United States Patent [19J
`Oshlack et al.
`
`[54] EXTRUDED ORALLY ADMINISTRABLE
`OPIOID FORMULATIONS
`
`[75]
`
`Inventors: Benjamin Oshlack, New York, N.Y.;
`Mark Chasin, Manalapan; Hua-Pin
`Huang, Englewood Cliffs, both of N.J.
`
`[73] Assignee: Euro-Celtique, S.A., Luxembourg,
`Luxembourg
`
`[21] Appl. No.: 08/833,948
`
`[22] Filed:
`
`Apr. 10, 1997
`
`Related U.S. Application Data
`
`[51]
`
`[63] Continuation-in-part of application No. PCT/US95/14745,
`Nov. 3, 1995, which is a continuation-in-part of application
`No. 08/334,209, Nov. 4, 1994.
`Int. Cl.6
`
`............................... A61K 9/16; A61K 9/22;
`A61K 9/52
`[52] U.S. Cl. .......................... 424/457; 424/456; 424/468;
`424/489; 514/772.3; 514/772.6; 514/781;
`514/784
`[58] Field of Search ..................................... 424/456, 468,
`424/469, 451, 457, 464, 489, 484, 485,
`486, 488
`
`[56]
`
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`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US005958452A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,958,452
`Sep.28,1999
`
`FOREIGN PATENT DOCUMENTS
`
`57224
`8976091
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`
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`
`(List continued on next page.)
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-James M. Spear
`Attorney, Agent, or Firm-Davidson, Davidson & Kappel,
`LLC
`
`[57]
`
`ABSTRACT
`
`Bioavailable sustained release oral opioid analgesic dosage
`forms, comprising a plurality of multiparticulates produced
`via melt extrusion techniques are disclosed.
`
`(List continued on next page.)
`
`69 Claims, 17 Drawing Sheets
`
`·----·-------------......----Rs-1
`
`I 00
`
`90
`
`80
`
`70
`
`60 t
`
`... /
`I
`I
`I
`I
`
`MEAN%
`OISSOLVEO
`
`10
`
`12
`HOURS
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`--0-EX I
`
`--e-EX 2
`
`1
`
`

`
`5,958,452
`Page 2
`
`U.S. PATENT DOCUMENTS
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`4,173,417 11/1979 Kruder ...................................... 366/89
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`3/1981 Lowey ...................................... 424/19
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`5/1981 Byrne et a!. .............................. 424/19
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`9/1981 Byrne et a!. .............................. 424/19
`4,310,483
`1!1982 Dorfel et a!.
`........................... 264/117
`8/1982 Kawata eta!. .......................... 424/461
`4,343,789
`..................................... 128/260
`4,344,431
`8/1982 Yolles
`4,346,709
`8/1982 Schmitt ................................... 128/260
`4,366,172 12/1982 Lednicer ................................. 424/330
`4,374,082
`2/1983 Hochschild ............................. 264/129
`4,380,534
`4/1983 Fukui et a!.
`.............................. 264/38
`4,389,393
`6/1983 Schor et a!.
`.............................. 424/19
`4,406,883
`9/1983 Byrne et a!. .............................. 424/80
`4,421,736 12/1983 Walters eta!. ............................ 424/21
`4,483,847 11/1984 Augart ...................................... 424/22
`4,533,562
`8/1985 Ikegami et a!. ............................. 427/3
`4,613,619
`9/1986 Sleigh eta!. ............................ 514/546
`4,621,114 11/1986 Watanabe ................................ 524/451
`4,649,042
`3/1987 Davis et a!.
`............................ 424/438
`4,720,384
`1!1988 DiLuccio eta!. ......................... 424/78
`8/1988 Keith eta!. ............................. 424/435
`4,764,378
`4,778,676 10/1988 Yang eta!. ............................... 424/79
`4,801,458
`1!1989 Hidaka et a!. .......................... 424/443
`4,801,460
`1!1989 Goertz et a!. ........................... 424/465
`4,806,337
`2/1989 Snipes et a!. ............................... 71/65
`4,818,450
`4/1989 Hall et a!. ................................. 264/39
`4,828,836
`5/1989 Elger eta!. ............................. 424/419
`4,834,984
`5/1989 Goldie et a!. ........................... 424/488
`4,842,761
`6/1989 Rutherford ................................ 252/90
`4,844,907
`7/1989 Elger eta!. ............................. 424/465
`4,844,909
`7/1989 Goldie eta!. ........................... 424/480
`4,861,598
`8/1989 Oshlack .................................. 424/468
`4,879,108 11/1989 Yang et a!.
`............................. 424/440
`4,880,585 11/1989 Klimesch eta!. ...................... 264/141
`4,880,830 11/1989 Rhodes .................................... 424/470
`4,882,151 11/1989 Yang et a!.
`............................. 424/440
`4,882,152 11/1989 Yang et a!.
`............................. 424/440
`4,882,153 11/1989 Yang et a!.
`............................. 424/440
`4,882,155 11/1989 Yang et a!.
`............................. 424/440
`4,882,156 11/1989 Yang et a!.
`............................. 424/440
`4,882,157 11/1989 Yang et a!.
`............................. 424/440
`4,882,159 11/1989 Yang et a!.
`............................. 424/440
`4,882,167 11/1989 Jang ........................................ 424/468
`4,894,234
`1!1990 Sharma et a!. .......................... 424/440
`4,917,899
`4/1990 Goeghegan et a!. ...................... 424/19
`4,925,675
`5/1990 Giannini et a!. .......................... 424/78
`4,935,246
`6/1990 Ahrens .................................... 424/490
`4,957,681
`9/1990 Klimesch et a!.
`................. 264/211.23
`4,959,208
`9/1990 Chakrabarti et a!. ..................... 424/78
`4,967,486 11/1990 Doelling ........................................ 34/1
`4,970,075 11/1990 Oshlack .................................. 424/451
`4,987,136
`1!1991 Kreek et a!. .
`4,990,341
`2/1991 Goldie eta!. ........................... 424/484
`4,992,100
`2/1991 Koepff et a!. ........................ 106/125 S
`4,994,227
`2/1991 Dietz et a!. ........................ 264/328.16
`5,007,790
`4/1991 Shell ....................................... 424/451
`5,013,306
`5/1991 Solomon et a!.
`....................... 604/265
`6/1991 Sakamoto et a!. ...................... 424/502
`5,023,089
`6/1991 Makino et a!.
`......................... 424/494
`5,026,560
`5,030,400
`7/1991 Danielson eta!. ...................... 264/101
`5,035,509
`7/1991 Kruder ...................................... 366/89
`5,049,394
`9/1991 Howard et a!. ......................... 424/490
`5,055,307 10/1991 Tsuru et a!. ............................. 424/693
`5,073,379 12/1991 Klimesch et a!.
`...................... 424/467
`5,102,668
`4/1992 Eichel et a!. ............................ 424/490
`5,126,145
`6/1992 Evenstad ................................. 424/465
`5,132,142
`7/1992 Jones eta!. ............................. 427/196
`5,133,974
`7/1992 Paradissis eta!. ...................... 424/480
`5,162,117 11/1992 Stupak et a!. ........................... 424/475
`
`5,165,952
`5,167,964
`5,169,645
`5,178,868
`5,183,690
`5,196,203
`5,202,128
`5,204,119
`5,229,148
`5,234,697
`5,240,400
`5,262,172
`5,266,331
`5,271,934
`5,273,758
`5,283,065
`5,290,560
`5,292,461
`5,296,266
`5,300,300
`5,340,581
`5,350,584
`5,354,856
`5,356,635
`5,378,462
`5,380,535
`5,395,626
`5,403,593
`5,443,846
`5,451,424
`5,453,283
`5,456,923
`5,472,710
`5,476,528
`5,478,577
`5,510,114
`5,516,205
`5,552,159
`5,567,439
`
`11/1992 Solomon eta!. ........................... 427/2
`12/1992 Muhammed et a!.
`.................. 424/482
`12/1992 Shukla et a!. ........................... 424/499
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`2/1993 Carr et a!. .......................... 427/213.31
`3/1993 Boehm .................................... 424/490
`4/1993 Morella et a!. ......................... 424/469
`4/1993 Shiobara et a!. ........................ 424/489
`7/1993 Copper ........................................ 426/5
`8/1993 Sipos ....................................... 424/490
`8/1993 Fujimoto et a!. ....................... 425/310
`11/1993 Sipos ....................................... 424/490
`11/1993 Oshlack et a!. ......................... 424/468
`12/1993 Goldberg et a!. ....................... 424/401
`12/1993 Royce ..................................... 424/465
`2/1994 Doyon et a!. ........................... 424/467
`3/1994 Autant ..................................... 424/438
`3/1994 Juch et a!.
`................................ 264/37
`3/1994 Kunugi eta!. .......................... 427/213
`4/1994 Egidio et a!. ........................... 424/456
`8/1994 Tseng et a!.
`............................ 424/401
`9/1994 McClelland et a!. ................... 424/501
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`10/1994 Raman et a!.
`.......................... 424/484
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`3/1995 Kotwal et a!. .......................... 424/472
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`8/1995 Yoshioka et a!. ....................... 424/498
`9/1995 Solomon eta!. ........................ 427/2.1
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`5/1996 Oda et a!. ................................. 366!75
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`
`FOREIGN PATENT DOCUMENTS
`
`204596
`208144
`0248548
`0249347
`0251459
`0253104
`0240904
`0254978
`0256127
`0267702
`0271193
`0275834
`0300897
`0021129
`0295212
`0327295
`0068450
`0351580
`0377518
`0354345
`0361680
`0361910
`0368247
`0375063
`0377517
`0298355
`0415693
`0430287
`0463833
`0241615
`0452145
`
`12/1986
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`5/1987
`5/1987
`5/1987
`6/1987
`10/1987
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`2/1988
`5/1988
`6/1988
`7/1988
`7/1988
`9/1988
`12/1988
`8/1989
`1!1990
`1!1990
`1!1990
`2/1990
`4/1990
`4/1990
`5/1990
`6/1990
`7/1990
`11/1990
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`6/1991
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`9/1991
`10/1991
`
`European Pat. Off.
`European Pat. Off.
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`
`A61K 9/16
`A61K 9/16
`A61K 9/22
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`A61K 9/22
`A61K 9/00
`A61K 9/20
`A61K 9/22
`.......... C12N 9/00
`......... A61K 9/14
`..... A61K 31!485
`A61K 9/20
`......... A61K 9/22
`......... A61K 9/16
`....... A61K 47/00
`A61K 9/52
`A61K 9/20
`A61K 9/22
`A61K 9/52
`.......... C09H 9/04
`A61K 9/46
`A61K 9/16
`A61K 9/26
`A61K 9/18
`....... A61K 31!52
`......... A61K 9/50
`....... A61K 37/02
`A61K 9/54
`A61K 9/26
`A61K 9/22
`A61K 9/14
`
`2
`
`

`
`5,958,452
`Page 3
`
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`0636370
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`4/1993
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`9318753
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`2/1994
`9403161
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`9405262
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`9423698 10/1994
`9423700 10/1994
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`6/1995
`9514460
`
`European Pat. Off ............ A61J 3/06
`European Pat. Off .......... A61K 9/16
`European Pat. Off ......... A61L 15/28
`European Pat. Off .......... A61K 9/02
`European Pat. Off ...... A61K 31/485
`European Pat. Off ........... B01F 5/22
`European Pat. Off.
`A61K 9/20
`European Pat. Off.
`A61K 9/54
`European Pat. Off.
`A61K 9/20
`European Pat. Off.
`A61K 9/46
`European Pat. Off ...... A61K 31/485
`European Pat. Off ........ A61K 31/60
`European Pat. Off.
`A61K 9/16
`European Pat. Off .......... A61K 9/26
`European Pat. Off .......... A61K 9/14
`European Pat. Off ............ BOlJ 2/16
`European Pat. Off ...... A61K 31!135
`European Pat. Off ........ A61K 31!44
`.. ... ... B30B 11/22
`European Pat. Off.
`European Pat. Off ...... A61K 31/485
`.. ... ... B30B 11/22
`European Pat. Off.
`European Pat. Off ...... A61K 31!135
`European Pat. Off ...... A61K 31/485
`European Pat. Off .......... A61K 9/22
`France .............................. A61J 3/06
`France ............................... BOlJ 2/10
`France ........................... C07C 55/10
`Germany ....................... B65G 65/06
`Germany ....................... A61K 45/06
`Germany ..................... A61K 31!205
`Germany ..................... A61K 31!135
`Japan ............................... A61K 9/22
`Japan ............................... A61K 9/10
`Japan ............................. A61K 47/14
`United Kingdom .
`United Kingdom ............. A61K 9/26
`United Kingdom ........... A61K 47/00
`United Kingdom .............. B29B 1/02
`United Kingdom .............. A61J 3/08
`United Kingdom ............. A61K 9/20
`United Kingdom ............. A61K 9/20
`United Kingdom ............. A61K 9/22
`United Kingdom ............. A61K 9/22
`United Kingdom .......... A61M 31/00
`United Kingdom ............. A61K 9/16
`United Kingdom ............. A61K 9/16
`United Kingdom ............. A61K 9/16
`WIPO .............................. A61K 9/16
`WIPO .............................. A61K 9/16
`WIPO .............................. A61K 9/16
`WIPO .............................. A61K 9/50
`WIPO .............................. A61K 9/22
`WIPO .............................. A61K 9/18
`WIPO .............................. A61K 9/16
`WIPO .............................. A61K 9/14
`WIPO .............................. A61K 9/02
`WIPO ............................... A61J 3/00
`WIPO .............................. A61K 9/51
`WIPO .............................. A61K 9/16
`WIPO ............................ A61K 31!16
`WIPO .............................. A61K 9/16
`WIPO .............................. A61K 9/50
`WIPO .............................. A61K 9/16
`WIPO .............................. A61K 9/22
`WIPO .............................. A61K 9/16
`WIPO .............................. A61K 9/32
`WIPO .............................. A61K 9/52
`WIPO .............................. A61K 9/16
`WIPO .............................. A61K 9/14
`WIPO .............................. A61K 9/16
`WIPO .............................. A61K 9/20
`WIPO .............................. A61K 9/14
`
`OTHER PUBLICATIONS
`
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`
`4
`
`

`
`U.S. Patent
`
`Sep.28,1999
`
`Sheet 1 of 17
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`5,958,452
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`Sep.28,1999
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`Sheet 5 of 17
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`U.S. Patent
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`Sep.28,1999
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`Sheet 8 of 17
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`F/6.9
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`EXTRUDER
`
`CONVEYOR BELT
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`CHOPPER
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`d •
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`HOT MELTED
`EXTRUDATE
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`E NCAPSJLA T I ON
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`13
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`

`
`U.S. Patent
`
`Sep.28,1999
`
`Sheet 10 of 17
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`5,958,452
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`
`U.S. Patent
`
`Sep.28,1999
`
`Sheet 11 of 17
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`5,958,452
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`
`FIG. 12
`
`CONC
`( ng/ml)
`
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`
`U.S. Patent
`
`Sep.28,1999
`
`Sheet 13 of 17
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`5,958,452
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`
`FIG. /4
`
`CONC
`( ng/ml)
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`FIG. IS
`
`CONC
`(ng/ml}
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`0.40
`0.30
`
`0.20
`0.10
`
`0
`0
`
`6
`
`12
`
`18
`
`-o-FAST
`
`24
`
`36
`30
`TIME(HR)
`---+-FED
`
`42
`
`48
`
`54
`
`60
`
`66
`
`-~- 01 LAUD I D
`
`19
`
`

`
`U.S. Patent
`
`Sep.28,1999
`
`Sheet 16 of 17
`
`5,958,452
`
`~
`C'-..1
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`

`
`FIG. 17
`
`I. 00
`
`I
`
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`
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`I
`I
`I
`
`CONC
`(ng /ml)
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`TIME(HR)
`
`l'lTTll""·'trrrn 1 1 1 1 1 1 1'-nT
`42
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`
`72
`
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`
`21
`
`

`
`5,958,452
`
`1
`EXTRUDED ORALLY ADMINISTRABLE
`OPIOID FORMULATIONS
`
`This application is a continuation-in-part of International
`Application PCT/US95/14745 filed Nov. 3, 1995, which is
`a continuation-in-part of U.S. Ser. No. 08/334,209 filed Nov.
`4, 1994.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`2
`In order to be absorbed, the active drug substance must be
`in solution. The time required for a given proportion of an
`active substance from a unit dosage form is determined as
`the proportion of the amount of active drug substance
`release from a unit dosage form over a specified time base
`by a test method conducted under standardized conditions.
`The physiologic fluids of the gastrointestinal tract are the
`media for determining dissolution time. The present stat of
`the art recognizes many satisfactory test procedures to
`10 measure dissolution time for pharmaceutical compositions,
`and these test procedures are described in official compendia
`world wide.
`Although there are many diverse factors which influence
`the dissolution of drug substance from its carrier, the dis(cid:173)
`solution time determined for a pharmaceutically active sub(cid:173)
`stance from the specific composition is relatively constant
`and reproducible. Among the different factors affecting the
`dissolution time are the surface area of the drug substance
`presented to the dissolution solvent medium, the pH of the
`solution, the solubility of the substance in the specific
`solvent medium, and the driving forces of the saturation
`concentration of dissolved materials in the solvent medium.
`Thus, the dissolution concentration of an active drug sub(cid:173)
`stance is dynamically modified in its steady state as com(cid:173)
`ponents are removed from the dissolution medium through
`absorption across the tissue site. Under physiologic
`conditions, the saturation level of the dissolved materials is
`replenished from the dosage form reserve to maintain a
`relatively uniform and constant dissolution concentration in
`the solvent medium providing for a steady state absorption.
`The transport across a tissue absorption site of the gas(cid:173)
`trointestinal tract is influenced by the Donnan osmotic
`equilibrium forces on both sides of the membrane since the
`direction of the driving force is the difference between the
`concentrations of active substance on either side of the
`membrane, i.e., the amount dissolved in the gastrointestinal
`fluids and the amount present in the blood. Since the blood
`levels are constantly being modified by dilution, circulatory
`changes, tissue storage, metabolic conversion and systemic
`excretion, the flow of active materials is directed from the
`gastrointestinal tract into the blood stream.
`Notwithstanding the diverse factors influen