111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20070190142Al
`
`(19) United States
`c12) Patent Application Publication
`BREITENBACH et al.
`
`(10) Pub. No.: US 2007/0190142 A1
`Aug. 16, 2007
`(43) Pub. Date:
`
`(54) DOSAGE FORMS FOR THE DELIVERY OF
`DRUGS OF ABUSE AND RELATED
`METHODS
`
`(21) Appl. No.:
`
`111625,705
`
`(22) Filed:
`
`Jan. 22,2007
`
`(75)
`
`Inventors:
`
`Jorg BREITENBACH, Mannheim
`(DE); Ute Lander, Dannenfels
`(DE); Jorg Rosenberg, Ellerstadt
`(DE); Markus Maegerlein,
`Mannheim (DE); Gerd Woehrle,
`Eppelheim (DE)
`
`Correspondence Address:
`ROBERT DEBERARDINE
`ABBOTT LABORATORIES
`100 ABBOTT PARK ROAD, DEPT. 377/AP6A
`ABBOTT PARK, IL 60064-6008
`
`(73)
`
`Assignee:
`
`Abbott GmbH & Co. KG,
`Wiesbaden (DE)
`
`(60)
`
`Related U.S. Application Data
`Provisional application No. 60/760,707, filed on Jan.
`21, 2006.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 9126
`(52) U.S. Cl. ....................................................... 424/469
`
`(57)
`ABSTRACT
`A dosage form and method for the delivery of drugs,
`particularly drugs of abuse, characterized by resistance to
`solvent extraction, tampering, crushing, or grinding, and
`providing an initial burst of release of drug followed by a
`prolonged period of controllable drug release.
`
`'-------_>
`
`F on:a transducer
`
`Tablet holder
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 1 of 22
`
`US 2007/0190142 A1
`
`Fig. 1
`
`80
`
`60
`
`40
`
`~
`0
`c
`Ql
`Ul
`!II
`Ql
`~
`Cl
`,_
`::1
`"C
`
`0
`
`2
`
`6
`
`8
`
`4
`time (hours)
`
`Fig. 2
`
`100
`
`80
`
`~ 0
`
`.=
`(I)
`til 60
`.. Cl
`ra
`Ql
`(ij
`... "tl
`
`::1
`
`40
`
`-.-Form 1
`-Form2
`-.-Form3
`-e-Form4
`-B-Form 5
`~Form6
`
`-.-Form 1
`-II-Form2
`-.-Form 3
`-9-Form 4
`-B-Form 5
`-h:-Form 6
`
`20
`
`0----------~----------~--------~--------~
`0
`6
`8
`2
`4
`time (hours)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 2 of 22
`
`US 2007/0190142 A1
`
`100
`
`Fig. 3
`
`time (min)
`
`Fig. 4
`
`-.-Form 7
`
`-.-Form 8
`
`-Ill-Form 9
`
`-.-Form 7
`
`-.-Form 8
`
`-Ill-Form 9
`
`100
`
`200
`
`300
`
`400
`
`500
`
`time (min)
`
`0
`
`80
`
`60
`
`:::e:
`.E
`Q)
`1/)
`nl
`Q)
`~
`Cl 40
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`
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`
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`
`60
`
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`Q)
`(/j
`nl
`Q)
`Qj ....
`Cl 40
`:I ....
`'C
`
`20
`
`0
`
`0
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 3 of 22
`
`US 2007/0190142 A1
`
`Fig. 5
`
`100
`
`60
`
`~ 80
`.E
`C1l
`t/)
`Ill
`C1l
`
`a; ...
`tn 40
`:::s
`....
`'t:l
`
`20
`
`0
`
`0
`
`100
`
`~ 80
`c
`.5
`Ql
`t/)
`Ill
`Ql
`
`60
`
`a; ...
`Ol 40
`:::s
`....
`'t:l
`
`.....-Form 7
`
`--+-Form 8
`
`-II-Form9
`
`100
`
`200
`
`300
`
`400
`
`500
`
`time (min)
`
`Fig. 6
`
`--+-Form 8
`
`-II-Form9
`
`20
`
`0
`
`0
`
`100
`
`200
`
`300
`
`400
`
`500
`
`time (min)
`
`Fig. 7
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 4 of 22
`
`US 2007/0190142 A1
`
`Force transrlucer
`
`T eblet holder
`
`E
`E
`-:;t
`......
`
`Fig. 8
`
`.... t0.5mm
`
`f.r4 30 mm 111-1
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 5 of 22
`
`US 2007/0190142 A1
`
`Fig. 9
`OH
`
`0
`
`NH
`
`(9A)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 6 of 22
`
`US 2007/0190142 A1
`
`Acetaminophen (Form 30)
`t 1/2 Cmax
`Tmax
`AUG
`(hr)
`(nglmL)
`(hr)
`(ng·hrlmL)
`6.8
`7074.0
`8.0
`98100
`3.6
`5368.0
`24.0
`110000
`5.0
`12.0
`6295.0
`111000
`4.7
`10577.0
`6.0
`102000
`8.0
`4.8
`7889.0
`119000
`6.2
`12.0
`4945.0
`97000
`5.0°
`7024.7
`11.7
`106000
`2048.0
`8760
`6.5
`
`Minipigs #
`1
`2
`3
`4
`5
`6
`Mean
`SEM
`
`(9.B)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 7 of 22
`
`US 2007/0190142 A1
`
`10000
`
`c 1000
`
`H-tl Oral
`
`-.....
`E -m
`-c
`0 ·-.. I! .. c
`
`G) u c
`0 u
`
`100
`
`10~--~--~--~--~--~--~--~--~
`36
`12
`48
`24
`0
`Hours After Dose
`
`(9 C)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 8 of 22
`
`US 2007/0190142 A1
`
`Fig. 10.
`
`Species
`
`Fonnulation
`
`Minipigs (n=6)
`26
`27
`Minipigs (n=6)
`Minipigs (n=6)
`28
`Minipigs (n=6)
`29
`Minipigs (n=6)
`30
`Minipigs (n=6) Control2
`Minipigs (n=6) Control1
`Human (n=8) Control1
`
`AUC
`Tmax
`Cmax
`t1/2
`(ng.hr/mL}
`(hr}
`(ng/mL)
`lhr)
`9 (3.3)
`5314 (805)
`5.8 (0.9)
`'101433 (13053)
`9 (1.4)
`87567 (4504)
`4181 (473)
`5.7 (0.8)
`98100 (9759)
`4.9 (1.2) 6310 (1384) 13 (3.8)
`97500 (8254)
`3.5 (0.2) 6567 (3587) 9.7 {7.2)
`5.2 (0.4) 7025 (2048) 11.7 (6.5) 106000 (8760)
`'10319 (3003) 5.3 (2.3) 102000 (20500)
`3.3 {0.1)
`110000 (21100)
`3.5 (0.2) 8508 (2324)
`4.2 (3)
`2262 (487)
`2.4 (3.9)
`23700 (5010)
`4.7 (0.2)
`
`(10A)
`
`-mean Acetaminophen human plasma n=B
`···of!!"" mean Acetaminophen minipig rnale plasma Fonn 26 n=B
`--+--mean Acetaminophen minipig male plasma Form 27 n=B
`-·"'1'-- mean Acetaminophen minipig male plasma Form 28 n=B
`·· -&-- mean Acctmninophen minipig male plasma Form 28n"'6
`·
`Contrnl1
`male plasma D>n11'ot2 n=G
`Form 30 (n~:b)
`
`......... mean A.cetarninophen
`rne2r /\c::Jt,~;Yiinopi':en
`
`(10 B)
`
`:::J'
`..§
`rn s
`c:
`0
`~ c:
`Cl) " c:
`0 u
`"'
`E
`"' "' D.
`
`107
`
`10e
`
`105
`
`104
`
`1000
`
`100
`
`10
`
`0.1
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`time (hr)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 9 of 22
`
`US 2007/0190142 A1
`
`Fig. 11
`
`~mean Acetaminophen human plasma 11=8
`···•··· mean Acetaminophen minipig male plasma Form 26 n=6
`--+-- mean Acetaminophen minipig male plasma Form 27 n=6
`__ ., ___ mean Acetaminophen minipig male plasma Form 28 n=6
`.. ·&- .. -mean Acetaminophen minipig male plasma Form 29 n=6
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`time {hr)
`
`_j
`~
`Ol c
`c
`0
`:;:::;
`(I]
`'-c (J)
`0 c
`0
`0
`(I]
`E m
`
`~
`0..
`
`105
`
`104
`
`1000
`
`100
`
`10
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 10 of 22 US 2007/0190142 A1
`
`Species
`
`Fonnulation
`
`Minipigs (n=G)
`Minipigs (n=G)
`Minipigs (n=G)
`Minipigs (n=2)
`Mini pigs (n=1)
`Minipigs (n=2)
`Hwnan (n=8)
`
`26
`27
`28
`29
`Control 2
`Control1
`
`Cantrol1
`
`Fig. 12
`Tmax
`Cmax
`t1/2
`AUC
`(ng.hr/mL)
`fng/mL)
`(hr)
`(hr}
`5.8 (0.9}
`'101433 (13053)
`9 (3.3)
`5314 (805)
`87567 (4504)
`9 (1.4)
`4181 (473)
`5.7 (0. 8)
`98100 (9759)
`4.9 (1.2) 6310 (1384) 13 (3.8)
`7 (1.4)
`120000 (4-/.50)
`3.5 (0.2) 8413 (5977)
`105000
`3.5
`13142
`4
`3.6 (0.2) 9255 (3962) 4.8 (4.6) 111 000 (38-/.00)
`4.7 (0.2)
`2262 (487)
`2.4 (3.9)
`23700 (5010)
`
`(12 A)
`
`(12
`
`C')
`
`:::::;-
`.§
`5
`c::
`0
`-~
`c
`"' Ll c
`"' E "' "' 0..
`
`0
`Ll
`
`--mean Acetaminophen human plasma n=G
`--111- ·mean Acetaminophen minipig male plasma Form 26 n=G
`-mean Acetaminophen minipig male plasma Form 27 n"'6
`-- v-- mean Acetaminophen minipig rna le plasma Form 28 n=G
`• · &· ·mean Acetaminophen minipig male plasma Form 29 n=2
`
`- ·.,- · mean Acetaminophen minipig rna le plasmaControl2 11"''1
`
`B)
`
`10°
`
`10°
`
`104
`
`1000
`
`100
`
`10
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`BO
`
`time (hr)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 11 of 22
`
`US 2007/0190142 A1
`
`Fig. 13
`
`(13 A)
`
`Species
`
`Formulation
`
`Minipigs
`Minipigs (n=1)
`Minipigs (n=·1}
`Minipigs
`Minipigs (n=·1)
`Minipigs
`Hum an (n=S)
`
`Form26
`Form27
`Form28
`Form29
`Control 2
`CDntro I 1
`::::ontrol 1
`
`t1/2
`(hr)
`n.c
`0.8
`2.5
`n.c
`n.c
`n.c
`6.5 (0.3)
`
`Cmax
`(ng/mL)
`n.c
`12.4
`30.6
`n.c
`1.9
`n.c
`18.5(1.3)
`
`Tmax
`(hrl
`n.c
`0.5
`1
`n.c
`3
`n.c
`8.6_{1.5)
`
`AUC
`_{ng.hr/mll
`n.c
`16.4
`85.9
`n.c
`5.2
`n.c
`331_{23.2)
`
`(13
`B)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 12 of 22
`
`US 2007/0190142 A1
`
`100
`
`o mean Hydrocodone human plasma n=B
`~mean Hydrocodone Form 27 minipig male plasma n=1
`__,.,..__mean Hydrocodone Form 28. minipig male plasma n=1
`.... ..;. .... rnean Hydrocodone C3PAS minipig male plasn1a n=1
`
`c
`0
`-~ ._
`....... c
`Cl..l u c
`0 u
`E Vl
`
`ro
`Cl..
`
`0.1
`
`0.01
`
`D
`
`10
`
`20
`
`30
`
`40
`time (hr)
`
`50
`
`60
`
`70
`
`BD
`
`(13 C)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 13 of 22 US 2007/0190142 A1
`
`::,!!
`0
`c::
`Q)
`til
`Ill
`Q)
`
`iii ...
`...
`
`Cl
`:I
`"C
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`Fig.14
`
`-ia-Form 33
`-+-Form 34
`-1111-Form 35
`-a-Form 36
`
`100
`
`200
`
`300
`
`400
`
`500
`
`time (min)
`
`Fig.15
`
`~--------------------------------~-1-Rnn~
`
`100
`
`-k-Rnn33
`-+-Rnn34
`----- Rnn351
`-B-Rnn3l
`
`100
`
`15)
`
`2:()
`
`tirre(nirj
`
`400
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 14 of 22 US 2007/0190142 A1
`
`Fig. 16
`
`100
`
`80
`
`60
`
`~ 0
`.5
`<II
`Ul
`n:l <II
`Q)
`0:::
`C) 40
`:I .... "0
`
`20
`
`0
`
`0
`
`100
`
`0
`
`~ 80
`.5
`
`60
`
`Q)
`(/)
`Ill
`Cl>
`Q)
`0:::
`C) 40
`:I .....
`"0
`
`-G-Form 31
`
`--A-Form 31
`40°C/75% r.h.
`....,._Form 31
`60°C/dry
`-II- Form 31
`25°C/75% r.h.
`
`300
`
`350
`
`400
`
`450
`
`500
`
`50
`
`100
`
`150
`
`200
`
`250
`time (min)
`
`Fig. 17
`
`-e-Form 31
`
`--A-Form 31
`40°C/75% r.h.
`.....-Form 31
`60°C/dry
`--II-Form31
`25°C/75% r.h.
`
`20
`
`0
`
`0
`
`50
`
`100
`
`150
`
`200
`
`250
`time (min)
`
`300
`
`350
`
`400
`
`450
`
`500
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 15 of 22
`
`US 2007/0190142 A1
`
`Fig. 18
`
`100
`
`-
`...a-:::a-...JIIII.
`....
`~--
`100
`0
`
`-llllr
`
`-
`-
`
`......
`=
`
`-o-Form 32
`
`__.___Form 34
`
`-Ill --11- Form 36
`
`-
`
`200
`
`300
`
`400
`
`500
`
`time (min)
`
`Fig. 19
`
`80
`
`60
`
`~ "
`r:::
`(!)
`If)
`Ill
`(!)
`...
`Qi
`::l ..
`Cl 40
`"
`
`20
`
`0
`
`100
`
`~ <>
`
`80
`
`60
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`·=
`Ill
`If)
`Ill
`..!!:!
`Ill ...
`::l ..
`Cl 40
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`
`...
`20 ~ -
`--
`0 ~-
`0
`
`100
`
`200
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`-o-Form 32
`
`-..-Form 34
`
`-II --11-Form 36
`
`.JIIIII.-
`
`-
`
`300
`
`400
`
`500
`
`time (min)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 16 of 22
`
`US 2007/0190142 A1
`
`Fig. 20
`
`100
`
`Cll
`II)
`
`60
`
`80
`
`~ c
`
`·=
`"' Cll
`~
`Cl 40
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`~
`
`-e-Form 32
`
`---;k- Form 34
`
`--111- Form 36
`
`20
`
`0
`
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`
`100
`
`80
`
`60
`
`40
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`20
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`Cll
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`,
`2
`
`0
`
`0
`
`100
`
`200
`
`300
`
`400
`
`500
`
`time (min)
`
`Fig. 21
`
`-e-Form 32
`
`---;k- Form 34
`
`--111- Form 36
`
`100
`
`200
`
`300
`
`400
`
`500
`
`time (min)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 17 of 22
`
`US 2007/0190142 A1
`
`100
`
`60
`
`~ 80
`Q c:
`Ql
`Ill
`CIS
`Ql a;
`....
`C) 40
`....
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`
`20
`
`0
`
`0
`
`100
`
`Fig. 22
`
`-.6r- Form 39
`
`-IIII-Form40
`
`100
`
`200
`
`300
`
`400
`
`500
`
`time (min)
`
`Fig. 23
`
`-e-Form 38
`
`-.-Form 39
`
`60
`
`~ Q
`
`80
`
`·=
`Ql
`Ill
`CIS
`Ql a;
`....
`C) 40
`....
`::J
`"0
`
`20
`
`0
`
`0
`
`100
`
`200
`
`300
`
`400
`
`500
`
`time (min)
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 18 of 22
`
`US 2007/0190142 A1
`
`Fig. 24
`
`1001
`
`(1)
`
`~ 0 .s
`801
`60
`* ~ .. .:=
`
`.:) -
`
`~
`"0
`
`1--.-r=orm~
`1----k- Form 39/
`
`2)-
`
`0 .L--------~---------~
`100
`"\':.IJ
`(j
`~\l\J
`2.~
`time (min)
`
`300
`
`35G
`
`400
`
`45[1
`
`Fig.25
`
`~~-~--~-~-- ·---------· ·-~
`
`-:x-
`
`"l €G
`
`!
`4D-\
`
`20 ~
`
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`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 19 of 22
`
`US 2007/0190142 A1
`
`Fig. 26
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`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 20 of 22 US 2007/0190142 A1
`
`Fig. 27
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`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 21 of 22 US 2007/0190142 A1
`
`Fig. 29
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`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`Patent Application Publication Aug. 16, 2007 Sheet 22 of 22 US 2007/0190142 A1
`
`Fig. 31
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`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`US 2007/0190142 AI
`
`Aug. 16, 2007
`
`1
`
`DOSAGE FORMS FOR THE DELIVERY OF
`DRUGS OF ABUSE AND RELATED
`METHODS
`
`TECHNICAL FIELD OF THE INVENTION
`[0001] The present invention relates to compositions for
`oral administration. The present invention preferably com-
`prises at least one abuse-resistant drug delivery composition
`for delivering a drug having abuse potential, related methods
`of preparing these dosage forms, and methods of treating a
`patient in need thereof comprising administering the inven-
`tive compositions to the patient.
`
`BACKGROUND OF THE INVENTION
`[0002] Abuse of prescription drugs has become a public
`health problem in many communities. One common class of
`drugs that is subject to abuse is the opioid class. Opioids are
`the major class of analgesics used in the management of
`moderate to severe pain in the United States of America
`because of their effectiveness, ease of titration, and favor-
`able risk-to-benefit ratio.
`[0003] One of the effects of opioid administration is the
`ability of such drugs in some individuals to alter mood and
`feeling in a manner so as to provide a desirable sense of
`"well-being" dissociated from therapeutic ameliorative
`effects. This mood-altering effect is found by some indi-
`viduals to be extremely pleasurable, and may be related to
`the fact that some users are at high risk of using the drugs
`illicitly and becoming addicted to opioids.
`[0004] Three basic patterns of opioid abuse have been
`identified in the United States. One involves individuals
`whose drug use begins in the context of medical treatment
`and initially obtain their drug through medical channels.
`Another involves persons who begin their drug use with
`experimental or "recreational" drug use and progress to
`more intensive drug use. Lastly, there are users who begin
`using drugs obtained from medical channels or through
`recreational drug channels, but later switch to oral opioids
`obtained from organized addiction treatment programs.
`[0005] Abuse of opioids by the oral route is significant.
`However, another significant problem for opioid abuse
`appears to be the abuse of the drugs by parenteral admin-
`istration, particularly by injection. Rapid injection of opioid
`agonists is known to produce a warm flushing of the skin and
`sensations. The state, known alternatively as a "rush,"
`"kick," or "thrill," typically lasts for only about 45 seconds
`but is found extremely pleasurable to addicts. Addicted
`individuals will extract solid dosage forms of opioids and
`then inject the same to attain such a state. Opioids have also
`been known to be abused via nasal administration, where the
`potential drug of abuse is crushed and powdered and snorted
`nasally.
`[0006] Some presently proposed pharmacological meth-
`ods for dissuading the extraction of oral opioids incorporate
`of one or more of opioid antagonists, mixed opioid agonist-
`antagonists and other adversative drug agents, with the
`therapeutic opioid agonist. In most proposed systems, the
`dose of opioid antagonist is not orally active but will block
`the effects desired by abusers of the agonist drug, or mixed
`agonist-antagonist drug, when the drug is dissolved to obtain
`the agonist (or mixed agonist-antagonist drug) and the
`opioid is subsequently administered parenterally. In these
`cases, however, physicians may be concerned that inappro-
`
`priate release of aversive drugs may cause harm and some
`have expressed a reluctance to prescribe opioids co-formu-
`lated with aversive agents.
`[0007] For example, a drawback of approaches that incor-
`porate opioid antagonists into the opioid preparation to
`dissuade abuse is that opioid antagonists themselves have
`side effects that may be disadvantageous. For example,
`nalorphine causes unpleasant reactions such as anxiety,
`irrational feelings, hallucinations, respiratory depression and
`miosis. Seizures have been reported with naloxone, albeit
`infrequently, and in postoperative patients, pulmonary
`edema and ventricular fibrillation have been seen with high
`dosages. Naltrexone has been reported to have the capacity
`to cause hepatocellular injury when given in doses as low as
`fivefold or less of therapeutic doses. Nalmefene, although
`usually well tolerated, has been reported to cause nausea,
`vomiting and tachycardia in some individuals. Small doses
`of any of these opioid antagonists can also precipitate
`withdrawal in opioid addicted individuals even at low doses,
`a phenomenon that can be extremely dangerous depending
`upon where the addicted individual takes the drug.
`[0008] Similarly to the opioids, many other classes of
`drugs are also subject to abuse, although the patterns and
`effects of the abuse differ to some degree.
`[0009] WO 2005/079760 (Euroceltique) discloses melt-
`extruded, multiparticulated, controlled release formulations
`containing a neutral poly(ethyl acrylate, methyl methacry-
`late) copolymer and an active ingredient. The formulations
`are said to show rubber-like properties such that they exhibit
`enhanced resistance to tampering.
`[0010] US 2003/0118641 (Boehringer Ingelheim) relates
`to a method for reducing the abuse potential of an oral
`dosage form of an opioid extractable by commonly available
`household solvents said method comprising combining a
`therapeutically effective amount of the opioid compound, a
`matrix-forming polymer and an ionic exchange resin. Pref-
`erence is given to ionic exchange resins that are strongly
`acidic.
`[0011] WO 00/041481 (Knoll) relates to medicament
`forms containing active substances with high water-solubil-
`ity in a matrix based on acrylate polymers.
`[0012] US Patent Application Publication No. 2006/
`0002860 (Bartholomaus et a!.) relates to tamper-resistant
`drug formulations useful in the context of drugs of abuse.
`[0013] While numerous compositions, formulations and
`methodologies exist to address abuse of drugs, all compo-
`sitions, formulations and methods have limitations to a
`greater or lesser extent. Accordingly, there is a need for
`providing new and/or improved formulations, compositions
`and methods of preventing abuse of drugs having abuse
`potential.
`[0014] This background information is provided for the
`purpose of making known some information believed by the
`applicant to be of possible relevance to the present inven-
`tion. No admission is intended, nor should be construed, that
`any of the preceding information constitutes prior art to the
`present invention.
`
`SUMMARY OF THE INVENTION
`
`[0015] Certain preferred embodiments of the present
`invention provide dosage forms and methods for the deliv-
`ery of drugs, particularly drugs of abuse, characterized by
`resistance to solvent extraction; tampering, crushing or
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`US 2007/0190142 AI
`
`2
`
`Aug. 16, 2007
`
`grinding, and providing an initial burst of release of drug
`followed by a prolonged period of controllable drug release.
`[0016] One exemplary embodiment of the present inven-
`tion provides an abuse-deterrent drug formulation compris-
`ing a melt-processed mixture of: a) at least one abuse-
`relevant drug, b) at least one cellulose ether or cellulose
`ester, and c) at least one alkyl alkacrylate polymer, alkacry-
`late polymer, or a combination thereof. In this embodiment,
`the amount of the drug that is extracted from the formulation
`by 40% aqueous ethanol within one hour at 37° C. is less
`than or equal to twice the amount of the drug that is extracted
`by 0.01 N hydrochloric acid within one hour at 37° C.; and
`the drug formulation is adapted so as to be useful for oral
`administration to a human 3, 2, or 1 times daily.
`[0017] Another exemplary embodiment of the present
`invention provides a monolithic, sustained release oral dos-
`age formulation comprising a melt-processed mixture of: a)
`an analgesically effective amount of at least one an abuse-
`relevant drug, b) at least one cellulose ether or cellulose
`ester, and c) at least one alkyl alkacrylate polymer, alkacry-
`late polymer, or a combination thereof. In this embodiment,
`the amount of the drug that is extracted from the formulation
`by 40% aqueous ethanol within one hour at 37° C. is less
`than or equal to twice the amount of the drug that is extracted
`by 0.01 N hydrochloric acid within one hour at 37° C.; and
`the drug formulation is adapted for sustained release so as to
`be useful for oral administration to a human 3, 2, or 1 times
`daily.
`[0018] Yet another exemplary embodiment of the present
`invention provides an oral sustained release dosage formu-
`lation of a drug characterized by at least two of the following
`features: a) the drug that is extracted from the formulation by
`40% aqueous ethanol within one hour at 37° C. is less than
`or equal twice the amount of the drug that is extracted by
`0.01 N hydrochloric acid within one hour at 37° C., b) the
`formulation does not break under a force of 150 newtons,
`preferably 300 newtons, more preferably 450 newtons, yet
`more preferably 500 newtons as measured by "Pharma Test
`PTB 501" hardness tester, and c) the formulation releases at
`least 15% of the one drug and not more than 45% of the one
`drug during the first hour in vitro dissolution testing and
`preferably also in vivo.
`[0019] Another exemplary embodiment of the present
`invention provides a non-milled, melt-extruded drug formu-
`lation comprising a drug with abuse potential.
`[0020] An exemplary embodiment of the present inven-
`tion also provides a monolithic, non-milled, non-multipar-
`ticulated, melt-extruded drug formulation comprising a drug
`with abuse potential having a diameter from about at least
`5.1 mm to about 10 mm and a length from about 5.1 mm to
`about 30 mm.
`[0021] Another exemplary embodiment of the present
`invention provides a process for the manufacture of an
`abuse-resistant drug dosage formulation comprising melt
`extruding a formulation comprising at least one therapeutic
`drug further comprising directly shaping the extrudate into
`a dosage form without (an intermediate) milling step or
`multiparticulating step.
`[0022] Yet another exemplary embodiment of the present
`invention provides a monolithic, non-milled, melt-extruded
`drug formulation comprising a drug with abuse potential
`wherein the monolithic formulation has a substantially simi-
`lar drug release profile to a crushed form of the monolithic
`formulation wherein the monolithic formulation is crushed
`
`at about 20,000 rpm to about 50,000 rpm in a coffee grinding
`machine for about 60 seconds in a grinder having stainless
`steel blades, about a 150 watt motor, and a capacity for about
`90 milliliters (i.e., about 3 ounces) of coffee beans.
`[0023] Another exemplary embodiment of the present
`invention provides an abuse-deterrent drug formulation
`comprising a melt-processed mixture of: a) at least one
`abuse-relevant drug, b) at least one rate altering pharmaceu-
`tically acceptable polymer, copolymer, or a combination
`thereof. In this embodiment, the amount of the drug that is
`extracted from the formulation by 40% aqueous ethanol
`within one hour at 37° C. is less than or equal to twice the
`amount of the drug that is extracted by 0.01 N hydrochloric
`acid within one hour at 37° C.; and
`the drug formulation is adapted so as to be useful for oral
`administration to a human 3, 2, or 1 times daily.
`[0024] Yet another exemplary embodiment of the present
`invention provides an abuse-deterrent drug formulation
`comprising a melt-processed mixture of: a) at least one
`abuse-relevant drug, wherein said drug is hydrocodone (or a
`pharmaceutically accepted salt like e.g. hydrocodone bitar-
`trate pentahemihydrate ), b) at least one cellulose ether or
`cellulose ester, and c) at least one acrylic polymer, meth-
`acrylic polymer, or a combination thereof. In this embodi-
`ment, the drug formulation is adapted so as to be useful for
`oral administration to a human 3, 2, or 1 times daily; and
`about ninety percent of the hydrocodone is released in vitro
`at about 4-6 hours when adapted to be administered 3 times
`a day, at about 6-10 hours when adapted to be administered
`2 times a day and about 16-22 hours when adapted to be
`administered 1 time a day.
`[0025] Another exemplary embodiment of the present
`invention also provides an abuse-deterrent drug formulation
`comprising a melt-processed mixture of: a) at least one
`opioid; and b) at least one rate altering pharmaceutically
`acceptable polymer, copolymer, or a combination thereof. In
`this embodiment, the amount of the drug that is extracted
`from the formulation by 40% aqueous ethanol within one
`hour at 37° C. is about 70% to about 110% of the amount of
`the drug that is extracted by 0.01 N hydrochloric acid within
`one hour at 37° C.; and the drug formulation is adapted so
`as to be useful for oral administration to a human 3, 2, or 1
`times daily. This and other embodiments have desirable
`pharmacokinetic profiles.
`In another exemplary embodiment, the present
`[0026]
`invention provides a method for treating pain in a human
`patient, comprising orally administering to the human
`patient a formulation from any one of the above embodi-
`ments.
`[0027] These and other objects, advantages, and features
`of the invention will become apparent to those persons
`skilled in the art upon reading the details of the methods of
`the invention and compositions used therein as more fully
`described below.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0028] FIG. 1 depicts the rate of dissolution of various
`drug dosage forms 1-6 in 0.01 M hydrochloric acid.
`[0029] FIG. 2 depicts the rate of dissolution of various
`drug dosage forms 1-6 in 20% aqueous ethanol.
`[0030] FIG. 3 depicts the rate of dissolution of various
`drug dosage forms 7-9 of hydrocodone in 0.01 N hydro-
`chloric acid.
`
`KASHIV1063
`IPR of Patent No. 9,492,392
`
`

`

`US 2007/0190142 AI
`
`3
`
`Aug. 16, 2007
`
`[0031] FIG. 4 depicts rate of dissolution of various drug
`dosage forms 7-9 of acetaminophen (APAP; also known as
`paracetamol) in 0.01 N hydrochloric acid.
`[0032] FIG. 5 depicts the rate of dissolution of various
`drug dosage forms 7-9 of hydrocodone in 40% aqueous
`ethanol.
`[0033] FIG. 6 depicts rate of dissolution of various drug
`dosage forms 7-9 of acetaminophen (APAP) in 40% aqueous
`ethanol.
`[0034] FIG. 7 depicts a force transducer and an exemplary
`tablet holder having a tablet used for measuring breaking
`strength of tablets.
`[0035] FIG. 8 depicts a cylinder with a wedge-shaped tip
`having certain exemplary dimensions useful for conducting
`"Pharma Test PTB 501" for measuring hardness of a tablet.
`[0036] FIG. 9 (A) depicts the chemical structure for
`acetaminophen (APAP), (B) depicts half-life, Cmax, Tmax
`and AUC for some embodiments of the inventive formula-
`tion (30) following oral dose administration of this formu-
`lation (30) in male minipigs Goettingen) (C) depicts mean
`(±SEM) plasma concentrations of acetaminophen following
`oral dose administration of an embodiment of the inventive
`formulation (30) in male minipigs (Goettingen).
`[0037] FIG. 10 (A) depicts half-life, Cmax, Tmax and
`AUC for certain embodiments of the inventive formulation
`(Forms 26, 27, 28, 29, 30), Control! and Control2 in male
`minipigs (Goettingen) and Control 1 formulation in human
`(B) depicts mean (±SEM) plasma concentrations of acetami-
`nophen following oral dose administration of certain
`embodiments of the inventive formulation (Forms 26, 27,
`28, 29, 30), control 1 and control 2 in male minipigs
`(Goettingen) and Control 1 formulation in human.
`[0038] FIG. 11 depicts mean (±SEM) plasma concentra-
`tions of acetaminophen following oral dose administration
`of certain embodiments of the inventive formulation (Forms
`26, 27, 28, 29 & 30), Control 1 and Control 2 in male
`minipigs (Goettingen) and Control 1 formulation in human.
`[0039] FIG. 12 (A) depicts half-life, Cmax, Tmax and
`AUC for certain embodiments of the inventive formulation
`(Forms 26, 27, 28 & 29), Control 1 and Control 2 in male
`minipigs (Goettingen) and Control 1 formulation; (B)
`depicts mean (±SEM) plasma concentrations of acetami-
`nophen following oral dose administration of certain
`embodiments of the inventive formulation (Forms 26, 27, 28
`& 29), Control 1 and Control 2 in male minipigs (Goettin-
`gen) and Control 1 formulation.
`[0040] FIG. 13 (A) depicts chemical structure for hydro-
`codone; (B) depicts half-life, Cmax, Tmax and AUC fol-
`lowing oral dose administration of certain embodiments of
`the inventiv