`1112008
`4/2009
`4/2009
`1112009
`6/1989
`4/1990
`4/1990
`4/1993
`6/1993
`6/1993
`3/1994
`4/1994
`
`KASHIV1010
`IPR of Patent No. 9,492,392
`
`
`
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`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
`99 32120 Al
`99/48481 Al
`9944591 Al
`W0/00/33835
`W00033835
`0040205
`01112230 Al
`0108661 A2
`0115667 Al
`01152651 A2
`01197783 Al
`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
`W0/2004/026262
`WO 2004026262 A2 *
`2004037230 Al
`2004037259 Al
`2004037260 Al
`2004/066910 A2
`2004/084869 Al
`2004/093801 A2
`2004/100894 A2
`2004093819 A2
`2005 016313
`2005 016314
`2005016314 AI
`2005/032524 A2
`2005/065646 A2
`2005 041968
`2005/053656 Al
`2005/055981 A2
`2005 063214
`2005/066183 Al
`2005063214 Al
`2005 102286
`2005102286 AI
`2006 002883
`2006 002884
`2006002884
`
`6/1995
`8/1995
`8/1995
`1111995
`111996
`2/1996
`5/1996
`9/1997
`5/1998
`5/1998
`7/1998
`8/1998
`3/1999
`7/1999
`9/1999
`9/1999
`* 6/2000
`* 6/2000
`7/2000
`2/2001
`2/2001
`3/2001
`7/2001
`12/2001
`4/2002
`4/2002
`4/2002
`1112002
`112003
`2/2003
`2/2003
`2/2003
`2/2003
`3/2003
`4/2003
`4/2003
`4/2003
`4/2003
`4/2003
`4/2003
`5/2003
`5/2003
`5/2003
`5/2003
`5/2003
`7/2003
`8/2003
`1112003
`1112003
`12/2003
`112004
`2/2004
`4/2004
`4/2004
`4/2004
`5/2004
`5/2004
`5/2004
`8/2004
`10/2004
`1112004
`1112004
`1112004
`2/2005
`2/2005
`2/2005
`4/2005
`4/2005
`5/2005
`6/2005
`6/2005
`7/2005
`7/2005
`7/2005
`1112005
`1112005
`112006
`112006
`112006
`
`US 8,114,383 B2
`Page 4
`
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`112006
`2006002886 Al
`5/2006
`2005102294
`8/2006
`2006 082097
`8/2006
`2006 082099
`112007
`2007/005716 A2
`112007
`2007 008752
`5/2007
`2007 048233
`5/2007
`2007 053698
`7/2007
`2007/085024 A2
`7/2008
`2008/086804 A2
`9/2008
`2008/107149 A2
`9/2008
`2008107149
`12/2008
`2008/148798 A2
`112009
`2009003776 Al
`7/2009
`2009/092601 AI
`7/2009
`2009092601
`1112009
`20091135680 Al
`2009135680
`1112009
`2011009602
`112011
`2011009603
`112011
`2011009604
`112011
`OTHER PUBLICATIONS
`Maggi eta!. (Biomaterials 2002, 23, 1113-1119).*
`DOW Technical Data, POLYOXTIM WSR, Feb. 2003. *
`DeJong (Pharmaceutisch Weekblad Scientific Edition 1987, p.
`24-28).*
`Observations by Third Parties Pursuant to Art 115 EPC, dated Feb. 2,
`2009.
`Letter of James W. McGinity, with attached experimental report,
`dated Jan. 26, 2009.
`V.K. Thoma eta!., "Bestimmung der In-vitro-Freigabe von schwach
`basischen Wirkstoffen aus Retardarzneiformen," Pharm. Ind. 51, Nr.
`3 (1989).
`F. E. Bailey eta!., "Some Properties of Poly( ethylene oxide) in
`Aqueous Solution," Journal of Applied Polymer Science, vol. 1, Issue
`No. 1, pp. 56-62 (1959).
`A. Apicella eta!., "Poly( ethylene oxide) (PEO) and different molecu-
`lar weight PEO blends monolithic devices for drug release,"
`Biomaterials 1993, vol. 14, No.2, pp. 83-90.
`S. Janicki eta!., "Slow-Release Microballs: Method of Preparation,"
`Acta Pharm. Techno!. 33(3) 154-155 (1987).
`R. Mank et al., "Darstellung wirkstoffhaltiger Extrusionsformlinge
`auf der Basis von Thermoplasten," Pharmazie 45 (1990), H. 8; pp.
`592-593.
`R. Mank et al., "Darstellung wirkstoffhaltiger Extrusionsformlinge
`auf der Basis von Thermoplasten," Pharrnazie 44 (1989) H. 11; pp.
`773-776.
`P. Shivanand et a!., "Factors Affecting Release of KCl from Melt
`Extruded Polyethylene Disks," Pharmaceutical Research, Official
`Journal of the American Association of Pharmaceutical Scientists;
`Oct. 1991, vol. 8, No. 10.
`L. Yang eta!., "Characterization of Compressibility and Compatibil-
`ity of Poly( ethylene oxide) Polymers for Modified Release Applica-
`tion by Compaction Simulator," Journal of Pharmaceutical Sciences,
`vol. 85, No. 10, Oct. 1996.
`F. Zhang eta!., "Properties of Sustained-Release Tablets Prepared by
`Hot-Melt Extrusion," Pharmaceutical Development and Technology,
`4(2), 241-250 (1999) pp. 241-250.
`M.M. Crowley et al., "Stability of polyethylene oxide in matrix
`tablets prepared by hot-melt extrusion," Biomaterials 23 (2002)
`4241-4248.
`M. Efentakis et a!., "Evaluation of High Molecular Weight
`Poly(Oxyethylene) (Polyox) Polymer: Studies of Flow Properties
`and Release Rates of Furosemide and Captopril from Controlled-
`Release Hard Gelatin Capsules," Pharmaceutical Development and
`Technology, 5(3), 339-346 (2000).
`N. Follonier et a!., "Various ways of modulating the release of
`diltiazem hydrochloride from hot-melt extruded sustained release
`pellets prepared using polymeric materials," Journal of Controlled
`Release 36 (1995) 243-250.
`N.B. Graham, "Poly(Ethylene Glycol) Gels and Drug Delivery,"
`Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical
`Applications, Chapter 17, 1992.
`
`KASHIV1010
`IPR of Patent No. 9,492,392
`
`
`
`US 8,114,383 B2
`Page 5
`
`C. D. Hanning eta!., "The Morphine Hydrogel Suppository," British
`Journal of Anaesthesia, 1988, 61, 221-227.
`Kim eta!., "Preparation and Evaluation of Eudragit Gels V. Rectal
`Gel Preparations for Sustained Release and Avoidance of First-Pass
`Metabolism of Lidocaine," Chern. Pharm. Bull. 40(10) 2800-2804
`(1992).
`Cherng-Ju Kim, "Drug Release from Compressed Hydrophilic
`POLYOX-WSR Tablets," Journal of Pharmaceutical Sciences, vol.
`84, No.3, Mar. 1995.
`S.L. Madorsky eta!., "Thermal Degradation of Polyethylene Oxide
`and Polypropylene Oxide," Journal of Polymer Science, vol.
`XXXVI, pp. 183-194 (1959).
`A. Moroni eta!., "Application ofPoly(Oxyethylene) Homopolymers
`in Sustained Release Solid Formulations," Drug Development and
`Industrial Pharmacy, 21(12), 1411-1428 (1995).
`N. Ohnishi et al., "Effect of the Molecular Weight of Polyethylene
`Glycol on the Bioavailability of Indomethacin Sustained-Release
`Suppositories Prepared with Solid Dispersions," Chern. Pharm.
`Bull., 35 (8) 3511-3515 (1987).
`T. Ozeki et al., "Control of medicine release from solid dispersion
`the poly(ethylene oxide)-carboxyvinylpolymer
`composed of
`interpolymer complex by varying molecular weight of poly( ethylene
`oxide)," Journal of Controlled Release 58 (1999) 87-95.
`Pharmaceutical Research, Official Journal of the American Associa-
`tion of Pharmaceutical Scientists, Sep. 1989 (Supplement), vol. 6,
`No.9, 6.S-98.
`Pharmaceutical Research, Official Journal of the American Associa-
`tion ofPharmaceutical Scientists, Oct. 1991 (Supplement), Vo. 8, No.
`10, 8.S-192.
`W. Prapaitrakul eta!., "Release of Chlorpheniramine Maleate from
`Fatty Acid Ester Matrix Disks Prepared by Melt-extrusion," J. Pharm.
`Pharmacol. 1991,43: 377-381.
`S. Radko et a!., "Molecular sieving by polymer solutions: depen-
`dence on particle and polymer size, independence of polymer
`entanglement," Applied and Theoretical Electrophoresis (1995), 5,
`79-88.
`J. Scheirs eta!., "Characterizing the solid-state thermal oxidation of
`poly( ethylene oxide) powder," Polymer, 1991, vol. 32, No. 11.
`O.L. Sprockel et a!., "Permeability of Cellolose Polymers: Water
`Vapour Transmission Rates," J. Pharm. Pharmacol. 1990, 42: 152-
`157.
`J.L. Stringer et al., "Diffusion of small molecular weight drugs in
`radiation-crosslinked poly( ethylene oxide) hydrogels," Journal of
`Controlled Release 42 (1996) 195-202.
`E. G. Rippie eta!., "Regulation of Dissolution Rate by Pellet Geom-
`etry," Journal of Pharmaceutical Sciences, Vo. 58, No.4, Apr. 1969,
`pp. 428-431.
`M. Adel El-Egakey et a!., "Hot extruded dosage forms Part I,"
`PharmaceuticaActa Helvetiae, vol. 46, Mar. 19, 1970.
`Remington's Pharmaceutical Sciences 17th ed., Mack Publishing
`Co., (1985) 1418.
`M.S. Mesiha eta!., "A Screening Study of Lubricants in Wet Powder
`Masses Suitable for Extrusion Spheronization," Drug Development
`and Industrial Pharmacy, 19(8), 943-959 (1993).
`N. Follonier et a!., "Evaluation of Hot-Melt Extrusion as a New
`Technique for the Production ofPolymer-BasedPellets for Sustained
`Release Capsules Containing High Loadings of Freely Soluble
`Drugs," Drug Development and Industrial Pharmacy, 20(8), 1323-
`1339 (1994).
`Remington's Pharmaceutical Sciences, Authur Asol editor, pp. 1553-
`1593, Chapter 89, 1980.
`Inert Gas from Wikipedia (Dec. 2009).
`Coppens et a!; "Hypromellose, Ethylcellulose, and Polyethylene
`Oxide Use in Hot Melt Extrusion"; Pharmaceutical Technology,
`62-70, Jan. 2005.
`Caraballo et a!., "Percolation Thresholds in Ultrasound Compacted
`Tablets", Journal of Controlled Release, vol. 69, pp. 345-355, (2000).
`El-Sherbiny et al., "Preparation Characterization, Swelling and in
`Vitro Drug Release Behaviour of Poly[N -acryloylglycine-chitosan]
`Interpolymeric pH and Thermally-responsice Hydrogels", European
`Polymer Journal, vol. 41, pp. 2584-2591 (2005).
`Griffith R., "Tablet Crushing and the Law: The Implications for
`Nursing", Drug Administration, vol. 19, No. 1, p. 41-42 (2003).
`
`Levina eta!., "The Effect of Ultrasonic Vibration on the Compaction
`Characteristic ofParacetamol", Journal of Pharmaceutical Sciences,
`vol. 89, No.6, pp. 705-723, Jun. 2000.
`Levina eta!., "The Effecto ofUltrasonic Vibration on the Compaction
`Characteristic oflbuprofen", Drug Development and Industrial Phar-
`macy, vol. 28, No.5, pp. 495-514 (2002).
`Miller, et al., "To Crush or Not to Be Crush", Nursing, p. 50-52, Feb.
`2000.
`Mitchell J.E., "Oral Dosage Forms That Should Not Be Crushed:
`2000 Update", Special Resource, vol. 35, No.5, pp. 553-557, (2000).
`Proeschel eta!., "Task-Dependence of Activity/Bite-force Relations
`and its Impact on Estimation of Chewing Force from EMG", J. Dent.
`Res., vol. 81, No.7, pp. 464-468 (2002).
`Jan. 6, 2011 Letter from Dr. Rick Matos, Ph.D.
`Seach result conducted on http:/ /www.unitconversion.org/force/
`newtons-to-kiloponds-conversion.htrnl on Jul. 5, 2011.
`Katz eta!., Clin. J. Pain, 23(8): 648-660 (2007).
`Arnold, "Teen Abuse of Painkiller OxyContin on the Rise," www.
`npr.org, Dec. 19, 2005.
`Baum eta!., Public Health Reports, 102(4): 426-429 (1987).
`Purdue News, "Purdue Pharma Provides Update on Development of
`New Abuse-Resistant Pain Medications; FDA Cites Patient Needs As
`First Priority; New Drug Application Delayed," www.headaches.
`about.com, Jun. 18, 2002.
`Strang, British Med. J., 302: 969 (1991).
`Tompkins eta!., Psychopharma., 210: 471-480 (2010).
`Waters eta!., Am. J. Psychiatry, 164(1): pp. 173-174 (2007).
`Tablet, www.docstoc.com (2011).
`Dachille, F. eta!., "High-Pressure Phase Transformation in Labora-
`tory Mechanical Mixers and Mortars", 1906., Nature, 186, pp. 1-2
`(abstract).
`Yarbrough et a!., Letters to Nature 322, 347-349 (Jul. 24, 1986)
`"Extraodinary
`effects of mortar-and-pestle
`grinding
`on
`microstructure of sintered alumina gel".
`Braun, eta!. Angel Orthodontist, 6(5) pp. 373-377, 1995.
`Dow Excipients Chern. of Poly. Water Soluble Resin 2004.
`Davis
`et
`al., European
`Journal of Pharmaceutics
`Biopharmaceutics, 67, 2007, pp. 268-276.
`Fell, eta!. Journal of Pharmaceutical Sciences, vol. 59, No.5, May
`1970, pp. 688-691.
`Lockhart eta!. "Packaging of Pharmaceuticals and Health Care Prod-
`ucts"; Blackie Academic & Professional; First Edition 1996.
`Manthena et al., Amer J Drug Deliv. 2004: 2(1): 43-57.
`Summers eta!; Journal of Pharmaceutical Sciences, vol. 66, No. 8,
`Aug. 1977, pp. 1172-1175.
`Tipler et a!. Physics for Scientists and Engineers, 6th Edition, pp.
`234-235, 2003.
`US Pharmacopoeia, Chapter 1217, Aug. 1, 2008.
`Waltimo et al. A novel bite force recorder and maximal isometric bite
`force values for healthy young adults. Scand J Dent Res. 1993, vol.
`101, pp. 171-175.
`Waltimo eta!. Maximal bite force and its association with signs and
`symptoms of crandiomandibular disorders in young Finnish non-
`patients. Acta Odonol. Scand. 1995, vol. 53, pp. 254-258.
`Conversion of 18.8 kiloponds to newtons, http://www.unitconver-
`sion.org/force/newtons-to-kiloponds-conversion.htrnl on Jul. 5,
`2011.
`Bauer, Coated Pharmaceutical Dosage Forms, CRC Press, 1998, pp.
`1-10.
`Dachille, T., eta!. "High-pressure phase transformation in laboratory
`mechanical mixers and mortars", 1960, Nature, 186, pp. 1-2
`(abstract).
`Maggi, L. eta!., "High molecular weight polyethylene oxides (PEOs)
`as an alternative to HPMC in controlled release dosage form", 2000,
`International Journal of Pharmaceutics, 195 pp, 229-238.
`Maggi, "Therapeutic Potential of Capsaicin-like Molecules: Studies
`in Animals and Humans", Life Sciences, vol. 51, pp. 1777-1781,
`(1992).
`2.9 Methoden derpharmazeutischen Techno Iogie, pp. 143-144, 1997
`(English Translation included).
`Handbuch der Kunststoff-Extrusionstechnik, "Grundlagen", Chap-
`ter 1.2 "Klassifizierung von Extrudern", pp. 3-7, 1989, (English
`Translation included).
`
`and
`
`KASHIV1010
`IPR of Patent No. 9,492,392
`
`
`
`US 8,114,383 B2
`Page 6
`
`Freed eta!. pH control ofnucleophilic/electrophilic oxidation. Inter-
`national Journal of Pharmaceutics. 2008, vol. 357, pp. 180-188.
`Waterman et al. Stabilization of Pharmaceuticals to Oxidative Deg-
`radation. Pharmaceutical Development and Technology. 2002, vol. 7,
`No. 1, pp. 1-32.
`J. Stafford, "Uberzogene feste Formen", H. Sucker, Georg Thieme
`Verlag 1991, pp. 347-368.
`"Pharmaceutical technical procedures", European Pharmacopofia,
`1997, p. 135.
`
`Granulierung hydrophober Wirkstoffe im Planetwalzenextruder
`2003.
`Pharmazeutische Biologie Drogen und ihre Inhaltsstoffe, Professor
`Dr. Hildebert Wagner, Munchen, 1982, pp. 82-92.
`Coated Pharmaceutical Dosage Forms, K.H. Bauer, eta!., CRC Press,
`1998, pp. 1-10.
`* cited by examiner
`
`KASHIV1010
`IPR of Patent No. 9,492,392
`
`
`
`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