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MAIMUUTTUNUT US009943513B1 PIU MIU MIUI (12 ) United States Patent ( 10 ) Patent No. : US 9 ,943 ,513 B1 Hughey et al. (45 ) Date of Patent: * Apr . 17 , 2018 (54 ) OPIOID ABUSE DETERRENT DOSAGE (58 ) Field of Classification Search FORMS None See application file for complete search history . (71 ) Applicant: BANNER LIFE SCIENCES LLC , High Point, NC (US ) (56 ) References Cited (72 ) Inventors : Justin Hughey , Asheboro , NC (US ) ; U .S . PATENT DOCUMENTS Saujanya Gosangari, Jamestown, NC (US ) ; Chue Hue Yang , Greensboro , NC 4 , 828 ,836 A 5 / 1989 Miller 4 ,861 , 598 A 8 / 1989 Oshlack (US ) 4 , 970 ,075 A 11/ 1990 Oshlack 5 ,266 ,331 A 11/ 1993 Oshlack (73 ) Assignee : BANNER LIFE SCIENCES LLC , 5 , 273 , 760 A 12 / 1993 Oshlack High Point, NC (US ) 5 , 286 ,493 A 2 / 1994 Oshlack 5 ,472 , 943 A 12 / 1995 Crain 5 , 478 , 577 A 12 / 1995 Kaiko ( * ) Notice : Subject to any disclaimer, the term of this 5 , 529 , 787 A 6 / 1996 Ayer patent is extended or adjusted under 35 5 , 549 , 912 A 8 / 1996 Kaiko U . S . C . 154 ( b ) by 0 days. 5 ,656 , 295 A 8 / 1997 Oshlack 5 ,672 , 360 A 9 / 1997 Kaiko This patent is subject to a terminal dis 5 , 702, 725 A 12 / 1997 Chadha claimer . 5 ,914 ,131 A 6 / 1999 Ayer 5 ,958 , 452 A 9 / 1999 Oshlack (21 ) Appl. No. : 15 /285 ,837 5 , 965, 161 A 10 / 1999 Oshlack 6 , 228 , 863 B1 5 /2001 Kaiko ( 22 ) Filed : Oct . 5, 2016 6 , 261, 599 B1 7 /2001 Huang Related U . S . Application Data ( Continued ) ( 60 ) Provisional application No . 62 /238 , 385, filed on Oct . Primary Examiner — Bethany P Barham 7 , 2015 , provisional application No. 62 /310 , 383, filed Assistant Examiner — Barbara Frazier on Mar . 18 , 2016 . (74 ) Attorney, Agent, or Firm — Brinks Gilson & Lione (51 ) Int . Ci. (57 ) ABSTRACT A61K 31 /485 ( 2006 .01 ) A61K 9 / 48 ( 2006 .01 ) Described herein are oral abuse deterrent pharmaceutical A61K 9 /00 ( 2006 .01 ) compositions, methods for making the same, and methods A61K 47 / 10 ( 2017 .01 ) for treating pain by administering the pharmaceutical com A61K 47 / 14 ( 2017 .01 ) position to a subject in need thereof. In particular, an oral (52 ) U . S . CI. abuse deterrent pharmaceutical composition comprising a CPC??? ...... A61K 31 /485 (2013 . 01 ) ; A61K 9 /0053 soft capsule and a controlled release matrix comprising ( 2013 .01 ); A61K 9/ 4858 ( 2013 .01 ); A61K oxycodone are described . 9/ 4866 (2013 .01 ); A61K 47/ 10 (2013 . 01 ) ; A61K 47 / 14 ( 2013 .01 ) 18 Claims, 30 Drawing Sheets

100 % - - - - WOWOWOT - - - - - 80 % WOWATT - - - PercentRelease 40 % --- -

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0 % 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hours ) US 9, 943 , 513 B1 Page 2

(56 ) References Cited 8 , 329 , 216 B2 12 / 2012 Baichwal 8 , 337 , 888 B2 12 / 2012 Wright U . S . PATENT DOCUMENTS 8 , 357, 399 B2 1 / 2013 Wright 8 ,361 , 499 B2 1 /2013 Oshlack 6 , 277 , 384 B1 8 / 2001 Kaiko 8 , 377 ,480 B2 2 / 2013 Raman 6 , 335 ,033 B2 1 / 2002 Oshlack 8 ,383 ,152 B2 2 / 2013 Galia 6 , 375 , 957 B1 4 / 2002 Kaiko 8 ,409 , 616 B2 4 /2013 Wadgaonkar 6 , 475 , 494 B2 11/ 2002 Kaiko 8 , 420 , 056 B2 4 / 2013 Kugelmann 6 ,488 ,963 B1 12 / 2002 McGinity 8 ,425 ,933 B2 4 / 2013 Mehta 6 , 627, 635 B2 9 / 2003 Kaiko 8 , 445 , 018 B2 5 / 2013 Habib 6 , 685 , 964 B1 2 / 2004 Bartholomaeus 8 , 445 , 023 B2 5 / 2013 Dargelas 6 , 696 , 066 B2 2 / 2004 Kaiko 8 , 449, 909 B2 5 / 2013 Kilbanov 6 , 696 , 088 B2 2 / 2004 Wright 8 , 465 , 774 B2 6 / 2013 Wright 6 , 706 , 281 B2 3 / 2004 Oshlack 8 , 518, 443 B2 8 / 2013 Wright 6 , 713 , 488 B2 3 / 2004 Wang 8 , 524 , 275 B2 9 / 2013 Oshlack 6 , 733 , 783 B2 5 / 2004 Oshlack 8 , 551 , 520 B2 10 / 2013 Oshlack 6 , 734 , 188 B1 5 / 2004 Rhodes 8 , 557 ,291 B2 10 / 2013 Hirsh 6 , 743 , 442 B2 6 / 2004 Huang 8 ,586 , 088 B2 11/ 2013 Wright 6 , 893 ,661 B1 5 / 2005 Odidi 8 , 597, 681 B2 12 / 2013 Park 7 , 129 ,248 B2 10 /2006 Hong 8 , 623 , 418 B2 | 1 / 2014 Tang 7 , 144 , 587 B2 12 / 2006 Wright 8 , 637, 540 B2 1 /2014 Wadgaonkar 7 , 172 , 767 B2 2 / 2007 Kaiko 8, 637 ,548 B2 1 /2014 Sun 7 , 201, 920 B2 4 / 2007 Wadgaonkar 8, 647, 667 B2 2 / 2014 Oshlack 7 ,276 , 250 B2 10 /2007 McCall 8 , 652 , 515 B2 2 /2014 Sackler 7 , 332 , 182 B2 2/ 2008 Sackler 8 , 652 , 529 B2 2 / 2014 Dargelas 7 , 384 , 653 B2 6 / 2008 Carpanzano 8 , 658 , 631 B1 2 / 2014 Devarakonda NNNN7 ,399 , 488 B2 7 / 2008 Swager 8 , 673 , 355 B2 3 / 2014 Kaiko 7, 419, 686 B2 9 / 2008 Kaiko 8 , 685 , 443 B2 4 / 2014 Boehm 7 ,476 , 402 B2 1 /2009 Wadgaonkar 8 , 685 , 444 B2 4 / 2014 Boehm 7 , 510 , 726 B2 3 / 2009 Wadgaonkar 8 , 703 , 186 B2 4 / 2014 Mehta 7 , 510 ,727 B2 3 / 2009 Oshlack 8 , 703 , 196 B2 4 / 2014 Curatolo 7 , 514 , 100 B2 4 / 2009 Oshlack 8 , 715 , 721 B2 5 / 2014 Oshlack 7 , 674 , 798 B2 3 /2010 Hong 8 , 741 , 885 B1 6 / 2014 Devarakonda 7 ,674 , 799 B2 3 / 2010 Hong 8 , 758 , 813 B2 6 / 2014 Rariy 7 , 674 , 800 B2 3 /2010 Hong 8 , 758, 825 B2 6 / 2014 Wright 7 ,682 , 633 B2 3 / 2010 Boehm 8 , 790, 694 B2 7 / 2014 Shelby 7 , 682 , 634 B2 3 / 2010 Boehm 8 , 808 , 737 B2 8 / 2014 Ahdieh 7 , 683 , 072 B2 3 / 2010 Hong 8 ,808 , 740 B2 8 /2014 Huang 7 , 691 , 877 B2 4 / 2010 Tran 8 , 808 , 741 B2 8 / 2014 Huang 7 , 696, 208 B2 4 / 2010 Kyle 8 , 815, 287 B2 8 / 2014 Wright 7 ,740 , 881 B1 6 / 2010 Kaiko 8 , 815 , 289 B2 8 /2014 Huang 7 ,749 , 542 B2 7 / 2010 Kaiko 8 , 821, 929 B2 9 /2014 Huang 7 , 771 , 707 B2 8 / 2010 Hirsh 8 ,822 ,487 B2 9 / 2014 Kaiko 7 ,776 , 314 B2 8 / 2010 Kugelmann 8 ,822 ,489 B2 9 / 2014 Wadgaonkar 7 , 776, 861 B2 8 / 2010 Sun 8 , 822 , 687 B2 9 / 2014 Hong 7 ,790 , 201 B2 9 / 2010 Raman 8 , 834 , 925 B2 9 / 2014 Huang 7 , 790 , 215 B2 9 / 2010 Oshlack 8 , 840, 928 B2 9 /2014 Varanasi 7 , 815 , 934 B2 10 / 2010 Boehm 8 , 846 , 086 B2 9 /2014 Huang 7 , 842 , 307 B2 11/ 2010 Wright 8 , 846, 090 B2 9 /2014 Broegmann 7 ,842 , 311 B2 11/ 2010 Wright 8 , 846 , 091 B2 9 / 2014 Broegmann 7 , 846 , 476 B2 12 / 2010 Oshlack 8 , 846 , 104 B2 9 / 2014 Boehm 7 ,858 , 119 B1 12 / 2010 Odidi 8 , 858, 963 B1 10 / 2014 Devarakonda 7 , 862 , 833 B2 1 / 2011 Moe 8 , 877 , 247 B2 11 / 2014 Boehm 7 ,906 , 141 B2 3 / 2011 Ziegler 8 , 883 , 204 B2 11 / 2014 Masselink 7 , 914 , 818 B2 3 /2011 Wright 8 , 894 , 987 B2 11/ 2014 Huang 7 , 943 , 173 B2 5 / 2011 Wright 8 , 894 , 988 B2 11/ 2014 McKenna 7 , 943 ,174 B2 5 / 2011 Oshlack 8 , 901, 113 B2 12/ 2014 Hall 7 ,981 , 439 B2 7 / 2011 Wadgaonkar 8 , 911 , 719 B2 . 12 / 2014 Huang 8 , 017, 148 B2 9 / 2011 Sackler 8 , 920, 836 B2 12 / 2014 Whitelock 8 , 030 , 310 B2 10 / 2011 Kyle 8, 932 ,630 B1 1 / 2015 Kaiko 8 , 075 , 872 B2 12 / 2011 Kugelmann 8 , 936, 808 B1 1/ 2015 Kaiko 8 , 101 , 630 B2 1/ 2012 Wadgaonkar 8 ,936 , 812 B2 1 /2015 Wright 8 , 105, 631 B2 1/ 2012 Kaiko 8 , 951 , 555 B1 2 / 2015 Oshlack 8 , 114 ,383 B2 2 / 2012 Kugelmann 8 , 969 , 369 B2 3 / 2015 Kao 8 , 114 , 384 B2 2 / 2012 Bartholomaus 8 ,975 ,273 B2 3 /2015 Oshlack 8 ,142 , 811 B2 3 / 2012 Oshlack 8 , 980 , 291 B2 3 / 2015 Intialaikumlila.dinlOshlack 8 , 158, 156 B2 4 / 2012 Boehm 8 , 980, 319 B2 3 / 2015 Park 8 , 178 , 560 B2 5 / 2012 Sun 8 , 992 , 975 B2 3 / 2015 Shelby 8 , 182 , 836 B2 5 / 2012 Mehta 9 , 023 , 401 B1 5 / 2015 Oshlack 8 , 192 , 722 B2 6 /2012 Kugelmann 9 , 034 ,377 B2 5 / 2015 Wright 8 , 231 , 898 B2 7 / 2012 Oshlack 9 , 044, 398 B2 6 / 2015 Rariy 8 , 231 , 901 B2 7/ 2012 Wright 9 , 044 ,402 B2 6 /2015 Overgard 8 , 236, 328 B2 8 / 2012 Curatolo 9 , 050, 335 B1 6 / 2015 Devarakonda 8 , 236 , 351 B2 8 / 2012 Wright 9 , 056 , 051 B2 6 / 2015 Kao 8 , 298 , 577 B2 10 / 2012 Moe 9 , 056 , 052 B1 6 / 2015 Oshlack 8 , 298 , 579 B2 10 / 2012 Abreu 9 , 056, 107 B1 6 /2015 Oshlack 8 ,309 , 060 B2 11/ 2012 Arkenau 9 ,060 , 940 B2 6 / 2015 Oshlack 8 , 309 , 122 B2 11 / 2012 Baichwal 9 ,060 , 976 B2 6 / 2015 Wright 8 , 323 ,889 B2 12 / 2012 Kugelmann 9 , 073 , 933 B2 7 / 2015 Hong US 9, 943 , 513 B1 Page 3

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/2008 Wright 9 , 205 , 082 B2 12 / 2015 Kaiko 2008 /0166405 Al 7 /2008 Mehta 9 , 216 , 176 B2 12 / 2015 Habib 2008 /0199530 A1 8 / 2008 Hirsh 9 , 301 , 918 B2 4 / 2016 Raman 2008 / 0247959 Al 10 / 2008 Arkenau 9 ,433 , 582 B2 9 / 2016 Shelby 2008 / 0260819 A1 10 / 2008 Hirsh 2001/ 0033865 Al 10 / 2001 Oshlack 2008 /0292694 AL 11 / 2008 Kaiko 2001/ 0036476 A1 11/ 2001 Huang 2008 /0292700 AL 11 /2008 Nghiem 2001/ 0038856 AL 11/ 2001 Ayer 2008 /0311049 Al 12 / 2008 Kugelmann 2002 /0004509 AL 1 / 2002 Kaiko 2008 / 0311187 Al 12 / 2008 Ashworth 2002 / 0006438 A1 1 /2002 Oshlack 2008 / 0312264 Al 12 / 2008 Bartholomaus 2002 /0013301 Al 1 / 2002 Kaiko 2008 / 0317854 A112 / 2008 Bartholomaeus 2002 /0058050 Al 5 / 2002 Kaiko 2009 /0004292 AL 1 / 2009 Wadgaonkar 2002 / 0058673 Al 5 / 2002 Kaiko 2009 / 0005408 A1 1 / 2009 Bartholomaus 2002/ 0192277 Al 12 / 2002 Oshlack 2009 / 0011024 Al 1 / 2009 Curatolo 2003/ 0026839 Al 2 / 2003 Oshlack 2009 /0022790 A1 1/ 2009 Flath 2003 /0031712 A1 2 / 2003 Kaiko 2009 /0081290 A1 3 / 2009 Huang 2003 / 0035837 A1 2 / 2003 Kaiko 2009 /0148517 Al 6 / 2009 Chasin 2003 / 0044458 Al 3 / 2003 Carpanzano 2009 / 0202629 Al 8 /2009 Oshlack 2003 / 0044464 Al 3 / 2003 Ziegler 2009 /0202634 A1 8 / 2009 Galia 2003 /0065002 Al 4 / 2003 Kao 2009 /0227615 Al 9 / 2009 Hong 2003 / 0068371 Al 4 / 2003 Wright 2009 / 0238868 A1 9 / 2009 Mehta 2003 / 0068392 Al 4 / 2003 Sackler 2009 /0253730 A1 10 / 2009 Wadgaonkar 2003 /0069263 A1 4 / 2003 Wright 2009 /0297617 A 12 /2009 Hirsh 2003 /0073714 Al 4 / 2003 Wright 2010 / 0028389 Al 2 / 2010 Merrill 2003/ 0104063 A1 6 / 2003 Curatolo 2010 / 0098771 Al 4 / 2010 Mehta 2003 /0124185 Al 7 / 2003 Wright 2010 /0151028 A1 6 / 2010 Kugelmann 2003 / 0157167 Al 8 / 2003 Baichwal 2010 /0152449 A1 6 / 2010 Hong 2003/ 0157168 Al 8 /2003 Wright 2010 /0172974 Al 7 / 2010 Chasin 2003 / 0190358 A1 10 / 2003 Oshlack 2010 / 0209351 A1 8 / 2010 Sackler 2003/ 0190362 Al 10 / 2003 Oshlack 2010 / 0209514 A1 8 / 2010 Sackler 2004 / 0047907 Al 3 / 2004 Oshlack 2010 /0216829 A2 8 / 2010 Tewari 2004 / 0052731 Al 3 / 2004 Lo 2010 /0240675 A1 9 /2010 Kyle 2004 / 0058946 A 3 / 2004 Rariy 2010 /0260834 A 10 / 2010 Hirsh 2004 /0081694 Al 4 / 2004 Oshlack 2010 / 0273730 A1 * 10 / 2010 Hsu A61K 9 / 1075 2004 / 0086561 A1 5 / 2004 Kaiko 514 / 49 2004 / 0170680 Al 9 / 2004 Oshlack 2010 / 0291203 A111/ 2010 Kaiko 2004 / 0185096 Al 9 / 2004 Oshlack 2010 / 0331369 Al 12 / 2010 Sun 2004 /0202717 Al 10 / 2004 Mehta 2011/ 0038927 AL 2 / 2011 Oshlack 2004 / 0234600 A1 11/ 2004 Ayer 2011 /0071192 Al 3 / 2011 Sun 2004 /0266807 Al 12 / 2004 Oshlack 2011 /0077238 A1 3 / 2011 Hall 2005 / 0031546 Al 2 / 2005 Bartholomaus 2011/ 0104214 A1 5 / 2011 Wright 2005 / 0063909 Al 3 / 2005 Carpanzano 2011 /0142943 Al 6 / 2011 Saim 2005 / 0089568 A1 4 / 2005 Oshlack 2011 / 0150989 Al 6 /2011 Dhanarajan 2005 /0112067 A1 5 / 2005 Wadgaonkar 2011 /0207762 A1 8 / 2011 Hong 2005 /0192309 A1 9 / 2005 Kaiko 2011 / 0230510 A1 9 / 2011 Wright 2005 /0214368 AL 9 / 2005 Odidi 2011/ 0256226 A1 10 / 2011 Wright 2005 /0222188 Al 10 / 2005 Hong 2011/ 0262532 A1 10 / 2011 Oshlack 2005 /0236741 A1 10 /2005 Bartholomaeus 2011 /0287095 A1 11/ 2011 Park 2005 / 0245483 A1 11/ 2005 Spitzley 2011/ 0300217 Al 12 / 2011 Ayer 2005 /0245556 AL 11 / 2005 Spitzley 2012 /0034171 A1 2 / 2012 Kugelmann 2005 / 0281748 A1 12 / 2005 Hirsh 2012 /0087982 A1 4 / 2012 Wadgaonkar 2006 /0002859 Al 1 / 2006 Bartholomaus 2012 /0088786 A1 4 / 2012 Hayes 2006 / 0128717 A1 6 / 2006 Sun 2012 /0107250 A1 5 /2012 Kugelmann 2006 /0173029 Al 8 / 2006 Hong 2012 /0108621 Al 5 /2012 Broegmann 2006 /0182801 Al 8 / 2006 Wright 2012 /0141583 A1 6 / 2012 Hahn 2006 / 0193782 A1 8 / 2006 Arkenau 2012 /0164220 A1 6 / 2012 Huang 2006 /0193914 AL 8 / 2006 Ashworth 2012 /0165359 Al 6 / 2012 Kaiko 2006 / 0258669 A1 11/ 2006 Kyle 2012 / 0183612 Al 7 /2012 Broegmann 2006 / 0269604 Al 11/ 2006 Kaiko 2012 /0201761 A1 8 / 2012 Sackler 2007/ 0003616 AL 1 / 2007 Bartholomaus 2012 /0225901 A1 9 /2012 Smith 2007/ 0014732 AL 1 / 2007 Sackler 2012 /0251637 A1 10 /2012 Kugelmann 2007 /0048228 AL 3 /2007 Kugelmann 2012 /0252832 Al 10 / 2012 Kao US 9, 943 , 513 B1 Page 4

(56 ) References Cited 2014 /0249185 Al 9 / 2014 Sun 2014 /0256764 Al 9 / 2014 Abreu U . S . PATENT DOCUMENTS 2014 / 0271840 A1 9 / 2014 Huang 2014 / 0275143 Al 9/ 2014 Gupta 2012 /0263788 A 10 / 2012 Oshlack 2014 / 0288113 Al 9 /2014 Gupta 2012 /0288567 A1 11/ 2012 Wright 2014 / 0294953 Al 10 / 2014 Vega 2012 / 0295988 A1 11/ 2012 Curatolo 2014 / 0294956 A1 10 /2014 Shelby 2013 /0004575 AL 1 / 2013 Jackson 2014 / 0296276 A1 10 / 2014 Wright 2013 / 0005977 Al 1 / 2013 Hong 2014 /0296277 A1 10 / 2014 Broegmann 2013 /0017255 Al 1 / 2013 Osvaldo 2014 /0322311 Al 10 / 2014 Kugelmann 2013 /0045960 A1 2 / 2013 Lo 2014 /0322323 A1 10 / 2014 Galia 2013 / 0090349 Al 4 / 2013 Geisler 2014 / 0329847 AL 11/ 2014 Ahdieh 2013 /0122087 Al 5 / 2013 Hillman 2014 /0336213 Al 11/ 2014 Wadgaonkar 2013 /0122101 A1 5 / 2013 Habib 2014 /0356294 Al 12 /2014 Kugelmann 2013 /0158061 Al 6 / 2013 Oshlack 2014 / 0357658 A1 12 / 2014 Kaiko 2013 /0165418 A1 6 / 2013 Colucci 2014 /0377348 AL 12 / 2014 Oshlack 2013 /0171075 A1 7 / 2013 Kugelmann 2014 / 0378498 Al 12 / 2014 Devarakonda 2013 / 0171257 A1 7 / 2013 Tewari 2015 / 0004244 Al 1 / 2015 Varanasi 2013 /0172382 A1 7 / 2013 Kao 2015 / 0005332 A1 1 / 2015 Varanasi 2013 / 0209560 Al 8 / 2013 Hamed 2015 / 0005335 A1 1/ 2015 Broegmann 2013 / 0230596 A1 9 / 2013 Mehta 2015 /0005336 A1 1/ 2015 Kaiko 2013 / 0251759 Al 9 / 2013 Bartholomuaes 2015 /0025101 A1 1 / 2015 Kaiko 2013 / 0251796 Al 9 /2013 Huang 2015 / 0028512 A1 1 / 2015 Huang 2013 /0251797 A1 9 / 2013 Huang 2015 / 0031718 A1 1 / 2015 Wright 2013 / 0251798 A1 9 / 2013 Huang 2015 / 0037409 A1 2 /2015 Oshlack 2013 / 0251799 Al 9 / 2013 Huang 2015 /0037411 A1 2 /2015 Huang 2013 /0251800 AL 9 /2013 Huang 2015 /0037412 A1 2 / 2015 Huang 2013 / 0251801 Al 9 /2013 Huang 2015 /0037413 A1 2 / 2015 Huang 2013 / 0251802 Al 9 /2013 Huang 2015 / 0080384 A1 3 / 2015 Hall 2013 / 0251812 A1 9 / 2013 Wright 2015 /0110870 A1 4 / 2015 Oshlack 2013/ 0259938 A1 10 / 2013 Huang 2015 /0110879 Al 4 /2015 Wright 2013/ 0259939 A1 10 / 2013 Huang 2015 /0118302 Al 4 / 2015 Haswani 2013 /0259940 Al 10 / 2013 Huang 2015 / 0118303 A1 4 /2015 Haswani 2013 /0260015 Al 10 / 2013 Huang 2015 /0140086 Al 5 / 2015 Masselink 2013 / 0273153 Al 10 / 2013 Dhanarajan 2015 /0140095 A1 5 / 2015 Wright 2013 /0280176 Al 10 / 2013 Diezi 2015 /0148366 A1 5 / 2015 Whitelock 2013 /0280177 A1 10 / 2013 Raman 2015 /0148367 A1 5 / 2015 Oshlack 2013 /0289062 Al 10 / 2013 Wadgaonkar 2015 /0150978 A1 6 /2015 Kugelmann 2013 /0295177 AL 11/ 2013 Oshlack 2015 / 0164808 Al 6 / 2015 Shelby 2013 / 0302418 AL 11/ 2013 Oshlack 2015 /0164811 A1 6 / 2015 Bartholomaeus 2013 /0309303 AL 11/ 2013 Wright 2015 /0174121 Al 6 / 2015 Oshlack 2013 / 0310413 AL 11/ 2013 Kilbanov 2015 /0182464 A1 7 / 2015 Kugelmann 2013 / 0317051 A1 11 / 2013 Oshlack 2015 /0182465 Al 7 / 2015 Kugelmann 2013 / 0320592 Al 12 / 2013 Bartholomaus 2015 /0182467 A1 7 / 2015 Wright 2014 / 0010873 A1 1 / 2014 Overgard 2015 /0196555 Al 7 / 2015 Guido 2014 / 0010875 A1 1/ 2014 Huang 2015 /0196556 A1 7 / 2015 Guido 2014 /0011832 A1 1 / 2014 Huang 2015 /0196557 Al 7 / 2015 Guido 2014 / 0017310 A1 1 / 2014 Castaneda 2015 / 0202300 A1 7 / 2015 Guido 2014 /0024669 A1 1/ 2014 Huang 2015 /0216809 A1 8 / 2015 Oshlack 2014 /0030327 Al 1/ 2014 Huang 2015 / 02 16810 A1 8 / 2015 Oshlack 2014 / 0031381 A1 1 / 2014 Huang 2015 /0231086 A1 8 / 2015 Wright 2014 /0031382 AL 1 / 2014 Smith 2015 /0231131 A1 8 / 2015 Wright 2014 / 0045877 Al 2 / 2014 Broegmann 2015 / 0238418 Al 8 / 2015 Oshlack 2014 /0045878 A1 2 / 2014 Broegmann 2015 /0246034 Al 9 / 2015 Devarakonda 2014 / 0079780 A1 3 / 2014 Kugelmann 2015 /0250781 Al 9 /2015 Habib 2014 / 0080858 Al 3 / 2014 Kugelmann 2015 / 0258086 Al 9 / 2015 Hong 2014 / 0080915 Al 3 / 2014 Kugelmann 2015 / 0258087 Al 9 / 2015 Kao 2014 / 0086847 A1 3 / 2014 Kugelmann 2015 / 0258088 Al 9 / 2015 Kao 2014 / 0086987 Al 3 / 2014 Park 2015 / 0258089 Al 9 / 2015 Oshlack 2014 /0099376 A2 4 / 2014 Wright 2015 / 0258090 A1 9 /2015 Oshlack 2014 /0105830 A1 4 / 2014 Kugelmann 2015 / 0265537 A1 9 / 2015 Oshlack 2014 /0105977 A1 4 / 2014 Shelby 2015 / 0265596 A1 9 /2015 Lo 2014 /0105987 A1 4 / 2014 Hirsh 2015 /0265597 Al 9 /2015 Hong 2014 /0107146 Al 4 / 2014 Kao 2015 / 0265598 Al 9 / 2015 Hong 2014 /0112981 Al 4 / 2014 Oshlack 2015 / 0265599 Al 9 / 2015 McKenna 2014 /0112984 Al 4 / 2014 Kugelmann 2015 / 0265600 A1 9 / 2015 McKenna 2014 /0113926 A1 4 / 2014 Bartholomaeus 2015 /0265601 A1 9 / 2015 McKenna 2014 / 0121232 A1 5 / 2014 Rariy 2015 /0290138 A1 10 /2015 Kugelmann 2014 /0135355 Al 5 / 2014 Kao 2015 / 0297527 Al 10 / 2015 Qi 2014 /0155425 Al 6 / 2014 Sackler 2015 /0335580 AL 11 /2015 McKenna 2014 /0155489 Al 6 / 2014 Kugelmann 2015 /0335582 AL 11 /2015 McKenna 2014 /0170079 Al 6 / 2014 Kugelmann 2015 /0335583 A1 11 /2015 Huang 2014 /0170217 A1 6 / 2014 Shelby 2015 / 0335584 A1 11/ 2015 Huang 2014 /0187572 A1 7 / 2014 Wright 2015 / 0335585 AL 11/ 2015 McKenna 2014 / 0194456 A1 7 / 2014 Kao 2016 /0000703 A1 1 / 2016 Micka 2014 /0199394 A1 7 / 2014 Oshlack 2016 /0008350 A1 1 / 2016 Oshlack 2014 / 0200236 A1 7 / 2014 Kaiko 2016 /0045449 Al 2 / 2016 Lamson 2014 /0220126 AL 8 / 2014 Overgard 2016 /0136152 AL 5 /2016 Baichwal 2014 /0221416 A18 / 2014 Guido 2016 /0184299 A1 6 /2016 Shelby US 9, 943 , 513 B1 Page 5

( 56 ) References Cited U . S . PATENT DOCUMENTS 2016 /0243041 A1 8/ 2016 Shelby 2016 /0250203 AL 9 / 2016 Haswani 2016 /0256392 AL 9/ 2016 Haswani * cited by examiner atent Apr . 17 , 2018 Sheet 1 of 30 US 9, 943 , 513 B1

FIGURE 1

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FIGURE 7

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FIGURE 8

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FIGURE 9

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FIGURE 14

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FIGURE 15

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FIGURE 16

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0 10 20 30 40 Time (hours ) US 9 , 943 , 513 B1 OPIOID ABUSE DETERRENT DOSAGE order to reduce the potential for misuse of prescription FORMS pharmaceutical compositions . Accordingly , there is a need for abuse deterrent pharma CROSS REFERENCE TO RELATED ceutical compositions that have controlled release proper APPLICATIONS 5 ties . This application claims priority to U . S . Provisional Patent SUMMARY Application No. 62 / 238 , 385 , filed on Oct. 7 , 2015 , and U . S . Provisional Patent Application No . 62/ 310 , 383 , filed on Described herein are pharmaceutical compositions com Mar. 18 , 2016 , each of which are incorporated herein in its 10 prising abuse deterrent controlled release matrices compris entirety by express reference thereto . This application is ing active pharmaceutical ingredients . The matrix is struc related to U . S . patent application Ser. No. 15 /285 ,814 hav - tured to prevent extraction of the active pharmaceutical ing the same title and contemporaneously filed on Oct. 5 , ingredients. Specifically, the matrix formulations described 2016 . herein minimize the likelihood of tampering, “ dose dump 15 ing , " or the extraction of active pharmaceutical ingredients TECHNICAL FIELD from the composition . In particular , there is a need for formulations that are resistant to active pharmaceutical Described herein are oral abuse deterrent controlled ingredient extraction under boiling conditions. release pharmaceutical compositions and methods for mak One embodiment described herein is an oral abuse deter ing the same. In particular, an oral abuse deterrent controlled 20 rent pharmaceutical composition comprising a tamper resis release pharmaceutical composition comprising a soft cap - tant controlled release matrix , wherein the tamper resistant sule and an abuse deterrent controlled release matrix com controlled release matrix comprises a means for preventing prising an active pharmaceutical ingredient are described the crushing , grating, grinding , cutting , solvating , or dis solving of the tamper resistant controlled release matrix BACKGROUND 25 comprising one or more active pharmaceutical ingredients . Another embodiment described herein is an abuse deter Increased attention has been drawn to the recreational use rent oral pharmaceutical composition comprising a tamper and abuse of prescription pharmaceutical compositions. The resistant controlled release composition comprising : ( a ) one abuse , or non -medicinal use , of prescription pharmaceutical or more flowability enhancers ; ( b ) one or more release compositions is an increasing problem . Accordingly , pre - 30 modifiers ; and ( c ) one or more active pharmaceutical ingre venting the abuse of prescription pharmaceuticals through dients ; wherein the matrix is resistant to tampering . the development of abuse deterrent pharmaceutical compo - One embodiment described herein is a pharmaceutical sitions has become a high public health priority for the U . S . composition comprising : (a ) one or more flowability Food and Drug Administration (FDA ) . Prescription phar enhancers ; ( b ) one or more release modifiers ; and ( c ) one or maceutical compositions that are typically misused or 35 more active pharmaceutical ingredients . In one aspect , the abused fall, primarily , into three groups: ( 1 ) opioids pre - composition further comprises one or more antioxidants . In scribed for pain ; (2 ) Central Nervous System ( CNS) depres - another aspect, the composition further comprises one or sants prescribed for anxiety or sleep problems; and ( 3 ) more viscosity modifiers . In another aspect, the flowability stimulants , prescribed , for example , for attention deficit enhancer comprises about 35 % to about 70 % of the com hyperactivity , narcolepsy , or obesity . 40 position by mass . In another aspect, the release modifier Methods for abusing prescription pharmaceutical compo - comprises about 20 % to about 50 % of the composition by sitions are varied and can include , for example , extraction , mass. In another aspect , the active pharmaceutical ingredient boiling , melting , volatilization , physical tampering ( e . g . , comprises about 0 . 5 % to about 35 % of the composition by grinding , grating , crushing , etc . ) , or direct administration . mass . In another aspect, the antioxidant comprises about For purposes of abuse , methods of administering active drug 45 0 . 05 % to about 0 . 5 % of the composition by mass . In another substances obtained from prescription pharmaceutical com - aspect, the viscosity modifier comprises about 0 . 5 % to about positions or of the pharmaceutical compositions themselves 10 % of the composition by mass . In another aspect , the ratio are similarly diverse and include , for example , injection , of the active pharmaceutical ingredient mass to the compo smoking , snorting , swallowing , sublingual or buccal admin - sition mass comprises a range of about 1 : 1000 to about 1 : 3 . istration , chewing , or administration as an anal or vaginal 50 In another aspect, a ratio of release modifier to flowability suppository . Alcohol- induced " dose dumping ,” i. e ., the rapid enhancer is about 1 : 2 . In another aspect , a ratio of active release of active pharmaceutical ingredients in the presence pharmaceutical ingredient to release modifier comprises a of a solvent such as ethanol , is also an abuse concern and range of about 1 : 1 to about 1 : 20 . In another aspect, the safety issue. Other methods include rapid extraction under flowability enhancer comprises a non - ionic surfactant, an aqueous boiling conditions. 55 anionic surfactant, a zwitterionic surfactant, a cationic sur There are a number of strategies for preventing the abuse factant, or a combination thereof. In another aspect, the of pharmaceuticals . Physical and chemical barriers can flowability enhancer comprises a non - ionic surfactant. In prevent the extraction of the drug or change the form of the another aspect, the flowability enhancer comprises a hydro drug making it less likely to be abused . Combinations of philic lipophilic balance of less than about 5 . In another agonists and antagonists can be used , wherein the antagonist 60 aspect, the flowability enhancer comprises a medium chain is only released upon product manipulation or tampering . mono - , di- , or tri - glyceride ; or a liquid lipophilic vehicle. In Another strategy is to use aversive compounds that produce another aspect , the flowability enhancer comprises glyceryl an unpleasant effect when the dosage form is tampered with . monocaprylate , glyceryl monocaprylcaprate , glyceryl In addition , prodrugs can be used , which are only changed monolinoleate , oleic acid , or a combination thereof. In into the active form of the drug in the gastrointestinal tract . 65 another aspect, the release modifier comprises polyethylene The pharmaceutical industry is utilizing these strategies to oxide , a carboxyvinyl polymer , or a combination thereof. In develop abuse -deterrent pharmaceutical compositions in another aspect , the release modifier comprises a polyethyl US 9 , 943 ,513 B1 enene oxide having a molecular weight ( M ) of about 1 ,000 , 0 .4 % by mass of BHA ; and (e ) about 0 .05 % to about 0 .1 % 000 ; about 2 ,000 , 000 ; about 3 ,000 ,000 ; about 4 ,000 ,000 ; by mass of BHT. In another aspect, the composition com about 5 ,000 ,000 ; about 6 ,000 , 000 ; about 7 , 000 ,000 ; about prises: 8 ,000 ,000 ; about 9 ,000 , 000 ; or about 10 , 000 ,000 . In another ( a ) about 50 % to about 70 % by mass of glyceryl monoli aspect, the release modifier comprises a polyethylene oxide 5 noleate ; (b ) about 25 % to about 40 % by mass of polyeth having a molecular weight ( M .) of about 4 ,000 , 000 . In ylene oxide ; ( c ) about 0 . 1 % to about 0 . 4 % by mass of BHA ; ( d ) about 0 .05 % to about 0 . 1 % by mass of BHT; and (e ) another aspect , the viscosity modifier comprises polyvinyl about 1 % to about 20 % of by mass of oxycodone hydro pyrrolidone , ethylcellulose , or a combination thereof. In chloride . another aspect, the antioxidant comprises alpha - tocopherol, 10 Another embodiment described herein is an oral abuse beta - tocopherol, gamma - tocopherol, delta -tocopherol , buty deterrent pharmaceutical composition comprising : ( a ) about lated hydroxyanisole ( BHA ), butylated hydroxytoluene 50 % to about 70 % by mass glyceryl monolinoleate ; ( b ) (BHT ) , citric acid , ascorbic acid , carnosic acid , carnosol, about 25 % to about 40 % by mass polyethylene oxide rosmanol, epirosmanol, isorosmanol, methyl carnosate , ros comprising a molecular weight of about 4 , 000 ,000 ; and (c ) marinic acid , eugenol, eugenyl acetate , clove bud extract , 15 about 1 % to about 20 % by mass of oxycodone hydrochlo methanolic extract, epigallocatechin gallate , epicatechin gal ride; and wherein the composition forms an abuse deterrent late , epigallocatechin , epicatechin , or a combination thereof. elastic semi- solid composition after being heated at a tem In another aspect , the composition forms an elastic , semi- perature of about 50° C . to about 80° C . for a time period of solid composition after being heated at a temperature of about 10 min to about 180 min and then cooling the about 50° C . to about 80° C . for a time period of about 10 20 composition to room temperature . In one aspect, the active min to about 180 min and then cooling the composition to pharmaceutical ingredient comprises about 5 mg, about 10 room temperature. In another aspect, the active pharmaceu - mg, about 15 mg, about 20 mg, about 30 mg, or about 40 mg tical ingredient comprises an opioid agonist . In another of oxycodone hydrochloride. In another aspect, the compo aspect , the active pharmaceutical ingredient comprises oxy - sition is encapsulated in a capsule . In another aspect, the codone, hydrocodone , oxymorphone , hydromorphone, mor - 25 composition is encapsulated in a soft capsule . In another phine, codeine , methadone , fentanyl, tapentadol, tramadol, aspect, the soft capsule comprises one or more film forming meperidine, propoxyphene, flunitrazepam , barbiturates , polymers , one or more plasticizers , one or more solvents , amytal, nembutal , seconal, phenobarbital; benzodiazepines , and optionally : one or more opacifying agents, one or more zolpidem , zaleplon , eszopiclone , amphetamines , methyl coloring agents , one or more pharmaceutical excipients , or In 30 combination thereof. In another aspect , the soft capsule phenidate , a salt thereof, or a combination thereof. In 30 comprises : ( a ) about 25 % to about 50 % of one or more another aspect, the active pharmaceutical ingredient com film - forming polymers ; ( b ) about 15 % to about 25 % of one prises oxycodone or a pharmaceutically acceptable salt or more plasticizers ; ( c ) about 20 % to about 40 % of one or thereof. In another aspect, the active pharmaceutical ingre more solvents ; and (d ) optionally , one or more opacifying dient comprises oxycodone hydrochloride or oxycodone 35 agents , one or more coloring agents , one or more pharma myristate . In another aspect , the active pharmaceutical ceutical excipients , or combination thereof. In another ingredient comprises oxycodone hydrochloride comprising aspect, the soft capsule comprises gelatin , glycerol, water, > 25 ppm of 14 -hydroxycodeinone . In another aspect, the and optionally , titanium oxide , and /or a coloring agent. In active pharmaceutical ingredient comprises about 5 mg to another aspect, the soft capsule is coated with one or more about 120 mg of oxycodone hydrochloride . In another 40 coatings . In another aspect, the coating comprises polyvinyl aspect, the active pharmaceutical ingredient comprises about alcohol. In another aspect, the coating comprises about 5 % 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, to about 15 % of weight gain to the dosage form . In another or about 40 mg of oxycodone hydrochloride . aspect, the coating thickness is about 150 um to about 200 In one embodiment described herein , the composition um . comprises : (a ) about 35 % to about 70 % by mass of one or 45 Another embodiment described herein is a method for more flowability enhancers ; ( b ) about 20 % to about 50 % by manufacturing a tamper resistant, abuse deterrent dosage mass of one or more release modifiers ; and ( c ) about 1 % to form comprising : ( a ) combining one or more flowability about 30 % by mass of one or more active pharmaceutical enhancers , one or more viscosity modifiers , and one or more ingredients . In one aspect, the composition further com - active pharmaceutical ingredients ; ( b ) encapsulating the prises : ( d ) about 0 . 05 % to about 0 . 5 % of one or more 50 composition into capsules ; ( c ) incubating the capsules at an antioxidants. In another aspect, the composition comprises : elevated temperature for a period of time; and ( d ) cooling the ( a ) glyceryl monolinoleate ; ( b ) polyethylene oxide ; and ( c ) capsules to room temperature. In one aspect, the capsules oxycodone hydrochloride . In another aspect , the composi- produced in step ( b ) are coated with a coating prior to the tion further comprises: ( d ) butylated hydroxytoluene (BHT ) ; annealing of step ( c ) . In another aspect, the capsules are and ( e ) butylated hydroxyanisole ( BHA ) . In another aspect, 55 incubated in step ( c ) at about 50° C . to about 80° C . for about the composition comprises : ( a ) about 50 % to about 70 % by 10 min to about 180 min . In another aspect, the capsules are mass of glyceryl monolinoleate ; (b ) about 25 % to about 40 % cooled in step (d ) by reducing the temperature at a rate of by mass of polyethylene oxide ; and ( c ) about 1 % to about about 2° C . to about 10° C . per about 5 to about 15 min ( e . g . , 20 % by mass of oxycodone hydrochloride . In another a decrease of about 5° C . every 10 min ) . aspect , the composition further comprises : ( d ) about 0 . 05 % 60 Another embodiment described herein is an oral tamper to about 0 . 4 % by mass of BHA ; and ( e ) about 0 .05 % to resistant dosage form produced by any of the methods about 0 . 2 % by mass of BHT. In another aspect, the com - described herein comprising oxycodone hydrochloride . position comprises: ( a ) about 55 % to about 65 % by mass of Another embodiment described herein is a n oral abuse glyceryl monolinoleate ; ( b ) about 30 % to about 35 % by deterrent controlled release dosage form comprising a cap mass of polyethylene oxide; and ( c ) about 1 % to about 15 % 65 sule encapsulating : ( a ) about 50 % to about 70 % by mass by mass of oxycodone hydrochloride . In another aspect, the glyceryl monolinoleate ; ( b ) about 25 % to about 40 % by composition further comprises: (d ) about 0 . 1 % to about mass polyethylene oxide comprising a molecular weight of US 9 ,943 ,513 B1 about 4 ,000 , 000 ; and ( c ) about 1 % to about 20 % by mass of Another embodiment described herein is an oral abuse oxycodone hydrochloride; and the dosage form having been deterrent controlled release pharmaceutical composition heated to about 50° C . to about 80º C . for about 10 min to comprising glyceryl monolinoleate , polyethylene oxide , and about 180 min , and cooled to room temperature by reducing oxycodone, the composition having been heated to about the temperature at a rate of about 2° C . to about 10° C . per 5 50° C . to about 80° C . for about 10 min to about 180 min , about 5 to about 15 min . In another aspect, the dosage form and cooled to room temperature, wherein the abuse deterrent exhibits an in vitro dissolution rate at pH 1 . 2 of about 50 % controlled release pharmaceutical composition comprises a after about 90 min . In another aspect, the pharmaceutical means for inhibiting the crushing, grating , grinding, cutting , dosage form exhibits an in vitro dissolution rate in water solvating , or dissolving of the composition . under boiling conditions of less than about 35 % to about 1 Another embodiment described herein is a kit for dis 60 % after about 10 minutes to about 45 minutes. In another pensing an abuse deterrent dosage form comprising: ( a ) one aspect , the pharmaceutical composition exhibits an in vitro or more dosage forms as described herein ; ( b ) one or more dissolution rate in an aqueous alcohol solution or distilled receptacles comprising a tamper evident, moisture proof water of less than about 20 % to about 50 % after about 30 15 packaging that reduces the ability of removing the dosage minutes to about 360 minutes . form comprising blister or strip packs, aluminum blister , Another embodiment described herein is a method for transparent or opaque polymer blister with pouch , polypro treating, reducing the symptomsof , or retarding the onset of pylene tubes , colored blister materials , tubes, bottles, and pain comprising administering to a subject in need thereofof bottles optionally containing a child - resistant feature , an oral pharmaceutical composition comprising glyceryl 20 optionally comprising a desiccant, such as a molecular sieve monolinoleate , polyethylene oxide , and oxycodone . In one or silica gel ; and (c ) optionally , an insert comprising instruc aspect , in the pharmaceutical composition comprises: ( a ) tions or prescribing information for the dosage form . about 50 % to about 70 % by mass glyceryl monolinoleate ; One embodiment described herein is an oral pharmaceu ( b ) about 25 % to about 40 % by mass polyethylene oxide ; tical composition comprising : ( a ) glyceryl monolinoleate ; and ( c ) about 1 % to about 20 % by mass of oxycodone 25 (b ) polyethylene oxide ; and ( c ) oxycodone or a salt thereof. hydrochloride . In another aspect, the pain arises from one or In one aspect, the composition forms an abuse deterrent more of diabetic neuropathy , chronic arthritis, osteoarthritis , elastic semi- solid composition after being heated at a tem rheumatoid arthritis , acute tendonitis , bursitis , headaches , migraines , chronic neuropathies, shingles, premenstrual perature of about 50° C . to about 80° C . for a time period of symptoms, sports injuries, malignancy , radiculopathy , sci - 30 about 10 min to about 180 min and then cooling the atica / sciatic pain , sarcoidosis , necrobiosis , lipoidica , granu composition to room temperature . In another aspect, a ratio loma annulare, trauma, cancer, or a combination thereof. of polyethylene oxide to glyceryl monolinoleate is about Another embodiment described herein is a method for 1 : 2 . In another aspect, a ratio of oxycodone to polyethylene delivering about 10 mg to about 120 mg of oxycodone oxide comprises a range of about 1: 1 to about 1 :15 . In comprising administering to a subject one or more doses of 2535 anothermm aspect, the glycerylmonolinoleate comprises about a pharmaceutical composition comprising glyceryl monoli 35 % to about 70 % of the composition by mass. In another noleate, polyethylene oxide , and oxycodone , the method aspect , the polyethylene oxide comprises about 20 % to capable of achieving one or more of the following pharma about 50 % of the composition by mass . In another aspect , cokinetic parameters : (a ) a mean plasma oxycodone T . , of the oxycodone comprises about 1 % to about 30 % of the about 1 hours to about 8 hours ; ( b ) a mean plasma oxyco771X - 40 composition by mass . In another aspect, the composition done Cmor of about 10 ng /mL to about 150 ng /mL ; or ( c ) a further comprises one or more antioxidants. In another mean plasma oxycodone AUC .- - of about 100 h .ng / mL to aspect, the antioxidant comprises about 0 .05 % to about about 1000 hing /mL . 0 .5 % of the composition by mass . In another aspect, the Another embodiment described herein is a method for antioxidant comprises butylated hydroxyanisole (BHA ) , delivering about 40 mg of oxycodone comprising adminis - 45 butylated hydroxytoluene (BHT ) , or a combination thereof. tering to a subject one or more dosage forms comprising In another aspect, the polyethylene oxide comprises a poly glycerylmonolinoleate , polyethylene oxide , and oxycodone , ethylene oxide having a molecular weight (M ) of about the method capable of achieving one or more of the follow - 1 , 00 , 000 to about 7 , 000 ,000 . In another aspect, the polyeth ing pharmacokinetic parameters : ( a ) a mean plasma oxyco - ylene oxide comprises a polyethylene oxide having an done Tmax of about 4 .5 hours to about 5 .0 hours ; ( b ) a mean 50 average molecular weight (M ) of about 4 ,000 ,000 . In plasma oxycodone Cmax of about 40 ng/ mL to about 65 another aspect, the oxycodone comprises oxycodone hydro ng /mL ; ( c ) a mean plasma oxycodone AUCO - of about 400 chloride or oxycodone myristate . In another aspect, the h .ng /mL to about 500 h .ng /mL ; ( d ) a mean plasma oxyco - oxycodone comprises about 5 mg to about 120 mg of done AUCO - s of about 400 . h .ng /mL to about 500 h .ng / mL ; oxycodone hydrochloride . In another aspect, the oxycodone ( e) a mean oxycodone half - life ( t1 /2 ) of about 4 .4 hours to 55 comprises about 5 mg, about 10 mg, about 15 mg, about 20 about 4 . 6 hours ; or ( f ) a mean oxycodone overall elimination mg, about 30 mg, or about 40 mg of oxycodone hydrochlo rate constant ( a ) of about 0 . 14 h - to about 0 . 17 h - 7 . In one ride . aspect, the pharmaceutical dosage form exhibits an in vitro In another embodiment, the composition comprises : ( a ) dissolution rate at pH 1 . 2 of about 50 % after about 90 about 35 % to about 70 % by mass of glycerylmonolinoleate ; minutes . 60 ( b ) about 20 % to about 50 % by mass of polyethylene oxide ; Another embodiment described herein is a method for and ( c) about 1 % to about 30 % by mass of oxycodone inhibiting extraction of oxycodone from a pharmaceutical hydrochloride . In one aspect , the composition further com composition , the method comprising : providing a dosage prises : ( d ) about 0 . 1 % to about 0 . 4 % by mass of BHA ; and form as described herein , wherein the dosage form is resis - ( e ) about 0 .05 % to about 0 . 1 % by mass of BHT. In another tant to crushing , grating , grinding , cutting , solvation , or 65 aspect , the composition comprises : ( a ) about 50 % to about dissolution in water or alcohol. In one aspect , the pharma - 70 % by mass of glyceryl monolinoleate ; ( b ) about 25 % to ceutical composition comprises a coated soft capsule . about 40 % by mass of polyethylene oxide ; (c ) about 0 . 1 % to US 9 ,943 ,513 B1 about 0 .4 % by mass of BHA ; (d ) about 0 .05 % to about 0 . 1 % mL ; ( e ) a mean oxycodone half- life ( t1/ 2 ) of about 4 . 4 hours by mass of BHT; and ( e ) about 1 % to about 20 % of by mass to about 4 . 6 hours ; or ( f ) a mean oxycodone overall elimi of oxycodone hydrochloride. nation rate constant (a ) of about 0 . 14 h - to about 0 . 17 h - ? . Another embodiment described herein is an oral abuse In one aspect, the pharmaceutical dosage form exhibits an in deterrent controlled release dosage form comprising a cap - 5 vitro dissolution rate at pH 1 . 2 of about 50 % after about 90 sule encapsulating : ( a ) about 50 % to about 70 % by mass minutes . glyceryl monolinoleate ; ( b ) about 25 % to about 40 % by Another embodiment described herein is an abuse deter mass polyethylene oxide comprising an average molecular rent oral pharmaceutical composition comprising a tamper weight ( M ) of about 4 ,000 ,000 ; and ( c ) about 1 % to about resistant controlled release composition comprising : ( a ) one 20 % by mass of oxycodone hydrochloride ; and the dosage 10 or more flowability enhancers ; ( b ) one or more release form having been heated to about 50° C . to about 80° C . for modifiers ; and ( c ) one or more active pharmaceutical ingre about 10 min to about 180 min , and cooled to room dients ; wherein the matrix is resistant to tampering . In one temperature by reducing the temperature at a rate of about 2° aspect described herein , the tamper resistant controlled C . to about 10° C . over about 5 to about 15 min (e . g ., a release matrix further comprises at least one antioxidant. In decrease of about 5° C . every 10 min ) . In one aspect , the 15 another aspect described herein , the tamper resistant con oxycodone hydrochloride comprises about 5 mg, about 10 trolled release matrix further comprises at least one or more mg, about 15 mg, about 20 mg, about 30 mg, or about 40 mg viscosity modifiers . In another aspect described herein , the of oxycodone hydrochloride . In another aspect, the capsule one or more flowability enhancers comprise about 35 % to is coated with a polyvinyl alcohol coating . In another aspect , about 70 % of the total matrix mass . In another aspect the dosage form exhibits an in vitro dissolution rate at pH 1 . 2 20 described herein , the at least one or more release modifiers of about 50 % after about 90 minutes . A method for treating , comprise from about 20 % to about 50 % of the total matrix reducing the symptoms of, or retarding onset of pain com - mass . In another aspect described herein , the at least one prising administering to a subject in need thereof a dosage active pharmaceutical ingredient comprise about 0 . 1 % to form as described herein . about 35 % of the total matrix mass. In another aspect Another embodiment described herein is a method for 25 described herein , the at least one antioxidant comprises inhibiting extraction of oxycodone from a pharmaceutical about 0 .05 % to about 0 . 5 % of the total matrix mass. In composition , the method comprising : providing a dosage another aspect described herein , the at least one or more form as described herein , wherein the dosage form is resis - viscosity modifiers comprise about 0 . 5 % to about 8 % of the tant to crushing , grating , grinding , cutting , solvation , or total matrix mass . In another aspect described herein , the dissolution in water or alcohol. 30 ratio of the active pharmaceutical ingredient percent mass to Another embodiment described herein is a kit for dis - the matrix percent mass is about 1 : 1000 to about 1 : 3 . In pensing an abuse deterrent dosage form comprising : ( a ) one another aspect described herein , the one or more flowability or more dosage forms as described herein ; ( b ) one or more enhancers comprises a non -ionic surfactant, an anionic sur receptacles comprising a tamper evident, moisture proof factant, a zwitterionic surfactant, or a cationic surfactant or packaging that reduces the ability of removing the dosage 35 a combination thereof. In another aspect described herein , form comprising blister or strip packs, aluminum blister, the one or more flowability enhancers comprises a non - ionic transparent or opaque polymer blister with pouch , polypro - surfactant. In another aspect described herein , the one or pylene tubes, colored blister materials , tubes, bottles , and more flowability enhancers have a hydrophilic lipophilic bottles optionally containing a child - resistant feature , balance of less than about 5 . In another aspect described optionally comprising a desiccant , such as a molecular sieve 40 herein , the one or more flowability enhancers comprise a or silica gel; and ( c ) optionally , an insert comprising instruc - medium chain mono - , di- , or tri - glyceride ; or a liquid tions or prescribing information for the dosage form . lipophilic vehicle . In another aspect described herein , the Another embodiment described herein is a method for one or more flowability enhancers comprise glyceryl mono manufacturing an abuse deterrent dosage form comprising: caprylate , glyceryl monocaprylcaprate , glyceryl monoli (a ) combining glyceryl monolinoleate , polyethylene oxide , 45 noleate , or oleic acid . In another aspect described herein , the and oxycodone ; ( b ) encapsulating the combination into one or more release modifiers comprise a high molecular capsules ; ( c ) incubating the capsules at an elevated tempera - weight polyethylene oxide . In another aspect described ture for a period of time; and ( d ) cooling the capsules to herein , the one or more release modifiers comprises a room temperature . In one aspect, the capsules produced in polyethylene oxide having , a carboxyvinyl polymer or a step ( b ) are coated with a coating prior to the incubating of 50 mixture thereof. In another aspect , the molecular weight of step ( c ) . In another aspect, the capsules are incubated in step the polyethylene oxide is about 5 ,000 ,000 ; about 6 , 000 , 000 , ( c ) at about 50° C . to about 80º C . for about 10 min to about about 7 ,000 , 000 , about 8 ,000 , 000 , about 9 ,000 ,000 , or about 180 min . In another aspect, the capsules are cooled in step 10 ,000 ,000 . In another aspect described herein , the one or ( d ) by reducing the temperature at a rate of about 2° C . to more viscosity modifiers comprises polyvinyl pyrrolidone or about 10° C . over about 5 to about 15 min ( e . g . , a decrease 55 ethylcellulose , or a mixture thereof. In another aspect of about 5° C . every 10 min ). described herein , the antioxidant comprises alpha - tocoph Another embodiment described herein is a method for erol , beta - tocopherol , gamma- tocopherol, delta - tocopherol , treating pain comprising administering to a subject a phar- butylated hydroxytoluene (BHT ) , butylated hydroxyanisole maceutical dosage form comprising glycerylmonolinoleate , (BHA ) , citric acid , ascorbic acid , carnosic acid , carnosol, polyethylene oxide , and about 40 mg oxycodone , the 60 rosmanol, epirosmanol, isorosmanol, methyl carnosate , ros method capable of achieving one or more of the following marinic acid , eugenol , eugenyl acetate , clove bud extract , pharmacokinetic parameters : ( a ) a mean plasma oxycodone methanolic extract, epigallocatechin gallate , epicatechin gal Tmax of about 4 .5 hours to about 5 .0 hours ; (b ) a mean late , epigallocatechin , epicatechin , or a combination thereof. plasma oxycodone Cmor of about 40 ng /mL to about 65 In another aspect described herein , the tamper resistant ng/ mL ; ( c ) a mean plasmamax oxycodone AUC . - > of about 400 65 controlled release matrix forms a semi- solid elastic compo hòng /mL to about 500 h?ng /mL ; ( d ) a mean plasma oxyco - sition after being heated at a temperature of about 50° C . to done AUCO - O of about 400 . h .ng /mL to about 500 hing about 90° C . for a period of time of about 0 . 1 hours to about US 9 ,943 ,513 B1 10 3 hours. In another aspect described herein , the active In one aspect described herein , the soft capsule shell pharmaceutical ingredient comprises at least one of: hydro comprises : ( a ) about 25 % to about 50 % of at least one codone, morphine , morphine analogues , or morphine film - forming polymer ; (b ) about 15 % to about 25 % of at antagonists , tapentadol , codeine ,morphine , methadone, fen least one plasticizer ; (c ) about 20 % to about 40 % of a tanyl and analogs , hydrocodone hydrochloride , hydroco - 5 solvent ; ( d ) optionally , an opacifying agent, a coloring agent, done bitartrate , hydromorphone, oxymorphone , oxycodone , a pharmaceutical excipient, or combination thereof. In another aspect described herein , the soft capsule shell com meperidine, propoxyphene , flunitrazepam , barbiturates , prises : ( a ) about 42 % of at least one film - forming polymer ; amytal , nembutal , seconal , phenobarbital; benzodiazepines , ( b ) about 20 % of at least one plasticizer; ( c ) about 38 % of zolpidem , zaleplon , eszopiclone, amphetamines , methyl+ 10 a solvent; (d ) optionally , about 0 .7 % of an opacifying agent; phenidate , or a combination thereof. In another aspect and ( e ) optionally , about 0 . 1 % at least one coloring agent. In described herein , the active pharmaceutical ingredient com another aspect described herein , the soft capsule shell com prises oxycodone or any pharmaceutically acceptable salt prises gelatin , glycerol, water, and optionally , titanium thereof. oxide , and a coloring agent. In another embodiment described herein , the active pharhar, 15 Another embodiment described herein is a method of maceutical ingredient comprises oxycodone and a second making the tamper resistant controlled release matrix dosage active pharmaceutical ingredient that reduces the symptoms form as described herein comprising the steps of ( a ) sus of, or onset of, or prophylaxis , of a bowel dysfunction due pending one or more release modifiers in one or more to acute or chronic opioid use . In another aspect described flowability enhancers to form a first mixture and ( b ) adding herein , the second active pharmaceutical ingredient com - 20 one or more active pharmaceutical ingredients to the first prises a peripherally acting mu - opioid receptor antagonist mixture to form a matrix mixture that may be encapsulated comprising methylnaltrexone , naltrexone , naloxone , nalox - in a soft capsule shell or a hard capsule shell. In one aspect , egol, alvimopan or a combination thereof. In another aspect step ( a ) further comprises dissolving one or more viscosity described herein , the peripherally actingmu -opioid receptor modifiers in the one or more flowability enhancers . antagonist comprises methylnaltrexone , naltrexone , nalox - 25 Another embodiment described herein is a method for one or a combination thereof. In another aspect described manufacturing a soft capsule shell and a tamper resistant herein , the peripherally acting mu -opioid receptor antagonist controlled release matrix comprising : ( a ) providing a matrix comprises naloxone. In another aspect described herein , the comprising the composition as described herein made by the active pharmaceutical ingredient comprises naloxone and methods of manufacturing described herein ; ( b ) providing a oxycodone . In another aspect described herein , the at least 30 soft capsule gel mass described herein ; ( c ) casting the soft one active pharmaceutical ingredient comprises naltrexone capsule gel mass into films using heat- controlled drums or and oxycodone . surfaces ; ( d ) forming a soft capsule comprising the matrix In another embodiment described herein , the tamper resis composition using rotary die encapsulation technology ; and tant controlled release matrix comprises: ( a ) glyceryl mono ( e ) heating the formed capsules for about 1 hour at about 70° caprylate , oleic acid , or glyceryl monolinoleate ; ( b ) poly - 35 C . to form an annealed soft capsule shell , wherein following ethylene oxide ; and ( c ) oxycodone ; and optionally one or heating , the matrix has tamper resistant controlled release more of (d ) a carboxyvinyl polymer; (e ) BHT; and (f ) BHA . properties . In one aspect, the tamper resistant controlled release matrix Another embodiment described herein is a soft or hard further comprises polyvinylpyrrolidone or ethylcellulose . In capsule comprising a tamper resistant controlled release another aspect described herein , the tamper resistant con - 40 matrix produced by the methods described herein . trolled release matrix comprises: ( a ) about 50 % to about Another embodiment described herein is an enteric soft 65 % mono - and diglycerides ( e .g . , Capmul® MCM ), oleic capsule comprising a tamper resistant controlled release acid , or glycerylmonolinoleate ; ( b ) about 25 % to about 35 % matrix produced by the method described herein . polyethylene oxide having a molecular weight of about Another embodiment described herein is a tamper resis 4 ,000 ,000 or about 7, 000 ,000 ; and (c ) about 2 % to about 45 tant oral pharmaceutical composition comprising a tamper 10 % of oxycodone ; and optionally ( d ) about 1 % of car - resistant controlled release matrix comprising : ( a ) about boxyvinyl polymer (e . g ., Carbopol® 974P ); ( e ) about 0 .25 % 50 % to about 65 % mono - and diglycerides ( e .g ., Capmul® BHT; and ( f) about 0 .1 % BHA . In another aspect, the tamper MCM ) ; (b ) about 25 % to about 35 % polyethylene oxide resistant controlled release matrix further comprises about having a molecular weight of about 4 ,000 , 000 or about 1 % to about 5 % of polyvinylpyrrolidone K90 or about 1 % 50 7 , 000 , 000 ; and ( c ) about 2 % to about 10 % of oxycodone ; to about 5 % ethylcellulose 20 CP ( e . g . , EthocelTM 20 CP ) . In and optionally ( d ) about 1 % of carboxyvinyl polymer ( e . g . , another aspect described herein , the tamper resistant con Carbopol® 974P ) ; ( e ) about 0 .25 % BHT; and ( f ) about 0 . 1 % trolled release matrix further comprises a peripherally acting BHA ; wherein the matrix is resistant to tampering and has mu- opioid receptor antagonist comprising naloxone , methyl controlled release properties; the matrix being encapsulated naltrexone , or naltrexone. In another aspect described 55 in a soft capsule shell comprising : ( g ) about 25 % to about herein , the weight percentage ratio of naloxone methyl 50 % gelatin ; ( h ) about 15 % to about 25 % glycerol; ( i ) about naltrexone or naltrexone to oxycodone is about 15 : 1 to about 20 % to about 40 % water; and (j ) optionally , an opacifying 1 : 18 . In another aspect described herein , the weight percent - agent, a coloring agent, a pharmaceutical excipient, or age ratio of naloxone to oxycodone is about 1 : 2 . combination thereof. In one aspect described herein , the In another embodiment described herein , the capsule shell 60 tamper resistant controlled release matrix further comprises comprises a soft capsule shell . In another embodiment a peripherally acting mu - opioid receptor antagonist com described herein , the capsule shell comprises a hard capsule prising naloxone , methyl naltrexone, or naltrexone . In shell . another aspect described herein , the weight percentage ratio In another embodiment described herein the soft capsule of naloxone, methyl naltrexone or naltrexone to oxycodone shell comprises a film forming polymer , a plasticizer , a 65 is about 15: 1 to about 1 : 18 . In another aspect described solvent, and optionally, an opacifying agent, a coloring herein , the weight percentage ratio of naloxone to oxyco agent, or a pharmaceutical excipient . done is about 1 : 2 . US 9 ,943 ,513 B1 12 Another embodiment described herein is a tamper resis - premenstrual symptoms, sports injuries, malignancy , radicu tant oral pharmaceutical composition comprising a tamper lopathy , sciatica / sciatic pain , sarcoidosis , necrobiosis , resistant controlled release matrix comprising : ( a ) about lipoidica or granuloma annulare comprising administering 50 % to about 65 % mono - and diglycerides ( e . g . , Capmul® to a subject in need thereof the pharmaceutical composition MCM ) ; (b ) about 25 % to about 35 % polyethylene oxide 5 as described herein . In one aspect described herein , the having a molecular weight of about 4 , 000 , 000 or about administration is sufficient to achieve a reduction of pain 7 ,000 ,000 ; and ( c) about 10 % of oxycodone ; ( g ) about 1 % relative to baseline in the subject without substantially to about 5 % of naloxone ; and optionally ( d ) about 1 % of carboxyvinyl polymer ( e . g ., Carbopol 974P ) ; ( e ) about inducing one or more of opioid induced bowel disfunction 0 . 25 % BHT; and ( f ) about 0 . 1 % BHA ; wherein the matrix is 10 (OIBD ) comprising constipation (opioid induced constipa resistant to tampering and has controlled release properties ; tion ; OIC ) , anorexia , nausea and vomiting, gastro - oesopha the matrix being encapsulated in a soft capsule shell com geal reflux, delayed digestion , abdominal pain , flatulence , prising: (g ) about 25 % to about 50 % gelatin ; (h ) about 15 % bloating , hard stools , incomplete evacuation or straining to about 25 % glycerol; ( i ) about 20 % to about 40 % water; during bowel movements . and (j ) optionally , an opacifying agent, a coloring agent, a 15 Another embodiment described herein is a method for pharmaceutical excipient, or combination thereof. delivering about a 10 mg to about 80 mg dose of oxycodone Another embodiment described herein is a tamper resis - comprising administering to a subject a pharmaceutical tant oral pharmaceutical composition comprising a tamper composition comprising oxycodone and other pharmaceuti resistant controlled release matrix comprising : ( a ) about cally acceptable excipients in a tamper resistant matrix in a 50 % to about 65 % mono - and diglycerides ( e. g ., Capmul® 20 soft gel capsule, the method capable of achieving one or MCM ) ; ( b ) about 25 % to about 35 % polyethylene oxide more of the following pharmacokinetic parameters : ( a ) a having a molecular weight of about 4 , 000 , 000 or about mean plasma oxycodone Tmor of about 1 hours to about 8 7 , 000, 000 ; ( c ) about 1 % to about 5 % polyvinylpyrrolidone hours; ( b ) a mean plasma oxycodone Cmax of about 10 K90 ( d ) about 2 % to about 10 % of oxycodone ; and option ng /mL to about 150 ng /mL ; ( c ) a mean plasma oxycodone ally ( e ) about 0 . 25 % BHT; and ( f ) about 0 . 1 % BHA; wherein 25 AUC . - - . of about 100 h ·mg / L to about 1000 h .mg / L . the matrix is resistant to tampering and has controlled In one aspect described herein , the method further com release properties; the matrix being encapsulated in a soft prises delivering a dose of a peripherally acting mu -opioid capsule shell comprising: ( g ) about 25 % to about 50 % receptor antagonist comprising naloxone, methyl naltrex gelatin ; ( h ) about 15 % to about 25 % glycerol; ( i ) about 20 % one, or naltrexone . In another aspect described herein , the to about 40 % water ; and ( 1 ) optionally , an opacifying agent, 30 weight percentage ratio of naloxone methyl naltrexone or a coloring agent, a pharmaceutical excipient, or combination naltrexone to oxycodone is about 15 : 1 to about 1 : 18 . In thereof. another aspect described herein , the weight percentage ratio Another embodiment described herein is a tamper resis - of naloxone to oxycodone is about 1 : 2 . tant oral pharmaceutical composition comprising a tamper I n another aspect described herein , the administration of resistant controlled release matrix comprising : ( a ) about 35 the compositions described herein is sufficient to achieve a 50 % to about 65 % oleic acid ; ( b ) about 25 % to about 35 % reduction of pain relative to baseline in the subject without polyethylene oxide having a molecular weight of about substantially inducing one or more of opioid induced bowel 4 ,000 ,000 or about 7 , 000 ,000 ; ( c ) about 1 % to about 5 % disfunction (OIBD ) comprising constipation (opioid ethylcellulose 20 CP ( e . g ., EthocelTM 20 CP ) ; ( d ) about 2 % to induced constipation ), anorexia , nausea and vomiting , gas about 10 % of oxycodone ; and optionally ( e ) about 0 . 25 % 40 tro - oesophageal reflux , delayed digestion , abdominal pain , BHT; and ( f ) about 0 . 1 % BHA ; wherein the matrix is flatulence , bloating , hard stools , incomplete evacuation , or resistant to tampering and has controlled release properties ; straining during bowel movements . the matrix being encapsulated in a soft capsule shell com - In another aspect described herein , the administration of prising : ( g ) about 25 % to about 50 % gelatin ; ( h ) about 15 % the compositions described herein provides an improvement to about 25 % glycerol; ( i) about 20 % to about 40 % water ; 45 of bowel function during pain therapy , comprising an and (j ) optionally , an opacifying agent, a coloring agent, a improvement of the mean bowel function score of at least pharmaceutical excipient, or combination thereof. about 5 , at least about 8 , at least about 10 , or at least about Another embodiment described herein is a tamper resis - 15 after steady state administration to human patients , tant oral pharmaceutical composition comprising a tamper wherein the mean bowel function score is measured with a resistant controlled release matrix comprising : ( a ) about 50 numerical analog scale ranging from 0 to 100 . In another 50 % to about 65 % glyceryl monolinoleate ( e . g ., MaisineTM aspect described herein , the pharmaceutical composition 35 - 1 ) ; ( b ) about 25 % to about 35 % polyethylene oxide comprises the tamper resistant controlled release matrix as having a molecular weight of about 4 ,000 , 000 or about described herein . 7 , 000 ,000 ; and ( c ) about 2 % to about 10 % of oxycodone ; In another aspect described herein , the pharmaceutical and optionally ( e ) about 0 . 25 % BHT; and ( f) about 0 . 1 % 55 composition exhibits an in vitro dissolution rate at pH 1 . 2 , BHA ; wherein the matrix is resistant to tampering and has of about 35 % to about 95 % after about 60 minutes to about controlled release properties ; the matrix being encapsulated 480 minutes. In another aspect described herein , the phar in a soft capsule shell comprising : ( g ) about 25 % to about maceutical composition exhibits an in vitro dissolution rate 50 % gelatin ; ( h ) about 15 % to about 25 % glycerol; ( i) about at pH 1 . 2 , of less than about 20 % after about 60 minutes to 20 % to about 40 % water ; and (j ) optionally , an opacifying 60 about 480 minutes . In another aspect described herein , the agent, a coloring agent, a pharmaceutical excipient, or pharmaceutical composition exhibits an in vitro dissolution combination thereof. rate under boiling conditions of less than about 35 % to about Another embodiment described herein is a method for 60 % after about 10 minutes to about 45 minutes. In another treating , reducing the symptoms or onset of, or prophylaxis aspect described herein , the pharmaceutical composition of pain stemming from diabetic neuropathy , chronic arthri- 65 exhibits an in vitro dissolution rate in an aqueous alcohol tis , osteoarthritis , rheumatoid arthritis , acute tendonitis , bur - solution or distilled water of less than about 20 % to about sitis , headaches , migraines , chronic neuropathies, shingles , 50 % after about 30 minutes to about 360 minutes . US 9 ,943 ,513 B1 13 14 Another embodiment described herein is method for pared to the percent release of oxycodone from a reference reducing the ability of a subject to extract an active phar - abuse deterrent pharmaceutical composition in FASSGF and maceutical ingredient from a pharmaceutical composition FASSIF buffer. though crushing , grating , grinding , cutting, or solvating or FIG . 8 . Representative thermogram data demonstrating dissolving the matrix comprising : providing the abuse deter - 5 PEO melting point depression results in various flowability rent composition as described herein , wherein the compo enhancers compared to a non - flowability enhancing excipi sition is resistant to crushing , grating , grinding , cutting , ent control. solvation , or dissolution . In one aspect described herein , the FIG . 9 . Percent release of oxycodone from annealed test pharmaceutical composition comprises a soft capsule shell abuse deterrent pharmaceutical compositions ( F7 -F9 ) com or hard capsule shell as described herein . 10 pared in FaSSGF and FaSSIF buffer. Another embodiment described herein is an abuse deter rent oral pharmaceutical composition comprising a tamper FIG . 10 . Representative image of ( A ) a reference abuse resistant controlled release matrix , wherein the tamper resis deterrent formulation after being struck with a hammer and tant controlled release matrix comprises a means for pre ( B ) the test abuse deterrent formulation F9 shown in Table venting the crushing , grating , grinding , cutting , solvating, or 15 - dissolving of the tamper resistant controlled release matrix FIG . 11 . Percent release of oxycodone from annealed test comprising one or more active pharmaceutical ingredients . abuse deterrent pharmaceutical compositions ( F7 - F9 ) com Another embodiment described herein is a kit for dis pared to the percent release of oxycodone from a reference pensing the abuse deterrent oral pharmaceutical composition abuse deterrent pharmaceutical composition in simulated described herein comprising : ( a ) at least one soft capsule 20 gastric fluid . comprising a tamper resistant controlled release matrix FIG . 12 . Percent release of oxycodone from annealed test comprising an active pharmaceutical ingredient; ( b ) at least abuse deterrent pharmaceutical compositions ( F7 -F9 ) com one receptacle comprising a tamper evident, moisture proof pared to the percent release of oxycodone from a reference packaging that reduces the ability of removing the oral abuse deterrent pharmaceutical composition in simulated pharmaceutical composition comprising blister or strip 25 gastric fluid containing 5 % ethanol. packs , aluminum blister, transparent or opaque polymer FIG . 13 . Percent release of oxycodone from annealed test blister with pouch , polypropylene tubes , colored blister abuse deterrent pharmaceutical compositions ( F7 - F9 ) com materials , tubes , bottles , and bottles optionally containing a pared to the percent release of oxycodone from a reference child -resistant feature , optionally comprising a desiccant, abuse deterrent pharmaceutical composition in simulated such as a molecular sieve or silica gel; and ( c ) optionally , an 30 gastric fluid containing 20 % ethanol. insert comprising instructions or prescribing information for FIG . 14 . Percent release of oxycodone from annealed test the active pharmaceutical ingredient. abuse deterrent pharmaceutical compositions (F7 - F9 ) com pared to the percent release of oxycodone from a reference BRIEF DESCRIPTION OF THE DRAWINGS abuse deterrent pharmaceutical composition in simulated 35 gastric fluid containing 40 % ethanol. FIG . 1 . Percent release of oxycodone from an annealed FIG . 15 . Percent release of oxycodone from an annealed test abuse deterrent pharmaceutical composition (F1 ) com intact test abuse deterrent pharmaceutical composition (F9 ) pared to the percent release of oxycodone from a reference compared to the percent release of oxycodone from an intact abuse deterrent pharmaceutical composition in fasted state reference abuse deterrent pharmaceutical composition under simulated gastric fluid FaSSGF and fasted state simulated 40 aqueous boiling conditions. intestinal fluid FaSSIF buffer . FIG . 16 . Percent release of hydrocodone from an intact FIG . 2 . Percent release of oxycodone from annealed and annealed test abuse deterrent pharmaceutical composition non - annealed test abuse deterrent pharmaceutical composi - (F10 ) compared to the percent release of hydrocodone from tions (F1 ) compared to the percent release of oxycodone 10 mg and 50 mg intact reference abuse deterrent pharma from a reference abuse deterrent pharmaceutical composi- 45 ceutical compositions under aqueous boiling conditions . tion under aqueous boiling conditions . FIG . 17 . Percent release of oxycodone from a physically FIG . 3 . Percent release of oxycodone from annealed test manipulated ( ground with a coffee grinder ) annealed test abuse deterrent pharmaceutical compositions (F1 and F2 ) abuse deterrent pharmaceutical composition (F9 ) compared with or without a viscosity modifier compared to the percent to the percent release of oxycodone from a physically release of oxycodone from a reference abuse deterrent 50 manipulated (crushed with a mortar and pestle ) reference pharmaceutical composition under aqueous boiling condi- abuse deterrent pharmaceutical composition under aqueous tions. boiling conditions . FIG . 4 . Percent release of oxycodone from annealed test FIG . 18. Percent release of oxycodone from a reference abuse deterrent pharmaceutical compositions (F2 and F3 ) abuse deterrent pharmaceutical composition intact or having different molecular weight polyethylene oxide com - 55 manipulated by crushing with a mortar and pestle , grinding pared to the percent release of oxycodone from a reference with a coffee grinder , or cutting under dissolution conditions abuse deterrent pharmaceutical composition under aqueous in FaSSGF using Apparatus III at 30 dips per minute . boiling conditions . FIG . 19 . Percent release of oxycodone from a test abuse FIG . 5 . Percent release of oxycodone from an annealed deterrent pharmaceutical composition (F9 ) intact or manipu test abuse deterrent pharmaceutical composition (F2 ) in 60 lated by grinding with a coffee grinder or cutting under either SGF or an 80 % ethanol solution . dissolution conditions in fasted simulated gastric fluid using FIG . 6 . Percent release of oxycodone from annealed test Apparatus III at 30 dips per minute . abuse deterrent pharmaceutical compositions (F4 -F6 ) in FIG . 20 . Percent release of hydrocodone from a test abuse aqueous conditions at 80° C . compared to a reference deterrent pharmaceutical composition (F10 ) intact or oxycodone abuse deterrent composition . 65 manipulated by grinding with a coffee grinder under disso FIG . 7 . Percent release of oxycodone from annealed test lution conditions in FaSSGF using Apparatus III at 30 dips abuse deterrent pharmaceutical compositions ( F4 -F6 ) com per minute . US 9 ,943 ,513 B1 15 16 FIG . 21 . Percent release of oxycodone from a test abuse soft capsule . In some embodiments described herein , the soft deterrent pharmaceutical composition (F9 ) compared to a capsule is an enteric hard capsule . reference abuse deterrent pharmaceutical composition The term “ abuse deterrent, ” or “ tamper resistant ” as used manipulated by cutting under dissolution conditions in herein , refers to a pharmaceutical composition that is resis FaSSGF using Apparatus III at 30 dips per minute . 5 tant to tampering or accessing the active pharmaceutical FIG . 22 . Percent release of oxycodone from a test abuse ingredient for recreational drug use or drug abuse . deterrent pharmaceutical composition (F9 ) manipulated by The phrase " recreational drug use , " as used herein , refers to the voluntary use of an active pharmaceutical agent or cutting compared to a reference abuse deterrent pharmaceu drug for a non -medical purpose to induce an effect, such as tical composition manipulated by crushing with a mortar and 10 pleasure , satisfaction , euphoria , dissociation , or to enhance pestle under dissolution conditions in FaSSGF using Appa an experience. ratus III at 30 dips per minute . The term “ drug abuse , " as use herein , refers to the FIG . 23 . Test for syringability of a reference abuse habitual, compulsive , or recurrent use of an active pharma deterrent pharmaceutical composition manipulated by ceutical agent or drug , often despite negative consequences. crushing with a mortar and pestle or cutting compared to a 15 The term “ tampering ." as used herein , refers to any kind test abuse deterrent pharmaceutical composition ( F9 ) of actual or attempted physical manipulation or interference manipulated by cutting or grinding with a coffee grinder thatmay result in particle size reduction of a pharmaceutical followed by shaking agitation for 30 minutes in container composition . Tampering , as used herein also includes any having 10 mL of water actual or attempted dissolution or extraction of active phar FIG . 24 . Test for syringability of a reference abuse 20 maceutical ingredients using solvents . Compositions that are deterrent pharmaceutical composition manipulated by resistant to physical tampering are formulated in such a way crushing with a mortar and pestle or cutting compared to a that the composition cannot readily reduced to a form that is test abuse deterrent pharmaceutical composition (F9 ) suitable for abuse , such as, for example, injection or snort manipulated by cutting or grinding with a coffee grinder ing , because the tablet cannot easily be ground , grated , followed by agitation for 30 minutes in container having 10 25 dissolved , extracted , and the like at any temperature . mL of water in a water bath at 200 RPM at 90 -95° C . Examples of physical tampering include, but are not limited FIG . 25 . Mean oxycodone concentration - time profiles to , crushing , grinding , grating , cutting , crisping , and other after administration of formulation F11 ( treatment a ) , for- methods of particle size reduction . Dissolution tampering mulation F8 ( treatment b ) , formulation F9 ( treatment c ), includes actual or attempted actions to dissolve or extract formulation F7 (treatment d ) , and the reference product 30 active pharmaceutical ingredients using aqueous or organic ( treatment e ) . solvents such as water , ethanol, isopropanol, ethyl acetate , FIG . 26 . Mean log - transformed oxycodone concentration - acetone, ether , or the like , at any temperature including time profiles after administration of formulation F11 ( treat- boiling. Tampering , as used herein , includes " dose dump mentm a ), formulation F8 ( treatment b ) , formulation F9 ( treating . " ment c ) , formulation F7 ( treatment d ) , and the reference 35 The term “ dose dumping ” or “ dumping ” as used herein product ( treatment e ). refers to the rapid release of the entire amount or a signifi FIG . 27 . A . Oval and oblong oxycodone dosage forms and cant fraction of an active pharmaceutical ingredient or drug . representative cross - sections . B . Micrograph of a dosage Drug abusers often intentionally pursue dumping of a drug form cross section showing the abuse deterrent matrix , from the dosage form . gelatin shell, and polyvinyl alcohol ( PVA ) coating . The PVA 40 The terms “ drug " , " active ingredient, " " active pharma coating layer is about 185 um and the gelatin shell layer is ceutical ingredient, ” or “ active pharmaceutical agent” as about 650 um , for a total encapsulation layer of about used herein refer to an agent, active ingredient, compound , 810 - 840 um . or substance , compositions , or mixtures thereof , that provide FIG . 28 . Dissolution of various oxycodone dosage forms a pharmacological, often beneficial, effect . Reference to a compared with a commercial reference . 45 specific active ingredient includes , where appropriate , the FIG . 29 . Mean plasma oxycodone concentrations as a active ingredient and any of its pharmaceutically acceptable function of time after dosing a 40 mg oxycodone formula salts or esters . tion ( Table 23 ) compared with a commercial reference. The term “ anti- OIC agent” as used herein refers specifi Panels A and B show the same data , with B having a cally to any agent, active ingredient, compound , substance , logarithmic y - axis . 50 composition , or mixture thereof, which reduces opioid FIG . 30 . Mean plasma oxycodone concentrations as a induced constipation (OIC ) or one or more symptoms function of time after dosing a 40 mg oxycodone formula - thereof. tion ( Table 23 ) under fasted and fed conditions. Panels A and The terms “ dosage” or “ dose” denote any form of the B show the same data , with B having a logarithmic y -axis . active ingredient formulation that contains an amount suf 55 ficient to produce a therapeutic effect with a single admin DETAILED DESCRIPTION istration . The dosage form used herein is for oral adminis tration . The oral dosage forms are soft capsules, enteric soft Described herein are abuse deterrent controlled release capsules , hard capsules, or enteric hard capsules. pharmaceutical compositions . The pharmaceutical compo The term " annealed ” as used herein refers to a pharma sitions described herein provide abuse deterrent matrices 60 ceutical composition that has been heated to an elevated and methods for preparation thereof. Also described herein temperature ( e . g ., 60° C . to 80° C . ) for a time period ( e . g . , are compositions and methods for manufacturing soft or from 10 min to 120 min ) and then slowly cooled at a specific hard capsules comprising abuse deterrent controlled release rate (e . g. , 2° C . per 10 min ) to form an annealed dosage pharmaceutical matrices . In some embodiments described form . In some aspects , pharmaceutical compositions com herein , the capsule is a soft capsule . In some embodiments 65 prising a capsule shell encapsulating a fill composition as described herein , the soft capsule is a hard capsule. In some described herein may be annealed at a temperature from embodiments described herein , the soft capsule is an enteric about 50° C . to about 90° C . for about 0 . 1 hours to about 5 US 9 ,943 ,513 B1 17 18 hours, including all integers within the specified ranges of estimated from a concentration to time curve , and is temperature and time. In some aspects described herein , expressed in units of mg/ L or ng /mL , as applicable . pharmaceutical compositions comprising a soft or hard The term " Cmin " as used herein refers to the minimum capsule shell encapsulating a matrix fill as described herein observed blood (plasma , serum , or whole blood ) concentra may be annealed at a temperature of about 70° C . from about 5 tion or the minimum blood concentration calculated or 20 min to about 90 min , including all integers within the estimated from a concentration to time curve, and is specified range . In some aspects described herein , pharma ceutical compositions comprising a soft or hard capsule shell expressed in units of mg/ L or ng /mL , as applicable . encapsulating a matrix fill as described herein may be The term “ Cave " as used herein refers to the blood annealed at a temperature of about 70° C . for about 1 hour. 10 ( plasma, serum , or whole blood ) concentration of the drug In some aspects, after annealing , the dosage form is slowly within the dosing interval , is calculated as AUC /dosing cooled to room temperature at a cooling rate of about 2° C . interval, and is expressed in units of mg/ L or ng/ mL , as to about 10° C . per about 5 min to about 20 min ( e . g . , 2 - 10° applicable . C ./ 5 - 20 min ) . In some aspects described herein , a capsule is The term “ Tmax " as used herein refers to the time after coated prior to the annealing step . 155 amadministration at which Cmax occurs, and is expressed in The term “ non - annealed ” refers to a pharmaceutical com - units of hours ( h ) or minutes (min ) , as applicable . position comprising a soft or hard capsule shell encapsulat The term “ AUCO " as used herein refers to area under ing a matrix fill described herein that has not been heated the blood (plasma , serum , or whole blood ) concentration following encapsulation . versus time curve from time zero to time tau ( T ) over a The terms “ active pharmaceutical ingredient load ” or 20 dosing interval at steady state , where tau is the length of the “ drug load ” as used herein refers to the quantity (mass ) of dosing interval, and is expressed in units of h ·mg / L or the active pharmaceutical ingredient comprised in a single hing /mL , as applicable . For example , the term AUC0 - 12 as soft or hard capsule fill . used herein refers to the area under the concentration versus The term " formulation ” or “ composition " as used herein time curve from 0 to 12 hours . refers to the active pharmaceutical ingredient or drug in 25 The term " AUCO - > 0 " as used herein refers to the area combination with pharmaceutically acceptable excipients. under the blood ( plasma, serum , or whole blood ) concen This includes orally administrable formulations as well as t ration versus time curve from time 0 hours to infinity , and formulations administrable by other means . is expressed in units of h mg/ L or hing /mL , as applicable . The term " titration ” as used herein refers to the incre The term " AUCost " as used herein refers to the area under mental increase in drug dosage to a level that provides the 30 the blood ( plasma, serum , or whole blood ) concentration optimal therapeutic effect. versus time curve at the last measurable concentration of the The term " controlled release ” as used herein encompasses analyte , and is expressed in units of h ·mg /L (or h ·ng /mL ) for the terms “ immediate release , " " modified release, " " sus - at least one or more doses of the pharmaceutical composi tained release , " " extended release , " and " delayed release ." tions described herein . The terms " extended release ” or “ sustained release” as 35 The term “ AUCOveral " as used herein refers to the com used herein refers to a composition that releases an active bined area under the blood (plasma , serum , or whole blood ) ingredient according to a desired profile over an extended concentration versus time curve , and is expressed in units of period under physiological conditions or in an in vitro test . h ·mg / L ( or h?ng/ mL ) for at least one or more doses of the By " extended period ” it is meant a continuous period of time pharmaceutical compositions described herein . In one of at least about 1 hour , about 2 hours ; about 4 hours , about 40 aspect, the “ AUCoversiverall ” refers to the combined area under 6 hours ; about 8 hours ; about 10 hours ; about 12 hours ; the blood concentration versus time curve for at least two about 14 hours ; about 16 hours ; about 18 hours ; about 20 doses of the pharmaceutical compositions described herein . hours about 24 hours ; or even longer ; specifically , over a The term “ treating ” refers to administering a therapy in an period of about 18 hours under physiological conditions or amount, manner, or mode effective to improve a condition , in an in vitro assay . 45 symptom , or parameter associated with a disorder . The term “ modified release” as used herein refers to a The term " prophylaxis” refers to preventing or reducing composition that releases an active ingredient at a slower the progression of a disorder , either to a statistically signifi rate than does an immediate release formulation under cant degree or to a degree detectable to one skilled in the art. physiological conditions or in an in vitro test. The term " substantially ” as used herein means to a great The term “ delayed ” release” as used herein refers to a 50 or significant extent, but not completely . composition that releases an active ingredient after a period The phrase " room temperature” as used herein refers to of time, for example minutes or hours , such that the active about 25° C . at standard atmospheric pressure . ingredient is not released initially . A delayed release com - The term “ about” as used herein refers to any values , position may provide , for example , the release of a drug or including both integers and fractional components that are active ingredient from a dosage form , after a certain period , 55 within a variation of up to + 10 % of the value modified by the under physiological conditions or in an in vitro test . term “ about. ” As used herein , the phrase " abuse deterrent controlled As used herein , “ a ” or “ an ” means one or more unless release ” refers to a pharmaceutical composition comprising otherwise specified . components or a formulation that prevents liberation of the Terms such as “ include, " " including ," " contain , " " con active pharmaceutical ingredient( s ) from the composition 60 taining ," " has, " or " having , " and the like , mean " compris for potential abuse or dose dumping and the composition ing . ” provides controlled release delivery of the active pharma The term “ or ” can be conjunctive or disjunctive. ceutical ingredient upon ingestion of the composition by a Described herein are pharmaceutical compositions com subject . prising abuse deterrent controlled release matrices compris The term " Cmax" as used herein refers to the maximum 65 ing active pharmaceutical ingredients . The matrix is struc observed blood (plasma , serum , or whole blood ) concentra - tured to prevent extraction of the active pharmaceutical tion or the maximum blood concentration calculated or ingredients . US 9 ,943 ,513 B1 19 20 One embodiment described herein is an oral abuse deter - pharmaceutical ingredient is suspended within the matrix . In rent controlled release pharmaceutical composition that one embodiment described herein is a soft capsule having a releases one or more active pharmaceutical ingredients over shell and an abuse deterrent controlled release matrix fill , a period of about 12 hours . wherein the matrix includes an active pharmaceutical ingre In some embodiments , the pharmaceutical composition 5 dient suspended as particles within the matrix . described herein comprises a soft or hard capsule compris - In one embodiment described herein , an exemplary abuse ing an abuse deterrent controlled release matrix comprising deterrent controlled release matrix has the composition of anactive active pharmaceutical pharmaceutical ingredient ingredient is . an In oneanalgesic embodiment . In another, the Table 1 , including all possible iterations of the specified embodiment, the active pharmaceutical ingredient is an 10 rangesir that provide 100 % for the total weight percentage , opioid agonist. In another embodiment , the active pharma including or excluding optional excipients . ceutical ingredient is an opioid analgesic . In another embodiment, the soft or hard capsule compris TABLE 1 ing a matrix can provide controlled release properties . Such _ Exemplary Abuse Deterrent Controlled Release Matrix Composition controlled release matrix fills are described in International 15 Patent Application Publication No . WO 2005/ 009409 and Composition WO 2006 / 096580 , U . S . Patent Application Publication Nos . Component Exemplary Components Range ( % ) US 2006 /0115527 and US 2007 /0053868 , and U . S . Pat . Nos . Flowability Mono -, di -, triglycerides , glyceryl 35 - 70 Enhancer monocaprylate ; oleic acid ; glyceryl 8 , 293, 270 and 8 ,333 , 989 , each of which are incorporated by monolinoleate ( e . g ., Maisine TM 35 - 1 ) reference herein for such teachings. In one aspect, the soft or 20 ReleaseRele Polyethylene oxide (PEO ) 20 -50 hard capsule and matrix can be configured to provide Modifier (e . g ., POLYOX TM ) controlled release , extended release , sustained release , Release Carboxyvinyl polymers 0 - 10 Modifier 2 ( e. g ., Carbopol ® polymers ) delayed release , or combinations thereof. Viscosity Polyvinylpyrrolidone; ethylcellulose 0 - 10 In other embodiments , the pharmaceutical composition Modifier described herein comprises abuse deterrent properties . 25 Antioxidant BHT, BHA 0 - 0 . 5 These abuse deterrent properties reduce the likelihood that Active Oxycodone , hydrocodone , tapentadol 0 . 1 - 50 the active pharmaceutical ingredient can be extracted from pharmaceutical the composition through mechanisms, including but not ingredient( s ) limited to crushing , grating , grinding , or cutting of the capsule to expose the matrix thereby facilitating solvation or 30 In one embodiment, the matrix may comprise one or more extraction of the active pharmaceutical ingredient . Exem - flowability enhancers . In one aspect, suitable flowability plary and non - limiting abuse deterrent matrices useful in the enhancers have surfactant like properties. Exemplary and pharmaceutical composition described herein may be those non - limiting flowability enhancers may comprise partial found in International Application No . PCT/ US2015 / triglyceride medium chain , monoglycerides , diglycerides 024464 ; U . S . patent application Ser. No. 14 /679 , 233 ; PCT 35 and triglycerides , polyethylene glycol (molecular weight of International Application No. PCT /US2015 /054443 ; U .S . about 200 or greater ) , medium chain triglycerides of patent application Ser . No . 14 /877 ,208 , each of which is caprylic /capric acid , glyceryl monooleate , glyceryl monos incorporated by reference herein in their entirety . In addi- tearate , glyceryl monolinoleate ( e . g . , MaisineTM 35 - 1 ) , tion , the abuse deterrent properties reduce the likelihood that polyglyceryl- 3 - dioleate , oleoyl macrogol- 6 glycerides , lino the active pharmaceutical ingredient can be extracted from 40 leoyl macrogol- 6 glycerides . In one aspect , the flowability the composition by dissolving or extracting in ethanol enhancer comprises a medium chain mono - and di- glycer solutions , dissolving in solutions having pH values from ides ( e . g ., glyceryl monocaprylate or Capmul® MCM ) In about 1 to about 12 , or dissolving in household chemical one aspect, the flowability enhancer comprises oleic acid . In compositions , including water, coffee , vinegar, cola , milk , another aspect, the flowability enhancer comprises oleic ethanol, isopropanol, acetone , ethyl acetate , or other com - 45 acid . In another aspect, the flowability enhancer comprises mon solvents . In addition , the abuse deterrent properties glyceryl monolinoleate ( e . g . , MaisineTM 35 - 1 ) . further reduce the likelihood that the active pharmaceutical In another embodiment, the matrix may comprise one or ingredient can be extracted by boiling in water or ethanol more surfactants as described herein . In one aspect , the solutions . flowability enhancer comprises a non - ionic surfactant, an In other embodiments described herein , the matrix com - 50 anionic surfactant, a zwitterionic surfactant, or a cationic prises a lipid or lipophilic vehicle that provides a suspension surfactant or a combination thereof. In another aspect , the or a solution of the active pharmaceutical ingredient. In one flowability enhancer comprises a non - ionic surfactant. aspect , a soft or hard capsule comprising an active pharma - Exemplary and non - limiting surfactants that may be useful ceutical ingredient provides controlled release of the active in the abuse deterrent matrices described herein comprise pharmaceutical ingredient. 55 Suitable surfactants include: Pluronic® 10R5, Pluronic® In other embodiments described herein , the pharmaceu - 17R2, Pluronic® 17R4 , Pluronic® 25R2, Pluronic® 25R4, tical composition provides matrix fills for the active phar - Pluronic® 31R1 , Pluronic® F 108, Pluronic® F 108 NF, maceutical ingredient, or derivatives thereof, based on lipids Pluronic® F 108 , Pluronic® F 108NF, Poloxamer 338 , or lipophilic materials . The matrices described herein have Pluronic® F 127 , Pluronic® F 127 NF, Pluronic® F 127 NF a hydrophobic (lipophilic ) surface in contact with a hydro - 60 500 BHT Prill , Pluronic® F 127 NF Prill , Poloxamer 407 , philic soft capsule shell to minimize any potential shell- fill Pluronic® F 38, Pluronic® F 38 Pastille , Pluronic® F 68 , interactions , such as when soft capsules are filled with Pluronic® F 68 LF Pastille , Pluronic® F 68 NF, Pluronic® hydrophilic materials . In one embodiment described herein F 68 NF Prill , Poloxamer 188 , Pluronic® F68 Pastille , are methods for manufacturing matrix fills comprising an Pluronic® F 77 , Pluronic® F 77 Micropastille , Pluronic® F abuse deterrent controlled release matrix comprising an 65 87 , Pluronic® F 87 NF, Pluronic® F 87 NF Prill, Poloxamer active pharmaceutical ingredient in a soft capsule in the 237 , Pluronic® F 88 , Pluronic® F 88 Pastille , Pluronic® F form of a suspension , where part or all of the active 98 , Pluronic® L 10 , Pluronic® L 101 , Pluronic® L 121, US 9 , 943, 513 B1 21 22 Pluronic® L 31 , Pluronic® L 35 , Pluronic® L 43 , Pluronic® having a molecular weight ( M ,) of about 600 ,000 to about L 61 , Pluronic® L 62 , Pluronic® L 62 LF , Pluronic® L 62D , 10 , 000 ,000 , including each integer within the specified Pluronic® L 64 , Pluronic® L 81, Pluronic® L 92 , Pluronic® range . In another aspect , the release modifier may comprise N 3 , Pluronic® P 103 , Pluronic® P 104 , Pluronic® P 105 , a high molecular weight polyethylene oxide having a Pluronic® P 123 Surfactant , Pluronic® P 65 , Pluronic® P 5 molecular weight ( M ) of about 5 , 000 , 000 to about 10 , 000 , 84 , Pluronic® P 85 , Adogen® 464 , Alkanol® 6112 , Brij 000 , including each integer within the specified range . In 52 , Brij 93 , Brij® S2 , Brij® S , Brij 58 , Brij C10 , Brij® another aspect, the release modifier may comprise a high L4 , Brij® 010 , Brij® 010 , BRIJ® 020 , Brij® S10, Brij® molecular weight polyethylene oxide having a molecular S20 , ethylenediamine tetrakis ( ethoxylate - block -propoxy - weight ( M ) of about 4 , 000 ,000 to about 7 ,000 ,000 , includ late ) tetrol, ethylenediamine tetrakis ( ethoxylate -block - 10 ing each integer within the specified range. In another propoxylate ) tetrol, ethylenediamine tetrakis (propoxylate - aspect, the release modifier may comprise a high molecular block - ethoxylate ) tetrol, IGEPAL® CA - 210 , IGEPAL® weight polyethylene oxide having a molecular weight ( M ) CA -520 , IGEPAL® CA - 720 , IGEPAL® CO -520 , of about 600 , 000 , about 700 ,000 , about 800 ,000 , about IGEPAL® CO -630 , IGEPAL® CO - 720 , IGEPAL® 900 , 000 , about 1 , 000 ,000 , about 2 , 000 , 000 , about 3 , 000 , CO - 890 , IGEPAL® DM -970 , MERPOL® DA , MERPOL® 15 000 , about 4 ,000 ,000 , about 5 ,000 ,000 , about 6 , 000 , 000 , HCS , MERPOL® OJ, MERPOL® SE , MERPOL® SH , about 7 , 000 , 000 , about 8 ,000 , 000 , about 9 ,000 , 000 or about MERPOL® A , Poly ( ethylene glycol) sorbitan tetraoleate , 10 ,000 ,000 . In another aspect, the release modifier may poly ( ethylene glycol) sorbitol hexaoleate , poly ( ethylene comprise a high molecular weight polyethylene oxide hav glycol ) (12 ) , poly ( ethylene glycol) ( 18 ) , polyethylene ing a molecular weight (M ) of about 4 ,000 ,000 . In another block - poly ( ethylene glycol) , sorbitan monopalmitate , 20 aspect, the release modifier may comprise a high molecular sodium lauryl sulfate , 2 , 4 , 7 , 9 -tetramethyl - 5 - decyne - 4 , 7 - diol weight polyethylene oxide having a molecular weight ( M ) ethoxylate , NonidetTM P -40 , TritonTM N - 101 , Span® 80 , of about 5 ,000 ,000 . In another aspect, the release modifier TritonTM X - 100 , TritonTM X -114 , TritonTM X -405 , may comprise a high molecular weight polyethylene oxide TWEEN® 20 , TWEEN® 40 , TWEEN® 60 , TWEEN® 85 , having a molecular weight ( M . ) of about 7 ,000 ,000 . Zonyl® FS - 300 , or Zonyl® FSN . 25 The molecular weight measurements of polyethylene Additional exemplary and non - limiting flowability oxide may be approximated using rheologicalmeasurements enhancers may include higher aliphatic alcohols ; higher using a viscometer . For example , polyethylene oxide is aliphatic acids ; long chain fatty acids ; saturated or unsatu considered to have an approximate molecular weight ( M ) of rated fatty acids ; hydrogenated fatty acids ; fatty acid glyc - 600 ,000 when a 5 % (by wt) aqueous solution of polyethyl erides; polyoxyethylated oleic glycerides ; monoglycerides 30 ene oxide using a Brookfield viscometer Model RVF , and diglycerides ; mono -, bi- or tri -substituted glycerides; spindle No . 2 , at 2 rpm , at 25° C . shows a viscosity range of glycerol; glyceryl palmitostearate ; glyceryl behenate ; dieth - 30 to 50 mPa s ( CP ). Polyethylene oxide is considered to yleneglycol palmitostearate ; polyethyleneglycol stearate ; have an approximate molecular weight ( M ) of 1 , 000 , 000 polyoxyethyleneglycol palmitostearate ; glyceryl mono when a 2 % (by wt) aqueous solution of polyethylene oxide palmitostearate ; cetyl palmitate ; polyethyleneglycol palmi- 35 using a Brookfield viscometer Model RVF, spindle No. 1, at tostearate ; dimethylpolysiloxane ; mono - or di- glyceryl 10 rpm , at 25° C . shows a viscosity range of 400 to 800 mPa behenate ; fatty alcohols associated with polyethoxylate fatty s ( CP ) . Polyethylene oxide is considered to have an approxi alcohols ; cetyl alcohol; octyl dodecanol ; myristyl alcohol; mate molecular weight ( M ) of 2 ,000 , 000 when a 2 % (by wt ) isopropylmyristate , isopropyl palmitate , stearic acid , stearyl aqueous solution of polyethylene oxide using a Brookfield alcohol, and others known in the art. 40 viscometer Model RVF , spindle No . 3 , at 10 rpm , at 25° C . In another embodiment, the flowability enhancer has a shows a viscosity range of 2000 to 4000 mPa s ( cP ) . hydrophilic lipophilic balance (HLB ) ranging from about 0 Polyethylene oxide is considered to have an approximate to about 20 . In one aspect, the flowability enhancer has an molecular weight ( M ) of 4 ,000 , 000 when a 1 % (by wt) HLB value of less than 10 . In another aspect, the flowability aqueous solution of polyethylene oxide using a Brookfield enhancer has an HLB value of between 1 and 6 . In another 45 viscometer Model RVF, spindle No . 2 , at 2 rpm , at 25° C . aspect, the flowability enhancer has an HLB value of less shows a viscosity range of 1650 to 5500 mPa s ( CP ) . than 5 . The HLB characteristic of surfactants and other Polyethylene oxide is considered to have an approximate compounds can be determined in accordance with “ Physical molecular weight ( M _ ) of 5 , 000 , 000 when a 1 % (by wt) Pharmacy : Physical Chemical Principles in the Pharmaceu aqueous solution of polyethylene oxide using a Brookfield tical Sciences, ” Fourth Edition , pp . 371 - 373 , A . Martin , Ed ., 50 viscometer Model RVF, spindle No . 2 , at 2 rpm , at 25° C . Lippincott Williams & Wilkins, Philadelphia ( 1993 ) . shows a viscosity range of 5500 to 7500 mPa s ( CP ) . In another embodiment, the matrix may further include a Polyethylene oxide is considered to have an approximate lipid or lipophilic vehicles, such as olive oil, soybean oil , molecular weight (M ) of 7 ,000 ,000 when a 1 % (by wt) sunflower oil, canola oil , palmitoleic acid , oleic acid ,myris - aqueous solution of polyethylene oxide using a Brookfield toleic acid , linoleic acid , arachidonic acid , vegetable oil, 55 viscometer Model RVF, spindle No. 2 , at 2 rpm , at 25° C . corn oil, sun flower oil , coconut oil, cocoa oil, peanut oil, shows a viscosity range of 7500 to 10 ,000 mPa s ( CP ) . almond oil , cottonseed oil, persic oil , sesame oil, squalane Polyethylene oxide is considered to have an approximate oil, castor oil , fish oil , paraffin oil , or mineral oil . molecular weight ( M ) of 8 , 000 , 000 when a 1 % (by wt) In another embodiment, the matrix may comprise one or aqueous solution of polyethylene oxide using a Brookfield more release modifiers . In one aspect , the release modifier 60 viscometer Model RVF, spindle No . 2 , at 2 rpm , at 25° C . comprises a high molecular weight polyethylene oxide or a shows a viscosity range of 10 ,000 to 15 ,000 mPa s ( CP ) . carboxyvinyl polymer , or a combination thereof. As Suitable polyethylene oxide polymers with the above described herein , high molecular weight polyethylene oxide described viscosity and molecular weight values that are polymers have an approximate molecular weight based on useful for the matrices described are, for example , viscosity or rheology ( M ) of at least about 600 ,000 to about 65 POLYOXTM polymers, such as WSR -205 , WSR - 1105 , WSR 10 , 000 ,000 or greater . In one aspect, the release modifier N - 12K , WSR N -60K , WSR -301 , WSR Coagulant, WSR may comprise a high molecular weight polyethylene oxide 303 , WSR 308 , UCARFLOC Polymers 300 , 302, 304 , and US 9 , 943 ,513 B1 23 24 309 commercially available from Dow Chemical Company . prises from about 50 % to about 60 % of the matrix fill mass , In one aspect, the polyethylene oxide polymer is including all integers within the specified range . In another POLYOXTM WSR -301 ( M , ~ 4 , 000 , 000 ) or POLYOXTM aspect , the one or more flowability enhancers comprises WSR - 303 ( M _ - 7 ,000 ,000 ) (Dow Chemical Co .) . In one from about 50 % to about 60 % of the matrix fill mass , aspect , the polyethylene oxide polymer is POLYOXTM 5 including all integers within the specified range . In another WSR - 301 ( M , ~ 4 ,000 ,000 ) . aspect, the one or more flowability enhancers comprises In another embodiment, the composition comprises one or from about 40 % , about 45 % , about 50 % , about 55 % , about more viscosity modifiers . Suitable and non - limiting viscos - 60 % , about 65 % , about 70 % , about 75 % , or about 80 % of ity modifiers that may be present in the matrices described the matrix fill mass . herein comprise methylcellulose , ethylcellulose , hydroxy - 10 In another embodiment , the one or more release modifiers propylmethyl cellulose , hydroxypropyl cellulose , hydroxy - comprises from about 20 % to about 50 % of the matrix fill ethyl cellulose , hydroxymethyl cellulose , polymethylmeth - mass, including all integers within the specified range. In acrylate , polyhydroxyethylmethacrylate , one aspect , the one or more release modifiers comprises polyvinylpyrrolidone, copovidone, polyvinyl alcohol, a from about 25 % to about 50 % of the matrix fill mass, copolymer of polyvinylpyrrolidone and polyvinyl acetate , or 15 including all integers within the specified range . In another combinations thereof. For example , polymers commercially aspect, the one or more release modifiers comprises from available as MethocelTM K100M , MethocelTM A4M , Etho - about 25 % to about 40 % of the matrix fill mass , including celTM Premium LV CR , K4M Premium CR ,K15M Premium all integers within the specified range . In another aspect, the CR , K100 Premium CR , E4M Premium CR , E1OM Pre - one or more release modifiers comprises from about 25 % to mium CR , or E4M Premium (Dow Chemical Co . ), CEL - 20 about 35 % of the matrix fill mass , including all integers LOSIZETM , or WALOCELTM CRT may be used in the abuse within the specified range . In another aspect, the one ormore deterrent matrices described herein . These viscosity modi- release modifiers comprises about 20 % , about 25 % , about fiers may comprise a viscosity of about 50 CP to about 30 % , about 35 % , about 40 % , about 45 % , or about 50 % of 100 ,000 cP , including each integer within the specified the matrix fill mass . range . For example , these additional release modifiers may 25 In another embodiment, the one or more viscosity modi comprise a viscosity of about 50 cP, about 100 CP , about 200 fiers may comprise from about 0 . 5 % to about 8 % of the cP , about 300 CP , about 400 CP , about 500 cP , about 750 CP , matrix fill mass, including all integers within the specified about 1, 000 CP , about 1, 500 CP, about 2 ,000 CP , about 2 ,500 range . In one aspect, the one or more viscosity modifiers CP , about 3 ,000 cP , about 3 ,500 cP, about 4 ,000 CP , about may comprise from about 0 . 5 % to about 5 % of the matrix fill 4 ,500 CP , about 5 ,000 CP , about 6 , 000 CP, about 7 ,000 cP , 30 mass, including all integers within the specified range . In about 8 , 000 cP , about 9 ,000 CP , or about 10 , 000 cP, about another aspect , the one or more viscosity modifiers may 15 ,000 CP, about 20 ,000 CP, about 30 ,000 cP , about 40 ,000 comprise from about 0 . 5 % to about 3 % of the matrix fill CP , about 50 ,000 cP , about60 ,000 cP, about 70 ,000 CP , about mass , including all integers within the specified range . In 80 , 000 cP , about 90 , 000 CP , about 100 ,000 cP , greater than another aspect , the one or more viscosity modifiers may 100 , 000 cP , or even greater. In one embodiment, the matrix 35 comprise from about 0 . 5 % to about 2 % of the matrix fill comprises hydroxylpropyl methylcellulose ( e . g ., Metho - mass , including all integers within the specified range . In celTM K100M ) . In another embodiment, the matrix com another aspect , the one or more viscosity modifiers may prises ethylcellulose ( e . g . , EthocelTM 20 cP ) . In another comprise about 0 . 5 % , about 0 .75 % , about 1 % , about 2 % , embodiment, the matrix comprises a polyvinylpyrrolidone about 3 % , about 4 % , about 5 % , about 6 % , about 7 % , or ( e . g ., polyvinylpyrrolidone K90 ) . 40 about 8 % , of the matrix fill mass . In another aspect, matrix In another embodiment, the abuse - deterrent matrix may fill mass may not have any viscosity modifier. optionally comprise one or more antioxidants. Suitable In another embodiment, one or more antioxidants may antioxidants comprise tocopherols ( e . g . , alpha - tocopherol, comprise from about 0 . 1 % to about 0 . 5 % of the matrix mass , beta - tocopherol, gamma -tocopherol , or delta - tocopherol) , including all integers within the specified range . In one butylated hydroxytoluene (BHT ) , butylated hydroxyanisole 45 aspect, the one or more antioxidants may comprise about (BHA ), citric acid , ascorbic acid , phenolic diterpenes ( e . g ., 0 . 3 % , 0 . 4 % , or 0 . 5 % of the matrix fill mass . carnosic acid , carnosol, rosmanol, epirosmanol, isorosma In another embodiment, the one or more hydrophilic nol, or methyl carnosate ) , rosmarinic acid , eugenol, eugenyl polymers comprises from about 1 % to about 50 % by weight acetate , clove bud extract , methanolic extract, tea catechins of the matrix fill mass, including all integers within the ( e . g ., epigallocatechin gallate , epicatechin gallate , epigallo - 50 specified range . In one aspect, the one or more hydrophilic catechin , or epicatechin ), or combinations thereof. polymer s comprises from about 1 % to about 30 % of the In one embodiment described herein , the abuse deterrent matrix fill mass, including all integers within the specified matrix may comprise one or more flowability enhancers, one range . In another aspect, the one or more hydrophilic or more release modifiers , one or more active pharmaceu - polymers comprises from about 25 % to about 40 % of the tical ingredients , optionally one or more antioxidants , 55 matrix fill mass , including all integers within the specified optionally one or more viscosity modifiers , optionally one or range . In another aspect, the one or more hydrophilic more hydrophilic vehicles , and optionally one or more other polymers comprises from about 25 % to about 35 % of the pharmaceutically acceptable excipients in a weight percent- matrix fill mass , including all integers within the specified age amount of the matrix fill mass as further described range . In one aspect, the one or more hydrophilic polymer s herein . 60 comprises from about 1 % to about 10 % of the matrix fill In another embodiment, the one or more flowability mass , including all integers within the specified range . In enhancers comprises from about 40 % to about 80 % of the another aspect , the one or more hydrophilic polymers com matrix fill mass , including all integers within the specified prises about 1 % , about 5 % , about 10 % about, 20 % , about range . In one aspect, the one or more flowability enhancers 25 % , about 30 % , about 35 % , about 40 % , about 45 % , or comprises from about 50 % to about 80 % of the matrix fill 65 about 50 % of the matrix fill mass. mass, including all integers within the specified range . In In another embodiment , the one or more active pharma another aspect , the one or more flowability enhancers com - ceutical ingredient comprises from about 0 . 1 % to about 50 % US 9 ,943 ,513 B1 25 26 of the matrix fill mass , including all integers within the herein . For example, using a conventional hydrophilic specified range . In another embodiment, the one or more vehicle , such as polyethylene glycol, it was demonstrated active pharmaceutical ingredient comprises from about 1 % that a carrier comprising polyethylene glycol had a high to about 50 % of the matrix fill mass, including all integers degree of miscibility with the high molecular weight poly within the specified range . In another embodiment, the one 5 ethylene oxide. The resulting mixtures of polyethylene or more active pharmaceutical ingredient comprises from oxide and polyethylene glycol became highly viscous at about 1 % to about 25 % of the matrix fill mass , including all room temperature, which complicates further processing integers within the specified range . In one aspect, the active steps. Further , it was found that certain oils and lipophilic pharmaceutical ingredient comprises about 5 % of the matrix vehicles are not suitable as a flowability enhancer for the one fill mass . In one aspect, the active pharmaceutical ingredient 10 or more release modifiers . comprises about 7 % of the matrix fill mass . In one aspect, Thus, without being bound by any theory , it is believed the active pharmaceutical ingredient comprises about 10 % that the flowable characteristics of the matrices described of the matrix fill mass . In one aspect, the active pharma- herein may be due to the limited miscibility of the one or ceutical ingredient comprises about 20 % of the matrix fill more release modifiers and the one or more flowability mass . In one aspect, the active pharmaceutical ingredient 15 enhancers described herein at room temperature . For comprises about 25 % of the matrix fill mass . example , it was found that mono - or diglycerides ( e . g . , In another embodiment, the weight percentage ratio of Capmul® MCM ), oleic acid , or glyceryl monolinoleate release modifier to flowability enhancer ranges from about ( e . g . ,MaisineTM 35 - 1 ) allows adequate matrix flowability at 0 . 2 : 1 to about 1 : 1 . 5 , including all iterations of ratios within room temperature due to solubilization of high molecular the specified range . In one aspect, the weight percentage 20 weight polyethylene oxide that allows standard encapsula ratio of release modifier to flowability enhancer ranges from tion techniques to be employed . It was further found that about 0 . 2 : 1 to about 0 .75 : 1 , including all iterations of ratios matrix compositions comprising a flowability enhancer with within the specified range . In one aspect, the weight per - surfactant- like properties, such as for example , mono - or centage ratio of release modifier to flowability enhancer diglycerides ( e . g . , Capmul® MCM ), oleic acid , or glyceryl ranges from about 0 . 2 : 1 to about 0 . 5 : 1 , including all itera - 25 monolinoleate ( e . g ., MaisineTM 35 - 1) and a high molecular tions of ratios within the specified range . In one aspect, the weight polyethylene oxide had a fluid - like consistency at weight percentage ratio of release modifier to flowability room temperature . enhancer ranges from about 0 .2 : 1 , about 0 . 3 : 1, about 0 . 4 : 1 , It was further demonstrated that the flowability enhancer about 0 . 5 : 1 , about 0 . 6 : 1 , about 0 . 7 : 1 , about 0 . 9 : 1 , about 1 : 1 , and polyethylene oxide became more miscible after being about 1. 1 : 1 , or about 1. 2 : 1 . 30 heated to about 70° C . Surprisingly , it was discovered that In another embodiment , the weight percentage ratio of these matrices having the flowability enhancers , such as active pharmaceutical ingredient to the total matrix fill mass mono - or diglycerides ( e .g . , Capmul® MCM ) , oleic acid , or ranges from about 1: 1000 to about 1 : 3 , including all itera - glyceryl monolinoleate ( e . g ., MaisineTM 35 - 1 ) when heated tions of ratios within the specified range . In another embodi to an elevated temperature of about 70° C . and then cooled ment, the weight percentage ratio of active pharmaceutical 35 to room temperature , became an elastic , rubbery , semi- solid ingredient to the total matrix fill mass ranges from about material having an increased Young ' s modulus . In contrast , 1 : 100 to about 1 : 2 , including all iterations of ratios within it was also unexpectedly demonstrated that this solidifying the specified range . In another embodiment, the weight effect did not occur for compositions having soybean oil as percentage ratio of active pharmaceutical ingredient to the a flowability enhancer. Furthermore , it was surprisingly and total matrix fill mass ranges from about 1 : 15 to about 1: 2 , 40 advantageously found that the process of heating and cool including all iterations of ratios within the specified range . ing the matrices comprising polyethylene oxide and a suit In one aspect, the weight percentage ratio of active phar - able flow ability enhancer further allow for reduced levels of maceutical ingredient to the total matrix fill mass is about polyethylene oxide to be used , while exhibiting effective 1 : 100 . In another aspect, the weight percentage ratio of abuse deterrent and controlled release properties, which has active pharmaceutical ingredient to the totalmatrix is about 45 previously been unrealized . 1 : 10 . In another aspect , the weight percentage ratio of active Without being bound by any theory , it is thought that the pharmaceutical ingredient to the total matrix fill mass is release modifier is suspended in the flowability enhancer about 1 : 7 . 5 . In another aspect , the weight percentage ratio of throughout the processing steps . During the annealing steps , active pharmaceutical ingredient to the total matrix fill mass the release modifier is believed to become molten . The two is about 1 : 5 . In another aspect , the weight percentage ratio 50 components , therefore , become miscible at this point . This of active pharmaceutical ingredient to the total matrix fill appears to be a synergistic effect wherein the flowability mass is about 1 : 3 . In another aspect, the weight percentage enhancer reduces the melting point of the release modifier ratio of active pharmaceutical ingredient to the total matrix and also solubilizes the release modifier at the elevated fill mass is about 1 : 2 . annealing temperature (which is lower than the typical In one embodiment described herein , the abuse deterrent 55 melting point of the release modifier by about 20 -50° C . ) . matrix may comprise one or more flowability enhancers , one When cooled , the release modifier and flowability enhancer or more release modifiers , one or more active pharmaceu recrystallizes and forms an elastic semi- solid composition tical ingredients , optionally one or more viscosity modifiers , enveloping the active pharmaceutical ingredient. For wherein the matrix comprises any one of the compositions example , high molecular weight polyethylene oxide is a of Tables 7 and 9 - 10 . 60 semi- crystalline polymer known to melt at about 100° C . In It was found that the addition of one or more flowability the presence of a suitable flowability enhancer, such as enhancers such as mono - or diglycerides ( e . g ., Capmul® mono - or di - glycerides ( e. g . , Capmul® MCM ) , oleic acid , or MCM ), oleic acid , and glyceryl monolinoleate ( e. g ., glyceryl monolinoleate ( e .g ., MaisineTM 35 - 1 ), polyethylene MaisineTM 35 - 1 ) increases the flowability of the one or more oxide becomes solubilized at about 50 to 80° C . After release modifiers ( e .g ., high molecular weight polyethylene 65 subsequent cooling , the polyethylene oxide and flowability oxide ) , and thus , provides for a flowable matrix suitable for enhancer mixture solidify to form an elastic , rubbery , semi encapsulation in the soft or hard capsule shells as described solid composition . Thus , the composition and annealing US 9 ,943 ,513 B1 27 28 process described herein unexpectedly resulted in the for active pharmaceutical ingredient is useful in treating pain . In mation of an elastic semi- solid composition with advanta one aspect , the active pharmaceutical ingredient is oxyco geous abuse deterrent properties . done , hydrocodone , oxymorphone , hydromorphone, tapen As described herein , the heated pharmaceutical compo tadol, morphine , or codeine . In one aspect, the active phar sitions comprising the abuse deterrent matrix fills are in 5 maceutical ingredient is oxycodone or hydrocodone . In one some embodiments annealed by heating the compositions. aspect, the active pharmaceutical ingredient is oxycodone . In some embodiments , the pharmaceutical compositions Examples of specific active drug substances suitable for comprising a soft or hard capsule shell encapsulating a use in the pharmaceutical compositions provided herein matrix fill as described herein may be annealed at a tem - include : anti - inflammatory and antirheumatic active drug perature of about 70° C . for about 1 hour or less . These 10 substances , such as, for example : butylpyrazolidine , phe annealed elastic semi- solid matrices comprise advantageous nylbutazone, mofebutazone , oxyphenbutazone, clofezone , abuse deterrent characteristics . kebuzone , acetic acid derivatives and related substances , A common method for extracting abuse prone drugs is by indometacin , sulindac , tolmetin , zomepirac, diclofenac , boiling the composition . It was found that the abuse deter - alclofenac , bumadizone, etodolac , lonazolac , fentiazac , rent matrix fills described herein further provide for abuse 15 acemetacin , difenpiramide , oxametacin , proglumetacin , deterrence by reducing the percentage of released active ketorolac, aceclofenac , bufexamac , oxicam , piroxicam , ten pharmaceutical ingredient released during boiling , suggest - oxicam , droxicam , lornoxicam , meloxicam , methotrexate , ing that the matrices described herein maintain a semi- solid propionic acid derivatives, ibuprofen , naproxen , ketoprofen , elastic material at high temperatures ( e . g . , in excess of fenoprofen , fenbufen , benoxaprofen , suprofen , pirprofen , 90 - 100° C . ) . Without wishing to be bound by any theory , it 20 flurbiprofen , indoprofen , tiaprofenic acid , oxaprozin , ibu is thought that the lipophilic and solubilizing nature of the proxam , dexibuprofen , flunoxaprofen , alminoprofen , dexke flowability enhancer in combination with high molecular toprofen , fenamates , mefenamic acid , tolfenamic acid , flufe weight polyethylene oxide provide abuse deterrent charac namic acid , meclofenamic acid , coxibs, celecoxib , teristics following an annealing step . The semi- solid elastic rofecoxib , valdecoxib , parecoxib , etoricoxib , lumiracoxib , characteristics of the abuse deterrent matrix fills described 25 nabumetone, niflumic acid , azapropazone , glucosamine , herein further prevent or reduce the likelihood for the benzydamine , glucosaminoglycan polysulfate , proquazone , extraction of active pharmaceutical ingredients through the orgotein , nimesulide , feprazone , diacerein , morniflumate, additional means of crushing , grating, grinding , or cutting tenidap , oxaceprol, chondroitin sulfate , feprazone , dipyro the dosage forms further described herein . cetyl, acetylsalicylic acid , quinolines , oxycinchophen , gold Another common method for extracting abuse prone 30 preparations, sodium aurothiomalate , sodium aurotiosulfate , drugs is through ethanol based extraction of the composi - auranofin , aurothioglucose , aurotioprol, penicillamine, or tion . It was found that the abuse deterrentmatrices described bucillamine . herein further reduce the extraction of one or more active in another embodiment, suitable active pharmaceutical pharmaceutical ingredients in high percentage Ethanol solu - ingredients can comprise analgesics, such as, for example: tions ( e . g . , 80 % ) , while maintaining desired release rates in 35 opioids, natural opium alkaloids , morphine , opium , hydro gastric - like environments . Thus, the presence of the com - morphone , nicomorphine, oxycodone, dihydrocodone , ponents of the abuse deterrent matrix compositions diamorphine , tapentadol, papaveretum , papaveretum , described herein function to inhibit drug release from the codeine , phenylpiperidine derivatives , ketobemidone , pethi pharmaceutical compositions described herein using com - dine, fentanyl, diphenylpropylamine derivatives, dextromor mon attempts of drug extraction . Thus , the matrix compo - 40 amide , piritramide , dextropropoxyphene, bezitramide , sitions described herein have abuse deterrent properties by methadone , benzomorphan derivatives , pentazocine , preventing the liberation of the active ingredient for injec - phenazocine , oripavine derivatives, buprenorphine , morph tion or insufflation and prevent solvation , dissolution , or inan derivatives , butorphanol, nalbuphine , tilidine , trama extraction of the active pharmaceutical ingredient by use of dol, dezocine , salicylic acid and derivatives, acetylsalicylic aqueous or organic solutions . Furthermore , the matrix com - 45 acid , aloxiprin , choline salicylate , sodium salicylate , salicy positions also provide controlled release delivery of the lamide , salsalate , ethenzamide, morpholine salicylate , dipy active pharmaceutical ingredient after ingestion by a subject. rocetyl, benorilate , diflunisal, potassium salicylate , guaceti In one embodiment, the matrix contains an active phar - sal, carbasalate calcium , imidazole salicylate , pyrazolones , maceutical ingredient in a suspended form , soluble form , phenazone , metamizole sodium , aminophenazone , propy insoluble form , or combinations thereof. The active phar - 50 phenazone , nifenazone , anilides, paracetamol, phenacetin , maceutical ingredient can be dispersed in the internal phase bucetin , propacetamol, other analgesics and antipyretics , as a suspension form . A suspension as used herein means the such as , for example : rimazolium , glafenine , floctafenine , API does not dissolve in one of the phases and remains as viminol, nefopam , flupirtine, or ziconotide. a solid . In another embodiment, suitable active pharmaceutical In another embodiment, the matrix contains an active 55 ingredients can comprise anaesthetics, such as, for example : pharmaceutical ingredient useful for the treatment of pain . In ethers , diethyl ether , vinyl ether , halogenated hydrocarbons, one embodiment, the API comprises one or more opioid halothane, chloroform , methoxyflurane , enflurane , trichlo receptor agonists . In one embodiment, the active pharma - roethylene , isoflurane , desflurane, sevoflurane , barbiturates , ceutical ingredient includes one or more of oxycodone , methohexital, hexobarbital , thiopental, narcobarbital, opioid hydrocodone, oxymorphone , hydromorphone , morphine , 60 anaesthetics , fentanyl, alfentanil , sufentanil , phenoperidine , codeine, methadone , fentanyl, tapentadol, tramadol, meperi - anileridine , remifentanil , other general anaesthetics , such as , dine , propoxyphene, flunitrazepam , barbiturates , amytal, for example: droperidol, ketamine, propanidid , alfaxalone , nembutal, seconal, phenobarbital; benzodiazepines , zolpi etomidate , propofol, hydroxybutyric acid , nitrous oxide , dem , zaleplon , eszopiclone, amphetamines, methylpheni- esketamine, xenon , esters of aminobenzoic acid , metabu date , salts thereof, or a combination thereof. 65 tethamine , procaine , tetracaine , chloroprocaine , benzocaine , In another embodiment, the matrix comprises one or more amides, bupivacaine , lidocaine , mepivacaine , prilocaine , active pharmaceutical ingredients (API ) . In one aspect, the butanilicaine, cinchocaine, etidocaine, articaine , ropiva US 9 ,943 ,513 B1 29 30 caine , levobupivacaine, esters of benzoic acid , cocaine, prothipendyl , risperidone , clotiapine , mosapramine , other local anaesthetics, such as, for example: ethyl chloride, zotepine , aripiprazole, or paliperidone . dyclonine , phenol, or capsaicin . In another embodiment , suitable active pharmaceutical In another embodiment, suitable active pharmaceutical ingredients can comprise anxiolytic active drug substances, ingredients can comprise antimigraine active drug sub - 5 such as , for example : benzodiazepine derivatives , diazepam , stances , such as , for example : ergot alkaloids , dihydroergot - chlordiazepoxide , medazepam , oxazepam , potassium clora amine , ergotamine , methysergide , lisuride, corticosteroid Zepate , lorazepam , adinazolam , bromazepam , clobazam , derivatives , flumedroxone , selective serotonin (5HT ' ) ago - ketazolam , prazepam , alprazolam , halazepam , pinazepam , nists , sumatriptan , naratriptan , zolmitriptan , rizatriptan , camazepam , nordazepam , fludiazepam , ethyl loflazepate , almotriptan , eletriptan , frovatriptan , other antimigraine 10 etizolam , clotiazepam , cloxazolam , tofisopam , diphenyl preparations , pizotifen , clonidine , iprazochrome, dimetoti methane derivatives, hydroxyzine, captodiame, carbamates , azine , or oxetorone . meprobamate , emylcamate , mebutamate , dibenzo - bicyclo In another embodiment, suitable active pharmaceutical octadiene derivatives , benzoctamine , azaspirodecanedione ingredients can comprise antiepileptic active drug sub - derivatives, buspirone , other anxiolytics, such as, for stances, such as , for example : barbiturates and derivatives , 15 example : mephenoxalone , gedocarnil , or etifoxine. methylphenobarbital , phenobarbital, primidone, barbexa - In another embodiment, suitable active pharmaceutical clone, metharbital , hydantoin derivatives, ethotoin , pheny - ingredients can comprise hypnotic and sedative active drug toin , amino (diphenylhydantoin ) valeric acid , mephenytoin , substances , such as, for example : barbiturates, pentobarbital, fosphenytoin , oxazolidine derivatives , paramethadione , amobarbital, butobarbital, barbital , aprobarbital, secobarbi trimethadione , ethadione , succinimide derivatives, ethosuxi- 20 tal, talbutal, vinylbital, vinbarbital , cyclobarbital, heptabar mide , phensuximide , mesuximide, benzodiazepine deriva - bital, reposal, methohexital, hexobarbital, thiopental, ethal tives, clonazepam , carboxamide derivatives, carbam - lobarbital, allobarbital , proxibarbal , aldehydes and azepine, oxcarbazepine , rufinamide, fatty acid derivatives, derivatives, chloral hydrate , chloralodol, acetylglycinamide valproic acid , valpromide , aminobutyric acid , vigabatrin , chloral hydrate , dichloralphenazone , paraldehyde , benzodi progabide , tiagabine , other antiepileptics , such as , for 25 azepine emepronium derivatives, flurazepam , nitrazepam , example : sultiame, phenacemide , lamotrigine , felbamate , flunitrazepam , estazolam , triazolam , lormetazepam , temaze topiramate , gabapentin , pheneturide, levetiracetam , zonis - pam , midazolam , brotizolam , quazepam , loprazolam , dox amide , pregabalin , stiripentol, lacosamide , or beclamide. efazepam , cinolazepam , piperidinedione derivatives , glute In another embodiment , suitable active pharmaceutical thimide , methyprylon , pyrithyldione , benzodiazepine ingredients can comprise anticholinergic active drug sub - 30 related drugs , zopiclone, zolpidem , zaleplon , ramelteon , stances , such as , for example : tertiary amines, trihexy other hypnotics and sedatives, such as, for example : meth phenidyl, biperiden , metixene, procyclidine, profenamine , aqualone, clomethiazole , bromisoval , carbromal, scopol dexetimide , phenglutarimide , mazaticol, bornaprine , tro - amine , propiomazine , triclofos, ethchlorvynol, valerian , patepine, ethers chemically close to antihistamines , etanau hexapropymate , bromides, apronal, valnoctamide, methyl tine , orphenadrine ( chloride ) , ethers of tropine or tropine 35 pentynol, niaprazine , melatonin , dexmedetomidine , or dip derivatives , benzatropine, or etybenzatropine . iperonylaminoethanol. In another embodiment, suitable active pharmaceutical In another embodiment, suitable active pharmaceutical ingredients can comprise dopaminergic active drug sub ingredients can comprise antidepressant active drug sub stances , such as, for example : dopa and dopa derivatives , stances , such as, for example: non - selective monoamine levodopa , melevodopa , etilevodopa , adamantane deriva - 40 reuptake inhibitors , desipramine, imipramine , imipramine tives , amantadine, dopamine agonists , bromocriptine , per - oxide, clomipramine, opipramol , trimipramine , lofepramine , golide , dihydroergocryptine mesylate , ropinirole , pramipex - dibenzepin , amitriptyline, nortriptyline , protriptyline , dox ole , cabergoline , apomorphine, piribedil, rotigotine , epin , iprindole , melitracen , butriptyline , dosulepin , amox monoamine , oxidase B inhibitors , selegiline, rasagiline , apine , dimetacrine , amineptine , maprotiline , quinupramine , other dopaminergic agents , such as , for example: tolcapone , 45 selective serotonin reuptake inhibitors , zimeldine , fluox entacapone, or budipine . etine, citalopram , paroxetine , sertraline , alaproclate , fluvox In another embodiment, suitable active pharmaceutical amine, etoperidone , escitalopram , monoamine oxidase ingredients can comprise antipsychotic active drug sub - inhibitors , isocarboxazid , nialamide , phenelzine , tranylcy stances, such as, for example : phenothiazines with aliphatic promine , iproniazide , iproclozide, monoamine oxidase A side - chain , chlorpromazine , levomepromazine , promazine, 50 inhibitors , moclobemide , toloxatone , other antidepressants , acepromazine , triflupromazine, cyamemazine , chlorproeth - such as, for example : oxitriptan , tryptophan , mianserin , azine , phenothiazines with piperazine structure , dixyrazine , nomifensine , trazodone , nefazodone, minaprine , bife fluphenazine, perphenazine , prochlorperazine , thiopro - melane, viloxazine , oxaflozane , mirtazapine ,medifoxamine , pazate , trifluoperazine, acetophenazine, thioproperazine , tianeptine, pivagabine, venlafaxine , milnacipran , rebox butaperazine , perazine, phenothiazines with piperidine 55 etine, gepirone, duloxetine, agomelatine , desvenlafaxine, structure , periciazine , thioridazine , mesoridazine, pipotiaz - centrally acting sympathomimetics , such as , for example : ine, butyrophenone derivatives, haloperidol, trifluperidol, amfetamine , dexamfetamine , lis dexamfetamine, metamfe melperone , moperone , pipamperone , bromperidol, benperi tamine , methylphenidate , dexmethylphenidate , pemoline , dol, droperidol, fluanisone , indole derivatives, oxypertine , fencamfamin , modafinil, fenozolone , atomoxetine , fenetyl molindone , sertindole , ziprasidone , thioxanthene deriva - 60 line , xanthine derivatives , caffeine, propentofylline, other tives , flupentixol, clopenthixol, chlorprothixene , tiotixene , psychostimulants and nootropics , such as , for example Zuclopenthixol, diphenylbutylpiperidine derivatives , fluspir - meclofenoxate , pyritinol , piracetam , deanol, fipexide , citi ilene , pimozide , penfluridol , diazepines , oxazepines , thiaz coline , oxiracetam , pirisudanol, linopirdine, nizofenone , epines, loxapine , clozapine , olanzapine , quetiapine , neuro - aniracetam , acetylcarnitine , idebenone , prolintane , pip leptics , tetrabenazine, benzamides , sulpiride , sultopride , 65 radrol, pramiracetam , adrafinil, or vinpocetine . tiapride , remoxipride , amisulpride , veralipride , levo - In another embodiment, suitable active pharmaceutical sulpiride, lithium , other antipsychotics, such as, for example ingredients can comprise anti -dementia active drug sub US 9 , 943 ,513 B1 32 stances, such as, for example : anticholinesterases, tacrine , droxy - 3 -methylfentanyl , beta -hydroxyfentanyl , betame donepezil, rivastigmine, galantamine , other anti -dementia prodine, betameprodine , betamethadol, betaprodine , drugs, memantine, or ginkgo biloba . bezitramide, bezitramide , boldenone, brolamfetamine, bro In another embodiment, suitable active pharmaceutical mazepam , brotizolam , bufotenine , buprenorphine , butabar ingredients can comprise other nervous system active drug 5 bital, butalbital, butobarbital, butorphanol, BZP ( A2 )( 1 substances , such as, for example : parasympathomimetics , benzylpiperazin ) , camazepam , cannabis, carfentanil , catha anticholinesterases , neostigmine, pyridostigmine , distig edulis , cathine , cathinone , chloral betaine, chloral hydrate , mine , ambenonium , choline esters, carbachol, bethanechol, chlordiazepoxide , chlorhexadol, chlorotestosterone ( same as and other parasympathomimetics , such as , for example , clostebol) , chlorphentermine , clobazam , clonazepam , cloni pilocarpine , or choline alfoscerate . 10 tazene , clonitazene, clorazepate , clortermine , clostebol , clo Active drug substances used in addictive disorders , such tiazepam , cloxazolam , coca leaves , cocaine , codeine , as, for example : nicotine , bupropion , varenicline, disulfiram , codeine and isoquinoline alkaloid , codeine methylbromide , calcium carbimide , acamprosate , naltrexone , buprenor codeine - N - oxide , codoxime , cyclobarbital (hexemal NFN ) , phine , methadone , levacetylmethadol, lofexidine, betahis - cyprenorphine, dehydrochlormethyltestosterone , deloraze tine , cinnarizine, flunarizine , acetylleucine , gangliosides and 15 pam , desomorphine , dexamfetamine , dexfenfluramine , dex ganglioside derivatives , tirilazad , riluzole , xaliproden , methylphenidate , dextromoramide, dextropropoxyphene, hydroxybutyric acid , or amifampridine . diacetylmorphine , diampromide , diazepam , dichloral In another embodiment, suitable active pharmaceutical phenazone , diethylpropion , diethylthiambutene, diethyl ingredients can comprise opium alkaloids and derivatives , tryptamine , difenoxin , dihydrocodone, dihydroetorphine , such as, for example : ethylmorphine , hydrocodone, codeine, 20 dihydromorphine , dihydrotestosterone, dimenoxadol, opium alkaloids with morphine, normethadone , noscapine , dimepheptanol, dimethylthiambutene , dimethyltryptamine , pholcodine, dextromethorphan , thebacon , dimemorfan , dioxaphetyl butyrate , diphenoxylate , dipipanone, diprenor acetyldihydrocodone, benzonatate , benproperine , clobuti phine , dronabinol, drostanolone , drotebanol, ecgonine , esta nol, isoaminile , pentoxyverine , oxolamine , oxeladin , clofe - zolam , ethchlorvynol, ethinamate , ethyl loflazepate , ethyl danol, pipazetate , bibenzonium bromide, butamirate , fedri - 25 estrenol, ethylmethylthiambutene , ethylmorphine , late , zipeprol, dibunate , droxypropine , prenoxdiazine , ethylmorphine , eticyclidine, etilamfetamine , etonitazene , dropropizine , cloperastine, meprotixol, piperidione, tipepi etorphine, etoxeridine, etryptamine, fencamfamin , fenethyl dine , morclofone, nepinalone, levodropropizine , or dime line, fenetylline , fenfluramine, fenproporex , fentanyl, fludi thoxanate . azepam , flunitrazepam , fluoxymesterone, flurazepam , In another embodiment, the active pharmaceutical ingre- 30 formebolone , fungi and spores of the species psilocybe dient may be a substance with abuse potential that presents semilanceata , furethidine , gamma hydroxybutyric acid , glu a safety risk . Such active drug substance may include : tethimide, halazepam , haloxazolam , heroine , hydrocodone , 1 - ( 1 - phenylcyclohexyl) pyrrolidine , 1 - ( 2 - phenylethyl) - 4 - hydrocodone & isoquinoline alkaloid , hydromorphinol, phenyl- 4 - acetoxypiperidine , 1 - [ 1 - ( 2 - thienyl) - cyclohexylpi- hydromorphone, hydroxypethidine , ibogaine , isobutyl peridine, 1 - [ 1 - ( 2 - thienyl ) cyclohexyl] pyrrolidine , 1 -methyl - 35 nitrite, isomethadone, ketamine, ketazolam , ketobemidone , 4 -phenyl - 4 -propionoxy -piperidine , levamfetamine , levo - alphacetylmethadol, levo -metham 1 -phenylcyclohexylamine , 1 - piperidinocyclohexanecarbo phetamine, levomethorphan , levomoramide, levophenacyl nitrile , 2 , 5 -dimethoxy - 4 - ethylamphetamine , 2 , 5 -dime - morphan , levorphanol, lis dexamfetamine , loprazolam , lora thoxyamphetamine , 2C - B - ( 4 - bromo - 2 , 5 - dimethoxypeneth zepam , lormetazepam , lysergic acid , lysergic acid amide , ylamine ), 2C - D ( 2, 5 - dimethoxy - 4 -methylphenethylamine ), 40 lysergic acid diethylamide , marijuana , mazindol, MBDN 2C -I ( 4 - iodo -2 , 5 - dimethoxy -phenethylamine ) , 2C - T -2 ( 2 , 5 ( N -methyl - 1 - ( 3 , 4 -methylenedioxyphenyl ) - 2 - butanamine ), dimethoxy - 4 - ethylthiophenethylamine ), 2C - T - 4 ( 2 , 5 - dime- mCPP ( 1 - ( 3 - chlorphenyl) piperazine ), mebutamate , meclo thoxy - 4 - isopropylthiophenethylamine ) , 2C - T - 7 ( 2 , 5 -dime - qualone , medazepam , mefenorex , MeOPP ( 1 - ( 4 -methoxy thoxy - 4 -( n ) -propylthiophenethylamine ), 3 , 4 -methylene phenyl) piperazine ) , meperidine, meperidine intermediate , dioxymethamphetamine, 3 ,4 , 5 - trimethoxyamphetamine , 45 meprobamate , mescaline , mesocarb , mesterolone , metamfe 3 , 4 -methylenedioxyamphetamine , 3 , 4 -methylenedioxy - N - tamine , metazocine , methadone , methadone intermediate , ethyl amphetamine , 3 -methylfentanyl , 3 -methylthiofenta - methamphetamine , methandienone , methandrolone , meth nyl, 4 -brorno - 2, 5 - dimethoxyamphetamine, 4 -bromo -2 , 5 -di - andriol, methandrostenolone , methaqualone , methcathi methoxyphenethylamine , 4 -methoxyamphetamine , none , methenolone, methohexital, methyldesorphine , meth 4 -methyl - 2 , 5 - dimethoxyamphetamine , 4 -methylaminorex 50 yldihydromorphine , methylphenidate , methylphenobarbital ( cis isomer ) , 5 - MeO -DIPT ( 5 -methoxy - N , N - diisopropyl- (mephobarbital ) , methyltestosterone , methyprylone , meto tryptamine ), 5 -MeO -DMT (5 -methoxy -N ,N - dimethyl- pone , mibolerone, midazolam , modafinil , moramide - inter tryptamine ), 5 -methoxy -3 ,4 -methylenedioxyamphetamine , mediate, morpheridine, morphine , morphine methylbro acetorphine, acetorphine, acetyl- alpha -methylfentanyl , mide , morphine methylsulfonate , morphine- N -oxide , acetyl- alpha -methylfentanyl , acetyldihydrocodone, acetyl- 55 myrophine, N , N - dimethylamphetamine, nabilone , nalor methadol, acetylmethadol, alfentanil , allobarbital, allyl phine , nandrolone, N - ethyl- 1 - phenylcyclohexylamine , prodine, alphacetylmethadol except levo - alphacetylmeth N - ethyl- 3 - piperidyl benzilate , N -ethylamphetamine , N -hy adol, alpha -ethyltryptamine , alphameprodine , droxy - 3 , 4 -methylenedioxyamphetamine , nicocodeine , alphamethadol, alphamethadol, alpha -methylfentanyl , nicocodine , nicodicodine , nicomorphine , nimetazepam , alpha -methylthiofentanyl , alphaprodine , alprazolam , amfe - 60 nitrazepam , N -methyl - 3 -piperidyl benzilate , noracymeth pramon , amfetaminil , amineptin , aminorex , amobarbital, adol, norcodeine, nordiazepam , norethandrolone , norlevor amphetamine , dextroamphetamine , amilnitrite ( all isomers phanol, normethadone, normorphine , norpipanone , norpi of the amyl group ) , anabolic steroids, anileridine, aprobar - panone , opium , oxandrolone , oxazepam , oxazolam , bital, barbital, barbituric acid derivative, BDB ( 3 , 4 -methyl - oxycodone , oxymesterone , oxymetholone, oxymorphone , enedioxyphenyl) -2 -butanamine ), benzethidin , benzethidine , 65 para- fluorofentanyl, parahexyl, paraldehyde, pemoline , pen benzoylecgonine , benzphetamine , benzphetamine , benzyl- tazocine , pentobarbital , petrichloral, peyote , phenadoxone , methylcetone , benzylmorphine ,betacetylmethadol , beta -hy phenampromide, phenazocine , phencyclidine, phendimetra US 9 , 943, 513 B1 33 34 zine, phenmetrazine, phenobarbital, phenomorphan , pheno depressants , CNS stimulants , cannabinoids, nicotine - like peridine , phentermine , phenylacetone , pholcodine , pimino - compounds, glutamate antagonists , or N -methyl -D -aspartate dine , pinazepam , pipradrol , piritramide, PMMA (NMDA ) antagonists . ( paramethyxymethyl amphetamine ) , prazepam , prohep In another embodiment , the active drug substance is an tazine, properidine, propiram , psilocybine , psilocine , pyrov - 5 analgesic . Examples of analgesics suitable for use in the alerone , quazepam , racemethorphane, racemoramide, rac pharmaceutical compositions described herein include, for emorphane, remifentanil , salvia divinorum , salvinorin A , example , opioids, natural opium alkaloids, morphine , secobarbital , secobarbital, sibutramine, SPA , stanolone , opium , hydromorphone, nicomorphine , oxycodone , dihy stanozolol, sufentanil, sulfondiethylmethane , sulfonethyl drocodone , diamorphine, tapentadol, papaveretum , codeine , methane , sulfonmethane, talbutal, temazepam , tenamfet- 10 phenylpiperidine derivatives , ketobemidone , pethidine, fen amine , testolactone , testosterone, tetrahydrocannabinols , tanyl, diphenylpropylamine derivatives , dextromoramide , tetrazepam , TFMPP ( 1 - ( 3 - triflourmethylphenyl) piperazine ) , piritramide , dextropropoxyphene, bezitramide , methadone , thebacon , thebaine , thiamylal, thiofentanyl, thiopental, tile - benzomorphan derivatives , pentazocine, phenazocine , ori tamine and zolazepam in combination , tilidine , trenbolone , 15 pavine derivatives , buprenorphine , morphinan derivatives , triazolam , trimeperidine , vinbarbital, zaleplon , zipeprol, butorphanol, nalbuphine, tilidine , tramadol , dezocine , sali zolpidem , or zopiclone. cylic acid and derivatives , acetylsalicylic acid , aloxiprin , Other suitable examples of active drug substances suitable choline salicylate , sodium salicylate , salicylamide , salsalate , for use in the pharmaceutical compositions described herein ethenzamide , morpholine salicylate , dipyrocetyl, benorilate , include, for example , alfentanil, allylprodine , alphaprodine , 20 diflunisal, potassium salicylate , guacetisal , carbasalate cal anileridine, benzylmorphine , bezitramide, buprenorphine , cium , imidazole salicylate , pyrazolones , phenazone, metam butorphanol , clonitazene , codeine , cyclazocine, desomor- izole sodium , aminophenazone , propyphenazone , nifena phine , dextromoramide , dezocine , diampromide, dihydroco - zone , anilides , paracetamol , phenacetin , bucetin , done , dihydromorphine , dimenoxadol, dimepheptanol, dim - propacetamol, other analgesics and antipyretics such as, for ethylthiambutene , dioxaphetyl butyrate , dipipanone , 25 example , rimazolium , glafenine , floctafenine , viminol , nefo eptazocine , ethoheptazine , ethylmethylthiambutene, ethyl pam , flupirtine, or ziconotide . morphine, etonitazene, fentanyl, heroin , hydrocodone , In another embodiment, the active drug substance is an hydromorphone , hydroxypethidine , isomethadone , dextro - opioid . Where an opioid is included as an active drug propoxyphene , ketobemidone, levallorphan , levorphanol, substance , the opioid may comprise naturally occurring levophenacylmorphan , lofentanil , meperidine , meptazinol, 30 opioids , synthetic opioids, or semisynthetic opioids. metazocine, methadone, metopon , morphine , morphine In other embodiment, the active drug substance comprises 6 - glucuronide, morphine 3 - glucuronide, myrophine , nalbu amfetamine , dexamfetamine , lisdexamfetamine , metamfet phine, narcine , nicomorphine , norlevorphanol, normetha amine, methylphenidate , dexmethylphenidate , or combina done , nalorphine , normorphine, norpipanone , opium , oxy - os tions thereof. codone, oxycodeine , oxymorphone , papaveretum , In another embodiment, the pharmaceutical compositions pentazocine, phenadoxone, phenomorphan , phenazocine , disclosed herein includes an opioid , the opioid is selected phenoperidine , piminodine, piritramide, proheptazine, from buprenorphine , codeine , dextromoramide , dihydroco promedol , properidine , propiram , propoxyphene , sufentanil , done , fentanyl, hydrocodone, hydromorphone, morphine , tilidine , tramadol, thebaine , levo - alphacetylmethadol 40 pentazocine, oxycodeine , oxycodone, oxymorphone , norhy (LAAM ) , remifentanil, carfentanyl, ohmefentanyl, MPPP , drocodone , noroxycodone , morphine- 6 -glucuronode , trama prodine , PEPAP, levomethorphan , etorphine , lefetamine , dol, tapentadol, or dihydromorphine . loperamide , diphenoxylate , or pethidine . Where an opioid is used as an active drug substance , the Other examples of active drug substances suitable for use opioid may be present in any of its crystalline , polymor in the pharmaceutical compositions described herein include 45 phous , semi- crystalline , and amorphous or polyamorphous anabolic steroids, cannabis, cocaine , or diazepam . forms. Furthermore, in another embodiment, an opioid used In another embodiment, the active drug substance com as an active drug substance may be present in one or more prises the therapeutic classes including non - steroidal anti- forms selected from its crystalline , polymorphous , semi inflammatory substances or antirheumatic active drug sub - crystalline , or amorphous or polyamorphous forms. stances . 50 Some embodiments of the pharmaceutical compositions In other embodiments , the active drug substance com - disclosed herein include an opioid as an active drug sub prises analgesics, opioids, antipyretics, anaesthetics , antimi- stance , the active drug substance is selected from morphine, graine agents, antiepileptics , anti - parkinson agents , dop - oxycodone, hydrocodone , hydromorphone , norhydroco aminergic agents , antipsychotics , anxiolytics, sedatives , done , oxymorphone , noroxycodone , morphine- 6 - glu antidepressants , psychostimulants agents , dopamine , nora - 55 curonode and pharmaceutically acceptable salts thereof, drenaline , nicotinic , alfa - adrenergic , serotonin , H3 antago including oxycodone hydrochloride, hydrocodone bitartrate , nists used for ADHD or nootropics agents used in addictive hydromorphone hydrochloride or morphine sulphate penta disorders . hydrate . In other embodiments , the active drug substance com In other embodiments , the pharmaceutical compositions prises therapeutic classes including anaesthetics , centrally 60 as described herein are suitable for use for water soluble as acting analgesics , sedative - hypnotics , anxiolytics, appetite well as slightly soluble or insoluble active drug substances . suppressants , decongestants , antitussives , antihistamines , In another embodiment, all of the above mentioned active antiemetics , antidiarrheals , and drugs used to treat narco drug substances may also be in the form of pharmaceutically lepsy , or attention deficit hyperactivity disorder. acceptable salts , uncharged or charged molecules, molecular In another embodiment, the active drug substance is 65 complexes, solvates, or anhydrates thereof, and , if relevant , associated with abuse syndromes and the active drug sub single isomers , enantiomers , racemic mixtures, or mixtures stance may , for example , be selected from opioids, CNS thereof . US 9 ,943 ,513 B1 35 36 In another embodiment, the pharmaceutical compositions carrageenan ). In one aspect of the enteric soft capsule shell described herein may comprise pharmaceutically acceptable described herein , the film - forming polymer is gelatin . In salts of any of the above mentioned active drug substances . another aspect of the enteric soft capsule shell described In another embodiment, the active pharmaceutical ingre herein , the film - forming polymer is carrageenan . dient is hydrocodone or oxycodone or a pharmaceutically 5 Plasticizers that are useful for creating soft capsules as acceptable salt form of either hydrocodone or oxycodone . described herein are glycerol, sorbitol , polyethylene glycols , Pharmaceutically acceptable salts forms are those formed by or combinations thereof. The weight ratio between the contacting hydrocodone or oxycodone free base with a film - forming polymer, plasticizer , and solvent is adjusted so suitable acid in a suitable solvent under suitable conditions that the gel mass is flowable and not too viscous, and can be that will form a form of hydrocodone or oxycodone acid " made into soft capsules using rotary die encapsulation addition salt . Suitable acids include hydrochloric acid , cam - methods . phorsulfonic acid , hydrobromic acid , sulfuric acid , meth In one embodiment, the enteric soft capsule shell has the anesulfonic acid , formic acid , acetic acid , oxalic acid , suc exemplary composition shown in Table 3 . cinic acid , tartaric acid , mandelic acid , malic acid , salicylic acid , fumaric acid , lactic acid , citric acid , glutamic acid , 13 TABLE 3 and / or aspartic acid . The term “ pharmaceutically acceptable salts ” of an active Exemplary Soft Capsule Shell Composition drug substance includes alkali metal salts such as , for Percent example , sodium or potassium salts , alkaline earth metal Component weight ( % ) salts such as , for example , calcium and magnesium salts, and 2 Gelatin 43 salts with organic or inorganic acid such as, for example , Glycerol 20 hydrochloric acid , hydrobromic acid , nitric acid , sulfuric Titanium dioxide ( optional) 0 . 7 acid , phosphoric acid , citric acid , formic acid , maleic acid , Coloring agent ( optional) 0 . 1 succinic acid , tartaric acid ,methanesulphonic acid , toluene Water 36 . 2 sulphonic acid etc . In another embodiment, pharmaceuti - 23 TOTAL 100 % cally acceptable opioid salts can comprise sulphate salts , Final pH ~ 4 - 7 hydrochloride salts , and bitartrate salts . Ratio total plasticizer to gelatin 20 :43 ( 0 .46 : 1 ) The concentration of the active pharmaceutical ingredient Water content in dried soft capsule shell : 8- 15 % in the pharmaceutical composition described herein depends on the specific active pharmaceutical ingredient substance , 30 the disease to be treated , the condition of the patient, the age , In one embodiment described herein , the soft capsule and gender of the patient, etc . The active pharmaceutical comprises about 43 % of at least one film - forming polymer ; ingredientmay be known and a person skilled in the art will about 20 % of at least one plasticizer ; about 36 % water; be able to find information as to the dosage of each active optionally , about 0 . 7 % titanium dioxide; and optionally , drug substance and , accordingly , will know how to deteror - 335 aboutabo 0 . 1 % of at least one coloring agent. mine the amount of each active drug substance in the In one embodiment described herein , the enteric soft pharmaceutical composition . capsule described herein comprises a composition of about The active pharmaceutical ingredient may be a new 3 % to about 10 % film forming polymer ( e . g ., a composition chemical entity for which the amount of information is of carrageenan ); about 10 % to about 30 % filler; about 10 % limited . In such cases , the dosage has to be evaluated based 40 to about 30 % plasticizer ; and about 30 % to about 70 % on available preclinical and /or clinical data . solvent . In some embodiments described herein , the pharmaceu In one embodiment, the weight percentage range of tical composition comprises a dosage form comprising a soft film - forming polymer of the soft capsule described herein is capsule shell or a hard capsule shell. about 35 % to about 45 % , including all integers within the In one embodiment, the soft capsule shell has the com - 4 specified range. In one aspect , the film - forming polymer position of Table 2 , including all possible iterations of the weight percentage is about 38 % . In another aspect , the specified ranges that provide 100 % for the total weight film -forming 1 polymer weight percentage is about 42 % . In percentage, including or excluding the optional colorings , another aspect, the film - forming polymer weight percentage flavorings, or excipients . 50 is about 44 % . In one embodiment, the weight percentage range of TABLE 2 film - forming polymer of the soft capsule described herein is Exemplary soft gelatin capsule composition about 3 % to about 15 % , including all integers within the specified range . In one aspect, the film - forming polymer Exemplary Weight 55 weight percentage is about 3 % . In one aspect , the film Component Component Percentage ( % ) forming polymer weight percentage is about 5 % . In one Film - forming polymer Gelatin 20 - 36 aspect, the film -forming polymer weight percentage is about (Gelatin ) 7 % . In one aspect , the film - forming polymer weight per Plasticizer Glycerol 10 - 30 Solvent Water 20 - 70 centage is about 10 % . In one aspect, the film - forming Opacifier (optional ) Titanium dioxide 0 . 5 - 1 . 5 60 polymer weight percentage is about 12 % . Coloring agent (optional ) Various 0 . 05 - 0 . 1 In one embodiment, the weight percentage range of plasticizer is about 15 % to about 22 % , including all itera TOTAL 100 % tions of integers with the specified range . In one aspect, the plasticizer weight percentage is about 17 % . In another Film - former polymers that are useful for creating soft 65 aspect, the plasticizer weight percentage is about 18. 5 % . In capsules are gelatin , hydroxypropylmethylcellulose another aspect, the plasticizer weight percentage is about (HPMC ) or carrageenan ( e. g ., iota carrageenan and kappa 20 % . US 9 ,943 ,513 B1 37 38 In one embodiment, the weight percentage ratio range of Application Publication No. US 2006 /0165778 ; and U . S . plasticizer to film - forming polymer is about 0 . 33 : 1 to about Pat. No . 8 ,685 ,445 , each of which is incorporated by refer 0 .56 :1 , including all iterations of iterations of ratios with the ence herein for such teachings . The enteric soft capsule shell specified range . In one embodiment, the weight percentage may comprise one or more film forming polymers, one or ratio range of plasticizer to film - forming polymer is about 5 more enteric acid - insoluble polymers, one or more plasti 0 .38 : 1 . In one embodiment, the weight percentage ratio cizers, one or more alkali -neutralizing agents , one or more range of plasticizer to film - forming polymer is about 0 .42 : 1 . solvents , optionally one or more colorants , and optionally In one embodiment, the weight percentage ratio range of one or more flavorings or other conventionally accepted plasticizer to film - forming polymer is about 0 .46 : 1 . In one pharmaceutical excipients or additives . embodiment, the weight percentage ratio range of plasticizer 10 Film - former polymers that are useful for creating enteric to film - forming polymer is about 0 .52 : 1. soft capsules are gelatin , hydroxypropylmethylcellulose In one aspect, soft capsules are made using a rotary die (HPMC ) or carrageenan ( e . g . , iota carrageenan and kappa apparatus as described in U . S . Pat . Nos . 5 ,459 ,983 ; 5 , 146 , carrageenan ) . In one aspect of the enteric soft capsule shell 730 ; and 6 ,482 ,516 , each of which are incorporated by described herein , the film -forming polymer is gelatin . In reference herein for such teachings . 15 another aspect of the enteric soft capsule shell described Another embodiment described herein includes a process herein , the film - forming polymer is carrageenan . of manufacturing soft capsules comprising the pharmaceu - Examples of enteric , acid - insoluble polymers are acrylic tical composition as described herein . The process includes and methacrylate acid copolymers, cellulose acetate phtha preparing a gel mass composition comprising a film - form late (CAP ) , cellulose acetate butyrate , hydroxypropylmeth ing , water- soluble polymer, an appropriate plasticizer , and 20 ylcellulose phthalate (HPMCP ) , alginic acid salts such as solvent; casting the gel mass into films or ribbons using sodium or potassium alginate , or shellac . Poly (methacylic heat - controlled drums or surfaces; and manufacturing a soft acid - co -methyl methacrylate ) anionic copolymers based on capsule comprising a matrix fill using rotary die technology. methacrylic acid and methyl methacrylate are particularly The thickness of the films or ribbons that form the soft stable and are preferred in some embodiments. Poly (meth ) capsule shell is from about 0 .010 inches ( ~ 0 .254 mm ) to 25 acrylates (methacrylic acid copolymer ) , available under the about 0 .050 inches ( ~ 1 .27 mm ), including all integers within trade name EUDRAGIT® ( Evonik Industries AG , Essen , the specified range. The shell thickness can be about 0 .010 Germany ) , are provided as powder or aqueous dispersions. inch ( 0 . 254 mm ) , about 0 .015 inch ( ~ 0 .381 mm ), about In one aspect, the methacrylic acid copolymer can be 0 .02 in ( - 0 .508 mm ) , about 0 .03 in ( ~ 0 . 762 mm ), about 0 .04 EUDRAGIT® L 30 D -55 ; EUDRAGIT® L 100 - 55 ; in (24 .02 mm ), or about 0 .05 in ( - 1 .27 mm ). In one 30 EUDRAGIT® L 100 ; EUDRAGIT® L 12 . 5 ; EUDRAGIT® embodiment, the thickness is about 0 .02 inches ( ~ 0 .508 mm ) S 100 ; EUDRAGIT® S 12 . 5 ; EUDRAGIT® FS 30 D : to about 0 .040 inches ( ~ 1 . 02 mm ) . In one embodiment, the EUDRAGIT® E 100 ; EUDRAGIT® E 12 . 5 ; EUDRAGIT® shell thickness is about 0 .028 inches (~ 0 .711 mm ). In E PO ; EUDRAGIT® RL 100 ; EUDRAGIT® RL PO ; another embodiment, the shell thickness is about 0 .033 EUDRAGIT® RL 30 D ; EUDRAGIT® RL 12 .5 ; inches ( ~ 0 .838 mm ) . In another embodiment, the shell 35 EUDRAGIT® RS 100 ; EUDRAGIT® RS PO ; thickness is about 0 . 038 inches ( ~ 0 . 965 mm ) . EUDRAGIT® RS 30 D ; EUDRAGIT® RS 12 .5 ; In one embodiment described herein , the soft capsule EUDRAGIT® NE 30 D ; EUDRAGIT® NE 40 D ; shell described herein , encapsulates a matrix fill as described EUDRAGIT® NM 30 D ; or other poly (methacrylate poly herein . In another embodiment described herein , the soft mers . In one aspect, the enteric polymer is EUDRAGIT® L capsule shell and encapsulated matrix fill comprises an outer 40 100 , a methacrylic acid copolymer , Type A . Acid - insoluble dimension from about 2 oval to about 30 oval including all polymer specifications are detailed in the United States iterations of capsule size within the specified range ( e . g ., 2 Pharmacopoeia and in various monographs . oval , 3 oval, 4 oval , 5 oval, 6 oval, 7 oval, 8 oval, 10 oval, Plasticizers that are useful for creating enteric soft cap 12 oval, 16 oval, 20 , or 30 oval ) . In another embodiment sules as described herein are glycerol, sorbitol, polyethylene described herein , the soft capsule shell and encapsulated 45 glycol, citric acid , citric acid esters , such as triethyl citrate , matrix fill comprises an outer dimension from about 2 round or combinations thereof. The weight ratio between the to about 28 round including all iterations of capsule size film - forming polymer , the enteric acid - insoluble polymer, within the specified range ( e . g . , 2 round , 3 round , 4 round , and plasticizer is adjusted so that the gel mass is flowable 5 round , 6 round , 7 round , 8 round , 10 round , 12 round , 16 and not too viscous, and can be made into soft capsules using round , 20 round or 28 round ) . In another embodiment 50 rotary die encapsulation methods . described herein , the soft capsule shell and encapsulated In one embodiment, enteric soft capsule shell composi matrix fill comprises an outer dimension from about 2 tions can be made by dissolving the enteric acid - insoluble oblong to about 22 oblong including all iterations of capsule polymer in an aqueous solution of an alkali neutralizing size within the specified range ( e . g . , 2 oblong , 3 oblong , 4 agent such as ammonia , sodium hydroxide , potassium oblong, 5 oblong, 6 oblong, 7 oblong , 8 oblong , 10 oblong , 55 hydroxide , or liquid amines such as tri- ethanol amine or 11 , oblong , 12 oblong , 14 oblong , 16 oblong , 20 oblong , or ethylene diamine . The amount of alkali is adjusted to give a 22 oblong ) . Dimension specifications of soft capsules and final pH value of the gel mass less than or equal to about pH tablets are known to those skilled in the art. See Remington ' s 9 . 0 . In one embodiment, the final pH does not exceed 8 . 5 . Essentials of Pharmaceutics, Pharmaceutical Press Publish - The volatile alkali neutralizing agent, ammonia is preferred . ing Company, London , UK , 1st Edition , 2013 , which is 60 The film - forming polymer can then be combined with the incorporated by reference herein for such teachings . plasticizer and solvent and then blended with the acid In another embodiment described herein , the pharmaceu - insoluble gel to make a final homogeneous mix in a heat tical composition comprises an enteric soft capsule shell controlled vessel and can be degassed by using vacuum . The comprising a matrix fill comprising an active pharmaceutical fugitive ammonia evaporates during degassing . Using the ingredient. 65 foregoing process , the alkali concentrations do not require Enteric soft capsules are described in International Patent an additional step such as heating or neutralizing with acid Application Publication No. WO 2004 /030658 ; U . S . Patent in order to neutralize the gel mass . US 9 ,943 ,513 B1 39 40 In another embodiment described herein , an enteric soft centage is about 18 . 9 % . In another aspect , the total plasti capsule shell can be made by using an aqueous dispersion of cizer weight percentage is about 19 . 3 % . the acid -insoluble polymer by adding alkalinematerials such In one embodiment, the alkali neutralizing -agent is as ammonium , sodium , or potassium hydroxides , other ammonia (ammonium hydroxide ; 30 % w /v ) that is added to alkalis , or a combination thereof that will cause the enteric 5 comprise a weight percentage of about 1 to about 5 % of the acid - insoluble polymer to dissolve. The plasticizer -wetted , total enteric soft capsule composition . In one aspect , 30 % film - forming polymer can then be mixed with the solution of w / v ammonia is added to comprise a weight percentage of about 2 % . In another aspect, 30 % w / v ammonia is added to the acid - insoluble polymer . In one embodiment, enteric a weight percentage of about 1 .7 % . In one aspect, ammonia acid - insoluble polymers in the form of salts of the above 10 is added to provide a final pH of about 9 in the enteric soft mentioned bases or alkalis can be dissolved directly in water capsule composition . In another aspect, ammonia is added to and mixed with the plasticizer -wetted , film - forming poly provide a final pH of about 8 . 5 in the enteric soft capsule mer . composition . In another aspect , after the capsules are filled In one embodiment, an enteric soft capsule shell has the and dried , the ammonia concentration is substantially composition of Table 4 , including all possible iterations of 15 reduced , owing to the fugitive nature of the volatile alkali. the specified ranges that provide 100 % for the total weight In one aspect, practically all of the ammonia is evaporated percentage, including or excluding the optional , excipients , except for ammonium ions comprising salts with other opacifiers , colorants , and flavorings . moieties in the composition . In one embodiment, the weight ratio range of film forming TABLE 4 20 polymer to enteric acid insoluble polymer ( film forming : enteric ) is about 25 :75 ( - 0 . 33 ) to about 40 :60 ( ~ 0 .67 ) ( i. e . , Exemplary Enteric Soft Capsule Shell Composition ~ 0 .33 - 0 .67 ) , including all iterations of ratios within the Exemplary Composition specified range . In one aspect, the ratio of film forming Component Component Range ( % ) polymer to enteric acid insoluble polymer is about 30 : 70 Film - forming polymer Gelatin 20 - 36 ( - 0 .43 ) . In another aspect , the ratio of film forming polymer Enteric , acid insoluble Methacrylic Acid 8 - 20 to enteric acid insoluble polymer is about 28 : 72 ( - 0 .38 ) . polymer Copolymer In another embodiment described herein , the weight ratio Plasticizer Glycerol, Triethyl citrate 15 - 22 range of film forming polymer (i . e ., total carrageenan com Alkali neutralizing agents NH ,OH (30 % ), NaOH 1 - 5 position to enteric acid insoluble polymer ( film forming : Solvent Water 20 - 40 Opacifier Titanium Dioxide 1 - 7 . 5 30 enteric ) in the enteric soft gel composition is about 3 : 9 Colorant (optional ) Various 0 .05 - 1 ( - 0 . 3 ) to about 4 : 3 ( 4 . 3 ) ( i . e . , - 0 . 3 - 1 . 3 ) , including all ratios Flavoring (optional ) Various 0 .05 - 2 within the specified range . In some aspects , the ratio of film Excipients ( optional) Various 1 - 5 forming polymer to enteric acid insoluble polymer in the gel mass is about 1 : 3 ( 0 .33 ) , about 1 : 2 . 5 ( - 0 . 4 ) , about 1 : 2 In one embodiment, an enteric soft capsule shell com - 35 ( + 0 . 5 ) , about 1 : 1 .6 ( 0 . 6 ), about 1 : 1 . 25 ( - 0 . 8 ), about 1 : 1 prises a composition of about 30 % film forming polymer (21 ) , about 1 . 1 : 1 ( - 1 . 1 ) , about 1 . 21 ( - 1 . 2 ) , or about 1 . 3 : 1 ( e . g . , gelatin ) ; about 10 % enteric , acid insoluble polymer ; (~ 1 . 3 ) . In one aspect , the ratio of film forming polymer to about 20 % plasticizer; about 1 % alkali neutralizing agent ; enteric acid insoluble polymer in the gelmass is about 1 : 2 . 5 and about 37 % solvent. ( ~ 0 . 4 ) . In another aspect , the ratio of film forming polymer In one embodiment described herein , the enteric soft 40 to enteric acid insoluble polymer is about 1 :3 ( - 0 . 3 ). capsule described herein comprises a composition of about In one embodiment, the weight ratio of total plasticizer to 3 % film forming polymer ( e . g . , a composition of carra film forming polymer is about 20 :40 to 21 : 30 ( i . e . , - 0 . 5 - 0 . 7 ) geenan ) ; about 10 % enteric , acid insoluble polymer; about including all iterations of ratios within the specified range . 10 % filler ; about 10 % plasticizer, about 1 % alkali neutral- In one aspect, the weight ratio of total plasticizer to film izing agent ; about 2 % sealant ; and about 60 % solvent . 45 forming polymer is about 20 : 40 ( - 0 . 5 ) . In another aspect, In one embodiment, the weight percentage range of total the weight ratio of total plasticizer to film forming polymer polymer content ( i . e . , film forming polymer and enteric is about 21: 30 ( - 0 . 7 ). In another aspect, the weight ratio of acid - insoluble polymer ) of the enteric soft capsule described total plasticizer to film forming polymer is about 19 : 29 herein is about 30 % to about 45 % , including all integers (20 .65 ) . In another aspect , the weight ratio of total plasti within the specified range . In another embodiment , the 50 cizer to film forming polymer is about 19 . 3 : 29 . 2 ( - 0 . 66 ) . weight percentage range of total polymer content (i . e ., film In one embodiment, the weight ratio of total plasticizer to forming polymer and enteric acid - insoluble polymer ) of the enteric acid insoluble polymer is about 1: 1 to about 2 :1 enteric soft capsule described herein is about 9 % to about (~ 1- 2 ) , including all iterations of ratios within the specified 35 % , including all integers within the specified range . In one range . In one aspect, the weight ratio of total plasticizer to aspect , the total polymer weight percentage is about 40 % . In 55 enteric acid insoluble polymer is about 11 : 10 ( ~ 1 . 1 ). In another aspect, the total polymer weight percentage is about another aspect, the weight ratio of total plasticizer to enteric 42 % . In another aspect, the total polymer weight percentage acid insoluble polymer is about 14 : 10 ( - 1 .4 ) . In another is about 45 % . In another aspect, the total polymer weight aspect, the weight ratio of total plasticizer to enteric acid percentage is about 38 % . In another aspect, the total poly - insoluble polymer is about 17 : 10 ( ~ 1 . 7 ) . In another aspect , mer weight percentage is about 12 % . In another aspect, the 60 the weight ratio of total plasticizer to enteric acid insoluble total polymer weight percentage is about 16 % . polymer is about 20 :10 ( ~ 2 ). In another aspect, the weight In one embodiment, the weight percentage range of total ratio of total plasticizer to enteric acid insoluble polymer is plasticizer is about 15 % to about 22 % , including all itera - about 19. 3 : 11. 2 ( ~ 1. 73 ) . tions of integers with the specified range . In one aspect , the In one embodiment, the weight ratio range of total plas total plasticizer weight percentage is about 19 % . In another 65 ticizer to total polymer (film forming and enteric acid aspect , the total plasticizer weight percentage is about insoluble polymer ) is about 18 :45 to about 20 :40 ( i . e . , 17 .7 % . In another aspect, the total plasticizer weight per - - 0 . 40 - 0 .5 ), including all iterations of ratios within the speci US 9 , 943, 513 B1 42 fied range . In one aspect , the weight ratio range of total One embodiment described herein provides an enteric plasticizer to total polymer is about 18 :45 ( ~ 0 .40 ). In acid - insoluble polymer dispersed within the film - forming another aspect, the weight ratio range of total plasticizer to polymer gel mass that provides the total soft gel composition total polymer is about 19 :40 ( - 0 . 475 ) . In another aspect, the with enteric acid - insoluble properties, at relatively low con weight ratio range of total plasticizer to total polymer is 5 centrations of the enteric acid - insoluble polymer ( e . g ., from about 20 :40 ( - 0 .5 ) . In another aspect, the weight ratio range about 8 % to about 20 % of the total wet gel mass composi of total plasticizer to total polymer is about 19. 3 :40 . 4 tion ) and without the need of excessive amounts of alkali , ( - 0 .477 ) . thus avoiding denaturation or degradation of the film - form In one embodiment, the solvent comprises about 20 % to ing polymer that can weaken the integrity of the enteric soft about 40 % of the enteric soft capsule composition , including 10 capsule shell . all integers within the specified range . In one embodiment, In some embodiments , the enteric soft capsule shell does the solvent is water . The quantity of water in the composition not dissolve or disintegrate in acids , such as 0 .1 N hydro varies depending on the quantities of the other ingredients . chloric acid or simulated gastric fluid (ca . pH 1 . 2 ), despite For example , the quantity of opacifier , colorant, flavoring , or the fact that the majority of the shell ingredients (i . e. , greater other excipients can change the percentage of water present 15 than 50 % ) normally dissolve in , or are miscible with , acids . the composition . In one embodiment, the weight percentage In some embodiments , the enteric soft capsules made using of water is as much as suffices to bring the total weight the compositions described herein remain intact in hydro percentage to 100 % ( i. e ., quantum sufficiat; q . s .) . In another chloric acid or simulated gastric fluid for at least two hours embodiment, the water comprises about 20 % , about 25 % , and the capsules readily release their contents upon shifting about 30 % , about 35 % , or about 40 % of the enteric soft 20 the pH of the solution to ca . 6 . 8 , such as that of simulated capsule composition . In another embodiment, water com intestinal fluid . In one aspect, the enteric soft capsule is prises about 35 % to about 40 % of the enteric soft capsule resistant to dissolution at about pH 1 . 2 for at least about 2 composition . In one embodiment , water comprises about hours . In another aspect, the enteric soft capsule begins 37 % of the composition . dissolution at pH of about 6 . 8 within about 10 min . In one embodiment, the final moisture (water ) content of 25 In another embodiment, the final enteric capsule compo the enteric soft capsule is from about 8 % to about 15 % , sition provides films of increased strength without substan including all integers within the specified range . In another tially compromising film elasticity . Moreover , films made embodiment, the moisture content is about 8 % to about frofrom the enteric soft capsule compositions as described 12 % , including all integers within the specified range . In one herein can be sealed at normal temperature range typically aspect, the final moisture content is about 8 % . In one aspect, 30 used for making traditional soft gel capsules . In one aspect, the final moisture content is about 9 % . In one aspect , the enteric soft capsules are made using a rotary die apparatus final moisture content is about 10 % . In one aspect , the final as described in U . S . Pat. Nos . 5 , 459 , 983 ; 5 , 146 , 730 ; and moisture content is about 11 % . In another aspect, the final 6 , 482 ,516 , each of which are incorporated by reference moisture content is about 12 % . herein for such teachings . In one embodiment, the enteric soft capsule shell has the 35 Another embodiment described herein includes a process exemplary composition shown in Table 5 . of manufacturing enteric soft capsules comprising the phar maceutical composition as described herein . The process TABLE 5 includes preparing a gel mass composition comprising a film - forming , water - soluble polymer and an enteric acid Exemplary Enteric Soft Capsule Shell Composition 40 insoluble polymer and mixing with appropriate plasticizers and solvent; casting the gel mass into films or ribbons using Component Percent weight heat - controlled drums or surfaces; and manufacturing a soft Gelatin 29 . 2 capsule comprising a matrix fill using rotary die technology . Methacrylic Acid Copolymer 11 . 2 ( EUDRAGIT ® L 100 ) The thickness of the films that form the enteric capsule and Glycerol 18 . 0 45 the dimensions of the capsules are similar to those described Triethyl citrate 1 . 3 herein . Ammonium hydroxide 1 . 7 In another embodiment , the capsule is a soft capsule Titanium dioxide 1. 5 comprising a film - forming polymer that is stable at higher Water 37 . 1 temperatures ( e . g ., about 50° C . to about 80° C . ) . An TOTAL 100 % 50 exemplary film -forming polymer is carrageenan ( e . g . , kappa Final pH - 4 - 9 or iota carrageenan ) . Exemplary, non - limiting soft capsules Total polymer % weight( gelatin + enteric ) 40 . 4 % Gelatin % wt of total polymer (gelatin + 72 . 4 % comprising carrageenan are described in the International enteric ) Patent Application Publication No . WO 2003 /061633 ; U . S . Enteric % wt of total polymer (gelatin + 27 . 6 % Patent Application Publication No. US 2004 / 0052839 ; and enteric ) 55 U . S . Pat. Nos . 6 , 949, 256 and 7 , 887 , 838 , each of which is Ratio of Enteric to Gelatin 11 . 2 :29 .2 ( 0 . 38 ) incorporated by reference herein for such teachings . In one Total plasticizer % weight ( glycerol + 19 . 3 % triethyl citrate ) aspect, soft capsules comprising a film - forming polymer Ratio of total plasticizer to total polymer 19 . 3 : 40 . 4 ( 0 .48 ) stable at high temperatures allow for matrix fills having a Ratio total plasticizer to gelatin 19 . 3 : 29 . 2 ( 0 .66 ) higher viscosity to be encapsulated minimizing the use of Ratio total plasticizer to enteric 19 . 3 : 11 . 2 ( 1 . 73 ) 60 additional plasticizers . The increased encapsulation tem Water content in dried enteric soft capsule : 8 - 15 % perature , for example , from about 50° C . to about 80° C . allows for a viscous matrix at a lower temperature to exhibit In one embodiment, the enteric soft capsule shell com - flowability for encapsulation by the methods described prises about 30 % gelatin ; about 10 % poly (methyl ) acrylate herein (e . g ., rotary die encapsulation ). copolymer ; about 18 % glycerol; about 1 % triethyl citrate ; 65 In another embodiment, the capsule shell is a hard capsule about 1 . 5 % ammonia ; about 37 % water ; and about 1 . 5 % shell . In one aspect, the hard capsule shell may comprise the titanium dioxide . abuse deterrentmatrices described herein . Any hard capsule US 9 ,943 ,513 B1 43 44 shell , for example hard capsule shells comprising gelatin , capsules are coated using a pan coater . After the coating HPMC , or pullulan , including hard capsule shells exhibiting suspension is applied , the coated capsules are dried in the enteric properties , maybe used with the abuse deterrent pan coater for a specific period of time at a specific tem matrix fills described herein . Hard capsule shells are known perature . in the art and are described by Kathpalia et al ., J. Adv. 5 Another embodiment described herein comprises a sub Pharm . Edu . & Res . 4 ( 2 ) : 165 - 177 ( 2014 ), which is incor - coating that is applied prior to applying a coating . In one porated by reference herein for the specific teachings related embodiment , the subcoating comprises hydroxpropyl meth to hard capsules. ylcellulose , methylcellulose , ethylcellulose , or a combina Another embodiment is a controlled release pharmaceu - tion thereof. tical composition comprising a capsule shell encapsulating a 10 Another embodiment described herein comprises a coat matrix fill comprising one or more active pharmaceutical ing that is applied directly on the exterior of the capsule . In ingredients , wherein the capsule shell comprises one or one embodiment, the coating comprises polyvinyl alcohol, more subcoatings , coatings, or topcoatings . Suitable coat - polyvinyl acetate hydroxpropyl methylcellulose , methylcel ings may be adherence coatings, enteric coatings , moisture lulose , ethylcellulose , or a combination thereof. barriers, air or gas barriers , polymer coatings, colorings, 15 Another embodiment described herein comprises a mois flavors , writings, or combinations thereof. ture barrier that is applied as a coating . The moisture barrier Exemplary polymers useful for coatings include cellulose can be applied directly to the capsule or on top of a acetate phthalate , hydroxypropylmethyl cellulose phthalate , subcoating . In one embodiment the moisture barrier com hydroxypropyl methylcellulose acetate succinate , polyvinyl prises one or more polyvinyl alcohols and appropriate acetate phthalate, polyvinyl alcohols , cellulose acetate trim - 20 pharmaceutically acceptable excipients . In one embodiment ellitate , carboxymethylcellulose , methacrylic acid copoly - the moisture barrier comprises polyvinyl alcohol, sodium mers such as, Eudragit L (polymethacrylic acid , methyl - lauryl sulfate , glyceryl mono - caprylate - caprate , and talc . In methacrylate , 1 : 1 ratio ) , or Eudragit S (polymethacrylic one aspect, the moisture barrier aids in preserving the acid , methylmethacrylate , 1 : 2 ratio ), shellac , zein , or com cosmetic appearance of the dosage forms by preventing binations thereof . 25 dimpling , sticking , or other processing or storage induced Suitable plasticizers include acetyl triethyl citrate , dibutyl blemishes. In one embodiment, the polyvinyl alcohol coat phthalate , tributyl citrate , triethyl citrate , acetyl tributyl i ng comprises Opadry® amb II , (Colorcon ) . citrate , propylene glycol, triacetin , polyethylene glycol, Without being bound by any theory , it is believed that a diethyl phthalate , or combinations thereof. coating such as polyvinyl alcohol applied to achieve about Suitable solubilizers include sodium lauryl sulfate , 30 10 % to about 15 % weight gain of the dosage form permits sodium lauroyl sarcosinate sodium dodecyl sulfate , polysor- the dosage form to be annealed at a temperature of about 60° bate 20 , polysorbate 80 , other detergents or surfactants , or C . to about 75° C . for about 10 min to about 90 min and combinations thereof. slowly cooled to room temperature without causing cos Anti -adherent agents serve to prevent potential agglom metic defects such as dimpling, flattening , sticking , or other eration in acid media . Suitable anti -adherents include talc , 35 defects . It is believed that the coating protects the soft magnesium stearate , calcium stearate , stearic acid , hydro - gelatin capsule and prevents it from becoming molten or genated vegetable oils , polyethylene glycols , fumed silica , tacky during the annealing and cooling steps . silicon dioxide , or combinations thereof. In one embodiment, a coating is applied to the capsule Pore - forming agents serve to create pores or channels in dosage form to achieve about a 10 % to about 15 % weight the enteric coating after administration to a human . Suitable 40 gain to the dosage form . In one aspect , the weight gain is pore -forming agents include sodium chloride , potassium about 10 % to about 20 % , including each integer within the chloride , sucrose , sorbitol , mannitol , polyethylene glycols specified range . In one aspect the weight gain is about 8 % , (PEG ) , propylene glycol, hydroxypropyl cellulose , hydroxy - about 9 % , about 10 % , about 11 % , about 12 % , about 13 % , propylmethylcellulose , polyvinyl alcohols ,methacrylic acid about 14 % , about 15 % , about 16 % , about 17 % , about 18 % , copolymers , poloxamers, or combinations thereof. 45 about 19 % , or about 20 % . In another embodiment, a first Many conventional coating excipients are described in the coating is applied to achieve about a 10 % weight gain . In art . See e . g ., Rowe et al. , Eds. Handbook of Pharmaceutical another embodiment, a second coating comprising one or Excipients , 7th ed . Royal Pharmaceutical Society , UK more coloring agents is applied to the first coated dosage ( 2012 ) . form to achieved about a 5 % weight gain , for a total coating In one embodiment, adjusting the amount of coating and 50 weight gain of about 12 % to about 15 % . In one embodiment, the ratio of polymer to other components allows for tuning about the release profile of the dosage form . The pharmaceutical composition described herein can Subcoats can be applied to the capsules prior to coating to comprise a soft or hard capsule comprising a matrix fill that prevent shell - coat interactions and improve coating adhe - is liquid , semi- solid , or solid . Capsules prepared as sion to the capsule . Exemplary subcoatings can comprise 55 described herein can contain a hydrophobic solution , sus polyvinylpyrrolidone , polyvinyl alcohols , hydroxpropyl pension , or lipid or lipophilic vehicle comprising vegetable methylcellulose , polyethylene glycol, oils , or combinations oils , shortening , or waxes , or combinations thereof. In some thereof. aspects described herein , the lipid or lipophilic vehicle may Coatings, top coatings, or subcoatings are applied to the comprise one or more hydrophilic polymers , but as exterior of a capsules using various methods know in the art . 60 described herein , the vehicle is considered a lipid or lipo The coatings are typically prepared as suspensions and philic vehicle . The composition can be formulated to prevent sprayed on capsules in perforated coating pans through one interaction with the capsule shell components and release or more spray nozzles at a specific temperature . Coating the pharmaceutical composition at a specified rate . solutions or dispersion may be applied at spray rates Additional pharmaceutical excipients useful for the phar between 100 and 400 g /min . The spray rate may be propor - 65 maceutical composition as described herein include, for tionately higher for coatings with higher solid content and example , the following : acidifying agents (acetic acid , gla lower for more dilute dispersions. In one embodiment, cial acetic acid , citric acid , fumaric acid , hydrochloric acid , US 9 ,943 ,513 B1 45 46 diluted hydrochloric acid , malic acid , nitric acid , phosphoric methyl isobutyl ketone , mineral oil , peanut oil, propylene acid , diluted phosphoric acid , sulfuric acid , tartaric acid ) ; carbonate , sesame oil , water for injection , sterile water for alkalizing agents (ammonia solution , ammonium carbonate , injection , sterile water for irrigation , purified water ); Sor diethanolamine , diisopropanolamine , potassium hydroxide , bents (powdered cellulose, charcoal, purified siliceous sodium bicarbonate , sodium borate , sodium carbonate , 5 earth ); carbon dioxide sorbents (barium hydroxide lime, sodium hydroxide , trolamine ) ; antifoaming agents ( dimethi soda lime) ; stiffening agents (hydrogenated castor oil , ceto cone , simethicone ) ; antimicrobial preservatives ( benzalko nium chloride, benzalkonium chloride solution , benzetho stearyl alcohol, cetyl alcohol, cetyl esters wax , hard fat, nium chloride , benzoic acid , benzyl alcohol, butylparaben , paraffin , polyethylene excipient, stearyl alcohol, emulsify cetylpyridinium chloride , chlorobutanol, chlorocresol, 10 ing wax , white wax, yellow wax ); Suspending and /or vis cresol , dehydroacetic acid , ethylparaben , methylparaben , cosity - increasing agents (acacia , agar, alginic acid , alumi methylparaben sodium , phenol, phenylethyl alcohol, phe num monostearate , bentonite , purified bentonite , magma nylmercuric acetate , phenylmercuric nitrate, potassium ben bentonite , carbomer , carboxymethylcellulose calcium , car zoate , potassium sorbate , propylparaben , Propylparaben boxymethylcellulose sodium , carboxymethylcellulose sodium , sodium benzoate , sodium dehydroacetate , sodium 15 sodium 12 , carrageenan , microcrystalline and carboxymeth propionate , sorbic acid , thimerosal, thymol ); antioxidants ylcellulose sodium cellulose, dextrin , gelatin , guar gum , (ascorbic acid , ascorbyl palmitate , butylated hydroxyani- hydroxyethyl cellulose, hydroxypropyl cellulose , hydroxy sole , butylated hydroxytoluene , hypophosphorous acid , propyl methylcellulose , magnesium aluminum silicate , monothioglycerol, propyl gallate , sodium formaldehyde sul methylcellulose, pectin , polyethylene oxide , polyvinyl alco foxylate , sodium metabisulfite , sodium thiosulfate , sulfur 20 hol, povidone, alginate , silicon dioxide , colloidal silicon dioxide , tocopherol, tocopherols excipient) ; buffering agents dioxide , sodium alginate , tragacanth , Xanthan gum ) ; sweet ( acetic acid , ammonium carbonate, ammonium phosphate , ening agents (aspartame , dextrates , dextrose , excipient dex boric acid , citric acid , lactic acid , phosphoric acid , potas trose , fructose , mannitol, saccharin , calcium saccharin , sium citrate , potassium metaphosphate , potassium phos - sodium saccharin , sorbitol, solution sorbitol, sucrose , com phate monobasic , sodium acetate , sodium citrate , sodium 25 pressible sugar , confectioner ' s sugar, syrup ) ; tablet binders lactate solution , dibasic sodium phosphate , monobasic (acacia , alginic acid , sodium carboxymethylcellulose , sodium phosphate ) ; chelating agents ( edetate disodium , eth - microcrystalline cellulose , dextrin , ethylcellulose , gelatin , ylenediaminetetraacetic acid and salts , edetic acid ) ; coating liquid glucose , guar gum , hydroxypropyl methylcellulose , agents ( sodium carboxymethylcellulose , cellulose acetate , methylcellulose , polyethylene oxide , povidone , pregelati cellulose acetate phthalate , ethylcellulose , gelatin , pharma - 30 nized starch , syrup ) ; tablet and /or capsule diluents ( calcium ceutical glaze , hydroxypropyl cellulose , hydroxypropyl carbonate , dibasic calcium phosphate , tribasic calcium phos methylcellulose , hydroxypropyl methylcellulose phthalate , phate , calcium sulfate , microcrystalline cellulose , powdered methacrylic acid copolymer , methylcellulose , polyvinyl c ellulose , dextrates , dextrin , dextrose excipient, fructose , alcohol, polyvinyl acetate phthalate , shellac, sucrose , tita - kaolin , lactose , mannitol, sorbitol, starch , pregelatinized nium dioxide , carnauba wax , microcrystalline wax , zein ) ; 35 starch , sucrose , compressible sugar, confectioner ' s sugar ) ; colorants ( caramel, red , yellow , black or blends , ferric tablet disintegrants ( alginic acid , microcrystalline cellulose , oxide ); complexing agents ( ethylenediaminetetraacetic acid croscarmellose sodium , crospovidone , polacrilin potassium , and salts (EDTA ) , edetic acid , gentisic acid ethanolamide , sodium starch glycolate , starch , pregelatinized starch ) ; Tab oxyquinoline sulfate ) ; desiccants (calcium chloride , calcium let and / or capsule lubricants ( calcium stearate , glyceryl sulfate , silicon dioxide ) ; emulsifying and / or solubilizing 40 behenate , magnesium stearate , light mineral oil , sodium agents ( acacia , cholesterol, diethanolamine (adjunct ), glyc - stearyl fumarate , stearic acid , purified stearic acid , talc , eryl monostearate, lanolin alcohols , mono - and di- glycer - hydrogenated vegetable oil, zinc stearate ); tonicity agent ides , monoethanolamine (adjunct ) , lecithin , oleic acid ( ad - (dextrose , glycerol, mannitol , potassium chloride , sodium junct) , oleyl alcohol ( stabilizer ), poloxamer, chloride ) ; vehicle : flavored and /or sweetened ( aromatic polyoxyethylene 50 stearate , polyoxyl 35 castor oil , poly - 45 elixir , compound benzaldehyde elixir , iso -alcoholic elixir, oxyl 40 hydrogenated castor oil , polyoxyl 10 oleyl ether, peppermint water , sorbitol solution , syrup , tolu balsam polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate , polysor- syrup ) ; vehicle : oleaginous ( almond oil , corn oil , cottonseed bate 20 , polysorbate 40 , polysorbate 60 , polysorbate 80 , oil, ethyl oleate , isopropyl myristate , isopropyl palmitate , diacetate , monostearate , sodium lauryl sulfate, sodium stear - mineral oil , light mineral oil , myristyl alcohol, octyldode ate , sorbitan monolaurate , sorbitan monooleate , sorbitan 50 canol, olive oil, peanut oil, persic oil , sesame oil, soybean monopalmitate , sorbitan monostearate , stearic acid , trola - oil , squalane ) ; vehicle : solid carrier ( sugar spheres) ; vehicle : mine , emulsifying wax ) ; filtering aids (powdered cellulose , sterile ( bacteriostatic water for injection , bacteriostatic purified siliceous earth ) ; flavors and perfumes ( anethole , sodium chloride injection ) ; viscosity - increasing ( see sus benzaldehyde , ethyl vanillin , menthol, methyl salicylate , pending agent ) ; water repelling agent (cyclomethicone , monosodium glutamate , orange flower oil, peppermint, pep - 55 dimethicone , simethicone ) ; and / or solubilizing agent (ben permint oil , peppermint spirit , rose oil , stronger rose water , zalkonium chloride, benzethonium chloride , cetylpyri thymol, tolu balsam tincture , vanilla , vanilla tincture , van dinium chloride , docusate sodium , nonoxynol 9 , nonoxynol illin ) ; humectants ( glycerol, hexylene glycol, sorbitol) ; plas 10, octoxynol 9 , poloxamer, polyoxyl 35 castor oil , polyoxyl ticizers (e . g. , castor oil , diacetylated monoglycerides , 40 , hydrogenated castor oil , polyoxyl 50 stearate , polyoxyl diethyl phthalate , glycerol, mono - and diacetylated mono - 60 10 oleyl ether , polyoxyl 20 , cetostearyl ether , polyoxyl 40 glycerides , propylene glycol, triacetin , triethyl citrate ); poly - stearate , polysorbate 20 , polysorbate 40 , polysorbate 60 , mers ( e . g. , cellulose acetate , alkyl celluloses, hydroxyalkyl, polysorbate 80 , sodium lauryl sulfate , sorbitan monolaurate , acrylic polymers and copolymers ) ; solvents (acetone , alco sorbitan monooleate , sorbitan monopalmitate , sorbitan hol, diluted alcohol, amylene hydrate, benzyl benzoate , monostearate, tyloxapol) . This list is not meant to be exclu butyl alcohol, carbon tetrachloride, chloroform , corn oil, 65 sive, but instead merely representative of the classes of cottonseed oil , ethyl acetate , glycerol, hexylene glycol, excipients and the particular excipients that may be used in isopropyl alcohol, methyl alcohol, methylene chloride, oral dosage forms as described herein . US 9 ,943 ,513 B1 48 One embodiment described herein , is a pharmaceutical ture ; ( f ) adding one or more release modifiers and the active composition comprising any of the formulations shown in pharmaceutical ingredient to the cooled mixture of step e the Tables or Examples described herein . Any of the com and mixing ; ( g ) filling the matrix fill mixture into capsule ponents of the formulations shown in the Tables or shells using standard rotary die encapsulation techniques; Examples can be increased , decreased , combined , recom - 5 ( h ) annealing the capsules at an elevated temperature for a bined , switched , or removed to provide for a formulation period of time; and ( i ) cooling the capsules to room tem comprising about 100 % by weight. perature in a controlled manner. In one aspect, the elevated Another embodiment described herein is a method for annealing temperature of step his from about 60° C . to about preparing abuse deterrent pharmaceutical compositions 80° C . and the period of time is from about 30 min to about comprising the abuse deterrent controlled release matrix 10 120 min . In one aspect, the controlled cooling comprises described herein comprising (a )mixing one or more optional cooling the capsules at a rate of about 5° C . per about 10 to viscosity modifiers , one or more release modifiers, and one about 15 min . or more antioxidants in one or more flowability enhancers to Another embodiment described herein is a method for form a firstmixture ; ( b ) adding one or more active pharma - manufacturing an abuse deterrent pharmaceutical composi ceutical ingredient to the first mixture to form a matrix fill 15 tion comprising ( a ) heating one or more flowability enhanc mixture ; ( c ) filling the matrix fill mixture into capsule shells e rs to about 55° C . to about 70° C . under nitrogen ; ( b ) adding using standard rotary die encapsulation techniques ; and ( d ) one or more antioxidants to the flowability enhancer and annealing the capsules at an elevated temperature for a mixing at about 50 to about 300 RPM until dissolved ; ( c ) period of time. In one aspect, the flowability enhancer is cooling the mixture of step b to about 25° C . to about 35° C . heated to a first elevated temperature prior to mixing the 20 while mixing at about 50 to about 300 RPM ; ( d ) adding the viscosity modifier and/ or release modifiers . In another active pharmaceutical ingredient and mixing at about 50 to aspect , the flowability enhancer or mixture comprising the about 300 RPM for about 30 min ; ( e ) adding a viscosity flowability enhancer is cooled to a second temperature . In modifier to the mixture of step d and mixing at about 50 to another aspect , the flowability enhancer or mixture com - about 300 RPM for about 30 min ; ( f ) deaerating the mixture prising the flowability enhancer is cooled to a third tem - 25 of step e for at least about 30 min ; ( g ) maintaining the perature . In another aspect , the one or more viscosity deaerated mixture at a third temperature with continuous modifiers are added to the heated flowability enhancer mixing at about 50 to about 100 RPM under nitrogen during before adding the one or more release modifiers . In another encapsulation ; ( h ) encapsulating the mixture of step g into aspect , the heated mixture is cooled to a second elevated soft capsule shells using rotary die encapsulation ; ( i ) drying temperature prior to adding the active pharmaceutical ingre - 30 the capsules ; ( i ) removing processing lubrication with iso dient and the one or more release modifiers . In another propyl alcohol; ( j) transferring the capsules to a coating pan aspect , the active pharmaceutical ingredient is added prior to operating at about 1 - 2 RPM at a temperature of about 30° C . adding the one or more release modifiers . In another aspect, to about 35° C . ; ( k ) coating the capsules of step i with a one or more antioxidants are added prior to adding the one coating composition at about 1 - 2 RPM until about 10 % to or more release modifiers . In another aspect, a first viscosity 35 about 20 % weight gain is achieved ; ( 1 ) heating the capsules modifier is added to the flowability enhancer at a first of step k to about 60° C . to about 80° C . for about 30 min temperature , followed by cooling the mixture to a second to about 90 min at about 1 - 2 RPM ; ( m ) cooling the capsules temperature and adding one or more antioxidants to the of step / to about 30° C . at a rate of about 2° C . to about 10° mixture , and cooling the mixture to a third temperature and C . per each about 5 min to about 20 min period while adding the active pharmaceutical ingredient and release 40 maintaining about 1 - 2 RPM ; ( n ) cooling the capsules of step modifier. m from about 30° C . to room temperature ( ca . 25° C . ) while In another embodiment, the method for preparing the maintaining about 1 - 2 RPM ; ( o ) printing labels on the abuse deterrent pharmaceutical compositions described capsule ; and ( p ) packaging the capsules . In one aspect herein comprise ( a ) heating one or more flowability enhanc - described herein , the coating and annealing process are ers to a first temperature ; ( b ) adding one or more antioxi- 45 conducted in a coating pan . dants and mixing ; ( c ) adding one or more release modifiers In one embodiment, the methods for preparing the abuse to the mixture of b ; ( d ) cooling the mixture to a second deterrent pharmaceutical compositions described herein temperature ; ( e ) adding one or more active pharmaceutical comprise heating the flowability enhancer or a mixture ingredients to the cooled mixture of step d ; ( f ) deaerating the comprising the flowability enhancer to a first temperature . In mixture of step e ; ( g ) filling the deaerated mixture of step f 50 one aspect, the first temperature is about 40° C . to about into capsule shells using rotary die encapsulation tech - 170° C ., including each integer within the specified range . In niques ; ( h ) annealing the capsules at an elevated temperature another aspect , the first temperature is about 120° C . to about for a period of time; and ( i ) slowly cooling the annealed 170° C ., including each integer within the specified range . In capsules of h to room temperature in a controlled manner. In another aspect, the first temperature is about 40° C . to about one aspect, the elevated annealing temperature of step h is 55 90° C . , including each integer within the specified range . In from about 60° C . to about 80° C . and the period of time is another aspect, the first temperature is about 40° C . to about from about 30 min to about 120 min . In one aspect, the 90° C . , including each integer within the specified range . In controlled cooling of step i comprises cooling the capsules another aspect, the first temperature is about 40° C . , about at a rate of about 5° C . per about 10 to about 15 min . 45° C ., about 50° C ., about 55° C . , about 60° C . , about 65° In another embodiment, the method for preparing the 60 C ., about 70° C ., about 75° C . , about 80° C ., about 90° C . , abuse deterrent pharmaceutical compositions described about 100° C . , about 110° C ., about 120° C . , about 130° C . , herein comprise ( a ) heating one or more flowability enhanc about 140° C ., about 150° C ., about 160° C ., or about 1700 ers to a first temperature ; ( b ) adding one or more viscosity C . modifiers to the heated flowability enhancer and mixing ; ( c ) In another embodiment , the methods for preparing the cooling the mixture of step b to a second temperature ; ( d ) 65 abuse deterrent pharmaceutical compositions described adding one or more antioxidants to the mixture of step c and herein comprise cooling the flowability enhancer or a mix mixing ; ( e ) cooling the mixture of step d to a third tempera ture comprising the flowability enhancer to a second tem US 9 ,943 ,513 B1 49 50 perature . In one aspect, the second temperature is about 25° years old ) . In one aspect, the subject is from 0 to 9 years of C . to about 100° C . , including each integer within the age . In another aspect, the human subject is from 10 to 17 specified range. In another aspect, the second temperature is years of age. In another aspect , the human subject is over 17 about 25° C . to about 50° C ., including each integer within years of age . In another aspect , the human subject is an adult the specified range . In another aspect, the second tempera - 5 ( > 18 years of age ) . ture is about 40° C . to about 90° C . , including each integer In one embodiment, the dosage may be administered to a within the specified range . In another aspect, the second human in need of management of moderate to severe temperature is about 40° C . to about 90° C ., including each chronic pain and neuropathic pain associated with diabetic integer within the specified range . In another aspect , the peripheral neuropathy (DPN ) , when a continuous, persistent second temperature is about 25° C ., about 30° C ., about 35° 10 ( around - the -clock ) opioid analgesic is needed for an C ., about 40° C . , about 45° C . , about 50° C ., about 55° C . , extended period of time. about 60° C ., about 65° C ., about 70° C ., about 75° C . , about The dosage form can be administered , for example , 1x , 80° C . , about 90° C . , or about 100° C . 2x, 3x , 4x , 5x , 6x , or even more times per day . One or more In another embodiment, the methods for preparing the dosage form can be administered , for example , for 1 , 2 , 3 , abuse deterrent pharmaceutical compositions described 15 4 , 5 , 6 , 7 days , or even longer. One or more dosage forms can herein comprise cooling the flowability enhancer or a mix - be administered , for example , for 1 , 2 , 3 , 4 weeks , or even ture comprising the flowability enhancer to a third tempera - longer . One or more dosage forms can be administered , for ture . In one aspect , the third temperature is about 25° C . to example , for 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 months, 1 year, about 100° C . , including each integer within the specified 2 , years, 3 years , 4 years, 5 years , over 5 years , a decade , range . In another aspect, the third temperature is about 25° 20 multiple decades , or even longer . One ormore dosage forms C . to about 50° C ., including each integer within the can be administered at a regular interval until the subject or specified range . In another aspect, the third temperature is subject in need thereof, does not require treatment, prophy about 40° C . to about 90° C ., including each integer within laxis , or amelioration of any disease or condition , including the specified range . In another aspect , the third temperature but not limited to , pain . is about 40° C . to about 90° C . , including each integer within 25 In one embodiment, the pharmaceutical composition the specified range . In another aspect , the third temperature described herein is administered in multiple dosages simul is about 25° C ., about 30° C ., about 35° C . , about 40° C ., taneously to achieve a desired dose . For example , two or about45° C ., about 50° C ., about 55° C . , about 60° C ., about more identical dosages are administered at one time to 65° C . , about 70° C . , about 75° C . , about 80° C . , about 90° achieve a desired dose . Two 40 mg dosage forms may be C . , or about 100° C . 30 administered simultaneously to provide 80 mg. Likewise , In another embodiment, the methods for preparing the three 40 mg dosage forms or four 30 mg dosage forms may abuse deterrent pharmaceutical compositions described be administered simultaneously to provide 120 mg. In herein comprise annealing the pharmaceutical composition another embodiment, two or more different dosages are comprising a soft or capsule shell and a matrix fill as administered at one time. Such dual or different simultane described herein at specified temperature for a period of 35 ous doses can be used to provide an effective dose of the time. In one aspect, the temperature ranges from about 45° pharmaceutical composition to a subject in need thereof. C . to about 120° C ., including each integer within the In one embodiment, the abuse deterrent oral composition specified range . In another aspect, the temperature ranges described herein , comprises one or more active pharmaceu from about 55° C . to about 85° C ., including each integer tical ingredients in an amount of about 5 mg, about 10 mg, within the specified range . In another aspect, the temperature 40 about 15 mg, about 20 mg, about 25 mg, about 30 mg , about is about 45° C ., about 50° C . , about 55° C . , about 60° C ., 35 mg, about 40 mg, about 45 mg , about 50 mg, about 55 about 65° C ., about 70° C ., about 75° C . , about 80° C ., about mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, 90° C ., about 100° C . , about 110° C ., or about 120° C . In about 80 mg, about 85 mg, about 90 mg, about 95 mg, about another aspect, the annealing time ranges from about 10 100 mg, about 105 mg, about 110 mg, about 115 mg, about minutes to about 160 minutes, including each integer within 45 120 mg , about 125 mg , about 130 mg, about 135 mg, about the specified range . In another aspect, the annealing time 140 mg , about 145 mg , about 150 mg , about 155 mg, about ranges from about 1 minute to about 80 minutes, including 160 mg, about 165 mg, about 170 mg, about 175 mg, about each integer within the specified range . In another aspect, 180 mg, about 185 mg, about 190 mg, about 195 mg, about the annealing time ranges from about 40 minutes to about 80 200 mg , about 205 mg , about 210 mg , about 215 mg, about minutes , including each integer within the specified range . 50 220 mg, about 225 mg, about 230 mg, about 235 mg, about In another aspect, the annealing time is about 1 min , about 240 mg, about 245 mg , about 250 mg , about 255 mg, about 3 min , about 6 min , about 9 min , about 12 min , about 15 260 mg, about 265 mg, about 270 mg, about 275 mg, about min , about 20 min , about 25 min , about 30 min , about 35 280 mg, about 285 mg, about 290 mg, about 295 mg, about min , about 40 min , about 45 min , about 50 min , about 55 300 mg, about 305 mg, about 310 mg , about 315 mg, about min , about 60 min , about 70 min , about 80 min , about 90 55 320 mg , about 325 mg , about 330 mg, about 335 mg, about min , about 100 min , about 110 min , about 120 min , about 340 mg , about 345 mg, about 350 mg, about 355 mg, about 130 min , about 140 min , about 150 min , or about 160 min . 360 mg , about 365 mg , about 370 mg , about 375 mg, about In another embodiment, the abuse deterrent pharmaceu - 380 mg, about 385 mg, about 390 mg, about 395 mg, about tical composition described herein provides a dosage of an 400 mg , about 405 mg , about 410 mg, about 415 mg, about active pharmaceutical ingredient described herein for 60 420 mg, about 425 mg, about 430 mg, about 435 mg, about administration to a subject. The dosage form can be admin - 440 mg , about 445 mg , about 450 mg , about 455 mg, about istered , for example , to a subject, or a subject in need 460 mg, about 465 mg, about 470 mg, about 475 mg, about thereof. In one aspect, the subject is a mammal, or a mammal 480 mg, about 485 mg, about 490 mg, about 495 mg, about in need thereof. In one aspect, the subject is a human , or 500 mg, or even more . human in need thereof. In one aspect, the human or human 65 In another embodiment, the abuse deterrent oral compo in need thereof is a medical patient. In one aspect , the human sition described herein , comprises one or more active phar subject is a child ( ~ 0 - 9 years old ) or an adolescent ( ~ 10 - 17 maceutical ingredients in the range of about 20 mg to about US 9 , 943 ,513 B1 51 52 250 mg, about 30 mg to about 250 mg, about 40 mg to about another aspect, the additional active pharmaceutical ingre 250 mg, about 50 mg to about 250 mg , about 60 mg to about dient reduces or prevents opioid induced side effects . 250 mg, about 70 mgto about 250 mg, about 80 mg to about In one embodiment, the active pharmaceutical ingredient 250 mg, about 90 mg to about 250 mg, about 100 mg to comprises oxycodone hydrochoride. The oxycodone may about 250 mg, about 110 mg to about 250 mg , about 120 mg 5 comprise trace amounts of impurities from the manufactur to about 250 mg, about 130 mg to about 250 mg, about 140 ing process . In one embodiment described herein , the oxy mg to about 250 mg, about 150 mg to about 250 mg, about codone hydrochloride comprises greater than 25 ppm of 160 mg to about 250 mg, about 170 mg to about 250 mg, 14 -hydroxycodeinone , but less than 100 ppm . In another about 180 mg to about 250 mg, about 190 mg to about 250 embodiment the oxycodone hydrochloride comprises about mg, about 200 mg to about 250 mg, about 210 mg to about 10 50 ppm of 14 -hydroxycodeinone . In another embodiment 250 mg, about 220 mg to about 250 mg, about 230 mg to the oxycodone hydrochloride comprises about 90 ppm of about 250 mg, about 240 mg to about 250 mg; about 250 mg 14 -hydroxycodeinone . In another embodiment the oxyco to about 500 mg, about 260 mg to about 500 mg, about 270 done hydrochloride comprises < 100 ppm of 14 -hydroxyco mg to about 500 mg , about 280 mg to about 500 mg, about deinone . 290 mg to about 500 mg , about 300 mg to about 500 mg, 15 In one embodiment, the abuse deterrent oral composition about 310 mg to about 500 mg, about 320 mg to about 500 described herein comprises a dose of opioid analgesic . In mg, about 330 mg to about 500 mg, about 340 mg to about one aspect, the dose of opioid analgesic is about 5 mg. In one 500 mg, about 350 mg to about 500 mg, about 360 mg to aspect, the dose of opioid analgesic is about 10 mg. In one about 500 mg, about 370 mg to about 500 mg, about 380 mg aspect, the dose of opioid analgesic is about 20 mg. In to about 500 mg, about 390 mg to about 500 mg, about 400 20 another aspect , the dose of opioid analgesic is about 30 mg . mg to about 500 mg , about 410 mg to about 500 mg, about In another aspect, the dose of opioid analgesic is about 40 420 mg to about 500 mg, about 430 mg to about 500 mg, mg. In another aspect , the dose of opioid analgesic is about about 440 mg to about 500 mg, about 450 mg to about 500 50 mg. In another aspect, the dose of opioid analgesic is mg , about 460 mg to about 500 mg, about 470 mg to about about 60 mg. In another aspect, the dose of opioid analgesic 500 mg, about 480 mg to about 500 mg, or about 490 mg to 25 is about 70 mg. In another aspect , the dose of opioid about 500 mg. analgesic is about 80 mg. In another aspect, the dose of In one embodiment described herein , the abuse deterrent opioid analgesic is about 90 mg. In another aspect , the dose oral composition described herein may comprise an active of opioid analgesic is about 100 mg. In another aspect, the pharmaceutical ingredient load (e .g ., a drug load of one or dose of opioid analgesic is about 120 mg. In another aspect, more active pharmaceutical ingredients ) of about 1 % to 30 the dose of opioid analgesic is about 140 mg. In another about 90 % , including each integer within the specified aspect, the dose of opioid analgesic is about 160 mg. In range . In one embodiment, the drug load can comprise about another aspect , the dose of opioid analgesic is about 180 mg. 1 % , about 2 % , about 2 . 5 % , about 5 % , about 10 % , about In another aspect, the dose of opioid analgesic is about 200 15 % , about 20 % , about 25 % , about 30 % , about 35 % , about mg. 40 % , about 45 % , about 50 % , about 55 % , about 60 % , about 35 In one embodiment, the abuse deterrent oral composition 65 % , about 70 % , about 75 % , about 80 % , about 85 % , about described herein comprises a dose of oxycodone . In one 90 % , or even higher. In one aspect, the drug load is about aspect, the dose of oxycodone is about 5 mg. In another 3 % . In one aspect , the drug load is about 5 % . In one aspect, aspect, the dose of oxycodone is about 10 mg. In another the drug load is about 6 % . In one aspect, the drug load is aspect , the dose of oxycodone is about 15 mg . In another about 9 % . In one aspect, the drug load is about 10 % . In one 40 aspect, the dose of oxycodone is about 20 mg. In another aspect , the drug load is about 12 % . In one aspect , the drug aspect , the dose of oxycodone is about 30 mg. In another load is about 15 % . In one aspect , the drug load is about 20 % . aspect, the dose of oxycodone is about 40 mg. In another In one aspect , the drug load is about 25 % . In one aspect , the aspect, the dose of oxycodone is about 50 mg. In another drug load is about 30 % . In one aspect , the drug load is about aspect, the dose of oxycodone is about 60 mg. In another 35 % . In one aspect, the drug load is about 40 % . In one 45 aspect, the dose of oxycodone is about 70 mg. In another aspect , the drug load is about 50 % . In one aspect, the drug aspect, the dose of oxycodone is about 80 mg. In another load is about 60 % . In one aspect , the drug load is about 28 % . aspect, the dose of oxycodone is about 100 mg. In another In one aspect, the drug load is about 32 % . In one aspect , the aspect, the dose of oxycodone is about 120 mg. In another drug load is about 44 % . In one embodiment, the drug load aspect, the dose of oxycodone is about 140 mg. In another is about 48 % . 50 aspect, the dose of oxycodone is about 160 mg. In another In one embodiment , the active pharmaceutical ingredient aspect, the dose of oxycodone is about 180 mg. In another is oxycodone , hydrocodone or codeine , or a salt , ether, ester, aspect, the dose of oxycodone is about 200 mg. variant, or derivative thereof. In one embodiment, the active In another embodiment, the total dosage of oxycodone pharmaceutical ingredient is oxycodone . In one embodi- administered in a 24 -hour period is about 20 mg to about 600 ment, the active pharmaceutical ingredient is oxycodone 55 mg per 24 - hour period . In one aspect , the total dosage of hydrochloride . In another embodiment , the active pharma- oxycodone or hydrocodone administered in a 24 -hour period ceutical ingredient is hydrocodone. See Prescribing Infor - is about 50 mg to about 250 mg per 24 -hour period . The mation for OxyContin® ER 04 /2014 ( Purdue Pharma LP ; dosage can contain a total amount of oxycodone effective for available at www . purduepharma. com ) and Zohydro® ER treatment , amelioration , prophylaxis , or reducing the onset 01/ 2015 ( Zogenix® Inc. ; available at : www .zogenix .com ), 60 of or symptoms of pain . which are incorporated by reference herein for such teach - In one embodiment, the recommended dosage is based ings . upon the condition of the subject in need thereof. The subject In another embodiment , the active pharmaceutical ingre - can comprise a human or mammal in need thereof. In one dient may comprise oxycodone , hydrocodone, or codeine aspect , the need is defined as a painful condition or percep and an additional active pharmaceutical ingredient. In one 65 tion of pain . In one embodiment, the perception of pain is aspect , the additional active pharmaceutical ingredient pre - described as a numerical scale . In one aspect, this numerical vents opioid abuse when an excess of opioid is used . In scale indicates O for no pain , 1 - 3 suggestive of mild pain ; US 9 ,943 ,513 B1 53 54 annoying or nagging pain that does not affect the activities In one embodiment, the recommended dosage is based of daily life , 4 -6 for moderate pain that interferes signifi- upon the condition of the subject in need thereof. The subject cantly with the activities of daily life, and 7 -10 for severe can comprise a human or mammal in need thereof. In one pain that is disabling for which the activities of daily life are aspect, the need is defined as a painful condition or percep not possible . Another aspect described herein comprises 5 tion of pain . In one embodiment, the initial dosage of orally administering a maximal dosage of about 10 mg to oxycodone is 10 mg to about 40 mg. In one aspect, an initial about 120 mg of oxycodone every 24 hours for humans or dose of about 10 mg to about 40 mg is suitable for a subject that not tolerant of an opioid and a dose . In one aspect, the mammals with a pain of 1 -3 . Another aspect described initial dose is about 10 mg of oxycodone . In another aspect, herein comprises orally administering a maximal dosage ofpe 10 the initial dose is about 20 mg of oxycodone . In another about 80 mg to about 400 mg of oxycodone every 24 hours aspect, the initial dose is about 20 mg of oxycodone. In for humans or mammals with a pain of 4 - 6 . Another aspect another aspect, the initial dose is about 30 mg of oxycodone . described herein comprises orally administering a maximal In another aspect , the initial dose is about 40 mg of oxyco dosage of 120 mg to about 600 mg of oxycodone every 24 done . In another aspect , the dose of oxycodone may be hours for humans or mammals with a pain of 7 - 10 . In one 15 maintained and given every 8 to 12 hours. In another aspect. aspect, the level of pain is assessed by observing the human the dose of oxycodone may be increased by about 10 mg to or mammal . about 20 mg every 8 hrs to 12 hrs until pain relief occurs. Another aspect described herein comprises orally admin In another embodiment, the initial dosage of oxycodone is istering a delayed release dosage of about 10 mg of oxyco - 40 mg to about 160 mg. In one aspect, an initial dose of done every 12 hours for a human or mammal with a pain of 20 about 40 mg to about 80 mg is suitable for a subject that has 1 - 3 . Another aspect described herein comprises orally an opioid tolerant phenotype . In one aspect , the initial dose administering a delayed release dosage of about 30 mg of is about 40 mg of oxycodone. In another aspect , the initial oxycodone 1 every 12 hours for a human or mammal with dose is about 50 mg of oxycodone . In another aspect, the a pain of 4 - 6 . Another aspect described herein comprises initial dose is about 60 mg of oxycodone . In another aspect, orally administering a delayed release dosage of about 80 25 the initial dose is about 70 mg of oxycodone . In another mg of oxycodone every 12 hours for a human or mammal aspect, the initial dose is about 80 mg of oxycodone . In with a pain of 7 - 10 . Another aspect described herein com another aspect, the initial dose is about 100 mg of oxyco prises increasing the delayed release dosage of oxycodone done . In another aspect, the initial dose is about 120 mg of by 10 mg increments every 24 hours to a maximal daily oxycodone . In another aspect , the initial dose is about 140 dosage of 600 mg if pain of any type is not ameliorated in 30 mg of oxycodone . In another aspect , the initial dose is about the human or mammal in need thereof. Another aspect 160 mg of oxycodone. In another aspect, the dose of described herein comprises decreasing the dosage of oxy oxycodone may be maintained and given every 8 to 12 codone as needed every 24 hours if pain of any type has hours . In another aspect, the dose of oxycodone may be decreased or has been ameliorated in the human or mammal increased by about 10 mg to about 20 mg every 8 hrs to 12 in need thereof. 35 hrs until pain relief occurs . In one embodiment, the recommended dosage is based Additionally , the abuse deterrent pharmaceutical compo upon the condition of the subject in need thereof. The subject sitions described herein may be useful for the treatment of can comprise a human or mammal in need thereof. In one pain stemming from , including but not limited to , chronic aspect, the need is defined as a painful condition or percep - arthritis, osteoarthritis , rheumatoid arthritis , acute tendon tion of pain . In one embodiment, the initial dosage of opioid 40 itis , bursitis , headaches , migraines , chronic neuropathies , analgesic is 10 mg to about 40 mg. In one aspect, an initial shingles , premenstrual symptoms, sports injuries, malig dose of about 10 mg to about 40 mg is suitable for a subject nancy , radiculopathy, sciatica /sciatic pain , sarcoidosis , that not tolerant of an opioid . In one aspect, the initial dose necrobiosis , lipoidica , trauma, or granuloma annulare . is about 10 mg of opioid analgesic . In another aspect , the Another embodiment described herein is an abuse deter initial dose is about 20 mg of opioid analgesic . In another 45 rent pharmaceutical composition as described herein for aspect , the initial dose is about 20 mg of opioid analgesic . In administration to a subject having pain , comprising a thera another aspect, the initial dose is about 30 mg of opioid peutically effective amount of one or more active pharma analgesic . In another aspect , the initial dose is about 40 mg c eutical ingredients , wherein the subject achieves a reduc of opioid analgesic . In another aspect, the dose of opioid tion of pain relative to baseline without substantially analgesic may be maintained and given every 8 to 12 hours . 50 experiencing one or more side effects including, but not In another aspect, the dose of opioid analgesic may be limited to , headache , vertigo , somnolence , nausea , consti increased by about 10 mg to about 20 mg every 8 hrs to 12 pation , vomiting , xerostomia , fatigue , pruritus, eructation , hrs until pain relief occurs . heartburn , abdominal discomfort, or loss of appetite . In another embodiment, the initial dosage of opioid anal- Another embodiment described herein is an abuse deter gesic is 40 mg to about 80 mg . In one aspect, an initial dose 55 rent pharmaceutical composition as described herein for of about 40 mg to about 80 mg is suitable for a subject that administration to a subject having pain , comprising a thera has an opioid tolerant phenotype. In one aspect, the initial peutically effective amount of one or more active pharma dose is about 40 mg of opioid analgesic . In another aspect, ceutical ingredients exhibiting an in vitro dissolution rate at the initial dose is about 50 mg of opioid analgesic . In another pH 1 . 2 comprising about 35 % to about 95 % dissolution after aspect , the initial dose is about 60 mg of opioid analgesic . In 60 about 60 minutes to about 480 minutes including each another aspect, the initial dose is about 70 mg of opioid integer within the specified ranges of dissolution and time. analgesic . In another aspect , the initial dose is about 80 mg In one aspect , the in vitro dissolution rate at pH 1 . 2 is about of opioid analgesic . In another aspect , the dose of opioid 35 % after about 60 min , about 50 % after about 120 min , analgesic may be maintained and given every 8 to 12 hours . about 70 % after about 240 min , about 85 % after about 480 In another aspect , the dose of opioid analgesic may be 65 min . increased by about 10 mg to about 20 mg every 8 hrs to 12 Another embodiment described herein is an abuse deter hrs until pain relief occurs . rent pharmaceutical composition as described herein for US 9 ,943 ,513 B1 55 56 administration to a subject having pain , comprising a thera - rate of the controlled release pharmaceutical composition in peutically effective amount of one or more active pharma - an aqueous alcohol solution is less than about 50 % after ceutical ingredients exhibiting an in vitro dissolution rate at about 360 minutes. pH 1 . 2 comprising about 15 % to about 95 % dissolution after Another embodiment described herein is an abuse deter about 60 minutes to about 480 minutes including each 5 rent pharmaceutical composition as described herein com integer within the specified ranges of dissolution and time. prising a therapeutically effective amount of one or more In one aspect, the in vitro dissolution rate at pH 1 . 2 is about active pharmaceutical ingredients for administration to a 10 % after about 60 min , about 20 % after about 90 minutes , subject having pain , exhibiting an in vitro dissolution rate at about 50 % after about 120 min , about 70 % after about 240 pH 1 . 2 of about 35 % to about 95 % after about 60 minutes min , about 85 % after about 480 min . 10 to about 480 minutes , an in vitro dissolution rate under In another embodiment, the abuse deterrent pharmaceu boiling conditions less than about 35 % to about 60 % after tical composition comprising an abuse deterrent matrix as about 10 minutes to about 45 minutes , and an in vitro described herein reduces the dissolution and extraction of an dissolution rate in an aqueous alcohol solution of less than active pharmaceutical ingredient. Suitable non - limiting 15 minabout 20 % to about 50 % after about 30 minutes to about 360 examples of extraction methods comprise incubating the Another. embodiment described herein is an abuse deter abuse deterrent pharmaceutical composition in boiling con - rent pharmaceutical composition as described herein com ditions, in aqueous solutions of alcohol, and in distilled prising a therapeutically effective amount of one or more water. These methods may be used in conjunction with active pharmaceutical ingredients for administration to a additional means of agitating , for example , with paddles , 20 subject having pain , exhibiting an in vitro dissolution rate as dipping, vigourous shaking , physicalmanipulations , and the described herein in any one of Drawings 1 - 7 , 9 , 11 - 22 , or 28 . like . Another embodiment described herein is a method for In another embodiment, the abuse deterrent pharmaceu - orally administering a dosage form of an abuse deterrent tical composition as described herein has an in vitro disso - pharmaceutical composition comprising an active pharma lution rate under boiling conditions in an aqueous media 25 ceutical ingredient described herein for the treatment, ame ( e . g . , a temperature of about 90° C . to about 120° C . ) is less lioration , prophylaxis , or reducing the onset of or symptoms than about 35 % to about 60 % after about 10 minutes to of pain . about 45 minutes , including each integer within the specified Another embodiment described herein is a method for ranges of dissolution and time. In one aspect, the in vitro treating , retarding the progression of, delaying the onset of, dissolution rate of the controlled release pharmaceutical 30 prophylaxis of, amelioration of , or reducing the symptoms composition under boiling conditions in an aqueous media is of pain , comprising administering to a subject in need less than about 50 % after about 5 minutes . In another aspect , thereof an oral pharmaceutical composition as described the in vitro dissolution rate of the controlled release phar - herein comprising a therapeutically effective amount of one maceutical composition under boiling conditions in an aque - or more active pharmaceutical ingredients for administration ous media is less than about 50 % after about 10 minutes . In 35 to a subject having pain , wherein the pharmaceutical com another aspect, the in vitro dissolution rate of the controlled position exhibits an in vitro dissolution rate at pH 1 . 2 , of release pharmaceutical composition under boiling condi - about 35 % to about 95 % after about 60 minutes to about 480 tions in an aqueous media is less than about 50 % after about minutes , an in vitro dissolution rate under boiling conditions 20 minutes . In another aspect , the in vitro dissolution rate of less than about 35 % to about 60 % after about 10 minutes to the controlled release pharmaceutical composition under 40 about 45 minutes, and an in vitro dissolution rate in an boiling conditions in an aqueous media is less than about aqueous alcohol solution of less than about 20 % to about 50 % after about 30 minutes. In another aspect, the in vitro 50 % after about 30 minutes to about 360 minutes . dissolution rate of the controlled release pharmaceutical Another embodiment described herein is a method for composition under boiling conditions in an aqueous media is treating , retarding the progression of, delaying the onset of, less than about 60 % after about 45 minutes . 45 prophylaxis of, amelioration of, or reducing the symptoms In another embodiment, the abuse deterrent controlled of pain , comprising administering to a subject in need release pharmaceutical composition as described herein has thereof an oral pharmaceutical composition as described an in vitro dissolution rate in an aqueous alcohol solution herein comprising a therapeutically effective amount of one (e . g. , an aqueous solution of ethanol of 80 % ) of less than ormore active pharmaceutical ingredients for administration about 20 % to about 50 % after about 30 minutes to about 360 50 to a subject having pain , exhibiting an in vitro dissolution minutes , including each integer within the specified ranges rate as described herein in any one of Drawings 1 - 7 , 9 , of dissolution and time . In one aspect , the in vitro dissolution 11 - 22 , or 28 . rate of the controlled release pharmaceutical composition in Another embodiment described herein is a method for an aqueous alcohol solution is less than about 10 % after treating an individual having pain , with a pharmaceutical about 30 minutes . In another aspect , the in vitro dissolution 55 composition described herein comprising an abuse deterrent rate of the controlled release pharmaceutical composition in matrix described herein comprising a dosage of about 10 mg an aqueous alcohol solution is less than about 20 % after of oxycodone to about 80 mg of oxycodone , wherein sub about 60 minutes . In another aspect, the in vitro dissolution jects administered a single dosage exhibit a mean plasma rate of the controlled release pharmaceutical composition in oxycodone Cmax of about 10 ng/ mL to about 150 ng /mL , an aqueous alcohol solution is less than about 50 % after 60 including each integer within the specified range . In one about 60 minutes . In another aspect, the in vitro dissolution aspect , the composition is provided in a dosage form con rate of the controlled release pharmaceutical composition in taining a total amount of about 10 mg of oxycodone, an aqueous alcohol solution is less than about 50 % after wherein subjects administered a single dosage exhibit a about 120 minutes . In another aspect , the in vitro dissolution mean plasma oxycodone Cmor of about 10 ng /mL . In another rate of the controlled release pharmaceutical composition in 65 aspect, the composition is provided in a dosage form con an aqueous alcohol solution is less than about 50 % after taining a total amount of about 20 mg of oxycodone , about 180 minutes . In another aspect , the in vitro dissolution wherein subjects administered a single dosage exhibit a US 9 , 943 ,513 B1 57 58 mean plasma oxycodone Cmax of about 20 ng /mL . In another of about 40 ng/ mL . In another aspect, the composition is aspect , the composition is provided in a dosage form con - provided in a dosage form containing a total amount of about taining a total amount of about 40 mg of oxycodone , 40 mg of opioid analgesic , wherein subjects administered a wherein subjects administered a single dosage exhibit a single dosage exhibit a mean plasma opioid analgesic Cmax mean plasma oxycodone Cmor of about 40 ng /mL . In another 5 of about 60 ng /mL . In another aspect, the composition is aspect , the composition is provided in a dosage form con - provided in a dosage form containing a total amount of about taining a total amount of about 80 mg of oxycodone , 80 mg of opioid analgesic , wherein subjects administered a wherein subjects administered a single dosage exhibit a single dosage exhibit a mean plasma opioid analgesic Cmax mean plasma oxycodone Cmax of about 100 ng /mL . of about 120 ng /mL . Another embodiment described herein is a method for 10 Another embodiment described herein is a method for treating an individual having pain , with a pharmaceutical treating an individual having pain , with a pharmaceutical composition described herein comprising an abuse deterrent composition described herein comprising an abuse deterrent matrix described herein comprising a dosage of about 10 mg matrix described herein comprising a dosage of about 10 mg of oxycodone to about 80 mg of oxycodone, wherein sub of opioid analgesic to about 80 mg of opioid analgesic , jects administered a single dosage exhibit a mean plasma 15 wherein subjects administered a single dosage exhibit a oxycodone AUC . - - . of about 100 h ·mg / L to about 1000 mean plasma opioid analgesic AUC . - of about 100 h ·mg / L , including each integer within the specified range. In h ·mg / L to about 1600 h .mg / L , including each integer within one aspect, the composition is provided in a dosage form the specified range . In one aspect, the composition is pro containing a total amount of about 10 mg of an oxycodone , vided in a dosage form containing a total amount of about 10 wherein subjects administered a single dosage exhibit a 20 mg of an opioid analgesic , wherein subjects administered a mean plasma oxycodone AUC of about 100 h ·mg / L . In single dosage exhibit a mean plasma opioid analgesic another aspect , the composition is provided in a dosage form AUC . - - . of about 150 h ·mg / L . In another aspect, the containing a total amount of about 20 mg of oxycodone , composition is provided in a dosage form containing a total wherein subjects administered a single dosage exhibit a amount of about 20 mg of opioid analgesic , wherein subjects mean plasma oxycodone AUCO - s of about 200 h .mg / L . In 25 administered a single dosage exhibit a mean plasma opioid another aspect, the composition is provided in a dosage form analgesic AUCO - of about 400 h .mg / L . In another aspect, containing a total amount of about 40 mg of oxycodone , the composition is provided in a dosage form containing a wherein subjects administered a single dosage exhibit a total amount of about 40 mg of opioid analgesic , wherein mean plasma oxycodone AUCO - s of about 400 h ·mg / L . In subjects administered a single dosage exhibit a mean plasma another aspect , the composition is provided in a dosage form 30 opioid analgesic AUC . - - - of about 850 h .mg / L . In another containing a total amount of about 80 mg of oxycodone , aspect, the composition is provided in a dosage form con wherein subjects administered a single dosage exhibit a taining a total amount of about 80 mg of opioid analgesic , mean plasma oxycodone AUCO - s of about 1000 h ·mg / L . wherein subjects administered a single dosage exhibit a Another embodiment described herein is a method for mean plasma opioid analgesic AUCO -> , of about 1600 treating an individual having pain , with a pharmaceutical 35 h•mg/ L . composition described herein comprising an abuse deterrent Another embodiment described herein is a method for matrix described herein comprising a dosage of about 10 mg treating an individual having pain , with a pharmaceutical of oxycodone to about 80 mg of oxycodone , wherein sub - composition described herein comprising an abuse deterrent jects administered a single dosage exhibits a Tmax of about matrix described herein comprising a dosage of about 10 mg 1 hr to about 8 hrs , including each integer within the 40 of opioid analgesic to about 80 mg of opioid analgesic , specified range . In one aspect, the composition is provided wherein subjects administered a single dosage exhibits a in a dosage form containing a total amount of about 10 mg T mor of about 3 hrs to about 8 hrs , including each integer to about 80 mg of oxycodone , wherein subjects administered within the specified range . In one aspect , the composition is a single dosage exhibit a TM of about 1 hr, about 1 . 5 hrs, provided in a dosage form containing a total amount of about about 2 hrs , about 2 . 5 hrs , about 3 hrs , about 3 . 5 hrs , about 45 10 mg to about 80 mg of opioid analgesic , wherein subjects 4 hrs , 4 .5 hrs, 5 hrs , 5 .5 hrs, 6 hrs , 6 .5 hrs , 7 hrs , 7 . 5 hrs , or administered a single dosage exhibit a Tmor of about 3 hrs , about 8 hrs. about 4 hrs, about 5 hrs , about 6 hrs, about 7 hrs , or about Another embodiment described herein is a method for 8 hrs . treating an individual having pain , with a pharmaceutical In another embodiment, the pharmaceutical compositions composition described herein comprising an abuse deterrent 50 described herein further comprise one or more active phar matrix described herein comprising a dosage of about 10 mg maceutical ingredient( s ) suitable for treating , ameliorating, of opioid analgesic to about 80 mg of opioid analgesic , or prophylactically treating a bowel dysfunction due to acute wherein subjects administered a single dosage exhibit a or chronic opioid use , often referred to as opioid induced mean plasma opioid analgesic Cmax of about 10 ng/ mL to bowel disfunction (OIBD ). Symptoms of OIBD typically about 120 ng/ mL , including each integer within the specified 55 comprise constipation (e .g . , opioid induced constipation ; range. In one aspect, the composition is provided in a dosage OIC ), anorexia , nausea and vomiting, gastro -oesophageal form containing a total amount of about 10 mg of an opioid reflux , delayed digestion , abdominal pain , flatulence , bloat analgesic, wherein subjects administered a single dosage ing , hard stools , incomplete evacuation or straining during exhibit a mean plasma opioid analgesic Cmax of about 20 bowelmovements . Alternative or additional uses for the one ng /mL . In another aspect , the composition is provided in a 60 or more active pharmaceutical ingredient ( s ) described dosage form containing a total amount of about 20 mg of herein may be to treat, reduce , inhibit , or prevent additional opioid analgesic , wherein subjects administered a single effects of acute or chronic opioid use including , e . g . , aber dosage exhibit a mean plasma opioid analgesic Cmax of rant migration or proliferation of endothelial cells ( e . g . , about 30 ng /mL . In another aspect, the composition is vascular endothelial cells ) , increased angiogenesis , and provided in a dosage form containing a total amount of about 65 increase in lethal factor production from opportunistic infec 30 mg of opioid analgesic , wherein subjects administered a tious agents ( e .g ., Pseudomonas aeruginosa ). Additional single dosage exhibit a mean plasma opioid analgesic Cmax advantageous uses of one or more active pharmaceutical US 9 , 943 ,513 B1 59 60 ingredient ( s ) include treatment of opioid - induced immune from about 50 mg to about 600 mg and the dose of the opioid suppression , inhibition of angiogenesis , inhibition of vascu - is from about 5 mg to about 150 mg, including every integer lar proliferation , treatment of pain , treatment of inflamma- within the specified ranges . In another aspect, the dose of an tory conditions such as inflammatory bowel syndrome, anti - OIC agent ranges from about 50 mg to about 550 mg treatment of infectious diseases and diseases of the muscu - 5 and the dose of the opioid is from about 5 mg to about 150 loskeletal system such as osteoporosis , arthritis , osteitis , mg, including every integer within the specified ranges . In periostitis , myopathies , and treatment of autoimmune dis - another aspect, the dose of an anti -OIC agent ranges from eases, terminally ill patients receiving opioid therapy such as about 5 mg to about 50 mg and the dose of the opioid is from an AIDS patient, a cancer patient , a cardiovascular patient; about 5 mg to about 100 mg, including every integer within subjects receiving opioid therapy for maintenance of opioid 10 the specified ranges . withdrawal. In one aspect, the subject is a subject using an In another embodiment, the weight percentage ratio range opioid for chronic pain management. In another aspect , the of an anti -OIC agent to opioid ( e . g ., oxycodone or other subject is a subject using an acutely using an opioid for opioid analgesic ) in the pharmaceutical composition temporary pain management. In another aspect, the subject described herein ranges from about 15 : 1 to about 1 : 18 , is a terminally ill patient . In another aspect , the subject is a 15 including each ratio within the specified range . In one person receiving opioid withdrawal maintenance therapy . aspect, the weight percentage ratio range of an anti -OIC In another embodiment, suitable active pharmaceutical agent to opioid is from about 13 : 1 to about 1 : 1 , including ingredients for treating a symptom or condition of opioid use each ratio within the specified range . In another aspect, the comprise one or more active pharmaceutical ingredients for weight percentage ratio range of an anti -OIC agent to opioid the treatment, amelioration , or prophylaxis of OIBD or OIC 20 is from about 1 : 16 to about 1 : 1 , including each ratio within referred to herein as an anti -OIC agent. In someaspects , the the specified range . In another aspect, the weight percentage anti -OIC agent comprises a peripherally acting mu - opioid ratio range of an anti -OIC agent to opioid is about 1 : 16 , receptor antagonist (PAMORA ). In some aspects , the about 1: 15 , about 1: 14 , about 1: 13, about 1: 12 , about 1 : 11, PAMORA comprises methylnaltrexone, naltrexone , nalox - about 1 : 10 , about 1 : 9 , about 1 : 8 , about 1 : 7 , about 1 :6 , about one , naloxegol, naldemadine, axelopran , or alvimopan , or a 25 1 :5 , about 1 :4 , about 1 :3 , about 1: 2 , about 1: 1 , about 2 : 1, mixture or combination thereof. about 3 : 1 , about 4 : 1 , about 5 : 1 , about 6 : 1 , about 7 : 1 , about In another embodiment, suitable active pharmaceutical 8 : 1 , about 9 : 1 , about 10 : 1 , about 11 : 1 , about 12 : 1 , about ingredients that function as an anti -OIC agent does not 13 : 1 , about 14 : 1, or about 15 : 1 . function as a PAMORA . Exemplary and non - limiting addi- In one embodiment, the pharmaceutical compositions tional non - PAMORA anti- OIC agents comprise a CLC - 2 30 described herein comprise a dose of an opioid ( e . g . , oxyco chloride channel agonist , such as lubiprostone ; a non - selec - done or other opioid analgesic ) and a dose of a PAMORA . tive opioid antagonist, such as levallorphan (naloxiphan ), In one aspect, the pharmaceutical compositions described etorphine , dihydroetorphine, or diprenorphine ; a mixed ago - herein comprise a dose of an opioid and a dose of a nist / antagonist , such as cyclazocine , nalorphine , or nalmex PAMORA comprising naloxone or a pharmaceutically one; a guanylate cyclase agonist, such as linaclotide ; or a 35 acceptable salt form thereof. In one aspect, the pharmaceu laxative , such as docusate , magnesium citrate , or senna . tical compositions described herein comprise a dose of an It is understood that activation of mu- opiod receptors opioid and a dose of a PAMORA comprising naltrexone or along the gastro intestinal tract are responsible for decreased a pharmaceutically acceptable salt form thereof. In another bowel function and constipation . Thus, without being bound aspect, the pharmaceutical compositions described herein by any theory , PAMORAS and other opioid receptor antago - 40 comprise a dose of an opioid and a dose of a PAMORA nists described herein are useful for preventing symptoms of comprising methylnaltrexone or a pharmaceutically accept OIBD , and specifically OIC , by inhibiting the action of the able salt form thereof. In another aspect , the pharmaceutical mu - opioid receptor peripherally along the gastro - intestinal compositions described herein comprise a dose of an opioid tract without inhibiting the mu- opiod receptors of the central and a dose of a PAMORA comprising naloxegol or a nervous system (CNS ) . Therefore , a combination of an 45 pharmaceutically acceptable salt form thereof. opioid agonist ( e . g ., oxycodone or other opioid analgesic ) In one embodiment, the pharmaceutical composition activates the CNS receptors and the co -administration of a described herein comprises a dose of naloxone and a dose of PAMORA or other opioid antagonist inhibits the peripheral an opioid comprising oxycodone or other opioid analgesic as gut mu - opioid receptors , which are believed to be respon - described herein . In one aspect, the dose of the naloxone sible for the incurrence of OIC . 50 ranges from about 2 . 5 mg to about 100 mg, including each It is further understood that alternative non - opioid antago - integer within the specified range . In another aspect, the nists , such as linaclotide and lubiprostone also prevent OIC dose of naloxone ranges from about 2 . 5 mg to about 50 mg, symptoms. For example , lubiprostone is known to activate including each integer within the specified range . In another the CIC - 2 chloride channels . This activation results in chlo - aspect, the dose of naloxone ranges from about 10 mg to ride - rich secretions, which soften stool and increase bowel 55 about 50 mg, including each integer within the specified motility resulting in bowel movements . In addition , the range . In another aspect, the dose of naloxone ranges from guanylate cyclase agonist linaclotide is thought to activate about 20 mg to about 40 mg , including each integer within clonic motor neurons , which results in the promotion of the specified range . In another aspect , the dose of naloxone bowel movements . Therefore , a combination of an opioid is about 2 . 5 mg, about 5 mg, about 7 . 5 mg, about 10 mg, agonist ( e . g . , oxycodone or other opioid analgesic ) activates 60 about 15 mg , about 20 mg, about 25 mg , about 30 mg, about the CNS receptors and the co -administration of a non - opioid 35 mg, about 40 mg , about 45 mg, about 50 mg, about 55 antagonist anti -OIC agent or laxative prevents OIC by mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, promoting bowelmovements . about 80 mg, about 85 mg, about 90 mg, about 95 mg, or In one embodiment , the pharmaceutical composition about 100 mg. described herein comprises a dose of an anti -OIC agent and 65 In another embodiment , the weight percentage ratio range a dose of an opioid ( e . g ., oxycodone or other opioid anal- of naloxone to opioid comprising oxycodone or other opioid gesic ). In one aspect, the dose of an anti- OIC agent ranges analgesic in the pharmaceutical composition described US 9 ,943 ,513 B1 61 62 herein ranges from about 1 : 10 to about 5 : 1, including all in one embodiment, the pharmaceutical composition iterations of ratios within the specified range . In one aspect, described herein comprises a dose of methylnaltrexone or the weight percentage ratio range of naloxone to opioid naltrexone and a dose of an opioid comprising opioid comprising hydrocodone or oxycodone is from about 1 : 5 to analgesic or oxycodone as described herein . In one aspect , about 1 : 1 , including all iterations of ratios within the speci- 5 the dose of the methylnaltrexone or naltrexone ranges from fied range . In another aspect, the weight percentage ratio about 2 . 5 mg to about 100 mg, including each integer within range of naloxone to opioid comprising oxycodone or other the specified range . In another aspect , the dose of methyln altrexone or naltrexone ranges from about 50 mg to about opioid analgesic is from about 1 :4 to about 1 :2 , including all 600 mg, including each integer within the specified range . In iterations of ratios within the specified range . In another 10 another aspect, the dose of methylnaltrexone or naltrexone aspect , the weight percentage ratio range of naloxone to ranges from about 100 mg to about 600 mg, including each opioid comprising oxycodone or other opioid analgesic is integer within the specified range . In another aspect, the about 1 : 10 , about 1 : 9 , about 1 : 8 , about 1 : 7 , about 1 : 6 , about dose of methylnaltrexone or naltrexone ranges from about 1 : 5 , about 1 : 4 , about 1 : 3 , about 1 : 2 , about 1 : 1 , about 2 : 1 , 300 mg to about 600 mg, including each integer within the about 3 : 1 , about 4 : 1 , or about 5 : 1 . In another aspectLect, methe 1515 specifiedsne range. In another aspect, the dose of methylnal weight percentage ratio range of naloxone to opioid com trexone or naltrexone ranges from about 400 mg to about prising oxycodone or other opioid analgesic is about 1 : 2 . 600 mg, including each integer within the specified range. In In another embodiment, the pharmaceutical composition another aspect, the dose of methylnaltrexone or naltrexone described herein comprises a dose of about 5 mg of naloxone is about 50 mg, about 75 mg, about 100 mg , about 125 mg, and a dose of about 10 mg of oxycodone. In another 20 about 150 mg, about 175 mg, about 200 mg, about 225 mg, embodiment, the pharmaceutical composition described about 250 mg, about 275 mg, about 300 mg, about 325 mg, herein comprises a dose of about 10 mg of naloxone and a about 350 mg, about 375 mg, about 400 mg, about 425 mg , dose of about 20 mg of oxycodone . In another embodiment, about 450 mg, about 475 mg, about 500 mg, about 525 mg , the pharmaceutical composition described herein comprises or about 550 mg. a dose of about 20 mg of naloxone and a dose of about 40 25 In another embodiment , the weight percentage ratio range mg of oxycodone . In another embodiment, the pharmaceu - of methylnaltrexone or naltrexone to opioid comprising tical composition described herein comprises a dose of about opioid analgesic or oxycodone in the pharmaceutical com 40 mg of naloxone and a dose of about 80 mg of oxycodone . position described herein ranges from about 13 : 1 to about In another embodiment, the pharmaceutical composition 1 : 1 , including all iterations of ratios within the specified described herein comprises a dose of about 80 mg of 30 range . In one aspect , the weight percentage ratio range of naloxone and a dose of about 160 mg of oxycodone . methylnaltrexone or naltrexone to opioid comprising opioid In another embodiment , the pharmaceutical composition analgesic or oxycodone is from about 10 : 1 to about 1 : 1 , described herein comprises a dose of about 5 mg of naloxone including all iterations of ratios within the specified range . and a dose of about 10 mg of opioid analgesic . In another In another aspect , the weight percentage ratio range of embodiment, the pharmaceutical composition described 35 methylnaltrexone or naltrexone to opioid comprising opioid herein comprises a dose of about 10 mg of naloxone and a analgesic or oxycodone is from about 5 : 1 to about 1 : 1 , dose of about 20 mg of opioid analgesic . In another embodi - including all iterations of ratios within the specified range . ment, the pharmaceutical composition described herein In another aspect , the weight percentage ratio range of comprises a dose of about 20 mg of naloxone and a dose of methylnaltrexone or naltrexone to opioid comprising opioid about 40 mg of opioid analgesic . In another embodiment, the 40 analgesic or oxycodone is about 1 : 1 , about 2 : 1 , about 3 : 1 , pharmaceutical composition described herein comprises a about 4 : 1 , about 5 : 1 , about 6 : 1 , about 7 : 1 , about 8 : 1 , about dose of about 40 mg of naloxone and a dose of about 80 mg 9 : 1 , about 10 : 1 , about 11 : 1 , about 12 : 1 , or about 13 : 1 . of opioid analgesic . In another embodiment, the pharma - In one embodiment, the pharmaceutical composition ceutical composition described herein comprises a dose of described herein comprises a dose of naloxegol and a dose about 80 mg of naloxone and a dose of about 160 mg of 45 of an opioid comprising oxycodone or other opioid analgesic opioid analgesic . as described herein . In one aspect, the dose of the naloxegol In another embodiment, the pharmaceutical composition ranges from about 2 . 5 mg to about 100 mg, including each described herein comprises a dose of about 40 mg of integer within the specified range . In another aspect, the oxycodone and a dose of about 20 mg of naloxone . In one dose of naloxegol ranges from about 2 . 5 mg to about 50 mg , aspect , the composition is provided in a dosage form con - 50 including each integer within the specified range . In another taining a total amount of about 40 mg of an oxycodone and aspect , the dose of naloxegol ranges from about 10 mg to about 20 mg of naloxone , wherein subjects administered a about 50 mg, including each integer within the specified single dosage exhibit a mean plasma oxycodone AUCO - s of range . In another aspect, the dose of naloxegol ranges from about 400 h ·mg / L to about 600 h ·mg / L and a mean plasma about 20 mg to about 40 mg, including each integer within naloxone AUC of about 500 h .mg /L to about 600 55 the specified range . In another aspect , the dose of naloxegol h .mg / L . In another aspect, the composition is provided in a is about 2 . 5 mg, about 5 mg, about 7 . 5 mg, about 10 mg, dosage form containing a total amount of about 40 mg of about 15 mg, about 20 mg, about 25 mg , about 30 mg, about oxycodone and about 20 mg of naloxone , wherein subjects 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 administered a single dosage exhibit a mean plasma oxyco - mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, done Cmar of about 30 ng /mL to about 50 ng /mL and a mean 60 about 80 mg, about 85 mg, about 90 mg, about 95 mg, or plasma naloxone Cmax of about 50 ng/ mL to about 70 about 100 mg. ng /mL . In another aspect , the composition is provided in a In another embodiment, the weight percentage ratio range dosage form containing a total amount of about 40 mg of of naloxegol to opioid comprising oxycodone or other oxycodone and about 20 mg of naloxone , wherein subjects opioid analgesic in the pharmaceutical composition administered a single dosage exhibit an oxycodone Tmar of 65 described herein ranges from about 1 : 10 to about 5 : 1 , about 1 hr to about 5 hrs and a naloxone Tmor of about 0 . 5 including all iterations of ratios within the specified range . hr to about 3 hrs . In one aspect, the weightpercentage ratio range of naloxegol US 9 ,943 ,513 B1 63 64 to opioid comprising oxycodone or other opioid analgesic is Another embodiment described herein is a method for from about 1 : 5 to about 1 : 1 , including all iterations of ratios improving the quality of life of subjects receiving opioids, as within the specified range . In another aspect, the weight well as to reduce complications arising from chronic con percentage ratio range of naloxegol to opioid comprising stipation , such as hemorrhoids, appetite suppression , oxycodone or other opioid analgesic is from about 1 : 4 to 5 mucosal breakdown , sepsis , colon cancer risk , and myocar about 1 :2 , including all iterations of ratios within the speci- dial infarction comprising the administration of a therapeu fied range . In another aspect, the weight percentage ratio tically effective amount of one or more abuse deterrent range of naloxegol to opioid comprising oxycodone or other pharmaceutical compositions described herein . opioid analgesic is about 1 : 10 , about 1 : 9 , about 1 : 8 , about In another embodiment, the pharmaceutical composition 1 : 7 , about 1 : 6 , about 1 : 5 , about 1 : 4 , about 1 : 3 , about 1 : 2 , 10 described herein provides a dosage form comprising an about 1 : 1 , about 2 : 1 , about 3 : 1 , about 4 : 1 , or about 5 : 1 . In opioid and a PAMORA as described in , which in terms of another aspect, the weight percentage ratio range of nalox - efficacy , is ranked good or very good by more than 50 % of egol to opioid comprising oxycodone or other opioid anal- patients, 60 % , 70 % , 80 % , 90 % , or more of patients. In gesic e is about 1 : 2 . aspect, the dosage form is provided which comprises an Another embodiment described herein is a method for 15 opioid and a PAMORA as described in , which in terms of treating, retarding the progression of, prophylaxis of, delay - tolerability , is ranked good or very good by more than 50 % ing the onset of, ameliorating, or reducing the symptoms of of patients , 60 % , 70 % , 80 % , 90 % , or more of patients . pain comprising the administration of a therapeutically I n another embodiment, the pharmaceutical composition effective amount of one or more abuse deterrent pharma- described herein provides a dosage form comprising an ceutical compositions described herein to a subject with 20 opioid and a PAMORA as described in , which provides a pain , wherein the administration is sufficient to achieve a reduction of days with laxative intake by at least 10 % , 20 % , reduction pain relative to baseline in the subject without 30 % , 40 % , 50 % , 60 % , 70 % , 80 % , or even 90 % . In one substantially inducing one or more side effects including , but aspect, the dosage form completely reduces the need for any not limited to , headache , vertigo , somnolence , nausea , con - laxatives to be taken independently . stipation , vomiting , xerostomia , fatigue , pruritus , eructation , 25 In some embodiments , bowel function is assessed by heartburn , abdominal discomfort , or loss of appetite . observing parameters that are associated with bowel func Another embodiment described herein is a method for tion . In particular, bowel function may be determined based treating , retarding the progression of, prophylaxis of, delay - on parameters selected from ease or difficulty of defecation , ing the onset of, ameliorating , or reducing the symptoms of feeling of incomplete bowel evacuation , and /or personal pain comprising the administration of a therapeutically 30 judgment of patient regarding constipation . Other param effective amount of one or more abuse deterrent pharma - eters which may be observed alternatively or in addition in ceutical compositions described herein to a subject with order to assess the bowel function of a patient include among pain , wherein the administration is sufficient to achieve a other things stool frequency , stool consistency, cramping , reduction pain relative to baseline in the subject without and painful laxation . In addition , the measurement of spon substantially inducing one ormore side effects including, but 35 taneous bowel movements indicates improved bowel func not limited to , opioid use , such as, for example , opioid tion . induced bowel dysfunction , opioid induced constipation , Bowel function may be assessed by measuring param gastrointestinal dysfunction ( e . g . , inhibition of intestinal eters , which are associated with bowel function using motility , constipation , GI sphincter constriction ), nausea , numerical analog scales (NAS ) for these parameters because emesis (vomiting ) , biliary spasm , colic , dysphoria , pruritus , 40 this may provide more accurate results . This approach is urinary retention , depression of respiration , papillary con particularly advantageous when assessing the bowel func striction , cardiovascular effects , chest wall rigidity and tion in patients receiving treatment with analgesics, because cough suppression , depression of stress response , and analgesic efficacy of drugs is usually assessed using a immune suppression associated with use of narcotic anal- numeric analog scale . gesia , etc , or combinations thereof. 45 In one embodiment, a reduction in OIC is assessed by Another embodiment described herein is a method for measuring a change in the spontaneous bowel movements treating , retarding the progression of, prophylaxis of, delay (SBMs ) frequency rate ( e . g ., SBMs/week ) . Patients are ing the onset of, ameliorating , or reducing the symptoms of , typically classified as having OIC when having less than 3 irritable bowel syndrome, colitis , post- operative or postpar - SBMs per week for about 4 weeks while taking an opioid . tum ileus , nausea and / or vomiting, decreased gastric motility 50 A positive response to an OIC agent is assessed as an and emptying , inhibition of the stomach , and small and / or increase in SBMs over a period of time following the large intestinal propulsion , increased amplitude of non - administration of the OIC agent. propulsive segmental contractions, constriction of sphincter I n another embodiment a reduction in OIC by an anti- OIC of Oddi, increased anal sphincter tone, impaired reflex agent is assessed by measuring the time to first SBM relaxation with rectal distention , diminished gastric , biliary , 55 following administration of the anti - OIC agent compared to pancreatic or intestinal secretions , increased absorption of a placebo agent . water from bowel contents , gastro - esophageal reflux , gas In another embodiment, a reduction in OIC by an anti troparesis , cramping , bloating , abdominal or epigastric pain OIC agent is assessed by measuring a change in stool and discomfort, constipation , idiopathic constipation , post consistency from baseline over a period of time. For operative gastrointestinal dysfunction following abdominal 60 example , the Bristol Stool Scale may be used to assess surgery (colectomy , e . g ., right hemicolectomy, left hemi- changes. colectomy, transverse hemicolectomy, colectomy takedown , In some embodiments, the pharmaceutical compositions low anterior resection ) , and delayed absorption of orally comprising an opioid and an anti- OIC agent as described administered medications or nutritive substances comprising herein provides improvement of the bowel function charac the administration of a therapeutically effective amount of 65 terized by an increase of the mean bowel function score of one or more abuse deterrent pharmaceutical compositions at least 5 , at least about 8 , at least about 10 or at least about described herein . 15 after administration at steady state or of a single dose to US 9 ,943 ,513 B1 65 66 human patients or healthy human subjects , wherein the In another embodiment, the abuse deterrent pharmaceu mean bowel function score is measured with a numerical tical composition described herein is contained and dis analog scale ranging from 0 to 100 . pensed from a tamper evident packaging . The term “ tamper In one embodiment, the bowel function is assessed by the evident” or “ tamper resistant” refers to a packaging of any bowel function index (BFI ) , which is measured in patients . 5 kind that readily displays or allows for an individual to The mean bowel function score may be determined by a observe any physical interference or manipulation of said method for assessing bowel function in a patient comprising packaging . The tamper evident packaging provides reason the steps of: providing the patient with a numeric analog able evidence to consumers that tampering has occurred . scale for at least one parameter , which parameter is associ The tamper evident packaging additionally contains appro ated with bowel function ; causing the patient to indicate on priate labelling statements describing the features and evi the numeric analog scale the amount and /or intensity of the dences of the tamper evident packaging . In one aspect, the parameter being experienced ; and observing the amount tamper evident packaging comprises : bottles, film wrappers , and / or intensity of the at least one parameter indicated on the blister or strip packs , bubble packs, heat shrink bands or numeric analog scale in order to assess bowel function . In 15 wrappers , foil, paper, or plastic pouches, container mouth one aspect the patient indicates the amount and /or intensity inner seals, tape seals, breakable caps, sealed metal tubes or of parameter being experienced during the last days or plastic heat- sealed tubes, sealed cartons , aerosol containers , weeks, e . g . during the last 1 , 2 , 3 , 4 , 5 , 6 , 7 , 10 , or 14 days . cans including metal and composite materials , or any com In another aspect , the numerical analog scale on which the bination thereof. The packaging may also contain appropri patient indicates his /her subjective experience of the 20 ate instructions for prescribing, instructions for use, warn observed parameter may have any size or form and may ings, or other appropriate information . range from 0 or any other number to any number, such as It will be apparent to one of ordinary skill in the relevant from 0 to 10 or from 0 to 50 or from 0 to 300 or from 1 to art that suitable modifications and adaptations to the com 10 . 25 positions, formulations, methods, processes , and applica In another embodiment, if more than one parameter is tions described herein can be made without departing from observed , a mean bowel function may be obtained in form the scope of any embodiments or aspects thereof. The of a numerical value . This numerical value is themean of the compositions and methods provided are exemplary and are parameters observed , e . g . , the three numeric analog scale not intended to limit the scope of any of the specified values for ease or difficulty of defecation , feeling of incom - 30 plete bowel evacuation and judgment of constipation . The embodiments . All of the various embodiments , aspects , and parameters , which are measures of bowel function or which options disclosed herein can be combined in any and all are associated with bowel function , may comprise opioid variations or iterations. The scope of the compositions , induced bowel dysfunctions (OIBD or OIC ) as described formulations, methods, and processes described herein herein . 35 include all actual or potential combinations of embodiments , In another embodiment , bowel function may be deter aspects , options , examples , and preferences herein mined based on the following parameters: ease or difficulty described . The exemplary compositions and formulations of defecation , for example during the last 7 days according described herein may omit any component, substitute any to the patient assessment, wherein 0 corresponds Wto no110 component disclosed herein , or include any component difliculties and 100 corresponds to severe difficulties ; feeling 40 disclosed elsewhere herein . The ratios of the mass of any of incomplete bowel evacuation , for example during the last component of any of the compositions or formulations 7 days according to the patient assessment, wherein 0 corresponds to no feeling of incomplete bowel evacuation disclosed herein to the mass of any other component in the and 100 corresponds to very strong feeling of incomplete formulation or to the total mass of the other components in bowel evacuation ; personal judgment of patient regarding 45 the formulation are hereby disclosed as 11 they were constipation , for example during the last 7 days , wherein 0 expressly disclosed . Should themeaning of any terms in any corresponds to no constipation at all and 100 corresponds to of the patents or publications incorporated by reference very heavy constipation . conflict with the meaning of the terms used in this disclo In another embodiment, bowel function may be assessed sure , the meanings of the terms or phrases in this disclosure with analogs scales as described in U . S . Pat . No . 6 , 258 ,042 50 are controlling . Furthermore , the foregoing discussion dis and International Patent Application Publication No . WO 2003 / 073937, which may be adapted to devices or analog closes and describes merely exemplary embodiments . All scales as described above as would be understood by one of patents and publications cited herein are incorporated by ordinary skill in the art. The disclosures of these two reference herein for the specific teachings thereof. references are hereby incorporated by reference for such 55 teachings . EXAMPLES In another embodiment, the pharmaceutical compositions described herein further comprise one or more active phar maceutical ingredient( s ) comprising a PAMORA may also Example 1 further limit or prevent drug abuse by inhibiting the action 60 or effects of an opioid . The PAMORAs described herein , for Abuse deterrent matrices as described herein were pre example , methylnaltrexone, naltrexone , naloxone , nalox - pared using the composition shown in Tables 6 - 10 . The egol, or alvimopan can function to have an aversive effect . compositions were prepared according to the method of This aversive affect may include any unpleasant side effect Example 2 and encapsulated in a hard capsule shell . Other comprising inducing opioid withdrawal symptoms, diarrhea , 65 suitable non - limiting capsule shells for the abuse deterrent nausea , reduced euphoria or a mixture or combination matrices described herein comprise a soft capsule shell , thereof. enteric soft capsule shell , and an enteric hard capsule shell . US 9, 943, 513 B1 67 68 TABLE 6 TABLE 10 Abuse Deterrent Controlled Release Matrix Compositions Abuse Deterrent Controlled Release Matrix Compositions Weight Percentage ( % ) Ingredient FO Weight Percentage ( % ) Maisine TM 35 - 1 60 . 7 Polyethylene oxide (WSR 301) 30 Ingredient ??? 0 .25 F1 F2 F3 BHT 0 . 10 10 Oxycodone HCI Capmul ® MCM 59 60 Polyethylene oxide (WSR 301) TOTAL 100 % Polyethylene oxide (WSR 303) O 1oooo Carbopol 974P Oxycodone HCl 10 10 15 TABLE 11 Abuse Deterrent Controlled Release Matrix Compositions TOTAL 100 % 100 % 100 % Weight Weight ( grams) Percentage ( % ) 20 Ingredient F10 Oleic Acid 15 . 5 TABLE 7 Ethocel TM 20CP 0 . 25 1 Polyethylene oxide ( 301 FP ) 7 . 5 30 Abuse Deterrent Controlled Release Matrix Compositions BHA 0 .05 0 . 2 BHT 0 . 02 0 . 9 Weight Percentage ( % ) 25 Sodium lauryl sulfate 1 .25 Ingredient F4 F5 F6 Hydrocodone bitartrate 0 . 42 1 . 7 TOTAL Polyethylene glycol 600 57 .6 25 100 % Polyethylene glycol 1000 7 . 6 Polyvinylpyrrolidone K90 180- 30 Methocel TM K100M TABLE 12 Carbopol 974P 1 5 -1 Polyethylene oxide (WSR 301) 10 . 7 9 . 6 Abuse Deterrent Controlled Release Matrix Compositions Polyethylene oxide (WSR 303 ) 10 . 7 9 . 6 10 . 7 Oxycodone HCI 8 . 6 Weight Percentage ( % ) 3535 Ingredient F11 TOTAL 100 % 100 % 100 % Soybean Oil 55 . 7 Ethocel TM 20CP 20 Polyethylene Glycol 20 BHA 0 . 25 TABLE 8 BHT 0 . 10 HPMC K100M 15 Abuse Deterrent Controlled Release Matrix Compositions Oxycodone HCI Weight Percentage ( % ) Ingredient F7 TOTAL 100 % Capmul ® MCM 63 . 4 A3 Polyethylene oxide (WSR 301) 27 Polyvinylpyrrolidone K90 1 .25 Example 2 BHA 0 .25 BHT 0 . 10 Abuse deterrent controlled release matrix compositions as Oxycodone HCI described herein comprise one or more flowability enhanc 50 ers , one or more release modifiers , optionally one or more TOTAL 100 % viscosity modifiers, optionally one or more antioxidants , and one or more active pharmaceutical ingredients . Flowability enhancers comprise any one or more of a medium chain TABLE 9 mono - and di- glyceride ( e. g ., Capmul® MCM ), oleic acid , or glycerylmonolinoleate ( e . g ., MaisineTM 35 - 1 ) ; the one or Abuse Deterrent Controlled Release Matrix Compositions more release modifiers comprises a high molecular weight Weight Percentage (% ) polyethylene oxide (e . g . , POLYOXTM WSR 301 or Ingredient F8 POLYOXTM WSR 303 ) and optionally a carboxyvinyl poly mer ( e . g ., Carbopol® 974P ) ; the optional one or more Oleic Acid 60 . 7 60 viscosity modifiers comprises a polyvinylpyrrolidone ( e . g . , Ethocel TM 20CP 1 Polyethylene oxide (WSR 301) 30 polyvinylpyrrolidone K90 ) or an ethylcellulose polymer BHA 0 .25 ( e . g ., EthocelTM 20 CP ) ; the optional one or more antioxi BHT 0 . 10 dants comprises BHA or BHT, and the one or more active Oxycodone HCI 8 pharmaceutical ingredients comprises oxycodone or other TOTAL 100 % 65 opioid analgesic . Abuse deterrent controlled release matrices according to compositions F1 -F3 of Table 6 were prepared by suspending US 9 ,943 ,513 B1 69 70 the specified amount of CarbopolTM 974P and POLYOXTM into films or ribbons using heat- controlled drums or sur WSR 301 or POLYOXTM WSR 303 in the specified amount faces ; and manufacturing a soft capsule comprising a matrix of Capmul® MCM to form a suspension mixture . Next, the fill using rotary die technology . During this process , the specified amount of oxycodone was added to the mixture abuse deterrent controlled release matrix is injected into the and thoroughly mixed to form a final matrix fill mixture and 5 lumen as the soft capsule is formed by rotary die encapsu this mixture was filled into soft capsule shells . The filled lation . The soft capsule can be a typical soft capsule (“ soft capsules were then annealed at 70° C . for about one hour. gel” ) or an enteric soft capsule. The abuse deterrent controlled release matrix according to The melting point of PEO in different flowability enhanc composition F7 of Table 8 was prepared by heating the ers including medium chain mono - and di- glyceride ( e . g . , specified amount of Capmul® MCM to 55° C . The specified 10 Capmul® MCM ), oleic acid , or glyceryl monolinoleate amount of polyvinylpyrrolidone K90 was mixed in the ( e . g ., MaisineTM 35 - 1 ) was tested . It is hypothesized that the heated Capmul® MCM until completely dissolved . Next PEO release modifier is suspended and not dissolved within BHA and BHT were added until completely dissolved . The the flowability enhancer throughout the processing steps . resulting mixture was cooled to approximately 30° C . and During the annealing steps , however, the release modifier is the specified amount of the active pharmaceutical ingredient 15 believed to become molten at the two components may be miscible . When subsequently cooled , the release modifier oxycodone HCl was added and mixed until uniformly dis subsequently recrystallizes and forms a semi- solid elastic persed . Next the polyethylene oxide 301 was added and matrix that encapsulates the flowability enhancer and an mixed uniformly to form a suspension mixture . The result active pharmaceutical ingredient. To test this hypothesis , the ing liquid mixture was encapsulated as a liquid suspension various flowability enhancers used in the abuse deterrent and was dried and cured at a high temperature for 45 : 15 20 matrix formulations of Tables 9 - 11 were tested . Thermo minutes at 70 + 2° C . grams show that PEO exhibits a surprising and significant The abuse deterrent controlled release matrix according to melting point depression in the presence of Capmul, which composition F8 of Table 9 was prepared by heating the impacts processability . Other flowability enhancers evalu specified amount of oleic acid to 140° C . The specified ated , including MaisineTM 35 - 1 , oleic acid , Span® 80 and amount of EthocelTM 20 CP was mixed in the heated oleic 25 Tween® 20 , also decreased the PEO melting point but to a acid until completely dissolved . This mixture was then lesser extent. An inert diluent powder, microcrystalline cooled to about 85° C . and BHA and BHT was added until cellulose , was used as a control, which demonstrated no completely dissolved . The resulting mixture was cooled to impact on the melting point ( FIG . 8 ). approximately 30° C . and the specified amount of the active pharmaceutical ingredient oxycodone HCl and polyethylene 30 Example 4 oxide 301 was added and mixed until uniformly suspended in a dispersion . The resulting liquid mixture was encapsuosu - The dissolution and release profiles under different dis lated as a liquid suspension into soft gelatin capsules and solution conditions for pharmaceutical compositions com was dried and cured for 45 : 15 minutes at 70 + 2° C . prising the test abuse deterrent matrix compositions The abuse deterrent controlled release matrix according to 35 described in Table 6 and Table 7 are shown in FIGS . 1 - 7 . composition F9 of Table 10 was prepared by heating the The percent release of oxycodone from the abuse deter specified amount of MaisineTM 35 - 1 to 65° C . BHA and rent controlled release matrix compositions shown in Table BHT were added until completely dissolved . This mixture 6 , generated by the methods described herein and encapsu lated in a hard shell capsule as described herein , were tested . was then cooled to about 30° C . and the specified amount of As shown in FIG . 1 , a test pharmaceutical composition the active pharmaceutical ingredient oxycodone HCl was 40 comprising the abuse deterrent matrix according to F1 of added and mixed until uniformly dispersed . Next the speci Table 6 comprising oxycodone in an annealed capsule shell fied amount of polyethylene oxide 301 was added and mixed demonstrated a similar release rate of oxycodone compared uniformly to form a suspension mixture . The resulting liquid to a reference oxycodone abuse deterrent pharmaceutical mixture was encapsulated as a liquid suspension into soft composition . The percent release of oxycodone was deter gelatin capsules and was dried and for 45 : 15 minutesutes at 4545 minmined by measuring the amount of oxycodone released from 70 + 2° C . the test and reference abuse deterrent compositions in fasted The abuse deterrent controlled release matrix according to state simulated gastric fluid ( FaSSGF ) at pH 1 . 2 for two composition F10 of Table 11 was prepared by heating the hours and in fasted state simulated intestinal fluid (FaSSIF ) specified amount of oleic acid to 140° C . The specified at pH 6 .8 for ten hours according to USP specifications using amount of EthocelTM 20 CP was mixed in the heated oleic 50 Apparatus III at 30 dpm . acid until completely dissolved . This mixture was then Next, non -annealed and annealed pharmaceutical compo cooled to about 85° C . and BHA and BHT was added until sitions generated by the annealing procedure described in completely dissolved . The resulting mixture was cooled to Example 2 were tested . As shown in FIG . 2 , the annealed test approximately 30° C . and the specified amount of the active pharmaceutical composition comprising the abuse deterrent pharmaceutical ingredient hydrocodone bitartrate , sodium 55 matrix according to F 1 of Table 6 released less oxycodone lauryl sulfate , and polyethylene oxide 301 was added and under aqueous boiling conditions compared to a reference mixed until uniformly suspended in a dispersion . The result - oxycodone abuse deterrent composition . However, the same ing liquid mixture was encapsulated as a liquid suspension composition (F1 of Table 6 ) that was not annealed demon into soft gelatin capsules and was dried and cured for 45 + 15 strated a higher release rate as compared to both the minutes at 70 + 2° C . 60 annealed test and reference abuse deterrent compositions . The abuse deterrent matrices prior to encapsulation and This result suggests that the annealing procedure listed in annealing demonstrated a viscous yet flowable aspect . Fol. Example 2 may be one contributor to the abuse deterrent lowing the annealing step at 70° C ., the capsules demon - properties of the compositions described herein . strated a semi- solid elastic aspect. The effects of the viscosity modifier Carbopol® 974P on The process for manufacturing a soft capsule comprising 65 oxycodone percent release under boiling conditions were the abuse deterrent matrices as described herein includes assessed . As shown in FIG . 3 , the oxycodone percent release preparing a gel mass for a soft capsule ; casting the gel mass difference between the annealed test pharmaceutical com US 9 , 943 ,513 B1 71 72 position comprising the abuse deterrent matrix according to Next, the abuse deterrent properties of a pharmaceutical F1 ( 1 % Carbopol® 974P ) and F2 (no Carbopol® 974P ) of composition comprising the different abuse deterrent matrix Table 6 was minimal . formulations (F7 - F10 ) of Tables 8 -11 were tested . These Next, the effects of different molecular weight polyeth compositions were subjected to a variety of common physi ylene oxide in annealed test pharmaceutical compositions 5 cal manipulations , including crushing , grating , grinding and comprising the abuse deterrent matrices were tested for cutting and compared to a similarly manipulated commer cially available reference abuse deterrent formulations . The under boiling conditions. As shown in FIG . 4 , the annealed test formulations were highly resistant to crushing with a test abuse deterrent composition having higher molecular hammer due to the matrix having rubbery, semi- solid , slip weight polyethylene oxide according to F3 of Table 6 10 pery characteristics (FIG . 10B ) . By comparison , a reference demonstrated a modestly higher percent release of oxyco - 1 abuse deterrent formulation was easily crushed into powder done compared to the composition having lower molecular like smaller pieces by a hammer or a mortar and pestle (FIG . weight polyethylene oxide according to F2 of Table 6 , but 10A ) . The smaller pieces of the reference formulation were was still lower than the percent release in the reference abuse then easily converted to a powder using a mortar and pestle , deterrent formulation after 40 minutes . 15 which likely could be snorted . In contrast , the test formu Next, the dissolution of the annealed test pharmaceutical lations could be cut into smaller pieces with a cheese grater , composition comprising the abuse deterrent matrix accord coffee grinder , or other sharp cutting tools , but these smaller ing to F2 of Table 6 was tested for oxycodone release in pieces would not form a powder suitable for insufflation . simulated gastric fluid or in an 80 % ethanol solution . As The dose dumping of oxycodone from the test abuse shown in FIG . 5 , this test abuse deterrent composition 20 deterrent formulations (F7 - F9 ) of Tables 8 - 10 using increas demonstrated a lower percentrelease in ethanol compared to ing concentrations of ethanol were next tested and compared the percent release in simulated gastric fluid (pH 1 . 2 ) . to a commercially available reference abuse deterrent for The percent release of oxycodone from the abuse deter - mulation containing oxycodone. These dissolution experi rent controlled release matrix compositions shown in Table ments were carried out in simulated gastric fluid (no 7 encapsulated in a soft gel capsule were tested in aqueous 25 enzymes ) with 0 % , 5 % , 20 % , and 40 % ethanol using an conditions at 80° C . These matrix compositions all had Apparatus I (baskets ) at 100 RPM according to USP speci reduced polyethylene oxide percentages compared to the fications for oxycodone HCI tablets . As shown in FIGS . matrix compositions of Table 6 and demonstrated a higher 11 - 14 , both the test abuse deterrent formulations and the percent release of oxycodone compared to the tested refer reference abuse deterrent formulation demonstrated resist ence abuse deterrent composition (FIG . 6 ). This resultesult 30 ence to alcohol extraction or alcohol dose dumping . indicates that higher levels of polyethylene oxide ( e . g ., Next, the extraction of oxycodone or other opioid anal 25 % -30 % ) may also contribute to the abuse deterrent char gesic from a test abuse deterrent formulation (F9 ) of Table acteristics in boiling or near boiling conditions . 10 under boiling conditions was tested and compared to commercially available reference abuse deterrent formula Next , the percent release of oxycodone from the reference 35 tions containing either oxycodone or other opioid analgesic . abuse deterrent composition and the compositions F4 - F6 of While intact, formulation F9 and F10 demonstrated signifi Table 7 were determined by conducting a dissolution test in cantly better boiling resistence for the extraction of oxyco FaSSGF at pH 1 . 2 for two hours and FaSSIF at pH 6 . 8 for done compared to the reference formulations as shown in ten hours according to USP specifications using Apparatus FIGS. 15 and 16 , respectively. The test abuse deterrent III at 30 dpm (FIG . 7 ) . 40 formulation (F9 ) and the reference abuse deterrent formu lation containing oxycodone were then physically manipu Example 5 lated using a mortar and pestle or a coffee grinder , respec The dissolution and release profiles under different dis tively . An amount of each formulation corresponding to the solution conditions for pharmaceutical compositions com approximate weight of each of the intact compositions was prising the test abuse deterrent matrix compositionss 45 used in an aqueous boiling extraction study. Accordingly , described in Tables 8 - 10 corresponding to F7 - F9 compared each formulation demonstrated similar release kinetics (FIG . to a reference abuse deterrent matrix are shown in Table 13 17) . below and in FIG . 9 . The release profiles during conditions The effects of physicalmanipulation on the dissolution of of non -abuse demonstrated a low variability between each of the test abuse deterrent formulation F9 of Table 10 and the compositions. The dissolution of these abuse deterrent+ 5030 formulation F10 of Table 11 and a commercially available matrices were determined by conducting a dissolution test in reference abuse deterrent formulation containing oxycodone FaSSGF at pH 1 .2 for two hours and FaSSIF at pH 6 . 8 for or hydrocodone were tested . The reference formulation was ten hours according to USP specifications using Apparatus manipulated by cutting, grinding , and crushing with a mortar and pestle and the test formulations (F9 and F10 ) were III at 30 dpm . manipulated by cutting and / or grinding with a coffee grinder. The manipulated formulations were dissolved in an Appa TABLE 13 ratus III ( reciprocating cylinder ) at 30 dips per minute (most Dissolution % of API from Abuse Deterrent Matrix F7 - F9 aggressive setting ) in FaSSGF media and evaluated for 2 hours (FIGS . 18 - 22 ) . Time % Release %% ReleaseRelease % Release % Release 60 Next, the ability to extractfront and inject oxycodone from a ( hr ) Ref F7 F8 F9 physically manipulated test abuse deterrent formulation F9 # 30 of Table 10 and a physically manipulated commercially m 50 available reference abuse deterrent formulation was ANA Nuw 70 assessed . The injectability /syringability of the compositions 97 85 12 100 100 65 was determined by grinding the test abuse deterrent formu lation F9 of Table 10 in a coffee grinder or cutting it using a sharpened edge . The reference abuse deterrent formulation US 9 , 943 ,513 B1 73 74 was manipulated by crushing it with a mortar and pestle or tion can pass through a cigarette filter and into a syringe for cutting it with a sharpened edge . The manipulated products injection . Like the needle study, the manipulated test for were then agitated for 30 minutes with a wrist action shaker mulation F9 was to viscous and could not be drawn into the at room temperature or in a water bath shaker at 95° C . at syringe , and thus, also passed this additional injectability 200 RPM . The extraction results of oxycodone from the 5 test ( data not shown ) . various physical manipulations are shown in FIGS . 23 and Example 6 24 . It was found that neither the test nor the reference abuse deterrent formulations were able to be drawn through a Additional exemplary abuse deterrent matrix composi syringe connected to a 29 .5 gauge needle due to the high tions useful for producing abuse deterrent pharmaceutical viscosity of the manipulated matrices, limiting the potential compositions as described herein are shown in Tables 14 - 15 . for injection (data not shown ) . Composition components are set forth by weight percentage The test abuse deterrent formulation F9 of Table 10 was of the total weight of the matrix mass composition . Such tested in an additional injectability test , which assays compositions may be encapsulated in soft capsules , enteric whether a physically manipulated pharmaceutical composi soft capsules, hard capsules or enteric hard capsules. TABLE 14 Exemplary Abuse Deterrent Controlled Release Matrix Compositions Weight Percentage (% )

Components EX 1 EX2 EX3 EX 4 EX 5 EX 6 Flowability Enhancer (e . g . , Capmul ® 68 65 56 50 52 40 MCM ; Oleic Acid ; and /or Maisine 35 - 1 ) Release Modifier ( e. g. , Polyethylene 30 30 30 30 35 50 oxide ; PVP K90 ; and /or Ethocel TM 20 CP ) Carboxyvinyl polymers ( Carbopol 1 - 4 - 3 - 974 P ) BHT 0. 1 0. 1 0. 1 0. 1 0 .1 0. 1 BHA 0 .25 0. 25 0. 25 0. 25 0. 25 0. 25 Active Pharmaceutical Ingredient( s ); 1 5 10 20 10 10 (e . g . , hydrocodone, oxycodone , naloxone , methylnaltrexone , naltrexone )

TOTAL 100 100 100 100 100 100

TABLE 15 Exemplary Abuse Deterrent Controlled Release Matrix Compositions Weight Percentage ( % ) Components EX 7 EX 8 EX 9 EX 10 EX 11 EX 12 1 Flowability Enhancer ( e. g. , Capmul ® 60 70 68 63 75 40 MCM ; Oleic Acid ; and /or Maisine TM 35 - 1 ) Release Modifier (e . g ., Polyethylene 25 15 22. 5 27. 5 23. 4 40 oxide ; PVP K90 ; and /or Ethocel TM 20 cp ) Carboxyvinyl polymers (Carbopol ® 5 5 1 974 P ) BHT 0 . 1 0 . 1 0 . 1 0 . . 1 0 . . 1 0 .. 1 BHA 0 . 25 0 . 25 0 . 25 0 . 25 0 . 25 0 . 25 Active Pharmaceutical Ingredient( s ); 10 10 10 10 1 20 ( e . g . , oxycodone , hydrocodone , naloxone , methylnaltrexone , naltrexone ) TOTAL 100 100 100 100 100 100 US 9 , 943 ,513 B1 75 76 Example 7 Bioanalytical Summary Plasma samples were analyzed for oxycodone by World A clinical study was performed with a single - dose , five - wide Clinical Trials Early Phase Services/ Bioanalytical Sci period , five- treatment, five -way crossover relative bioavail ences, Inc . (WCT ) using a validated LC -MS mass spectrom ability study comparing four test abuse deterrent formula - etry procedure . The method was validated for a range of tions (F7 - F9 and F11) of a 40 mg oxycodone hydrochloride 0 . 250 to 125 ng/ mL for oxycodone, based on the analysis of capsule and compared with a commercial abuse deterrent 40 0 . 250 mL of human EDTA plasma . Data were stored in mg oxycodone tablet reference under fasted conditions Watson Laboratory Information Management System This study was a pilot, single- dose, open - label, random - 10 (LIMS ; Version 7 .2 .0 .03 , Thermo Fisher Scientific ). ized , five - period , five -treatment , five -sequence , five -way crossover study . Twenty - five healthy subjects were enrolled . Pharmacokinetic Analysis Subjects who successfully completed the screening process Concentration time data were transferred from Watson checked into the research center the evening before first Laboratory Information Management System directly to dose . Subjects who continued to meet inclusion / exclusion 15 PhoenixTM WinNonlin® ( Version 6 .3 , Pharsight Corpora criteria the morning of dose were assigned a subject number, tion ) using the Custom Query Builder option for analysis . based on the order in which they successfully completed the Data were analyzed by noncompartmental methods in Win screening process and procedures as outlined in the study Nonlin . Concentration time data that were below the limit of protocol . Subjects were randomly assigned to a treatment quantification (BLQ ) were treated as zero in the data sum sequence and received five separate single -dose administra - 20 marization and descriptive statistics . In the pharmacokinetic tions of study medication , one treatment per period , accord analysis , BLQ concentrations were treated as zero from ing to the randomization schedule . Dosing days were sepa time- zero up to the time at which the first quantifiable rated by a washout period of at least 7 -days . Subjects concentration was observed ; embedded and / or terminal received each of the treatments listed below during the five BLQ concentrations were treated as “ missing ” . Full preci treatment periods as shown in Table 16 . 25 sion concentration data (not rounded to three significant figures ) and actual sample times were used for all pharma TABLE 16 cokinetic and statistical analyses . Study Treatment Protocol The following pharmacokinetic parameters were calcu Treatment A : FORMULATION F11 30 lated : peak concentration in plasma (Cmax ) , time to peak Oxycodone hydrochloride extended concentration ( Tm X ), elimination rate constant (a . ) , terminal release capsule , 40 mg half - life (t12 ) , area under the concentration - time curve from Dose = 1 x 40 mg capsule Treatment B : FORMULATION F8 time- zero to the time of the last quantifiable concentration Oxycodone hydrochloride extended ( AUCiast) , and area under the plasma concentration time release capsule , 40 mg Dose = 1 x 40 mg capsule 35 curve from time- zero extrapolated to infinity ( AUCO - > ). Treatment C : FORMULATION F9 Analysis of variance ( ANOVA ) and the Schuirmann ' s two Oxycodone hydrochloride extended one sided t -test procedures at the 5 % significance level were release capsule , 40 mg applied to the log - transformed pharmacokinetic exposure Dose = 1 x 40 mg capsule Treatment D : FORMULATION F7 parameters , Cmax , AUCiast , and AUC . > . The 90 % confi Oxycodone hydrochloride extended 40 dence interval for the ratio of the geometric means ( Test / release capsule , 40 mg Reference ) was calculated . Bioequivalence was declared if Dose = 1 x 40 mg capsule Treatment E : Reference Product the lower and upper confidence intervals of the log - trans Commercial (oxycodone hydrochloride ) formed parameters were within 80 % to 125 % . extended - release tablet, 40 mg 45 Dose = 1 x 40 mg tablet Example 8 Clinical Procedures Summary The test abuse - deterrent formulations F7 -F9 described During each study period , 4 mL blood samples were herein were tested for in vivo bioequivalence to a commer obtained prior to each dosing and following each dose at 50 cially available reference product and a comparative formu selected times through 36 -hours post -dose . A total of 95 lation F11 . Data from 25 subjects who completed at least one pharmacokinetic blood samples were to be collected from study period were included in the pharmacokinetic and each subject, 19 samples in each study period . In addition , statistical analyses . Mean concentration - time data are shown blood was drawn and urine was collected for clinical labo in Table 17 and FIGS. 25 - 26 . Results of the pharmacokinetic ratory testing at screening and study exit . > and statistical analyses are shown below in Tables 18 -22 . In each study period , subjects were admitted to the study The 90 % confidence interval for comparing the maximum unit in the evening prior to the scheduled dose . Subjects exposure , based on ln ( Cmax ), is within the accepted 80 % to were confined to the research center during each study 125 % limits for Treatments FORMULATION F9 and FOR period until completion of the 36 -hour blood collection and 60 MULATION F7. other study procedures . The 90 % confidence intervals for comparing total sys Procedures for Collecting Samples for Pharmacokinetic temtemic exposure , based on In ( AUC ) and In ( AUC00 ) , are Analysis within the accepted 80 % to 125 % limits for all test formu Blood samples (1x4 mL ) were collected in vacutainer lations. Therefore , test formulations FORMULATION F9 tubes containing K2- EDTA as a preservative at pre - dose ( 0 ) 65 and FORMULATION F7 of oxycodone hydrochloride and at 0 . 5 , 1 , 1 . 5 , 2 , 2 . 5 , 3 , 3 . 5 , 4 , 4 . 5 , 5 , 5 . 5 , 6 , 7 , 8 , 12 , 18 , extended -release capsule are bioequivalent to a commercial 24 , and 36 - hours after dosing . oxycodone product under fasted conditions . US 9 ,943 ,513 B1 77 78 TABLE 17 TABLE 17 -continued Oxycodone Concentration - Time Data after Administration of FORMULATION F11 ( Treatment A ), FORMULATION F8 Oxycodone Concentration - Time Data after Administration ( Treatment B ) , FORMULATION F9 ( Treatment C ) , 5 of FORMULATION F11 (Treatment A ) , FORMULATION F8 FORMULATION F7 ( Treatment D ) , and the Commercially ( Treatment B ), FORMULATION F9 ( Treatment C ) , Available Reference Product ( Treatment E ) FORMULATION F7 ( Treatment D ), and the Commercially Time Mean SD ?? Available Reference Product ( Treatment E ) ( h ) n (ng / mL) ( ng / mL ) ( % ) 10 Time Treatment A : Mean SD CV FORMULATION F11 ( h n ( ng/ mL) (ng / mL ) ( % ) 0 . 00 0 .00 0 . 00 NC Treatment D : 0 . 50 2 . 18 4 . 24 193. 98 FORMULATION F7 1 . 00 26 . 1 17 . 5 66 .89 15 1 . 50 41 . 1 17 . 8 43 . 28 2 .00 54 . 0 26 . 0 48 . 18 0 .00 23 0 .00 0 . 00 NC 2 . 50 57 . 8 23 . 0 39 . 86 0 . 50 3 . 77 4 . 19 111 . 10 3 .00 60 . 5 18 . 7 30 .91 Nm3 . 50 58 . 2 16 . 9 29 . 10 1 .00 ~ 18 . 4 8 . 21 44 . 66 4 . 00 56 . 9 13 . 3 23 . 31 20 1 . 50 ~ 27 . 2 8 .95 32 . 92 4 . 50 ????? 55 . 3 15 . 5 28 .00 2 .00 ~ 33 . 6 9 .79 29 . 11 5 . 00 15 . 0 29 .69 50 . 4 ~ 5 . 50 45 . 2 15 . 2 33. 57 2 .50 38 . 5 11 . 3 29 .32 6 . 00 41. 0 13 . 6 33 .07 3 . 00 ~ 41 , 0 10 . 7 26 . 07 7 . 00 34 . 3 12 . 9 37 . 59 3 . 50 42 . 6 11. 7 27 . 50 8 . 00 11. 5 40 .67 28 . 3 25 4 . 00 ~ 43 . 7 12. 0 27. 57 12 .00 12 . 0 6 . 45 53 . 76 ?? 18 . 00 4 .18 2 . 86 68 . 40 4 .50 ~ 47 . 6 13. 4 28 . 21 24 . 00 1 . 57 1 . 28 81. 99 5 . 00 ~ 46 . 8 12. 9 27 .68 36 . 00 0 . 226 0 . 333 147 . 23 5 . 50 ~ 44 . 7 12 . 3 27 . 49 Treatment B : ~ FORMULATION F8 30 6 .00 42. 6 12 . 6 29 .62 7 .00 ~ 37 .9 11. 2 29 . 47 0 . 00 0 .00 0 .00 NC 8 .00 0 33 . 3 9 .73 29 . 22 0 . 50 1 . 72 104 .64 1. 80 0 12 .00 18 . 0 24 . 47 1 . 00 13 . 8 8 . 76 63. 69 4 .41 1 . 50 22. 5 12 . 4 54. 92 18 .00 023 7 . 07 07 2 . 21 31. 28 2 . 00 28 . 7 13 . 3 46 .50 35 24 .00 023 2 . 80 0 . 963 34 . 40 2 . 50 32 . 2 13. 3 41 . 29 36 . 00 0 0 . 469 0 . 291 62 . 14 3 . 00 34 . 8 12 . 2 35 .03 3 . 50 36 . 3 11 . 6 31. 95 Treatment E : 4 . 00 37 . 1 11. 9 32 .04 Commercially Available Reference Product 4 . 50 ?? 38 . 1 13 . 6 35 .60 5 . 00 37 . 2 13 . 4 36 . 11 40 5 . 50 35 .4 11. 6 32 .75 0 .00 ~ 0 .00 0 .00 NC 6 . 00 33. 5 10 . 8 32 . 31 0 .50 ~ 7 .04 5 .73 81 . 40 7 .00 31. 4 9 .51 30 .33 40 . 20 8 . 00 29 . 5 8 .92 30 . 24 1 .00 17 . 6 7 .06 12 . 00 20 . 1 33 .09 1 .50 24 . 7 10 . 5 42 . 39 6 .65 45 18. 00 10 . 4 5 . 32 51. 34 2 .00 29 . 8 11. 6 38 .91 24 .00 4 . 98 3 . 62 72 .61 36 . 0 11 . 3 31. 30 36 . 00 0 .893 0 . 734 82 .20 2 . 50 ?? Treatment C : 3 . 00 ~ 40 . 4 13 . 0 32 . 11 FORMULATION F9 3 . 50 42 . 8 10 . 0 23 . 36 50 4 . 00 45 . 2 8 . 91 0 . 00 ~ 0 .00 0 .00 NC 19 . 72 0 . 50 ~ 4 . 33 7 . 96 183. 53 4 . 50 48. 5 10 . 7 22 . 06 1 . 00 16 . 9 11. 4 67 . 30 5 . 00 47 . 7 10 . 9 22. 83 1 . 50 23. 5 10 . 3 43 . 94 2 . 00 29 . 3 8 . 40 28 .64 5 . 50 43 . 3 9 . 96 23 . 00 2 . 50 ?? NNA 33 . 5 8 . 16 24 . 34 55 6 .00 41 . 2 9 . 30 22 .60 3 . 00 0 35 . 8 8 . 15 22 . 76 7 .00 ?? 36 . 3 8 . 49 23 .39 3 . 50 36 . 6 8 . 50 23 .23 0 4 . 00 37. 4 . 9 . 21 24 . 66 8 .00 ?? 31 . 4 7 .76 24 . 74 4 . 50 40 . 5 10 . 2 25 . 28 12. 00 0?? 15 . 9 5 . 97 37 .62

5 . 00 11 . 5 27 . 87 0 41. 3 18. 00 ?? 6 .01 51. 34 5 . 50 40 . 4 10 . 5 26 .09 3 .09 60 0 6 .00 39 . 5 11 . 1 28 . 15 24 . 00 ?? 2 .21 1 . 43 64 . 48 | 7 . 00 36 . 7 10 . 2 27 . 73 36 .00 23 0 . 313 0 .346 110 . 42 8 . 00 31. 7 9 . 04 28 . 49 12 . 00 18 . 5 6 . 15 33 . 22 * Plasma samples analyzed using a bioanalytical method with a validated range 0 .250 to 18 . 00 ~ 8 . 65 4 . 76 55 . 07 125 ng /mL , concentrations reported in ng/ mL to 3 significant figures ; concentrationsbelow 24. 00 ~ 3 .83 2 .54 66 . 39 65 limit of quantification set to zero ( 0 .00 ng /mL ) in the data summarization 36 .00 ~uuuuuuuuuuuuuuuuuuu 0 .653 0 .562 86 . 17 * * NC = Not calculated US 9, 943 ,513 B1 79 80 TABLE 18 Pharmacokinetic Parameters of Oxycodone Treatment A : Treatment B : FORMULATION F11 FORMULATION F8

Parameter n Mean SD CV % n Mean SD CV % Tmax (h ) 23 2 .90 0 . 84 28. 99 23 4 . 17 1 . 56 37 . 29 Cmax ( ng /mL ) 23 69 . 3 19 . 0 27 .40 23 41. 2 14 . 3 34 .67 AUCK ( * ng/ mL ) 23 487. 1 161 . 1 33. 08 23 501 . 7 135. 4 26. 99 AUC = ( 1 * ng/ mL) 23 491. 3 162 . 2 33. 01 23 509. 1 139. 3 27 .36 AUCExtrap ( % ) 23 0 . 90 0 . 37 40 . 85 23 1 . 37 1 .06 77. 24 ^ , (h -1 ) 23 0 . 1720 0 .0303 17 . 60 23 0 . 1469 0 .0258 17 . 56 t1/ 2 (h ) 23 4 . 16 0 .78 18 .69 23 4 .87 0 . 96 19 .73 Tlast (h ) 23 29 . 22 6 .08 20 .82 23 35 .48 2 . 50 7 . 05 Ciast (ng / mL ) 23 0 .731 0 .338 46 . 16 23 0 . 968 0 .726 75 . 08 Treatment C : Treatment D : FORMULATION F9 FORMULATION F7 Parameter n Mean SD CV % n Mean SD CV % Tmax ( h ) 25 4 .88 1. 10 22. 55 23 4 .46 0 .94 21. 10 Cmax (ng /mL ) 43 . 6 11. 0 25 . 33 23 50 . 0 13 . 4 26 . 85 AUCK ( * ng/ mL ) 25 496. 6 141 . 4 28. 47 23 506. 3 116. 4 22 . 99 AUCo ( h * ng/ mL ) 503 . 2 143 . 7 28. 56 23 510 . 6 116 . 8 22 . 88 AUCExtrap ( % ) 1 . 28 0 . 80 62 .95 23 0 . 86 0 . 53 61. 71 Àz (h - 1 ) 25 0 .1534 0 .0296 19 . 30 23 0 . 1566 0. 0200 12 .80 t12 (h ) 25 4 .71 1 .05 22 . 35 23 4 .49 0 .56 12 . 36 Tiast (h ) 25 33 .61 4 .90 14. 59 23 34. 43 4 . 13 12 .00 Ciast (ng /mL ) 25 0 . 940 0 .559 59 . 45 23 0 .665 0 .410 61. 57

Treatment E : Reference Product

Parameter n Mean SD CV % Tmax (h ) 23 4 .37 0 .72 16 . 59 Cmax ( ng /mL ) 23 50 . 6 11. 3 22 . 40 AUCK ( * ng/ mL ) 23 471. 0 125 . 0 26. 55 AUC6 % ( h * ng/ mL) 23 475. 9 125 . 8 26. 44 AUCExtrap ( % ) 23 1 .04 0 .53 50 .51 Àz (h - 1 ) 0 . 1723 0 .0272 15 . 76 t1/ 2 ( h) 4 . 12 0 .63 15 .26 Tlast ( h ) 30 . 79 6 .08 19 . 75 Ciast (ng / mL ) 23 0 . 850 0 .453 53 . 34

TABLE 19 Statistical Analysis of the Log - Transformed Systemic Exposure Parameters of Oxycodone Comparing FORMULATION F11 ( Treatment A ) to the Reference Product ( Treatment E ) Dependent Geometric Mean ” Ratio ( % ) 90 % CIC ANOVA Variable Test Ref ( Test /Ref ) Lower Upper Power CV % In ( more ) 66 .3159 49. 0244 135 .27 126 .68 144 . 44 0 .9999 13 . 38 In (AUClast ) 465 . 1938 457. 8338 101. 61 97 . 31. 106 . 09 1 .0000 8 . 79 In (AUC ) 469 .4403 462 .6757 101. 46 9 7 . 20 105. 91 1 .0000 8 .73 "Geometric Mean for FORMULATION F11 ( Test ) and Reference Product (Ref ) based on Least SquaresMean of log- transformed parameter values " Ratio ( % ) = Geometric Mean ( Test )/ Geometric Mean (Ref ) " 90 % Confidence Interval US 9, 943, 513 B1 81 TABLE 20 Statistical Analysis of the Log - Transformed Systemic Exposure Parameters of Oxycodone Comparing FORMULATION F8 ( Treatment B ) to the Reference Product ( Treatment E ) Dependent Geometric Mean Ratio ( % ) 90 % CIC ANOVA Variable Test Ref ( Test/ Ref ) Lower Upper Power CV % In (Cmax ) 38. 9240 49. 0244 79 .40 74 . 36 84. 78 0 .9999 13 .38 In ( AUCjast) 488. 7861 457 .8338 106 .76 102 . 25 111. 47 1 .0000 8 . 79 In (AUCO ) 495 . 7325 462. 6757 107. 14 102. 65 111. 84 1 . 0000 8 .73 aGeometric Mean for FORMULATION F11 ( Test ) and Reference Product (Ref ) based on Least Squares Mean of log - transformed parameter values " Ratio ( % ) = Geometric Mean ( Test )/ Geometric Mean (Ref ) C90 % Confidence Interval

TABLE 21 Statistical Analysis of the Log - Transformed Systemic Exposure Parameters of Oxycodone Comparing FORMULATION F9 ( Treatment C ) to the Reference Product ( Treatment E ) Dependent Geometric Meana _ Ratio ( % )' _ 90 % CIC ANOVA Variable Test Ref ( Test / Ref ) Lower Upper Power CV % In ( Cmar) 42 .2828 49. 0244 86 .25 80 .79 92 .07 0 . 9999 13 .38 In ( AUCjost ) 479 . 8001 457 .8338 104 .80 100. 38 109 .41 1 .0000 8 .79 In ( AUCO ) 486 .0219 462 .6757 105. 05 100. 64 109 . 64 1 .0000 8 . 73 Geometric Mean for FORMULATION F11 ( Test ) and Reference Product (Ref ) based on Least Squares Mean of log - transformed parameter values " Ratio ( % ) = Geometric Mean ( Test ) /Geometric Mean (Ref ) " 90 % Confidence Interval

TABLE 22 Statistical Analysis of the Log - Transformed Systemic Exposure Parameters of Oxycodone Comparing FORMULATION F7 ( Treatment D ) to the Reference Product ( Treatment E ) Dependent Geometric Meana Ratio ( % ) 90 % CIC ANOVA Variable Test Ref ( Test/ Ref) Lower Upper Power CV % In (Cmax ) 48 .0481 49 .0244 98 .01 91. 79 104 .65 0 . 9999 13 . 38 In ( AUClost) 493 .6964 457 .8338 107 .83 103 .27 112 . 59 1 .0000 8 .79 In (AUCO ) 497 .9574 462. 6757 107. 63 103. 11 112 . 34 1 .0000 8 .73 aGeometric Mean for FORMULATION F11 ( Test ) and Reference Product (Ref ) based on Least Squares Mean of log - transformed parameter values " Ratio ( % ) = Geometric Mean ( Test )/ Geometric Mean (Ref ) " 90 % Confidence Interval

50 Example 9 TABLE 23 Oxycodone Hydrochloride Clinical Formulation Dosage 40 mg oxycodone hydrochloride Based on the results of the pilot study, the formulation 55 shown in Table 23 was prepared for pivotal bioequivalence Component Mass (mg ) % weight Glycerylmonolinoleate 201. 1 57. 5 studies . The formulation was encapsulated in a soft gelatin (Maisine TM ) capsule , coated with a polyvinyl alcohol coating ( e. g . , PEO 301 FP 105 . 0 30 . 0 ??? 1 . 1 0 .31 Opadry® amb II, Colorcon ) to provide a 10 - 12 % weight 60 BHT 0 . 4 0 . 13 gain , and then annealed in the coating pan by heating the Oxycodone HCl 42 . 4 12 . 1 capsules to 65 -70° C . for about 30 min to about 90 min , then TOTAL 350 . 0 100 . 0 % slowly cooling the capsules to room temperature by reduc Ratio PEO :Maisine TM 35 - 1 1 : 1 . 9 ing the temperature 5° C . over a 5 min to 15 min period ( e. g ., 65 Ratio API: PEO 1 : 2 . 5 a 0 . 3 - 1° C . decrease per min ). US 9, 943, 513 B1 83 84 Example 10 - continued Based on the results of the pilot study, a single - dose , Treatment Opioid Antagonist open - label , three -way crossover bioequivalence study Drug Name: Naltrexone hydrochloride involving three -period , two - sequence , three - treatment was Strength : 50 mg Dosage Form : Film - coated tablets conducted with the dosage form described in Table 23 . Manufactured Accord Healthcare , Inc . , U . S . In the first two periods, the subjects received a single dose by / for : of oxycodone 40 mg extended - release capsules (Banner Life Dose : 1 x 50 mg Sciences ; Table 23 ) or OXYCONTIN® ( oxycodone hydro - 10 chloride ) 40 mg extended -release tablets (Purdue Pharma Fasting Conditions L . P . ) under fasting conditions in a randomized , crossover Following at least a 10 -hour overnight fasting period , fashion with balanced sequence . In the third period , all subjects were dosed and were required to continue to fast for subjects received a single dose of oxycodone 40 mg at least 4 hours after dosing . extended - release capsules ( Banner Life Sciences ) with a 15 Following the fasting period of at least 4 -hours after high -fat meal according to the FDA Guidance on food effect dosing , subjects were given standardized meals and caf evaluation . Twenty - six subjects were enrolled . feine /methylxanthine - free beverages at scheduled times. In Healthy , non -smoking ( for at least 6 months prior to first this study, meals were served at approximately - 14 . 5 and study drug administration ) , male and non -pregnant female 20 - 11 hours prior to study drug administration and at approxi volunteers , 18 - 55 years of age , inclusive , with a body mass mately 4 .5 , 9 . 5, 13 .5 , 24 , 28 .5 , 33 .5 (Only for Period 3 ) and index (BMI ) within 18 - 33 kg/ m² , inclusive. Six ( 6 ) addi 37. 5 hours after dosing. Meals and beverages during con tional subjects were on stand- by . All eligible subjects took finement were identical between each study period . Except naltrexone hydrochloride ( Accord Healthcare , Inc . , U . S ) , for water given with study medication , no fluid was allowed both at - 13 hours and at - 1 hour prior to Period 1 study drug 25 from 1 hour before dosing until 1 - hour post- dose . Water was administration to ensure that at least 26 qualified subjects allowed / provided ad libitum at all other times. would continue study participation , who in the opinion of Fed Conditions the PI/ Sub - Investigator, did not experience side effects that Following at least a 10 -hour overnight fasting period , would preclude them from advancing in the study based on subjects will start an FDA -recommended high - fat , high safety concerns. Once 26 subjects have received the study 30 calorie breakfast 30 minutes prior to dosing. Study subjects drug in Period 1 , the remaining subjects were released from completely consumed this high fat meal within 30 minutes or less . The drug products were administered 30 minutes the study. after the start of the high fat/ high calorie breakfast . The assignment of treatment groups ( randomization Following a fasting period of at least 4 -hours after dosing , scheme ) was be generated by a computer program designed 35 subjects were given standardized meals and caffeine /meth and run in SAS® Version 9 . 4 at BPSI . This was an open - ylxanthine - free beverages at scheduled times . Meals were label study and subjects as well as clinic staff were not be served at approximately - 14 . 5 and - 11 hours prior to study blinded to the randomization . The bioanalytical laboratory drug administration and at approximately 4 . 5 , 9 . 5 , 13 . 5 , 24 , staff was blinded and did not have access to the random 28 .5 , 33 . 5 (Only for Period 3 ) and 37 . 5 after dosing. Meals ization scheme until the bioanalytical analysis is complete . 40 and beverages during confinement were identical between Subjects who met the eligibility criteria were be assigned each study period No food was allowed from at least 10 hours before the equally into one of the following two sequence groups: FDA -recommended high - fat , high - calorie breakfast. Except for the fluids served with breakfast and the water given with 45 study medication , no fluid was allowed from 1 hour before Period 1 Period 2 Period 3 dosing until 1 -hour post- dose . Water was allowed /provided Sequence 1 ad libitum at all other times . Sequence 12 cmB A Procedures for Collecting Samples for Pharmacokinetic Analysis 50 Blood were obtained by direct venipuncture in the arm . Each subject received a total of three treatments by the Blood samples ( 1x4 mL ) were collected in vacutainer tubes end of the study. containing K2- EDTA as a preservative at pre -dose ( 0 ; within 2 -hours pre -dosing ) and at 0 .5 , 1 , 1 .5 , 2 , 2 .5 , 3 , 3 .5 , 4 , 4 . 5 , 5 , 5 . 5 , 6 , 7 , 8 , 12 , 18 , 24 , and 36 - hours after dosing Treatment Code ( Test ) B (Reference ) C (Test ) 55 Plasma samples were assayed for oxycodone using a Drug Name: Oxycodone OXYCONTIN® Oxycodone validated analytical method according to the principles of hydrochloride (oxycodone hydrochloride Good Laboratory Practice . hydrochloride ) Data from the following subjects were included in the Strength : 40 mg 40 mg 40 mg final pharmacokinetics and statistical analyses : Dosage Form : Extended Extended Extended release release release 60 1 . Subjects who completed at least two study periods with capsules tablets capsules test formulation and reference formulation under same Manufactured Banner Life Purdue Pharma Banner Life gastrointestinal condition or test formulation under by / for: Sciences L . P . Sciences different gastrointestinal condition . Dose : 1 x 40 mg 1 x 40 mg 1 x 40 mg under fasting under fasting under fed 2 . Subjects who missed samples that have been pre 65 determined prior to the start ofbioanalytical analysis to conditions conditions conditions not significantly impact the overall outcome of the study. US 9 , 943 ,513 B1 85 86 Data from subjects who were dismissed or withdrew due to TABLE 24 AE ( S ) were not be included in the PK and statistical analysis . Pharmacokinetic parameters were calculated using non Mean Plasma Oxycodone compartmental analysis (NCA ) method using SAS® Version Concentration as a Function of Time after Dosing 9 .4 . The following pharmacokinetic parameters were esti - 5 A Test ( Fasted ) mated for oxycodone and included in the pharmacokinetic Time Mini- Maxi Std . Coeff. of and statistical analysis for the subjects in the final data set : Variable ( h ) N mum mum Mean Dev. Variation Cmor : The maximal observed plasma concentration . C1 Pre - 26 O0 0 . 81 0 .07 0 . 19 269 .58 Tmari Time when the maximal plasma concentration is dose observed . 10 C2 0 . 5 26 0 4 .41 0 .42 0 . 94 221. 67 1 . 0 26 0 28 . 81 10 . 48 8 .66 82 .69 AUCO - x : Area under the concentration -time curve from 1 . 5 26 0 43 . 33 19 . 79 11 . 9 60 . 11 time zero until the last measurable concentration or last 83in 2. 0 26 0 51 . 84 27 . 37 13 . 08 47 .78 N sampling time t , whichever occurs first. AUC . - » is C6 ? 26 0 61 . 85 33. 26 14 . 92 44 . 85 estimated using the trapezoidal method . C7 ? 26 3 . 4 67 .69 36 . 15 13 . 78 38 . 11 C8 3 . 5 26 19 . 15 65 .51 38 . 38 11 . 7 30 .48 AUCO : Area under the concentration - time curve from 15 C9- +? 26 67 .01 39 .48 11 . 39 28 .85 time zero to infinity , calculated as AUC . - > z + Ciasta , C10 + 26 23 . 63 66 . 32 40 . 66 11 .27 27 .72 where Ciast is the last measurable concentration . C11 5 . 0 26 24 . 44 74 . 2 43 .05 12 . 07 28 .04 a : Terminal elimination rate constant, estimated by linear C12 5. 5 26 24 . 71 73 .04 42 . 71 12 . 02 28 . 14 regression analysis of the terminal portion of the natu C13 6 . 0 26 22 . 36 67 .57 39 . 73 11 .27 28 . 35 C14 7 . 0 26 21 . 07 56 . 38 34. 6 9 .77 28 .24 ral log of concentration ( In -concentration ) vs. time plot. 20 C15 8 . 0 26 18 41 .41 28 . 86 6 . 94 24 . 04 tuz: Terminal elimination half - life , estimated as ln ( 2 ) . C16 12 . 0 26 6 . 7 23. 53 14 . 7 4 . 71 32 . 06 During pharmacokinetic and statistical analyses , drug 017Ovau 18 . 0 26 1. 97 9 .67 5 .68 2 .42 42 .55 concentrations below the lower limit of quantitation of the c18 24 .0 26 0 .72 4. 44 2 . 19 1 . 1 50 .42 assay were considered as zero prior to the first measurable c19 36 . 0 26 0 0 .78 0 . 31 0 . 28 89 .76 concentration . Drug concentrations thatwere below the limit 25 of quantitation following a measurable result were consid ered as missing during pharmacokinetic calculations and TABLE 25 estimations . Missed samples and non -reportable concentrations (e .g . Mean Plasma Oxycodone quantity not sufficient ) from the analytical laboratory were 30 Concentration as a Function of Time after Dosing treated in the pharmacokinetic analysis as if they had not B Reference (Fasted ) been scheduled for collection . Vari - Time Mini Maxi Std . Coeff . of The à , t1 /2 , and AUCO - > parameters were not estimated able mum mum Mean Dev. Variation for plasma concentration - time profiles where the terminal C1 Pre - 26 0U 0 . 28 0 ..01 0 .05 509. 9 linear phase was not clearly defined ( R < 0 . 8 ) . 35 C1 dose Descriptive statistics (min . ,max . , median , mean , standard C2 0 . 5 26 0 .66 14 . 45 4 .09 3 .51 85 .81 deviation , and coefficient of variability ) of all pharmacoki 1 . 0 26 4 . 86 38 . 35 16 .52 8 . 8 53 . 27 netic parameters were calculated for monomethyl fumarate 1 . 5 26 11 . 23 46 .21 . 22 . 73 9 . 75 42 .91 2 .0 26 11 . 2 60 . 27 28 . 38 11. 13 39 . 22 for the Test and Reference products . 2 . 5 26 13 .04 67 . 82 31. 46 10 .62 33 . 77 ANOVA including sequence , subjects nested within 40 C7 3 . 0 26 17 . 98 70 . 57 35 . 92 9 .64 26 . 83 sequence , period and treatment were performed on the 3 . 5 26 21 . 51 69 . 79 37 . 36 9 .02 24 . 15 883858C9 4 . 0 26 21. 92 75 . 07 38 .07 10 . 22 26 . 85 In - transformed data for AUC . - > , AUCo - > , and Cmar and on C10 4 . 5 26 25 .71 70 .87 38 .65 9 . 38 24 .27 the untransformed data for Tmax , à , and t1 / 2. Tmax was C11 5 . 0 26 25 . 19 68 .07 39 . 84 10 . 35 25 . 97 analyzed using the non -parametric Wilcoxon test. C12 5 .5 26 22 . 1 63 . 53 38 . 86 10 . 38 26 . 71 The 90 % Confidence Interval of the Test/ Reference ratios 45 C13 6 . 0 26 20 . 91 61 .07 36 .7 9 . 96 27 . 15 C14 7. 0 26 18 .65 51. 79 31 . 88 8 .08 25 . 34 of geometric means for AUCo- > , AUC . - 7 . , and Cmax was C15 8 . 0 26 17 . 89 45 .48 27 .65 7 . 38 26 .69 calculated based on the LSMEANS and ESTIMATE of the C16 12 . 0 26 7 . 57 27 .21 15 . 34 5 . 11 33 . 3 ANOVA . Additional statistical and alternate tests were per C17 18 . 0 26 2 . 56 12 . 88 6 .51 2 .47 37 . 88 formed as necessary . C18 24 . 0 26 0 . 93 5 .65 2 .79 1 . 25 44 .67 Bioequivalence between Test ( A ) and Reference (B ) prod - 50 C19 36 . 0 26 0 1 .78 0 .44 0 .39 88 .04 ucts is demonstrated under fasting conditions when the 90 % CI for the AB ratios of geometric least - squares means for AUCOX , AUCO . , and Cmor are completely contained TABLE 26 within the U . S . FDA defined acceptance range of 80 .00 % 125 .00 % for oxycodone . 55 Mean Plasma Oxycodone Concentration as a Function of Time after Dosing Example 11 C Test ( Fed ) Vari Time Mini Maxi Std . Coeff . of Comparative Bioavailability Study Results able ( h ) N mum m um Mean Dey. Variation Mean plasma oxycodone concentrations from the bio - 60 Pre - 26 0 . 53 0 . 12 0 . 17 135 .68 availability study described in Example 10 are shown in dose Olo Tables 24 - 26 . The mean plasma oxycodone concentration 0. 5 26 0 .58 0 . 04 0 . 13 303 .47 1 .0 26 15 . 76 1 . 79 3 .68 206 . 37 data are plotted in FIGS. 29 and 30 , respectively . The 1 . 5 26 10 . 5 10 . 56 100 .53 reference drug ( B , Reference ) in both studies is OXYCON 2 . 0 26 110 . 66 26 .62 24 .12 90 .61 TIN® ( oxycodone hydrochloride ) 40 mg extended -release 65 C6 2 .5 26 0 . 36 93 . 17 35 .57 23 . 99 67 . 46 tablets , CII (Purdue Pharma L . P .) . Pharmacokinetic param 888888 3 . 0 26 1 . 48 87 . 06 41. 37 21 .71 52 . 48 eters are shown in Tables 27 - 28 for the Tests and Reference . US 9, 943, 513 B1 87 TABLE 26 - continued TABLE 26 - continued Mean Plasma Oxycodone Mean Plasma Oxycodone Concentration as a Function of Time after Dosing Concentration as a Function of Time after Dosing C Test ( Fed ) C Test ( Fed ) Vari Time Mini- Maxi Std . Coeff . of Vari Time Mini Maxi Std . Coeff . of able ( h ) N mum mum Mean Dev. Variation able ( h ) N mum m um Mean Dev. Variation C8 3 . 5 26 7 . 6 89 . 26 40 . 1 C9 26 25 . 29 85 . 98 51. 82 14 . 76 28 . 49 C15 8 . 0 26 20 .57 56 . 5 36 .79 9 . 6 26 . 09 C10 26 36 . 81 81 .69 54 . 08 12 . 25 22 . 66 10 C16 12 . 0 26 7 . 75 27 . 82 15 . 96 5 . 45 34 . 14 C11 ttin5. 0 26 36 . 85 82 . 93 58 . 32 11 . 39 19 . 53 C17 18 . 0 26 2 .63 10 .51 5 .73 2 . 29 40 . 06 C12 5 . 5 26 35 . 1 76 . 76 54 .63 11 .03 20 . 2 C18 24 . 0 26 0 . 74 4 . 51 2 . 2 0 . 96 43 . 66 C13 6 .0 26 32 . 16 70 .05 50 . 95 10 .99 21 . 56 C1936. 0 26 0 1 .05 0 .37 0 . 28 75 . 25 C14 7 . 0 26 25 .72 63 . 73 43. 61 10 .75 24 . 66

TABLE 27 Pharmacokinetic Parameters for Plasma Oxycodone AUCE AUC Cmax AUCT ( h · ng/ ( h · ng (ng / m Tmax ( h · ng huy 12 In In In mL) mL ) L ) (h )* mL) ( 1 /h ) * ( h )* ( AUC ) (AUC ) (Cmax ) A Test (Fasted ) N 26 26 26 26 26 26 26 26 26 26 Max 658 . 33 662 .43 0 . 9968 74 . 2 7 0 . 2371 5 . 42 6 .4897 6 . 4959 4 . 3068 Min 248. 62 257 . 8 0 . 9644 25 . 96 2 . 5 0 . 1278 2 . 92 5 . 5159 5 . 5522 3 . 2566 Median 436 .66 442 .63 0 . 9905 43. 94 UN 0 . 1574 4 . 4 6 .0791 6 . 0927 3 .7827 Mean 428 . 81 433 . 53 0 . 988 45 . 99 4 . 63 0 . 1625 4 . 36 6 . 0253 6 .0374 3 .7974 Std . Dev . 114 .63 114 . 13 0 . 0078 11 . 94 1 . 12 0 .026 0 . 62 0 . 2762 0 . 2713 0 . 2531 CV % 26 .73 26 . 33 0 .79 25 . 96 24 . 17 16 .03 14 . 33 4 . 58 4 . 49 6 . 67 B Reference (Fasted )

26 26 26 26 26 26 2626 2626 26 26 Max 760 . 14 764 . 18 0 .996 75 .07 5 . 53 0 . 1945 7 .59 6 .6335 6 .6388 4 .3184 Min 259 .4 267 .95 0 . 9493 28 . 49 0 . 0913 3 . 56 5 .5584 5 .5908 3 . 3496 Median 428 . 28 430 . 29 0 .9922 41 . 41 UNA5 0 . 1581 4 .38 6 .0597 6 . 0644 3 . 7234 Mean 435 . 2 440 .68 0 . 9867 42. 03 4 . 56 0 . 1539 4 .62 6 .0466 6 .0601 3 . 71 Std . Dev. 109 .41 109 .07 0 .0117 10 . 73 0 .92 0 .0233 0 . 85 0 . 2456 0 . 2415 0 .2382 CV % 25 . 14 24 . 75 1 . 19 25 .52 20 . 19 15 .11 18 . 46 4 .06 3 . 99 6 .42 C Test (Fed ) N 26 26 26 26 26 26 26 26 26 26 Max 658 .33 662 . 43 0 . 9968 74 . 2 7 0 . 2371 5 . 42 6 . 4897 6 . 4959 4 . 3068 Min 248 .62 257. 8 0 . 9644 25. 96 2 . 5 0 .1278 2 . 92 5 . 5159 5 . 5522 3 .2566 Median 436 .66 442 .63 0 . 9905 43. 94 5 0 . 1574 4 . 4 6 .0791 6 . 0927 3 . 7827 Mean 428 . 81 433. 53 0 . 988 45 . 99 4 . 63 0 . 1625 4 . 36 6 . 0253 6 .0374 3 .7974 Std . Dev. 114 .63 114 . 13 0 . 0078 11 . 94 1 . 12 0 .026 0 .62 0 . 2762 0 . 2713 0 . 2531 CV % 26 .73 26 . 330 . 79 25 . 96 24 . 17 16 .03 14 .33 4 .58 4 .49 6 .67

TABLE 28 Summary of Comparative Bioavailability Analysis for Oxycodone Randomized , 4 -way crossover , open - label, single - dose, fasting design Geometric Mean * Arithmetic Mean % CV ) AUCO AUCO- 300 Cmax Tmax te i AUC hn( ( h - ng/ mL) ( ng/ mL) ( h) * ( h ) * ( 1/ h ) * AUC -oi A Test 413 . 76 418 . 81 44 .58 5 .00 4 . 36 0 . 1625 0 . 9880 (Fasted ) 428 . 81 433 . 53 45. 99 (2 . 50 -7 . 00 ) (14 . 33 ) ( 16 .03 ) (0 . 79 ) (26 .73 ) ( 26 . 33 ) ( 25 . 96 ) C Test 486 . 29 490 .61 60 . 57 4 .53 4 .56 0 . 1569 0 . 9912 (Fed ) 499 . 59 503 . 73 62. 24 ( 2 .03 -6 . 00 ) ( 16 .93 ) ( 19 . 29 ) (0 .57 ) ( 23 . 09 ) (22 .85 ) (24 . 79 ) B 422 .68 428 . 4 40. 85 5 .00 4 .62 0 . 1539 0 . 9867 Reference 435 . 2 440 .68 42. 03 ( 2 . 00 - 5 .53 ) ( 18 .46 ) ( 15 . 11 ) ( 1 . 19 ) ( 25 . 14 ) (24 .75 ) (25 .52 ) US 9 , 943 ,513 B1 89 90 TABLE 28 -continued Summary of Comparative Bioavailability Analysis for Oxycodone Randomized , 4 -way crossover , open - label, single -dose , fasting design Ratio of Geometric 90 % Confidence Intra -subject CV Means ( Test :Ref ) Interval A Test/ B AUCO 97 . 89 93 .00 - 103. 04 10 . 85 Reference AUCOCO 97 . 76 92 .98 - 102 . 79 10 .62 ???? 109 . 13 102 . 39 - 116 . 31 13 .51 Ratio of Geometric 90 % Confidence Intra - subject CV Means ( Fasted :Fed ) Interval ( % ) A Test/ AUCO 117 . 5 103 . 96 - 132. 87 26 . 33 C Test AUCO. 117 . 14 103 .81 - 132. 19 25 .93 ????? 135 . 87 121. 02 - 152. 53 24 . 79 Test A , C : oxycodone hydrochloride , 40 mg extended- release capsules . See Table 23 . Reference : OXYCONTIN ® ( oxycodone hydrochloride ) 40 mg extended - release tablets, CII ( Purdue Pharma L . P . ) . * Arithmetic mean ( % CV ) only *Median and range only

Example 9 TABLE 29 -continued Abuse deterrent dosage formsforms werewere prepared usingusing the 25ne _ Abuse Deterrent Controlled Release Oxycodone Compositions compositions shown in Table 29 and encapsulated in a soft BHT 0 . 4 0 . 13 capsule shell with a polyvinyl alcohol coating as a moisture Oxycodone HCI 42 . 4 12 . 1 barrier . The dosage forms were annealed in the coating pan TOTAL 350 . 0 100 . 0 % after coating at 60 - 70° C . for 30 to 90 min and then slowly Ratio PEO :Maisine TM 35 - 1 1 : 1 . 9 cooled to room temperature (dropping about 5° C . every 5 30 Ratio API: PEO 1 : 2 . 5 to 15 min .) . What is claimed is : TABLE 29 1 . A method for treating, reducing the symptoms of, or Abuse Deterrent Controlled Release Oxycodone Compositions 35 retarding the onset of pain comprising administering to a subject in need thereof of an oral pharmaceutical composi Dosage 10 mg 15 mg tion comprising about 35 % to about 70 % by mass glyceryl Component Mass (mg ) % weight Mass (mg ) % weight monolinoleate , about 20 % to about 50 % by mass polyeth ylene oxide having a molecular weight ( M ) of about Glycerylmonolinoleate 222. 0 63. 4 218 .5 62. 4 (Maisine TM ) 40 1 , 000 , 000 to about 7 , 000 , 000 , and oxycodone or a salt PEO 301 FP 115 . 9 33 . 1 114 . 1 32 . 6 thereof . BHA 1 . 1 0 . 3 1 . 1 0 . 3 2 . The method of claim 1 , wherein the pharmaceutical BHT 0 . 4 0 . 1 0 . 4 0 . 1 composition comprises : Oxycodone HCI 10 . 6 3 . 0 15 . 9 4 . 5 ( a ) about 50 % to about 70 % by mass glyceryl monoli TOTAL 350. 0 100. 0 % 350 .0 100 .0 % 45 noleate ; Ratio PEO :Maisine TM 35 - 1 1 : 1 . 9 1 : 1 . 9 ( b ) about 25 % to about 40 % by mass polyethylene oxide Ratio API: PEO 1 : 10 . 9 1 : 7 . 2 having a molecular weight ( M ) of about 1 ,000 ,000 to about 7 ,000 ,000 ; and Dosage 20 mg 30 mg ( c ) about 1 % to about 20 % by mass of oxycodone or a salt Component Mass (mg ) % weight Mass (mg ) % weight 50 thereof. Glycerylmonolinoleate 215. 0 61. 4 208. 1 59. 4 3 . The method of claim 1 , wherein the pain arises from (Maisine TM ) one or more of diabetic neuropathy , chronic arthritis , PEO 301 FP 112 . 3 32 . 1 108 . 6 31 . 0 osteoarthritis , rheumatoid arthritis, acute tendonitis , bursitis , BHA 1 . 1 0 . 3 1 . 1 0 . 3 headaches , migraines, chronic neuropathies, shingles , pre BHT 0 . 4 0 . 1 0 . 4 0 . 1 55 menstrual symptoms, sports injuries, malignancy , radicu Oxycodone HCI 21 . 2 6 . 1 31 . 8 9 . 1 - lopathy, sciatica / sciatic pain , sarcoidosis, necrobiosis , TOTAL 350 . 0 100 . 0 % 350 . 0 100 . 0 % lipoidica , granuloma annulare, trauma, cancer , or a combi Ratio PEO :Maisine TM 35 - 1 1 : 1 . 9 1 : 1 . 9 nation thereof. Ratio API: PEO 1 : 5 . 3 1 : 3 . 4 4 . The method of claim 1 , wherein upon ingestion by the 60 subject the composition is capable of achieving one or more Dosage 40 mg of the following pharmacokinetic parameters :

Component Mass (mg ) % weight ( a ) a mean plasma oxycodone Tmax771 AX of about 1 hours to Glyceryl monolinoleate 201 . 1 57 . 5 about 8 hours ; (Maisine TM ) ( b ) a mean plasma oxycodone Cmax of about 10 ng/ mL to PEO 301 FP 105 . 0 30 . 0 65 about 150 ng/ mL ; or ??? 1 . 1 0 . 31 ( c ) a mean plasma oxycodone AUC . -~ of about 100 h?ng /mL to about 1000 h .ng / mL . US 9 , 943 ,513 B1 91 92 5 . The method of claim 1, wherein the pharmaceutical ( d ) a mean plasma oxycodone AUCo -> of about composition forms an abuse deterrent elastic semi- solid 400 .h .ng /mL to about 500 h .ng /mL ; composition after having been heated at a temperature of ( e ) a mean oxycodone half - life (t12 ) of about 4 . 4 hours to about 50° C . to about 80° C . for about 10 min to about 180 about 4 . 6 hours ; or min , and cooled to room temperature . 5 ( f ) a mean oxycodone overall elimination rate constant 6 . The method of claim 1 , wherein the pharmaceutical (a ) of about 0 . 14 h - l to about 0 . 17 h - 1 . composition comprises a mass ratio of polyethylene oxide to 15 . The method of claim 14 , wherein the pharmaceutical glyceryl monolinoleate of about 1 :2 . dosage form exhibits an in vitro dissolution rate at pH 1 . 2 of 7 . The method of claim 1 , wherein the pharmaceutical about 50 % after about 90 minutes . composition comprises a mass ratio range of oxycodone to| 10 16 . The method of claim 14 , wherein the dosage form polyethylene oxide of about 1 : 1 to about 1 : 20 . comprises a capsule encapsulating an abuse deterrent elastic 8 . The method of claim 1, wherein the oxycodone com - semisem - solid composition comprising : prises about 0 . 5 % to about 20 % of the composition by mass . ( a ) about 35 % to about 70 % by mass glyceryl monoli 9 . The method of claim 1 , wherein the composition further noleate ; comprises one or more antioxidants . ** 15 (b ) about 20 % to about 50 % by mass polyethylene oxide 10 . The method of claim 9 , wherein the antioxidant having a molecular weight (M ,) of about 1, 000 ,000 to comprises about 0 .05 % to about 0 . 5 % of the composition by about 7 ,000 , 000 ; and mass . ( c ) about 1 % to about 20 % by mass of oxycodone or a salt 11 . The method of claim 1 , wherein the polyethylene thereof; and oxide comprises a polyethylene oxide having an average 20 the dosage form having been heated to about 50° C . to molecular weight ( M ) of about 4 ,000 , 000 . about 80° C . for about 10 min to about 180 min , and 12 . The method of claim 1 , wherein the oxycodone cooled to room temperature . comprises about 5 mg, about 10 mg, about 15 mg, about 20 17 . A method for inhibiting extraction of oxycodone from mg, about 30 mg, or about 40 mg of oxycodone hydrochlo - a pharmaceutical composition , the method comprising : ride . 25 dumnDICINadministering a dosage form comprising a capsule encap 13 . The method of claim 1 , whereinwherein the composition is sulatingsul a : encapsulated in a capsule . ( a ) about 35 % to about 70 % by mass glyceryl monoli 14 . A method for delivering about 40 mg of oxycodone noleate ; comprising administering to a subject one or more pharma ( b ) about 20 % to about 50 % by mass polyethylene oxide ceutical dosage forms comprising about 35 % to about 70 % 30 comprising having a molecular weight ( M ) of about by mass glycerylmonolinoleate , about 20 % to about 50 % by 1 ,000 , 000 to about 7 , 000 , 000 ; and mass polyethylene oxide having a molecular weight (M _) of ( c ) about 1 % to about 20 % by mass of oxycodone or a salt about 1 , 000 , 000 to about 7 ,000 ,000 , and oxycodone or a salt thereof; and thereof , the method capable of achieving one or more of the the dosage form having been heated to about 50° C . to following pharmacokinetic parameters following ingestion 35 about 80° C . for about 10 min to about 180 min , and by the subject : cooled to room temperature ; and ( a ) a mean plasma oxycodone Tmax of about 4 . 5 hours to wherein the dosage form is resistant to crushing , grating , about 5 . 0 hours ; grinding, cutting , solvation , or dissolution in water or ( b ) a mean plasma oxycodone Cmar of about 40 ng/ mL to alcohol. about 65 ng /mL ; 40 18 . The method of claim 17 , wherein the capsule com ( c ) a mean plasma oxycodone AUCLOT . of about 400 prises a coated soft capsule . hºng/ mL to about 500 h .ng /mL ; * * * * *