United States Patent: Rariy Et Al

US010525053B2
United States Patent ( 10 ) Patent No.: US 10,525,053 B2

Rariy et al. (45 ) Date of Patent: * Jan . 7 , 2020
(54 ) ABUSE - DETERRENT PHARMACEUTICAL 9/1664 (2013.01); A61K 9/2013 (2013.01);
COMPOSITIONS OF OPIOIDS AND OTHER A61K 9/4808 (2013.01); A61K 9/4858
DRUGS (2013.01 ); A61K 9/5015 (2013.01 ); A61K
( 71 ) Applicant: COLLEGIUM 9/5042 ( 2013.01 ); A61K 31/13 ( 2013.01) ;
PHARMACEUTICAL , INC ., Canton ,
A61K 31/20 ( 2013.01 ); A61K 45/06 (2013.01 );
A61K 47/12 ( 2013.01 )
MA (US ) (58) Field of Classification Search
(72 ) Inventors: Roman V. Rariy , Allston , MA (US); CPC A61K 9/1617 ; A61K 31/485; A61K 9/14 ;
Alison B. Fleming , North Attleboro , A61K 47/12
MA (US ); Jane Hirsh , Wellesley, MA See application file for complete search history .
(US ); Alexander M. Klibanov , Boston ,
MA (US) ( 56 ) References Cited
(73 ) Assignee : Collegium Pharmaceutical, Inc., U.S. PATENT DOCUMENTS
Stoughton , MA (US )
1,349,326 A 8/1920 Davis
( * ) Notice : Subject to any disclaimer, the term of this 2,404,319 A 7/1946 Shelton
patent is extended or adjusted under 35 (Continued )
U.S.C. 154 (b ) by 0 days.
This patent is subject to a terminal dis FOREIGN PATENT DOCUMENTS
claimer .
CA 2273808 A1 9/2000
EP 0179583 A1 4/1986
(21 ) Appl. No .: 15 /727,134
(Continued )
(22 ) Filed : Oct. 6 , 2017
OTHER PUBLICATIONS
(65 ) Prior Publication Data
US 2018/0028529 A1 Feb. 1, 2018 [Author Unknown ], “ OxyContin Diversion and Abuse.” Depart
ment of Justice, National Drug Intelligence Center, Information
Bulletin , Jan. 2001 ; 3 pages, https://www.justice.gov/archive/ndic//
Related U.S. Application Data pubs/651/abuse.htm .
(60 ) Continuation of application No. 15/457,153 , filed on (Continued )
Mar. 13 , 2017 , now abandoned , which is a
continuation of application No. 14 /946,275 , filed on Primary Examiner — Lakshmi S Channavajjala
Nov. 19 , 2015 , now Pat. No. 9,592,200 , which is a
continuation of application No. 14 /054,513, filed on ( 74 ) Attorney , Agent, or Firm -Cooley LLP
Oct. 15 , 2013 , now Pat. No. 9,248,195 , which is a
division of application No. 12 /473,073 , filed on May
27 , 2009 , now Pat. No. 8,557,291, which is a (57) ABSTRACT
continuation -in -part of application No. 11/149,867,
filed on Jun . 10 , 2005, now Pat. No. 7,771,707 , and a An abuse -deterrent pharmaceutical composition has been
continuation - in -part of application No. 12 /112,993 , developed to reduce the likelihood of improper administra
filed on Apr. 30 , 2008 , now abandoned , which is a tion ofdrugs, especially drugs such as opioids. In a preferred
division of application No. 10 /614,866 , filed on Jul. embodiment, a drug is modified to increase its lipophilicity .
(Continued ) In some embodiments the modified drug is homogeneously
( 51 ) Int. Cl.
dispersed within spherical microparticles composed of a
A61K 31/485 ( 2006.01) material that is either slowly soluble or not soluble in water.
A61K 9/14 ( 2006.01) In some embodiments the drug containing microparticles or
A61K 31/20 ( 2006.01) drug particles are coated with one or more coating layers,
A61K 47/12 ( 2006.01) where at least one coating is water insoluble and /or organic
A61K 9/16 ( 2006.01 ) solvent insoluble. The abuse -deterrent composition retards
A61K 9/20 ( 2006.01) the release of drug , even if the physical integrity of the
A61K 31/13 ( 2006.01 )
A61K 9/48 (2006.01) formulation is compromised (for example , by chopping with
A61K 9/50 ( 2006.01) a blade or crushing ) and the resulting material is placed in
A61K 45/06 ( 2006.01 ) water, snorted , or swallowed . However, when administered
A61K 9/00 ( 2006.01) as directed , the drug is slowly released from the composition
(52 ) U.S. CI. as the composition is passes through the GI tract .
CPC A61K 31/485 ( 2013.01) ; A61K 9/0053
(2013.01); A61K 9/145 (2013.01); A61K 9/148
(2013.01 ); A61K 9/1617 (2013.01); A61K 12 Claims, No Drawings
US 10,525,053 B2
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Related U.S. Application Data 4,765,989 A 8/1988 Wonq et al .

4,769,372 A 9/1988 Kreek
7 , 2003, now Pat. No. 7,399,488 , said application No. 4,785,000 A 11/1988 Kreek et al .
12/ 473,073 is a continuation - in -part of application 4,806,341
4,812,446
A
A
2/1989
3/1989
Chien et al .
Brand
No. 12 / 112,937, filed on Apr. 30 , 2008, now aban 4,834,984 A 5/1989 Goldie et al .
doned , which is a continuation - in - part of application 4,844,909 A 7/1989 Goldie et al .
No. 10 /614,866 , filed on Jul. 7 , 2003 , now Pat. No. 4,861,598 A 8/1989 Oshlack
7,399,488 . 4,869,904 A 9/1989 Uekama et al.
4,957,681 A 9/1990 Klimesch et al .
4,970,075 A 11/1990 Oshlack
(60 ) Provisional application No.60 /579,191, filed on Jun . 4,990,341 A 2/1991 Goldie et al .
12, 2004 , provisional application No. 60 / 463,514 , 4,992,277 A 2/1991 Sangekar et al.
filed on Apr. 15 , 2003 , provisional application No. 5,026,556 A 6/1991 Drust et al.
10/1991 Gawin et al .
60/463,518, filed on Apr. 15, 2003 , provisional 5,059,600 A
application No. 60 /443,226 , filed on Jan. 28 , 2003, 5,069,909 A 12/1991 Sharma et al.
5,111,942 A 5/1992 Bernardin
provisional application No.60 /436,523 , filed on Dec. 5,113,585 A 5/1992 Rogers et al.
23 , 2002 , provisional application No. 60 /393,876 , 5,114,942 A 5/1992 Gawin et al.
filed on Jul. 5 , 2002. 5,130,311 A 7/1992 Guillaumet et al.
5,139,790 A 8/1992 Snipes
(56 ) References Cited 5,149,538 A 9/1992 Granger et al.
5,169,645 A 12/1992 Shukla et al.
U.S. PATENT DOCUMENTS 5,183,654 A 2/1993 Speck et al.
5,190,947 A 3/1993 Riess et al .
5,202,128 A 4/1993 Morella et al .
3,015,128 A 1/1962 Somerville, Jr. 5,215,758 A 6/1993 Krishnamurthy
3,065,143 A 11/1962 Christenson et al. 5,225,199 A 7/1993 Hidaka et al.
3,133,132 A 5/1964 Loeb et al . 5,232,685 A 8/1993 Speck et al.
3,146,167 A 8/1964 Lantz , Jr. et al. 5,232,934 A 8/1993 Downs
3,172,816 A 3/1965 Swintosky et al. 5,240,711 A 8/1993 Hille et al.
3,173,876 A 3/1965 Zobrist et al . 5,266,331 A 11/1993 Oshlack et al.
3,260,646 A 7/1966 Paulsen 5,273,758 A 12/1993 Royce
3,276,586 A 10/1966 Rosaen 5,273,760 A 12/1993 Oshlack
3,336,200 A 8/1967 Krause et al. 5,283,065 A 2/1994 Doyon et al.
3,402,240 A 9/1968 Cain et al. 5,286,493 A 2/1994 Oshlack et al.
3,541,005 A 11/1970 Strathmann et al. 5,290,816 A 3/1994 Blumberg
3,541,006 A 11/1970 Bixler et al. 5,300,302 A 4/1994 Tachon et al.
3,546,876 A 12/1970 Fokker et al. 5,321,012 A 6/1994 Mayer et al.
3,773,955 A 11/1973 Pachter et al. 5,324,351 A 6/1994 Oshlack et al.
3,845,770 A 11/1974 Theeuwes et al. 5,330,766 A 7/1994 Morella et al.
3,879,555 A 4/1975 Pachter et al . 5,354,863 A 10/1994 Dappen et al.
3,916,889 A 11/1975 Russell 5,356,467 A 10/1994 Oshlack et al.
3,965,256 A 6/1976 Leslie 5,376,705 A 12/1994 Leys et al.
3,966,940 A 6/1976 Pachter et al. 5,378,474 A 1/1995 Morella et al.
3,980,766 A 9/1976 Shaw et al. 5,399,351 A 3/1995 Leschiner et al.
4,063,064 A 12/1977 Saunders et al. 5,403,868 A 4/1995 Reid et al.
4,070,494 A 1/1978 Hollmeister et al. 5,409,944 A 4/1995 Black et al.
4,088,864 A 5/1978 Theeuwes et al . 5,411,745 A 5/1995 Oshlack et al .
4,098,575 A 7/1978 Matsushita 5,422,123 A 6/1995 Conte et al .
4,132,753 A 1/1979 Blichare et al. 5,422,134 A 6/1995 Hart et al.
4,160,020 A 7/1979 Ayer et al. 5,436,265 A 7/1995 Black et al.
4,175,119 A 11/1979 Porter 5,460,826 A 10/1995 Merrill et al.
4,200,098 A 4/1980 Ayer et al. 5,472,712 A 12/1995 Oshlack et al.
4,235,870 A 11/1980 Leslie 5,472,943 A 12/1995 Crain et al.
4,285,987 A 8/1981 Ayer et al. 5,474,995 A 12/1995 Ducharme et al .
4,293,539 A 10/1981 Ludwiq et al. 5,478,577 A 12/1995 Sackler et al.
4,366,310 A 12/1982 Leslie 5,500,227 A 3/1996 Oshlack et al.
4,385,057 A 5/1983 Bjork et al. 5,502,058 A 3/1996 Mayer et al.
4,389,393 A 6/1983 Schor et al. 5,505,959 A 4/1996 Tachon et al .
4,424,205 A 1/1984 LaHann et al. 5,508,042 A 4/1996 Oshlack et al.
4,443,428 A 4/1984 Oshlack et al . 5,508,043 A 4/1996 Krishnamurthy
4,457,933 A 7/1984 Gordon et al. 5,510,368 A 4/1996 Lau et al.
4,459,278 A 7/1984 Porter 5,514,680 A 5/1996 Weber et al.
4,483,847 A 11/1984 Augart 5,521,213 A 5/1996 Prasit et al.
4,569,937 A 2/1986 Baker et al. 5,536,752 A 7/1996 Ducharme et al.
4,588,580 A 5/1986 Gale et al. 5,545,628 A 8/1996 Deboeck
4,599,326 A 7/1986 Marvola et al. 5,549,912 A 8/1996 Oshlack et al.
4,599,342 A 7/1986 LaHann 5,550,142 A 8/1996 Ducharme et al .
4,610,870 A 9/1986 Jain et al . 5,552,422 A 9/1996 Gauthier et al.
4,612,008 A 9/1986 Wong et al. 5,556,838 A 9/1996 Mayer et al.
4,629,623 A 12/1986 Balazs et al.
5,580,578 A 12/1996 Oshlack et al.
4,661,492 A 4/1987 Lewis et al . 12/1996 Shell
4,666,705 A 5/1987 Decrosta et al. 5,582,837 A
4,675,140 A 6/1987 Sparks et al. 5,593,695 A 1/1997 Merrill et al.
4,710,384 A 12/1987 Rotman 5,593,994 A 1/1997 Batt et al .
4,713,243 A 12/1987 Schiraldi et al . 5,604,253 A 2/1997 Lau et al.
4,722,941 A 2/1988 Eckert et al . 5,604,260 A 2/1997 Guay et al.
4,737,151 A 4/1988 Clement et al. 5,616,601 A 4/1997 Khanna et al.
4,764,378 A 8/1988 Keith et al. 5,635,159 A 6/1997 Fu Lu et al.
US 10,525,053 B2
Page 3
( 56 ) References Cited 6,419,954 B1 7/2002 Chu

6,436,441 B1 8/2002 Sako et al.
U.S. PATENT DOCUMENTS 6,440,464 B1 8/2002 Hsia et al.
6,468,559 B1 10/2002 Chen et al.
5,639,476 A 6/1997 Oshlack et al . 6,468,560 B2 10/2002 Sauer et al.
5,639,789 A 6/1997 Lau et al. 6,475,494 B2 11/2002 Kaiko et al .
5,656,295 A 8/1997 Oshlack et al. 6,488,963 B1 12/2002 McGinity et al.
5,667,805 A 9/1997 Merrill et al. 6,491,949 B2 12/2002 Faour et al .
5,672,360 A 9/1997 Sackler et al. 6,552,031 B1 4/2003 Burch et al.
5,679,650 A 10/1997 Fukunaga et al. 6,559,159 B2 5/2003 Carroll et al .
5,681,585 A 10/1997 Oshlack et al. 6,572,885 B2 6/2003 Oshlack et al.
5,695,781 A 12/1997 Zhang et al. 6,593,367 B1 7/2003 Dewey et al.
5,700,410 A 12/1997 Nakamichi et al. 6,627,635 B2 9/2003 Palermo et al .
5,702,725 A 12/1997 Merrill et al. 6,645,527 B2 11/2003 Oshlack et al.
5,730,716 A 3/1998 Beck et al . 6,692,767 B2 2/2004 Burnside et al.
5,741,524 A 4/1998 Staniforth et al. 6,696,088 B2 2/2004 Oshlack et al .
5,756,123 A 5/1998 Yamamoto et al. 6,706,281 B2 3/2004 Oshlack et al.
5,756,483 A 5/1998 Merkus 6,723,343 B2 4/2004 Kugelmann
5,762,963 A 6/1998 Byas -Smith 6,733,783 B2 5/2004 Oshlack et al.
6/1998 6,743,442 B2 6/2004 Oshlack et al.
9/1998 Aryes et al.
5,766,623 A
5,811,126 A Krishnamurthy 6,808,720 B2 10/2004 Unger
5,843,480 A 12/1998 Miller et al. 6,919,372 B1 7/2005 Yamashita et al.
5,849,240 A 12/1998 Miller et al . 6,984,403 B2 1/2006 Hagen et al.
5,866,161 A 2/1999 Childers et al. 6,995,169 B2 2/2006 Chapleo et al.
5,866,164 A 2/1999 Kuczynski et al. 7,011,846 B2 3/2006 Shojaei et al.
5,879,705 A 3/1999 Heafield et al. 7,141,250 B2 11/2006 Oshlack et al.
5,891,471 A 4/1999 Miller et al. 7,144,587 B2 12/2006 Oshlack et al .
5,891,919 A 4/1999 Blum et al. 7,157,103 B2 1/2007 Sackler
5,914,129 A 6/1999 Mauskop 7,201,920 B2 4/2007 Kumar et al .
5,914,131 A 6/1999 Miller et al. 7,261,529 B2 8/2007 Persyn et al.
5,948,787 A 9/1999 Merrill et al. 7,276,250 B2 10/2007 Baichwal et al .
5,952,005 A 9/1999 Olsson et al . 7,332,182 B2 2/2008 Sackler
5,958,452 A 9/1999 Oshlack et al. 7,399,488 B2 7/2008 Hirsh et al.
5,958,459 A 9/1999 Chasin et al . 7,510,726 B2 3/2009 Kumar et al.
5,965,163 A 9/1999 Miller et al . 7,670,612 B2 3/2010 Miller
5,965,161 A 10/1999 Oshlack et al . 7,727,557 B2 6/2010 Sackler
5,968,551 A 10/1999 Oshlack et al. 7,771,707 B2 8/2010 Hirsh et al.
6,008,355 A 12/1999 Huang et al. 7,776,314 B2 8/2010 Bartholomaus
6,024,982 A 2/2000 Oshlack et al . 7,842,307 B2 * 11/2010 Oshlack A61K 9/1635
6,048,736 A 4/2000 Kosak 424/450
6,068,855 A 5/2000 Leslie et al. 7,943,174 B2 5/2011 Oshlack et al .
6,096,722 A 8/2000 Bennett et al . 7,981,439 B2 7/2011 Kumar et al.
6,103,261 A 8/2000 Chasin et al . 8,017,148 B2 9/2011 Sackler
6,120,751 A 9/2000 Unger 8,075,872 B2 12/2011 Arkenau -Maric et al.
6,124,282 A 9/2000 Sellers et al. 8,101,630 B2 1/2012 Kumar et al.
6,126,969 A 10/2000 Shah et al. 8,114,383 B2 2/2012 Bartholomaus
6,136,864 A 10/2000 Nichols et al . 8,114,384 B2 2/2012 Arkenau et al.
6,143,322 A 11/2000 Sackler et al. 8,192,722 B2 6/2012 Arkenau -Maric et al.
6,153,621 A 11/2000 Hamann 8,309,060 B2 11/2012 Bartholomaus et al.
6,156,764 A 12/2000 Asmussen et al. 8,337,888 B2 12/2012 Wright et al.
6,162,467 A 12/2000 Miller et al. 8,389,007 B2 3/2013 Wright et al.
6,177,567 B1 1/2001 Chiu et al . 8,409,616 B2 4/2013 Kumar et al.
6,210,712 B1 4/2001 Edgren et al. 8,449,909 B2 5/2013 Hirsh et al.
6,210,714 B1 4/2001 Oshlack et al. 8,524,275 B2 9/2013 Oshlack et al.
6,223,075 B1 4/2001 Beck et al . 8,529,948 B1 9/2013 Wright et al.
6,228,863 B1 5/2001 Palermo et al. 8,557,291 B2 10/2013 Rariy et al .
6,245,357 B1 6/2001 Edaren et al. 8,569,228 B2 10/2013 Jenkins et al .
6,248,363 B1 6/2001 Patel et al. 8,609,683 B2 12/2013 Wright et al.
6,251,430 B1 6/2001 Zhang et al. 8,637,540 B2 1/2014 Kumar et al.
6,255,502 B1 7/2001 Penkler et al. 8,652,497 B2 2/2014 Sackler
6,261,599 B1 7/2001 Oshlack et al. 8,652,515 B2 2/2014 Sackler
6,267,985 B1 7/2001 Chen et al. 8,758,813 B2 6/2014 Hirsh et al.
6,277,384 B1 8/2001 Kaiko et al. 8,840,928 B2 9/2014 Rariy et al.
6,277,398 B1 8/2001 Caruso 8,871,265 B2 10/2014 Wright et al.
6,290,990 B1 9/2001 Grabowski et al. 8,999,961 B2 4/2015 Wright et al.
6,294,194 B1 9/2001 Horhota et al. 9,034,376 B2 5/2015 Wright et al.
6,294,195 B1 9/2001 Oshlack et al. 9,040,084 B2 5/2015 Wright et al.
6,309,663 B1 10/2001 Patel et al. 9,044,398 B2 6/2015 Hirsh et al.
6,309,668 B1 10/2001 Bastin et al. 9,044,435 B2 6/2015 Wright et al.
6,310,072 B1 10/2001 Smith et al . 9,060,976 B2 6/2015 Wright et al.
6,312,704 B1 11/2001 Farah et al. 9,155,717 B2 10/2015 Sackler
6,328,979 B1 12/2001 Yamashita et al. 9,248,195 B2 2/2016 Rariy et al.
6,335,033 B2 1/2002 Oshlack et al. 9,308,170 B2 4/2016 Wright et al.
6,344,212 B2 2/2002 Reder et al . 9,308,171 B2 4/2016 Wright et al.
6,348,469 B1 2/2002 Seth 9,387,173 B2 7/2016 Wright et al.
6,352,721 B1 3/2002 Faour 9,387,174 B2 7/2016 Wright et al.
6,375,957 B1 4/2002 Kaiko et al . 9,592,200 B2 3/2017 Rariy et al.
6,379,707 B2 4/2002 Vladyka , Jr. et al. 9,682,075 B2 6/2017 Rariy et al.
6,403,056 B1 6/2002 Unger 9,693,961 B2 7/2017 Wright et al.
US 10,525,053 B2
Page 4
( 56 ) References Cited 2006/0251721

2007/0003616
Al
A1
11/2006 Cruz et al.
1/2007 Arkenau -Maric et al.
U.S. PATENT DOCUMENTS 2007/0003617 A1 1/2007 Fischer et al.
2007/0054002 A1 3/2007 Persyn et al.
9,737,530 B1 8/2017 Saim et al. 2007/0110807 A1 5/2007 Vergnault et al.
9,763,883 B2 9/2017 Hirsh et al. 2007/0166234 Al 7/2007 Kumar et al.
9,968,598 B2 5/2018 Saim et al. 2007/0264327 Al 11/2007 Kumar et al.
10,004,729 B2 * 6/2018 Rariy A61K 9/4808 2008/0063725 A1 3/2008 Guimbertau et al.
10,188,644 B2 1/2019 Saim et al. 2008/0095843 A1 4/2008 Nutalapati et al.
10,206,881 B2 2/2019 Wright et al. 2008/0176955 Al 7/2008 Heck et al.
2001/0006650 Al 7/2001 Burnside et al. 2008/0199530 A1 8/2008 Hirsh et al.
2001/0031278 A1 10/2001 Oshlack et al. 2008/0254123 Al 10/2008 Fischer et al.
2001/0036476 A1 11/2001 Oshlack et al . 2008/0260815 Al 10/2008 Haves et al .
2002/0032166 Al 3/2002 Shefter et al. 2008/0260819 Al 10/2008 Fleming et al.
2002/0036154 A1 3/2002 Murari et al. 2009/0081290 Al 3/2009 McKenna et al.
2002/0081333 Al 6/2002 Oshlack et al. 2009/0142378 A1 6/2009 Frisbee
2002/0131988 A1 9/2002 Foster et al. 2009/0169587 A1 7/2009 Baichwal et al .
2002/0142039 Al 10/2002 Claude 2009/0215808 Al 8/2009 Yum et al.
2002/0187192 A1 12/2002 Joshi et al . 2009/0297617 A1 12/2009 Rariy et al.
2003/0004177 Al 1/2003 Kao et al . 2010/0216829 A2 8/2010 Kumar et al.
2003/0021841 A1 1/2003 Matharu et al. 2010/0221293 Al 9/2010 Cruz et al.
2003/0026838 A1 2/2003 Farrell 2010/0260834 A1 10/2010 Hirsh et al .
2003/0035839 Al 2/2003 Hirsh et al. 2011/0142943 A1 6/2011 Rariy et al.
2003/0044446 Al 3/2003 Moro et al. 2011/0262532 Al 10/2011 Oshlack et al .
2003/0059397 A1 3/2003 Hughes 2012/0164220 A1 6/2012 Huang
2003/0059471 A1 3/2003 Compton et al. 2013/0045960 A1 2/2013 Hirsh et al.
2003/0064099 A1 4/2003 Oshlack et al. 2013/0217716 A1 8/2013 Wright et al.
2003/0064122 Al 4/2003 Goldberg et al. 2013/0245055 Al9/2013 Wright et al.
2003/0068276 Al 4/2003 Hughes et al. 2013/0310413 A1 11/2013 Hirsh et al.
2003/0068370 A1 4/2003 Sackler 2014/0105987 A14/2014 Rariy et al.
2003/0068371 A1 4/2003 Oshlack et al. 2014/0121232 A15/2014 Hirsh et al.
2003/0068375 Al 4/2003 Wright et al. 2014/0213606 A17/2014 Wright et al.
2003/0068392 Al 4/2003 Sackler 2014/0271835 Al9/2014 Wengner
2003/0082230 A1 5/2003 Baichwal et al. 2014/0371257 12/2014
A1 Wright et al.
2003/0124061 A1 7/2003 Roberts 2015/0004244 A1 1/2015 Rariy et al.
2003/0125347 A1 7/2003 Anderson et al . 2015/0005332 A1 1/2015 Rariy et al.
2003/0126428 A1 7/2003 Liu et al. 2015/0031718 Al 1/2015 Wright et al.
2003/0170181 Al 9/2003 Midha 2015/0140083 Al 5/2015 Wright et al.
2003/0232081 Al 12/2003 Doshi et al . 2015/0147391 Al 5/2015 Wright et al.
2004/0010000 A1 1/2004 Ayer et al. 2015/0148319 Al 5/2015 Wright et al.
2004/0047907 Al 3/2004 Oshlack et al. 2015/0164835 A1 6/2015 King et al.
2004/0052731 Al 3/2004 Hirsh et al. 2015/0182628 A1 7/2015 Wright et al.
2004/0062778 A1 4/2004 Shefer et al . 2015/0238481 Al 8/2015 Wright et al.
2004/0126428 A1 7/2004 Hughes et al. 2015/0265596 A1 9/2015 Hirsh et al.
2004/0131552 Al 7/2004 Boehm 2015/0265602 A1 9/2015 Wright et al.
2004/0151791 A1 8/2004 Mato - Alvarez et al. 2015/0265603 A1 9/2015 Wright et al.
2004/0170680 A1 9/2004 Oshlack et al. 2015/0265604 Al 9/2015 Wright et al.
2004/0224020 A1 11/2004 Schoenhard 2015/0265605 A1 9/2015 Wright et al.
2004/0228802 A1 11/2004 Chang et al. 2015/0265606 A1 9/2015 Wright et al.
2004/0241234 A1 12/2004 Vikov 2015/0265607 Al 9/2015 Wright et al.
2004/0253310 A1 12/2004 Fischer et al. 2015/0273064 Al 10/2015 Wright et al.
2005/0013862 A1 1/2005 Tobyn et al. 2015/0283128 Al 10/2015 Wright et al.
2005/0020613 Al 1/2005 Boehm et al. 2015/0283129 A1 10/2015 Wright et al.
2005/0031546 Al 2/2005 Bartholomaus et al. 2015/0283130 A1 10/2015 Wright et al.
2005/0063909 Al 3/2005 Wright et al. 2015/0283250 A1 10/2015 Wright et al .
2005/0106249 A1 5/2005 Hwang et al. 2015/0374628 A1 12/2015 Wright et al.
2005/0112067 Al 5/2005 Kumar et al . 2015/0374631 Al 12/2015 Wright et al.
2005/0112201 Al 5/2005 Baichwal et al. 2016/0000712 A1 1/2016 Wright et al.
2005/0118267 Al 6/2005 Baichwal et al. 2016/0000717 Al 1/2016 Wright et al.
2005/0158382 A1 7/2005 Cruz et al. 2016/0000718 A1 1/2016 Wright et al.
2005/0163717 Al 7/2005 Anderson et al. 2016/0000719 Al 1/2016 Wright et al.
2005/0181050 A1 8/2005 Hirsh et al. 2016/0000776 A1 1/2016 Wright et al.
2005/0186139 A1 8/2005 Bartholomaeus et al. 2016/0058716 Al 3/2016 Wright et al.
2005/0186285 A1 8/2005 Ray et al. 2016/0074326 A1 3/2016 Rariy et al.
2005/02 14223 A1 9/2005 Bartholomaeus et al . 2016/0151277 A1 6/2016 Wright et al.
2005/0236741 Al 10/2005 Arkenau et al. 2016/0151289 Al 6/2016 Wright et al.
2005/0276853 Al 12/2005 Baichwal et al . 2016/0151290 A1 6/2016 Wright et al.
2005/0281748 A1 12/2005 Hirsh et al. 2016/0151291 Al 6/2016 Wright et al.
2006/0002860 A1 1/2006 Bartholomaus et al . 2016/0151297 Al 6/2016 Wright et al.
2006/0018837 A1 1/2006 Preston et al . 2016/0151355 Al 6/2016 Wright et al.
2006/0039864 A1 2/2006 Bartholomaus et al . 2016/0151356 Al 6/2016 Wright et al.
2006/0104909 Al 5/2006 Vaghefi et al. 2016/0151357 A1 6/2016 Wright et al.
2006/0110457 Al 5/2006 Labrecque et al. 2016/0151358 A1 6/2016 Wright et al.
2006/0111383 A1 5/2006 Casner et al. 2016/0151360 A1 6/2016 Wright et al.
2006/0165790 A1 7/2006 Walden et al. 2016/0151499 A1 6/2016 Wright et al.
2006/0188447 Al 8/2006 Arkenau -Maric et al. 2016/0151502 A1 6/2016 Wright et al.
2006/0193782 A1 8/2006 Bartholomaus et al. 2017/0020863 A1 1/2017 Wright et al.
US 10,525,053 B2
Page 5
( 56 ) References Cited WO WO 2004/026283 4/2004

WO WO 2004/037259 5/2004
U.S. PATENT DOCUMENTS WO WO 2004/075877 A1 9/2004
WO WO 2005/053587 6/2005
2017/0020864 Al 1/2017 Wright et al. WO WO 2005/123039 Al 12/2005
2017/0065524 Al 3/2017 Wright et al. WO WO 2010/078486 7/2010
2017/0065525 A1 3/2017 Wright et al. WO WO 2017/222575 Al 12/2017
2017/0112765 A1 4/2017 Wright et al.
2017/0182032 A1 6/2017 Rariy et al. OTHER PUBLICATIONS
2017/0296533 A1 10/2017 Wright et al.
2017/0319575 Al 11/2017 Rariy et al.
2017/0360710 A1 12/2017 Hirsh et al. “ Castor oil, hydrogenated ,” European Pharmacopoeia V.5 , p . 1197
2017/0368057 Al 12/2017 Saim et al . 1198 ( 2005).
2018/0028528 A1 2/2018 Hirsh et al. “ International Preliminary Report on Patentability ,” 3 pages, PCT
2018/0125788 A1 5/2018 Wright et al. appl. No. PCT/US03/21095 (dated Apr. 25 , 2005).
2018/0147151 A1 5/2018 Wright et al. " International Preliminary Report on Patentability ,” 6 pages, PCT
2018/0289697 A1 10/2018 Saim et al .
2018/0369236 A1 12/2018 Rariy et al. appl. No. PCT/US2005/020588 (dated Oct. 2 , 2006 ).
2019/0167662 A1 6/2019 Rariy et al. “ International Search Report,” 2 pages, PCT appl. No. PCT/US03 /
2019/0255038 Al 8/2019 Saim et al . 21095 ( dated Nov. 6 , 2003).
2019/0262335 A1 8/2019 Rariy et al. “ International Search Report ,” 2 pages, PCT appl. No. PCT/US2016 /
050092 ( dated Nov. 22 , 2016 ).
FOREIGN PATENT DOCUMENTS “ International Search Report,” 4 pages, PCT appl.No.PCT/US2005/
020588 ( dated Sep. 9 , 2005).
EP 0253104 A1 1/1988 “ Supplementary European Search Report ,” 7 pages, EP appl. No.
EP 318262 5/1989 03763229.6 ( dated Sep. 19 , 2008).
EP 0375063 A1 6/1990 Extended European Search Report for European Patent Application
EP 0578231 A1 1/1994
EP 0647448 A1 4/1995 No. EP 17188009.9 , dated Apr. 10 , 2018 , 7 pages .
EP 0661045 5/1995 “ Written Opinion of the International Searching Authority,” 6 pages ,
EP 0 661 045 A1 7/1995 PCT appl. No. PCT/US2005/020588 ( dated Sep. 9 , 2005) .
EP 0698389 2/1996
1/2000
“ Written Opinion of the International Searching Authority,” 7 pages,
EP 0 974 345 PCT appl. No. PCT/US2016 /050092 (dated Nov. 22 , 2016 ).
EP 1293195 3/2003 “ Written Opinion ,” 4 pages, PCT appl. No. PCT/US03/21095 (dated
EP 0 828 802 6/2003
GB 1513166 A 6/1978 Jun . 20 , 2004 ).
GB 2162061 A 1/1986 Abuse and Mental Health Services Administration , “ Results from
WO WO 91/07950 6/1991 the 2004 National Survey on Drug Use and Health : National
WO WO 1993/10765 6/1993 Findings,” pp . 1-310 (2005) .
WO WO 1993/010765 A1 6/1993 Berkland , et al., “Fabrication of PLG microspheres with precisely
WO WO 95/18602 7/1995 controlled and monodisperse size distributions.” Journal of Con
WO WO 95/20947 8/1995
WO WO 1995/020947 Al 8/1995 trolled Release ( 2001); 73 ( 1 ): 59-74 .
WO WO 96/06528 3/1996 Bourret, et al., “ Rheological Behaviour of Saturated Polyglycolyzed
WO WO 97/12605 4/1997 Glycerides." Journal of Pharmacy and Pharmacology ( 1994 ); 46 :
WO WO 1997/014438 A1 4/1997 538-541 .
WO WO 97/37689 10/1997 Buist et al., “ Four salt phases of theophylline,” Struct. Chem . Acta
WO WO 97/48385 12/1997 Crystal. Sect. C C70 :220-224 (2014 ).
WO WO 97/49384 12/1997 Bush et al., “ A comparison of a theophylline -ephedrine combination
WO WO 1997/049384 A1 12/1997
WO WO 1997/049402 A1 12/1997 with terbutaline,” Ann . Allergy 41: 13-17 ( 1978 ) abstract.
WO WO 1998/002187 Al 1/1998 Chemical Abstract Society (CAS), Properties for HPMC (CAS reg .
WO WO 1998/018827 A1 5/1998 No. 9004-65-3 ) accessed Jun . 29 , 2013 .
WO WO 1999/001111 A1 1/1999 Choi et al., “Hydrophobic ion pair formation between leuprolide
WO WO 99/20255 4/1999 and sodium oleate for sustained release from biodegradable poly
WO WO 99/32119 7/1999 meric microspheres,” Int. J. Pharm . 203 : 193-202 ( 2000 ).
WO WO 99/32120 7/1999 Choi, et al., “ Effect of polymer molecular weight on nanocomminu
WO WO 1999/042086 A1 8/1999 tion of poorly soluble drug.” Drug Delivery ( 2008 ); 15 (5 ): 347-353.
WO WO 99/44591 9/1999 Cortesi, et al., " Sugar cross -linked gelatin for controlled release :
WO WO 1999/63971 A1 12/1999 microspheres and disks,” Biomaterials 19: 1641-1649 ( 1998).
WO WO 2000/033835 6/2000
WO WO 2000/38649 Al 7/2000 Emås and Nyqvist, “Methods of studying aging and stabilization of
WO WO 2000/050007 Al 8/2000 spray -congealed solid dispersions with carnauba wax.” Interna
WO WO 2001/008661 A2 2/2001 tional Journal of Pharmaceutics ( 2000 ); 197 ( 1-2 ): 117-127 , 13
WO WO 2001/058447 8/2001 pages .
WO WO 2001/058447 A1 8/2001 Gandhi, et al., “ Extrusion and spheronization in the development of
WO WO 2001/072338 A1 10/2001 oral controlled -release dosage forms." Pharmaceutical Science &
WO WO 2002/013786 A2 2/2002 Technology Today ( 1999); 2 ( 4 ): 160-170 .
WO WO 2002/087512 A2 11/2002 Gennaro, ed ., Remington : The Science and Practice of Pharmacol
WO WO 2002/087558 11/2002 ogy , 20th ed ., Lipincott : Baltimore ,MD, pp . 704-706 ( 2000 ).
WO WO 2002/094254 11/2002 Guidance for Industry Q1A (R2) Stability Testing of New Drug
WO WO 2003/004029 A1 1/2003 Substances and Products, U.S. Department of Health and Human
WO WO 2003/015531 2/2003
WO WO 2003/024430 3/2003 Services Food and Drug Administration , Center for Drug Evalua
WO WO 2003/026743 4/2003 tion and Research ( CDER ), Center for Biologics Evaluation and
WO WO 2003/035090 5/2003 Research (CBER ) (“ FDA Guidance ” ), Nov. 2003 , ICH , Revision 2 ,
WO WO 2003/092676 11/2003 25 pages.
WO WO 2004/004693 A1 1/2004 Hawley's Condensed Chemical Dictionary, 13th ed ., John , Wiley &
WO WO 2004/026256 1/2004 Sons, Inc., New York , 1997, p . 1178, defining “ wax ” , 4 pages.
US 10,525,053 B2
Page 6
( 56 ) References Cited Detailed Statement of the Factual and Legal Bases for Collegium
Pharmaceutical, Inc.'s Paragraph IV Certification With Respect to
OTHER PUBLICATIONS U.S. Pat.Nos. 7,674,799 , 7,674,800 , 7,683,072 , 7,776,314 , 8,309,060 ,
8,808,741, 8,894,987 , 8,894,988 , 9,060,976 , 9,073,933 , 9,492,389 ,
Kim and Pack , Microspheres for Drug Delivery , in BioMEMS and 9,492,391, 9,492,392 , 9,492,393 , 9,522,919 , and 9,675,610 dated
Biomedical/Nanotechnology, pp. 19-50 , Springer US (2006 ), 34 Aug. 25 , 2017 , 65 pages.
pages . Collegium's Prelim . Invalidity Contentions in C.A. No. 15 - cv
Lan et al., " Studies on the Synthesis and Thermal Properties of 13099 -FDS dated Aug. 19 , 2016 , 117 pages.
Copoly ( L - lactic acid /glycolic acid ) by Direct Melt Polycondensa Collegium's Prelim . Invalidity Contentions in 15 -cv - 13099 -FDS
tion ," J. Appl. Polymer Sci. 92 : 2163-2168 ( 2004 ). dated Oct. 5 , 2016 , 100 pages .
Leuner and Dressman , “ Improving drug solubility for oral delivery Collegium's Prelim . Invalidity Contentions in 15 -cv - 13099 - FDS
using solid dispersions.” European Journal of Pharmaceutics and dated Jun . 16 , 2017, 59 pages.
Biopharmaceutics (2000 ); 50 ( 1): 47-60 . Collegium's Prelim . Invalidity Contentions in 15 -cv - 13099 -FDS
Meyer and Manning, “ Hydrophobic Ion Pairing : Altering the Solu dated Apr. 25 , 2017, 55 pages .
bility Properties of Biomolecules.” Pharmaceutical Research ( 1998); Collegium's MOL ISO Motion for Summary Judgment in C.A. No.
15 (2 ): 188-193. 15 -cv -13099 (FDS ) dated Feb. 14 , 2017 , 52 pages .
Murthy and Ghebre -Sellassie, “ Current perspectives on the disso Collegium's Reply MOL ISO its Motion for Summary Judgment in
lution stability of solid oral dosage forms.” Journal of Pharmaceu C.A. No. 15 -cv - 13099 ( FDS ) dated May 12 , 2017 , 52 pages.
tical Sciences (1993) ; 82 (2 ): 113-126 . Concerta tablets Highlights of Prescribing Information , Nov. 2010 ,
27 pages.
Nakamura , et al., “ Development of an oral sustained release drug U.S. Appl. No. 60/376,470 to Ayer et al., 67 pages.
delivery system utilizing pH -dependent swelling of carboxyvinyl Declaration of Todd Scungio dated Mar. 12 , 2018 , 2 pages.
polymer” , J. Control. Rel., 111: 309-315 ( 2006 ). Collegium Pharmaceutical Study: Intravenous Abuse Comparison
Ozturk et al., “Mechanism of Release from Pellets Coated with an of Oxycodone DETERxTM Versus OxyContinTM ( Filed Under Seal),
Ethylcellulose - Based Film ,” J. Control. Rel. 14 :203-213 ( 1990 ). dated Apr. 30 , 2010, 16 pages.
Pöyhia , et al., “ The pharmacokinetics and metabolism of oxycodone Complaint, Purdue Pharma L.P. et al., v. Collegium Pharmaceuti
after intramuscular and oral administration to healthy subjects.” cal, Inc., 17 -cv - 11814 [DKT 1], dated Sep. 21 , 2017, 10 pages .
British Journal of Clinical Pharmacology ( 1992 ); 33(6 ): 617-621. Order Granting Consolidation , Purdue Pharma, L.P. et al. v. Col
Raffin et al., "Sodium pantoprazole- loaded enteric microparticles legium Pharmaceutical, Inc., 15 - cv - 13099 [DKT 152 ], dated Dec.
prepared by spray drying: Effect of the scale of production and 14 , 2017 , 4 pages .
process validation,” Int. J. Pharm . 324 : 10-18 (2006 ). Joint Claim Construction and Prehearing Statement , Purdue Pharma,
Redden et al., “ In vitro hydrolysis of polyunsaturated fatty acid L.P. et al. v. Collegium Pharmaceutical, Inc., 15 - cv -3099 [DKT
N -acyloxymethyl derivatives of theophylline,” Int. J. Pharm . 165:87 116 ], dated Mar. 2 , 2017, 12 pages.
96 ( 1998 ). A.Gennaro ed ., Remington : The Science and Practice of Pharmacy
Rodriguez et al., “ Description and preliminary evaluation of a new ( 20th ed . 2000 ), pp . 1444-1449 .
ultrasonic atomizer for spray -congealing processes,” Int. J. Pharm . E. Cone et al., “ An Iterative Model for in vitro Laboratory Assess
183 ( 2 ): 133-143 ( 1999 ). ment of Tamper Deterrent Formulations” , 131 Drug and Alcohol
Sjökvist, et al., “Physicochemical aspects of drug release . XIV . The Dependence 100-105 ( 2013 ).
effects of some ionic and non -ionic surfactants on properties of a FDA , Abuse-Deterrent Opioids — Evaluation and Labeling : Guid
ance for Industry (Apr. 2015 ), 29 pages .
sparingly soluble drug in solid dispersions.” International Journal of Plaintiffs ' Opening Claim Construction Brief, Purdue Pharma L.P.
Pharmaceutics ( 1992); 79( 1-3 ): 123-133 . et al. v. Collegium Pharmaceutical, Inc., 15 -cv - 13099 [DKT 99 ]
Takka et al., “ Effect of anionic polymers on the release of propanol (Redacted version filed in district court ), dated Dec. 20 , 2016 , 26
hydrochloride from matrix tablets,” Eur. J. Pharm . Biopharm . pages.
52 :75-82 (2001). S. Passik et al., “ Psychiatric and Pain Characteristics of Prescription
Toxicological Evaluation of Some Food Colours, Emulsifiers , Sta Drug Abusers Entering Drug Rehabilitation ” , 20:2 J. of Pain &
bilizers, Anti -Caking Agents and Certain Other Substances FAO Palliative Care Pharmacotherapy 5-13 (2006 ).
Nutrition Meetings Report Series No. 46A WHO / FOOD ADD / 70 . Bulletin Technique Gattefosse Report ( 1988 ), 101 pages.
36 , Report on Deliberations of the Joint FAO /WHO Expert Com S. Harris et al., “ Abuse Potential, Pharmacokinetics, Pharmacodynam
mittee on Food Additives, Rome, May 27 - Jun . 4 , 1969 (“ FAO /WHO ics, and Safety of Intranasally Administered Crushed Oxycodone
report ” ) , 162 pages. HCI Abuse -Deterrent Controlled -Release Tablets in Recreational
U.S. Department of Health and Human Services et al., “ Abuse Opioid Users” , 54 (4 ) J. of Clinical Pharmacology 468-477 (2013 ).
Deterrent Opioids — Evaluation and Labeling. Guidance for Indus B. Lara -Hernandez et al., “Effect of Stearic Acid on the Properties
try ,” http://www.fda.gov/Drugs/GuidanceCompliance
>>
of Metronidazole /Methocel K4M Floating Matrices” , 45 ( 3) Brazil
RegulatoryInformation /Guidances/default.htm , 29 pages (Apr. 2015 ). ian J. of Pharm . Scis. 497-505 ( 2009).
Yow et al., “ Combined Streptomycin and Erythromycin Therapy in B. Alberts et al., Essential Cell Biology ( 2nd ed . 2004), 4 pages .
Subacute Bacterial Endocarditis.” Am . J. Med . ( 1954 ); 16 ( 4 ):613 . C. Smith et al ., “Oral and Oropharyngeal Perceptions of Fluid
Declaration by Dr. Alison Fleming , dated Jun . 29, 2007, submitted Viscosity Across the Age Span ”, Dysphagia (2006 ), 9 pages .
in U.S. Appl. No. 11/ 149,867, filed Nov. 2 , 2009. Rowe et al. eds., Handbook of Pharmaceutical Excipients ( 7th ed .
Amended Petition for Post Grant Review ; PGR2018-00048; U.S. 2012 ), 10 pages .
Pat. No: 9,693,961; dated Mar. 28, 2018 . Y. Zhang et al., “Effect of Processing Methods and Heat Treatment
Breitenbach , J., Melt Extrusion : from Process to Drug Delivery on the Formation of Wax Matrix Tablets for Sustained Drug
Technology, 54 Eur. J. Pharm . & Biopharm ., 107-17 (2002). Release” , 6 (2 ) Pharm . Dev. And Tech . 131-144 (2001).
Chemistry: The Central Science , Theodore L. Brown et al, 9th I. Ghebre -Sellassie ed ., Pharmaceutical Pelletization Technology
Edition ( 2003 ) pp . 492-494 . ( 1989 ), 26 pages.
Collegium Pharmaceutical, “ XtampzaTM ER (Extended -Release Transcript of Conference Call - Aug. 3, 2018, 21 pages.
Oxycodone),” FDA Advisory Committee Briefing Document, Sep. Non -Addressed PGGs — Exhibit from Deposition of Panayiotis P.
11, 2015 , 93 pages. Constantinides , dated Mar. 20 , 2019 , 1 page .
Detailed Statement of the Factual and Legal Bases for Collegium Ratsimbazafy, “Effect of Formulation on the Rheology of Theoph
Pharmaceutical, Inc.'s Paragraph IV Certification With Respect to ylline Compound Suspensions in Gelucires ” J. Pharm . Pharmacol.
U.S. Pat. Nos. 6,488,963; 7,674,799 ; 7,674,800 ; 7,683,072 ; 7,776,314 ; 1997 , 49 : 855-857.
8,114,383 ; 8,309,060 ; 8,337,888 ; 8,808,741 ; 8,894,987 ; and 8,894,988 A. Kibbe ed ., Handbook of Pharmaceutical Excipients 3rd Ed .
dated Feb. 11, 2015 , 46 pages . (2000 ) Index , pp . 645-665.
US 10,525,053 B2
Page 7
( 56 ) References Cited Handbook of Pharmaceutical Excipients, ( Ainley Wade & Paul J.

Weller eds., 2nd ed . 1994 ), 13 pages .
OTHER PUBLICATIONS S. Hulsmann et al., Melt Extrusion - An Alternative Method for
R. C. Rowe et al., ed ., Handbook of Pharmaceutical Excipients 6th
Enhancing the Dissolution Rate of 17ß -estradiol Hemihydrate, 49
European Journal of Pharmaceutics and Biopharmaceutics 237-242
Ed . ( 2009 ) Index , pp . 885-888 . ( 2000)
R. C. Rowe et al., ed ., Handbook of Pharmaceutical Excipients 6th Manish K. Gupta et al., Hydrogen Bonding With Absorbent During
Ed. (2009 ) Polyoxylglycerides , pp . 557-561. Storage Governs Drug Dissolution From Solid -Dispersion Gran
J. W. McGinity et al., “ Hot-Melt Extrusion as a Pharmaceutical ules, 19 ( 11 ) Pharmaceutical Research , 1663-1762 (2002).
Process ” American Pharmaceutical Review , vol. 4 , Issue 2 , Summer Deposition Transcript ofWalter G.Chambliss, Ph.D., in PGR20018
2001, pp . 25-36 . 00048 (Jan. 9 , 2019 ) , 75 pages .
Purdue Appeal Brief in IPR 2016-01027 and IPR 2016-01028 filed Supplemental Declaration of Panayiotis P. Constantinides,Ph.D., in
Jul. 2 , 2018 , 178 pages. PGR20018-00048 , ( dated Jan. 30 , 2019 ) 104 pages .
Deposition Transcript of Panayiotis P. Constantinides in PGR20018 Paul W.S. Heng et al., Role of Surfactant on Drug Release From
00048, taken on Mar. 20 , 2019 , 86 pages. Tablets, 16 (6 ) Drug Development and Industrial Pharmacy 951-962
Gennaro , “ Remington : The Science and Practice of Pharmacy's ( 1990 ).
(20th ed . 2000 ), pp . 693 . FDA Guidance for Industry Q1A (R2) Stability Testing of New
Lund , W , ed , The Pharmaceautical Codex ( 12th Ed .) p . 5 , 1994 . Drug Substances and Products, Nov. 2003 Revision 2 , 25 pages.
Damian et al, “ Physicochemical characterization of solid disper FDA's 1996 Inactive Ingredient Guide, 167 pages.
sions of the antiviral agent UC -781 with polyethylene glycol 6000 Goldberg et al., “ Abuse -resistant compositions,” U.S. Appl. No.
and Gelucire 44/14 ” European Journal of Pharmaceutical Sciences, 60/292,809 , filed May 23, 2001.
vol. 10 , pp . 311-322 (2000 ). Handbook of Pharmaceutical Excipients, 2nd ed ., ( eds. Wade and
Lewis, R.J. ed , Hawleys Condensed Chemical Dictionary (13th Weller), American Pharmaceutical Association (1994 ), pp . 82-83 ,
Ed.), pp . 580-581 ( 1997 ). 325-328, 544-545 ; 552-553 ; and 558-561, 16 pages.
Krowczynski, “ Extended -Release Dosage Forms” pp . 97-158 ( 1987 ) . Kraßnig et al., “ Optimization of the Synthesis of Oxycodone and
Supplemental Declaration of Dr.Walter G. Chambliss in PGR20018 5 -Methyloxycodone ,” Arch . Pharm . Pharm . Med . Chem . 329 , 325
00048, dated Apr. 12 , 2019 , 33 pages . 326 (1996 ).
Gelucire USPTO Trademark Registration Certificate No. 1,345,393 , L. Lachman et al., The Theory and Practice of Industrial Pharmacy
Jul. 2 , 1985 , 1 page . (3rd ed . 1986 ), 5 pages .
U.S. Appl. No. 15 /015,722 , Feb. 2 , 2017, Response to Office Action , Material Safety Data Sheet for Myristic Acid (Dec. 11, 1990 ), 2
7 pages. pages.
A. Kibbe ed ., Handbook of Pharmaceutical Excipients 3rd Ed . National Drug Intelligence Center, “ OxyContin Diversion and Abuse”
(2000 ) Docusate Sodium , pp . 188-190 , GlycerylMonostearate, pp . Information Bulletin , Product No. 2001- L0424-001, Jan. 2001, 6
225-227; Polyoxyethylene Sorbitan Fatty Acid Esters, pp . 416-419 ; pages.
Sorbitan Esters, pp . 511-514 . Oxycodone, 11 pages, May 16 , 2005, retrieved from : http://www .
swgdrug.org/monographs/oxycodone.pdf
Declaration of Panayiotis P. Constantinides, Ph.D. In PGR20018
00048, dated Jul. 10 , 2018 , 101 pages. Oxycodone Monograph in the United States Pharmacopeia (2000 )
Curriculum Vitae of Panayiotis P. Constantinides ( Jun . 2018 ), 33 (“ USP 24 " ) 34 pages .
pages. Oxycontin Label ( 2001 ) 22 pages .
Oxford Dictionary of Science (Alan Isaacs et al. eds., 4th ed . 1999 ), Oxycontin Label (2010 ) 39 pages.
p . 382. Patent Owner's Preliminary Response to Petition for Post-Grant
U.S. Appl. No. 15/015,722, Apr. 8 , 2016 office action , 7 pages. Review ; PGR2018-00048 ; U.S. Pat. No. 9,693,961; dated Jul. 10 ,
U.S. Appl. No. 15 /015,722 , Nov. 2, 2016 office action , 7 pages . 2018, 93 pages.
U.S. Appl. No. 15 /015,722 , May 17 , 2017 notice of allowability, 9 Patent Owner's Response to Petition for Post-Grant Review ; PGR2018
pages . 00048 ; U.S. Pat. No. 9,693,961; dated Jan. 30 , 2019 , 92 pages .
Oral Route Excipients by Gattefosse Group (2004 ), 6 pages. Petitioner's Reply; PGR2018-00048 ; U.S. Pat.No.9,693,961; dated
U.S. Appl. No. 14 /946,275 , Aug. 2 , 2016 amendment, 11 pages . Apr. 12, 2019 , 40 pages.
Material safety data sheet for myristic acid (Jul. 6 , 2010 ) Proska , “ 10 -Hydroxythebaine,” Arch . Pharm . Pharm . Med . Chem .
(COLL1080872-74 ), 3 pages . 332 , 369-370 ( 1999 ) .
Material safety data sheet for stearic acid (Feb. 24 , 2005), 3 pages. Ramanathan et al., “ Dihydrocodeine , Dihydrocodeinone,
Statement Regarding Suspension of 160 mg OxyContin® Tablets 14 -Hydroxydihydrocodeinone & Their Derivatives,” Indian Jour.of
(May 11, 2001), 1 page . Technology, vol. 2, No. 10 , 350-351 (1964).
Knothe et al., A Comprehensive Evaluation of the Melting Points of Remington , The Science and Practice of Pharmacy ( 19th Edition
Fatty Acids and Esters Determined by Differential Scanning Calo 1995) p . 206 .
rimetry, J. Am . Oil Chem . Soc., 86 :843-56 (2009 ). Spansule® Capsule Technology, 2013, 11 pages.
Constantinides, P.P., Lipid Microemulsions for Improving Drug J. Sprowls, Ph.D., Prescription Pharmacy (2nd Ed . 1970 ), 16 pages.
Dissolution and Oral Absorption : Physical and Biopharmaceutical Teva's Amended Preliminary Invalidity Contentions in C.A. No.
Aspects, Pharm . Res., 12 ( 11 ):1561-72 (1995 ). 18-300 -LPS -CJB dated Dec. 21, 2018 , 545 pages .
Crew M., The Second Quadrant: Analysis of the Historical Use of Detailed Factual and Legal Bases for Teva Pharmaceuticals USA's
Solubilization Techs., Drug. Devel. & Delivery, 14 (2 ):22-25 (Mar. Paragraph IV Certification that the Claims of U.S. Pat. Nos.
2014 ). 7,399,488 ; 7,771,707; 8,449,909; 8,557,291; 8,758,813 ; 8,840,928 ;
Orange Book listing for Xtampza 9 mg (last accessed Jul. 3 , 2018 ), 9,044,398 ; 9,248,195 ; 9,592,200; 9,682,075,9,737,530 ; and , 9,763,883
2 pages. Are Invalid , Unenforceable and/ orNot Infringed dated Jan. 9 , 2018 ,
Semjonov , K. et al., The formation and physical stability of two 104 pages.
phase solid dispersion systems of indomethacin in supercooled Detailed Factual and Legal Bases for Teva Pharmaceuticals USA's
molten mixtures with different matrix formers, Euro . J. Pharm . Sci. Paragraph IV Certification That the Claimsof U.S. Pat.No.9,968,598
97:237-46 (2017 ). Are Invalid , Unenforceable and /or Not Infringed dated Oct. 18 ,
Hearing transcript, Purdue Pharma L.P. v. Collegium Pharmaceu 2018, 23 pages.
ticals , Inc., C.A. No. 15-13099 -FDS (D.Mass. Jun . 1 , 2017 ), 136 Detailed Factual and Legal Bases for Teva Pharmaceuticals USA's
pages . Paragraph IV Certification That the Claimsof U.S. Pat.No. 10,004,729
R. C. Rowe et al., ed ., Handbook of Pharmaceutical Excipients, 6th Are Invalid , Unenforceable and / or Not Infringed dated Oct. 18 ,
ed . (2009 ), Polyoxylglycerides, pp . 557-561, 9 pages. 2018 , 35 pages .
US 10,525,053 B2
Page 8
( 56 ) References Cited Deighan, C.J. , et al., “ Ehabdomyolysis and Acute Renal Failure
Resulting From Alcohol and Drug Abuse,” OJMed ., vol. 93 , 2000 ,
OTHER PUBLICATIONS pp . 29-33.
Dexter, M.B., et al., “ The Evaluation of the Force to Expel Oily
Detailed Factual and Legal Bases for Teva Pharmaceuticals USA's Injection Vehicles from Syringes,” J. Pharm . Pharmacol., vol. 31,
Paragraph IV Certification That the Claimsof U.S. Pat. No. 10,188,644 Aug. 1979 , The Pharmaceutical Society of Great Britain , p . Nos.
Are Invalid , Unenforceable and /or Not Infringed dated Mar. 27 , 497-500 .
2019 , 25 pages. Exhibit 1001 of IPR2016-00849, Dated Apr. 6 , 2016 : U.S. Pat. No.
Teva's Preliminary Invalidity Contentions for Consolidated Patents 8,389,007, 24 pages .
in - Suit in C.A. No. 18-300 -LPS -CJB dated Feb. 8 , 2019 , 648 pages . Exhibit 1001 of IPR2016-01027 and IPR2016-01028 , dated May
Weiss, “ Derivatives of Morphine . II. Demethylation of 11, 2016 : U.S. Pat. No. 9,060,976 ( The 976 Patent), 24 pages.
14 - hydroxycodeinone . 14 -Hydroxymorphinone and 8,14 Exhibit 1002 of IPR2016-00849 , Dated Apr. 6 , 2016 : Expert Dec
Dihydroxydihydromorphinone,” J. Org . Chem ., 1957, 22 ( 11), pp . laration of Arthur H. Kibbe (Dated Apr. 6 , 2016 ), 140 pages .
1505-1508 . Exhibit 1002 of IPR2016-01027 and IPR2016-01028, dated May
World Health Organization , “ Specifications for the Identity and 11, 2016 : U.S. Pat. No. 8,337,888 ( The 888 Patent), 25 pages.
Purity of Food Additives and Their Toxicological Evaluation ," Exhibit 1003 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Pat. No.
World Health Organization Technical Report Series No. 445, FAO 8,337,888, 25 pages .
Nutrition Meetings Report Series No. 46 , Jun . 1969 , 43 pages . Exhibit 1003 of IPR2016-01027 and IPR2016-01028 , dated May
U.S. Department of Health and Human Services et al., “Guidance 11, 2016 : Purdue Pharma L.P. et al. v. Amneal Pharmaceuticals
for Industry Q1A (R2) Stability Testing of New Drug Substances LLC , No. 13-cv -3372- SHS (S.D.N.Y. Apr. 8, 2015) Findings of
and Products,” Nov. 2003 , Revision 25 pages, retrieved from : Facts and Conclusion of Law (" SDNY Decision ” ), 69 pages .
https://www.fda.gov/downloads/drugs/guidances/ucm073369.pdf. Exhibit 1004 of IPR2016-00849 , Dated Apr. 6 , 2016 : Purdue
U.S. Appl. No. 60 /287,509, “ Pharmaceutical composition which Pharma LP., et. al. v . Amneal Pharmaceuticals, LLC , No. 13 -cv
reduces or eliminates drug abuse potential,” Joshi et al., 15 pages, 3372 (SHS) (S.D.N.Y. Apr. 8 , 2015) (Findings of Fact and Conclu
filed Apr. 30 , 2001. sions of Law ), 69 pages .
U.S. Appl. No.60/288,211, “ Once -a -day oxycodone formulations,” Exhibit 1004 of IPR2016-01027 and IPR2016-01028 , dated May
Oshlack et al., 43 pages, filed May 2 , 2001. 11, 2016 : Purdue Pharma L.P. et al. v. Amneal Pharmaceuticals
U.S. Appl.No.60 /393,876 ,“ Abuse-resistant formulations of OxyContin LLC, No. 2015-1654 (Fed . Cir. Apr. 8 , 2016 ) Order (“ Federal
and other drugs,” Klibanov et al., 35 pages, filed Jul. 5 , 2002. Circuit Decision ” ), 2 pages.
U.S. Appl. No. 60/579,191, “ Abuse -deterrent drug formulations," Exhibit 1005 of IPR2016-00849 , Dated Apr. 6 , 2016 : Physicians '
Fleming et al., 35 pages, filed Jun . 12, 2004 . Desk Reference, 54th Edition (2000), 15 pages.
Zhang, “ Hot-Melt Extrusion As a Novel Technology to Prepare Exhibit 1005 of IPR2016-01027 and IPR2016-01028, dated May
Sustained -Release Dosage Forms,” Dissertation , University of Texas 11, 2016 : U.S. Pat. No. 8,101,630 (“ Kumar Patent” ). 21 pages .
at Austin , Dec. 1999 , 286 pages . Exhibit 1006 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Patent
Apicella, A., “ Poly( ethylene oxide )(PEO ) and Different Molecular Publication No. 2002/0187192 , 6 pages .
Weight PEO BlendsMonolithic Devices for Drug Release,” Biomateri Exhibit 1006 of IPR2016-01027 and IPR2016-01028 , dated May
als, vol. 14 , No. 2, 1993 , pp . 83-90 . 11, 2016 : U.S. Patent Publication No. 2010/0216829 (“ Kumar
Apicella, et al. “Poly (ethylene oxide)(PEO ) Constant Release Mono Publication ” ), 23 pages.
lithic Devices,” Polymers in Medicine: Biomedical and Pharma Exhibit 1007 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Appl.No.
60 /287,509 , filed Apr. 30 , 2001, 15 pages .
ceutical Applications, Chapter 3 (1992 ), pp . 23-37 . Exhibit 1007 of IPR2016-01027 and IPR2016-01028 , dated May
Apicella , et al., “ Poly ( ethylene oxide) -Based Delivery Systems,” 11, 2016 : Complaint, Purdue Pharma LP. et al. v. Amneal Phar
Polymeric Drugs and Drug Administration , ACS Symposium Series maceuticals LLC , 15 -cv - 831, filed Sep. 17 , 2015 , 9 pages.
545 , Chapter 9 ( 1994 ), pp . 111-125 . Exhibit 1008 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Patent
Audebrand et al. Gelation of pectin - alginate mixture : ultrastructure Publication No. 2003/0064122 , 7 pages.
and rheological properties. Proceedings of the 3rd International Exhibit 1008 of IPR2016-01027 and IPR2016-01028 , dated May
Symposium on Food Rheology and Structure, Feb. 9-13 , 2003 , 11, 2016 : Complaint, Purdue Pharma LP. et al. v. Amneal Phar
Zurich , Switzerland , pp . 517-518 . maceuticals LLC, 15 -cv - 1152 , filed Dec. 15, 2015 , 36 pages.
Bettini, et al., “ Translocation of drug particles in HPMC matrix gel Exhibit 1009 of IPR2016-00849, Dated Apr. 6 , 2016 : U.S. Appl. No.
layer: effect ofdrug solubility and influence on release rate,” Journal 60 /292,809 , filed May 23 , 2001, 12 pages .
of Controlled Release, vol. 70 , No. 3 , Feb. 2001, pp . 383-391. Exhibit 1009 of IPR2016-01027 , dated May 11 , 2016 : Declaration
Bhatia , R., “ Effect ofMolecular Mass, Concentration and Tempera of Dr. Anthony Palmieri (“ Palmieri Declaration ” ), 43 pages.
ture on the Rheological Properties of Non -Newtonian Aqueous Exhibit 1009 of IPR2016-01028 , dated May 11 , 2016 : Declaration
Polymeric Solutions,” University of Cincinnati, 2011, 202 pgs. of Dr. Anthony Palmieri (“ Palmieri Declaration ” ), 45 pages .
Chien , View ., et al., “Syringeability of Nonaqueous Parenteral Exhibit 1011 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Pat. No.
Formulations— Development and Evaluation of Testing Apparatus,” 3,980,766 , 5 pages .
Journal of Parenteral Science and Technology, vol. 35 , No. 6 , Nov. Exhibit 1011 of IPR2016-01027 and IPR2016-01028, dated May
1981, p . Nos . 281-284 . 11 , 2016 : International Patent Publication No. WO 99/32120
CRC Handbook of Chemistry and Physics, p . F -56 (59th ed . 1978 ), (“ Palermo” ), 47 pages .
8 pages. Exhibit 1012 of IPR2016-00849, Dated Apr. 6 , 2016 : U.S. Pat. No.
Decision to Institute Trial for Inter Partes Review , IPR2016-01027 4,070,494 , 6 pages.
of U.S. Pat. No. 9,060,976 , dated Nov. 9 , 2016 , 32 pages. Exhibit 1012 of IPR2016-01027 and IPR2016-01028 , dated May
Decision to Institute Trial for Inter Partes Review , IPR2016-01028 11, 2016 : The Handbook of Pharmaceutical Excipients 399-400,
of U.S. Pat . No. 9,060,976 , dated Nov. 2016 , 40 pages. 655 ( 3rd ed . 2000 ), 5 pages .
Decision to Institute Trial for Inter Partes Review , IPR2016-01412 Exhibit 1013 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Pat. No.
of U.S. Pat. No. 9,034,376 , dated Feb. 14 , 2017 , 25 pages . 8,337,888 Prosecution File History (Notice of Allowance, dated
Decision to Institute Trial for Inter Partes Review , IPR2016-01413 Dec. 3 , 2012), 6 pages.
of U.S. Pat. No. 9,034,376 , dated Jan. 18 , 2017 , 25 pages . Exhibit 1013 of IPR2016-01027 and IPR2016-01028, dated May
Declaration of Dr. Anthony Palmieri for IPR2016-01412, dated Jul. 11, 2016 : International Patent Publication No.WO 97/49384 (“McGin
15 , 2016 , 67 pages. ity ” ), 29 pages.
Declaration of Dr. Anthony Palmieri for IPR2016-01413 , dated Jul. Exhibit 1014 of IPR2016-00849, Dated Apr. 6 , 2016 : U.S.Appl. No.
15, 2016 , 56 pages . 60 /310,534 , filed Aug. 6 , 2001, 67 pages .
US 10,525,053 B2
Page 9
( 56 ) References Cited Exhibit 1025 of IPR2016-01027 and IPR2016-01028 , dated May

11, 2016 : U.S. Appl. No. 10 /214,412, Originally Filed Specification ,
OTHER PUBLICATIONS Aug. 6 , 2002, 62 pages.
Exhibit 1026 of IPR2016-00849 , Dated Apr. 6 , 2016 : European
Exhibit 1014 of IPR2016-01027 and IPR2016-01028 , dated May Patent Publication No. EP 0974345 A2 , 4 pages .
11, 2016 : U.S. Patent Publication No. 2002/0187192 (“ Joshi” ), 6 Exhibit 1026 of IPR2016-01027 and IPR2016-01028 , dated May
pages. 11 , 2016 : U.S. Appl. No. 60 /310,534 , 64 pages.
Exhibit 1015 of IPR2016-00849 , Dated Apr. 6 , 2016 : Brief of Exhibit 1027 of IPR2016-00849 , Dated Apr. 6 , 2016 : Waugh , et. al.,
Plaintiffs -Appellant, Purdue Pharma LP., et. al. v. Amneal Phar Peroperative venography to ensure accurate sapheno -popliteal vein
maceuticals, LLC , No. 15-1654 (Fed . Cir. Aug. 12 , 2015 ), 198 ligation , British Medical Journal ( Jun . 28 , 1980 ), pp . 1578-1579 , 2
pages . pages .
Exhibit 1015 of IPR2016-01027 and IPR2016-01028 , dated May Exhibit 1028 of IPR2016-00849, Dated Apr. 6 , 2016 : Abdala , et al.,
11, 2016 : International Patent Publication No. WO95 /20947 (“ Bastin " ), Can HIV - 1 -Contaminated Syringes Be Disinfected ?, Journal of
39 pages. Acquired Immune Deficiency Syndromes 28 :487-494 (2001), 8
Exhibit 1016 of IPR2016-00849 , Dated Apr. 6 , 2016 : Reply Brief of pages .
Plaintiffs- Appellant, Purdue Pharma LP., et. al. v. Amneal Phar Exhibit 1028 of IPR2016-01027 and IPR2016-01028 , dated May
maceuticals, LLC , No. 15-1654 ( Fed . Cir. Dec. 23 , 2015 ), 41 pages. 11, 2016 : U.S. Appl. No. 13 /726,324 , Preliminary Amendment,
dated Dec. 24 , 2012, 8 pages.
Exhibit 1016 of IPR2016-01027 and IPR2016-01028, dated May Exhibit 1029 of IPR2016-00849, Dated Apr. 6 , 2016 : Needle, et al.,
11, 2016 : OxyContin , Physicians ' Desk Reference 2569-2574 (53rd HIV Risk Behaviors Associated with the Injection Process : Multiperson
ed . 1999), 8 pages. Use of Drug Injection Equipment and Paraphernalia in injection
Exhibit 1017 of IPR2016-00849 , Dated Apr. 6 , 2016 : Meier, “ U.S. Drug User Networks, Substance Use and Misuse 33 ( 12 ): 2401-2423
Asks Painkiller Maker to Help Curb Wide Abuse” NY Times (May ( 1998), 22 pages .
1, 2001), 3 pages. Exhibit 1029 of IPR2016-01027 and IPR2016-01028 , dated May
Exhibit 1017 of IPR2016-01027 and IPR2016-01028 , dated May 11 , 2016 : U.S. Appl. No. 13/ 726,324 , Supplemental Amendment,
11 , 2016 : Purdue Pharma LP. et al. v . Amneal Pharmaceuticals dated Jan. 23, 2013 , 10 pages .
LLC , No. 2014-1306 , -1307 ( Fed . Cir. Feb. 1, 2016 ), 27 pages. Exhibit 1030 of IPR2016-00849 , Dated Apr. 6 , 2016 : Neilloud , et al.
Exhibit 1018 of IPR2016-00849 , Dated Apr. 6 , 2016 : Department of ( ed .), Pharmaceutical Emulsions and Suspensions (2000 ), 29 pages.
Justice , Information Bulletin : OxyContin Diversion and Abuse ( Jan. Exhibit 1030 of IPR2016-01027 and IPR2016-01028 , dated May
2001), 6 pages . 11, 2016 : U.S. Appl. No. 13 /726,324 , Office Action , dated Jul. 15 ,
Exhibit 1018 of IPR2016-01027 and IPR2016-01028 , dated May 2013, 10 pages.
11, 2016 : Department of Justice , Information Bulletin : OxyContin Exhibit 1031 of IPR2016-00849 , Dated Apr. 6 , 2016 : European
Diversion and Abuse ( Jan. 2001) , 6 pages . Patent No. EP 082880281, 17 pages.
Exhibit 1019 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Pat. No. Exhibit 1031 of IPR2016-01027 and IPR2016-01028 , dated May
6,309,663, 55 pages. 11, 2016 : U.S. Appl. No. 13 /726,324 , Amendment and Response,
Exhibit 1019 of IPR2016-01027 and IPR2016-01028, dated May dated Jan. 15 , 2014 , 27 pages .
11, 2016 : Barry Meier, U.S. Asks Painkiller Maker to Help Curb Exhibit 1032 of IPR2016-00849, Dated Apr. 6 , 2016 : Buhler,
Kollidon : Polyvinylpyrrolidone for the pharmaceutical industry,
Wide Abuse , The New York Times (May 1, 2001 ), 3 pages. BASF, 4th Edition ( 1998 ), 288 pages.
Exhibit 1010 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Pat. No. Exhibit 1032 of IPR2016-01027 and IPR2016-01028 , dated May
5,183,654, 6 pages . 11, 2016 : U.S. Appl. No. 13 /726,324 , Notice of Allowance , dated
Exhibit 1010 of IPR2016-01027 and IPR2016-01028 , dated May Oct. 31, 2014 , 8 pages .
11, 2016 : Curriculum Vitae of Anthony Palmieri, Ph.D., 13 pages . Exhibit 1033 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Pat. No.
Exhibit 1020 of IPR2016-00849 , Dated Apr. 6 , 2016 : International 4,737,151, 6 pages .
Patent Publication No. WO 99/44591 , 57 pages . Exhibit 1033 of IPR2016-01027 and IPR2016-01028 , dated May
Exhibit 1020 of IPR2016-01027 and IPR2016-01028 , dated May 11 , 2016 : U.S. Appl. No. 13 / 726,324 , Request for Continued
11, 2016 : Brief of Plaintiffs - Appellants in Purdue Pharma LP. etal. Examination , dated Jan. 5 , 2015, 3 pages.
V. Amneal Pharmaceuticals LLC , No. 2015-1654 (Fed . Cir. Aug. 12 , Exhibit 1034 of IPR2016-00849, Dated Apr. 6 , 2016 : Chien , et al.,
2015) , 198 pages. Syringeability of Nonaqueous Parenteral Formulations
Exhibit 1021 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Pat. No. Development and Evaluation of a Testing Apparatus , PDA Journal
4,710,384, 6 pages. of Science and Technology 35 :281-284 (1981), 6 pages .
Exhibit 1021 of IPR2016-01027 and IPR2016-01028, dated May Exhibit 1034 of IPR2016-01027 and IPR2016-01028 , dated May
11, 2016 : Reply Brief of Plaintiffs-Appellants in Purdue Pharma 11, 2016 : U.S. Appl. No. 13/ 726,324 , Communication from Appli
LP. et al. v. Amneal Pharmaceuticals LLC , No. 2015-1654 (Fed . Cir . cant, dated Jan. 29 , 2015 , 1 page .
Dec. 23 , 2015), 41 pages . Exhibit 1035 of IPR2016-00849 , Dated Apr. 6 , 2016 : Budavari, et
Exhibit 1022 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Patent al. (ed .), The Merck Index , 12th Edition , 1996 , 4 pages .
Publication No. 2002/0142039 , 9 pages . Exhibit 1035 of IPR2016-01027 and IPR2016-01028 , dated May
Exhibit 1022 of IPR2016-01027 and IPR2016-01028 , dated May 11, 2016 : U.S. Appl. No. 13 /726,324 , Information Disclosure State
11, 2016 : U.S. Appl. No. 13 /726,324 ,Originally Filed Specification , ment, dated Apr. 14 , 2015 , 8 pages
Dec. 24 , 2012 , 62 pages . Exhibit 1036 of IPR2016-00849 , Dated Apr. 6 , 2016 : Maggi, et. al.,
Exhibit 1023 of IPR2016-00849 , Dated Apr. 6 , 2016 : Banker, High molecular weight polyethylene oxides (PEOs) as an alterna
Modern Pharmaceutics, 3rd Edition (1996 ), 66 pages. tive to HPMC in controlled release dosage forms, International
Exhibit 1023 of IPR2016-01027 and IPR2016-01028, dated May Journal of Pharmaceutics 195 :229-238 ( 2000 ), 10 pages.
11, 2016 : U.S. Appl.No. 13/349,449, Originally Filed Specification , Exhibit 1036 of IPR2016-01027 and IPR2016-01028, dated May
Jan. 12 , 2012 , 62 pages . 11 , 2016 : U.S. Appl. No. 13 /726,324 , Notice of Allowance , dated
Exhibit 1024 of IPR2016-00849, Dated Apr. 6 , 2016 : Kibbe, May 12 , 2015 , 9 pages .
Handbook of Pharmaceutical Excipients , 3rd Edition (2000 ), 18 Exhibit 1037 of IPR2016-00849 , Dated Apr. 6 , 2016 : The United
pages . States Pharmacopeia ( 2000 ), 10 pages.
Exhibit 1024 of IPR2016-01027 and IPR2016-01028 , dated May Exhibit 1037 of IPR2016-01027 and IPR2016-01028 , dated May
11, 2016 : U.S. Appl.No. 12 /653,115 , Originally Filed Specification , 11, 2016 : U.S. Pat . No. 4,861,598 (“Oshlack ” ), 5 pages .
Dec. 8 , 2009, 62 pages. Exhibit 1038 of IPR2016-00849 , Dated Apr. 6 , 2016 : Mark , et. al.,
Exhibit 1025 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Pat. No. Encyclopedia of Polymer Science and Engineering ( 1986 ), vol. 6 ,
5,422,134 , 11 pages . 100 pages.
US 10,525,053 B2
Page 10
( 56 ) References Cited Hardman , Joel G., et al., Goodman & Gilman's The Pharmacologi
cal Basis of Therapeutics, 9th Edition , 1996 , p . Nos. 3-27, 521-555 ,
OTHER PUBLICATIONS 557-577 , McGraw -Hill, United States.
Hem , Stanley , et al., “ Tissue Irritation Evaluation of Potential
Exhibit 1038 of IPR2016-01027 and IPR2016-01028 , dated May Parenteral Vehicles,” Drug Development Communications, 1: 5,
11, 2016 : U.S. Appl. No. 60 / 287,509 (“ Joshi Provisional” ), 14 1974 , p . Nos. 471-477 , Marcel Dekker, Inc.
pages. Heng, Paul, et al., “ Role of Surfactant on Drug Release from
Exhibit 1039 of IPR2016-00849, Dated Apr. 6 , 2016 : Pöll, The Story Tablets” , Drug Development and Industrial Pharmacy, ( 1990 ), 16 (6 ),
of the Gauge, Anaesthesia, 54 : 575-581 ( 1999 ), 7 pages. p . Nos. 951-962 , Taylor & Francis, London , United Kingdom .
Exhibit 1039 of IPR2016-01027 and IPR2016-01028 , dated May Huang, H., et al., “ Preparation of Controlled Release Oral Dosage
11 , 2016 : Gennaro (ed .), Oral Dosage Forms, Remington : The Forms by Low Temperature Melt Extrusion ,” The AAPS Journal,
Science and Practice of Pharmacy, 19th Ed ., pp. 1653-1654 , 1666 AAPS PharmaSci , 2000 , 2 (S1), 3 pages.
1669 ( 1995), 9 pages . Bailey, Jr., “ High Molecular Weight Polymers of Ethylene Oxide,"
Exhibit 1040 of IPR2016-00849 , Dated Apr. 6 , 2016 : Bellingham , Industrial and Engineering Chemistry I/EC , vol. 50 , No. 1, Jan. 10 ,
A reference guide to insulin pens, The Pharmaceutical Journal (Jun . 1958, p . Nos. 8-11, American Chemical Society, Easton , PA , United
States .
10 , 2000 ), vol. 264 No. 7100 , p . 890 , 3 pages. Kalant, H., et al., “ Death in Amphetamine Users: Causes and
Exhibit 1041 of IPR2016-00849, Dated Apr. 6 , 2016 : Purdue Rates," CMA Journal, vol. 112 , Feb. 8 , 1975 , pp . 299-304 .
Pharma L.P. et al. v. Acura Pharmaceuticals, Inc., et. al., 15 -cv Kibbe, Arthur, H., “ Polyethylene Oxide,” Handbook of Pharmaceu
00292-RGa (D. Del). (Egalet Proof of Service ), 2 pages. tical Excipients, Third Edition , 2000 , pp . 399-400 , PhP Pharma
Exhibit 1042 of IPR2016-00849 , Dated Apr. 6 , 2016 : Purdue ceutical Press, London , United Kingdom .
Pharma L.P. et al. v . Acura Pharmaceuticals, Inc., et. al., 15 - cv Kim , C., “ Drug Release from Compressed Hydrophilic POLYOX
00292-RGA (D. Del). (Acura Proof of Service), 1 page . WSR Tablets,” Journal of Pharmaceutical Sciences, vol. 84 , No. 3 ,
Exhibit 1043 of IPR2016-00849, Dated Apr. 6 , 2016 : Purdue Mar. 1995 , pp . 303-306 .
Pharma LP., et. al. v. Amneal Pharmaceuticals, LLC , No. 13 -cv Levy et al. The effect of certain additives on the gel point of
3372 (SHS ) ( Trial Transcript on Jul. 14 , 2014 ), 198 pages. methylcellulose. J. Am . Pharm . Assoc. Am . Pharm . Assoc ., 1958,
Exhibit 1044 of IPR2016-00849 , Dated Apr. 6 , 2016 : Bailey, et. al., 47 ( 1 ):44-46 .
High Molecular Weight Polymers of Ethylene Oxide, Industrial and Maggi, L., et al, “ Dissolution Behaviour of Hydrophilic Matrix
Engineering Chemistry 50 ( 1):8-11 ( Jan. 1958 ), 4 pages. Tablets Containing Two Different Polyethylene Oxides ( PEOs) for
Exhibit 1045 of IPR2016-00849 , Dated Apr. 6 , 2016 : Garde , FDA the Controlled Release of a Water- Soluble Drug . Dimensionality
advisers side against Purdue’s new painkiller, citing dosing dangers, Study,” Biomaterials, vol. 23 , pp . 1113-1119 ( 2002).
Fierce Biotech (Sep. 11, 2015 ), 2 pages. Masuda et al., Swelling of poly( ethylene oxide) gel in aqueous
Exhibit 1046 of IPR2016-00849 , Dated Apr. 6 , 2016 : International solutions of sodium dodecyl sulfate with added sodium chloride ,
Patent Publication No. WO 96/06528 , 66 pages. Colloid . And Polymer Science, 2002 , 280 ( 5):490-494 .
Exhibit 1047 of IPR2016-00849 , Dated Apr. 6 , 2016 : International Medical Economics Company, Inc., The 1997 Physician's Desk
Patent Publication No.WO 95/18602, 29 pages . Reference (“ PDR ” ) entry for Oxycontin® , 51st edition , Nov. 1996 ,
Exhibit 1048 of IPR2016-00849 , Dated Apr. 6 , 2016 : Markus, et. Montvale, NJ pp . 955-958, 988-990 , and 2163-2167.
al., Microscopic air embolism during cerebral angiography and Meier, Barry, “U.S. Asks Painkiller Maker to Help Curb Wide
strategies for its avoidance, The Lancet 341:784-87 ( 1993), 4 pages. Abuse,” The New York Times, May 1, 2001, 3 pgs.
Meunier, Multicomponent Biopolymer Gels: The Agarose -Carrageenan
Exhibit 1049 of IPR2016-00849 , Dated Apr. 6 , 2016 : U.S. Pat. No. Gellan System , 3rd International Symposium on Food Rheology and
6,096,722, 85 pages. Structure, 2003, Zurich , Switzerland, pp. 493-494 .
Exhibit 1050 of IPR2016-00849, Dated Apr. 6 , 2016 : Singh , et. al., Moroni, et al.,“ Application of Poly (oxyethylene ) Homopolymers in
Transdermal iontophoretic delivery of methvlphenidate HCI in Sustained Release Solid Formulation ,” Drug Dev . And Indus . Phar
vitro , International Journal of Pharmaceutics 178 : 121-128 ( 1999 ), macy , 21( 12 ), pp . 1411-1428 (1995 ).
8 pages. Opinion & Order filed May 27 , 2014 , Case 1:04 -md -01603-SHS, 24
Exhibit 1051 of IPR2016-00849 , Dated Apr. 6 , 2016 : Webster's pgs .
Third New International Dictionary ( 1986 ), p . 432 , 3 pages . Opioid bill passes, but there's little money to act on its wish list,
Exhibit 1052 of IPR2016-00849 , Dated Apr. 6 , 2016 : Henderson's Politics & Government (Jul. 13 , 2016 ), available at http ://www .
Dictionary of Biological Terms, 10th Edition (1989 ), p. 99,3 pages. newsoberver.com/news/politics-government/article89403007.html( last
Exhibit 1053 of IPR2016-00849 , Dated Apr. 6 , 2016 : Apicella , et. visited Jul. 14 , 2016 ), 3 pages .
al., Poly (ethylene oxide) (PEO ) and differentmolecularweight PEO Order, In re Oxycontin Litigation , Case15-1654 , Document 78, pp .
blends monolithic devices for drug release, Biomaterials 14 (2 ): 83 1-2 , (CAFC Apr. 8 , 2016 ).
90 ( 1993 ), 9 pages. Ortho -McNeil- Janssen Pharmaceuticals, Inc. (2010 ). Prescribing
Expert Declaration of Dr. Eric M.Gaier for IPR2016-01027 ofU.S. Information for Concerta Extended -Release Tablets , 27 pgs.
Pat. No. 9,060,976 , dated Aug. 12 , 2016 , 63 pages . Paragraph IV Patent Certification Notice for Amendment to ANDA
Expert Declaration of Dr. Eric M.Gaier for IPR2016-01028 of U.S. 202762 (2011) .
Pat . No. 9,060,976 , dated Aug. 12 , 2016 , 63 pages . Paragraph IV Patent Certification Notice for ANDA 202352 (2013 ),
Expert Declaration of Dr. Stephen Byrn for IPR2016-01027 of U.S. 16 pages.
Pat . No. 9,060,976 , dated Aug. 12 , 2016 , 116 pages. Paragraph IV Patent Certification Notice for ANDA 202372 ( 2011),
Pat. No. 9,060,976 , dated Aug. 12 , 2016 , 113 pages. Paragraph IV Patent Certification Notice for ANDA 202372 (2013),
Pat. No. 9,034,376 , dated Nov. 18 , 2016 , 96 pages . Paragraph IV Patent Certification Notice for ANDA 202434 (2011 ),
Pat. No. 9,034,376 , dated Oct. 21, 2016 , 94 pages . Paragraph IV Patent Certification Notice for ANDA 202434 ( 2013 ),
Findings of Fact and Conclusions of Law , in re: Oxycontin Antitrust 28 pages.
Litigation , Case 1:04-md-01603-SHS , Apr. 8 , 2015 , pp . 1-69 . Paragraph IV Patent Certification Notice for ANDA 202455 (2011 ),
Handbook of Pharmaceutical Excipients, Povidone, 1986 , p . Nos. 16 pages.
234-239 , American Pharmaceutical Association , Washington D.C., Paragraph IV Patent Certification Notice for ANDA 202455 (2013 ),
United States. 26 pages.
Kibbe (ed.), Handbook of Pharmaceutical Excipients, Hydroxypropyl Paragraph IV Patent Certification Notice for ANDA 202483 ( 2011 ),
Methylcellulose, pp . 252-255 , 655 (3rd ed . 2000 ), 7 pages . 24 pages.
US 10,525,053 B2
Page 11
( 56 ) References Cited Zhang, F., et al., “ Properties of Sustained -Release Tablets Prepared
by Hot-Melt Extrusion,” Pharmaceutical Development and Tech
OTHER PUBLICATIONS nology, vol. 4 , No. 2 , pp . 241-250 ( 1999 ).
Zhang , Feng, Dissertation : “ Hot-Melt Extrusion as a Novel Tech
Paragraph IV Patent Certification Notice for ANDA 202483 (2013 ), nology to Prepare Sustained -Release Dosage Forms,” The Univer
7 pages. sity of Texas at Austin , pp . V -XXV , 1-260, Dec. 1999 , UMIMicro
Paragraph IV Patent Certification Notice for ANDA 202762 ( 2011 ), form 9959618 , Bell & Howell Information and Learning Company,
22 pages. Ann Arbor, MI, United States.
Paragraph IV Patent Certification Notice for ANDA 203235 (2011 ), Ansel, Howard C., et al., “ Pharmaceutical Dosage Forms and Drug
21 pages. Delivery Systems,” 7th Edition , 1999, p. Nos. 1-2, 23-163, 179-243 ,
Paragraph IV Patent Certification Notice for ANDA 203235 (2013 ), 397-449, 552-562, Lippincott Williams & Wilkins, United States.
21 pages .
Paragraph IV Patent Certification Notice for ANDA 203915 , Jul. 26 , Aulton , Michael E. ( ed .), “ Pharmaceutics, the Science of Dosage
2013 , 63 pgs. Form Design,” Reprinted 2000 , p . Nos. 1-2, 17-37, 62-80, 131-211 ,
Patent Owner Response for Inter Partes Review , IPR2016-01027 of 304-321, 359-380 , 550-677, Churchill Livingston , China.
U.S. Pat. No. 9,060,976 , dated Aug. 12 , 2016 , 81 pages . Banker, Gilbert S. (ed .) et al., “Modern Pharmaceutics,” Third
Patent Owner Response for Inter Partes Review , IPR2016-01028 of Edition , Revised and Expanded , Drugs and the Pharmaceutical
U.S. Pat. No. 9,060,976 , dated Aug. 12 , 2016 , 74 pages . Sciences, vol. 72 , 1996 , p . Nos. 21-73 , 75-119 , 121-153 , 155-178 ,
Patent Owner Response for Inter Partes Review , IPR2016-01412 of 333-394 , 441-487 , 575-609 , 727-772 , Marcel Dekker, Inc., United
U.S. Pat. No. 9,034,376 , dated Nov. 18 , 2016 , 77 pages . States.
Patent Owner Response for Inter Partes Review , IPR2016-01413 of Bodmeier, R., et al., “ Process and Formulation Variables in the
U.S. Pat. No. 9,034,376 , dated Oct. 21, 2016 , 74 pages . Preparation of Wax Microparticles by a Melt Dispersion Technique.
Petition for Inter Partes Review , IPR2016-01412 of U.S. Pat. No. I. Oil- in -water technique for water-insoluble drugs,” Journal of
9,034,376 , dated Jul. 15 , 2016 , 75 pages . Microencapsulation , 1992 , vol. 9 , No. 1, pp . 89-98 .
Petition for Inter Partes Review , IPR2016-01413 of U.S. Pat. No. Gennaro , Alfonso ( ed .), “ Remington : The Science and Practice of
9,034,376 , dated Jul. 15 , 2016 , 66 pages . Pharmacy," 20th Edition , 2000 , p . Nos. 1-3 , 335-355 , 654-666 ,
Petition for Inter Partes Review , IPR2016-00849 of U.S. Pat. No. 669-752 , 780-820 , 858-929,995-1004 , 1098-1155 , 1175-1182 , 1395
8,389,007 , dated Apr. 6 , 2016 , 73 pages . 1399, 2037-2038 , Lippincott Williams & Wilkins, Baltimore, MD ,
Petition for Inter Partes Review , IPR2016-01027 of U.S. Pat. No. United States .
9,060,976 , dated May 11, 2016 , 70 pages. Hillery, Anya M. ( ed.) et al., “ Drug Delivery : Fundamentals &
Petition for Inter Partes Review , IPR2016-01028 of U.S. Pat. No.
9,060,976 , dated May 11, 2016 , 70 pages. Applications,” 2017 , Second Edition , Section 1.3 , pp . 3-4 , CRC
Philip , George, et al., “ The Human Nasal Response to Capsaicin ," Press, Taylor & Francis Group , United States .
J. Allergy Clin . Immonul., vol. 94 , No. 6 , Part 1, Dec. 1994 , p . Nos. Hillery, Anya M. (ed .) et al., “Drug Delivery and Targeting for
1035-1045 ,Mosby- Year Book , Inc., Baltimore, MD , United States . Pharmacists and Pharmaceutical Scientists,” 2001, Section 1 , Chap
Sarkar, N., “ Kinetics of thermal gelation of methylcellulose and ter 1, pp . 1-48, Taylor & Francis, United States.
hydroxypropylmethylcellulose in aqueous solutions,” Carbohydrate Berge et al., “ Pharmaceutical Salts," J. Pharma Sci, Jan. 1977 ,
Polymers, vol. 26 , No. 3, Jan. 1995 , pp . 195-203 . 66 ( 1 ): 1-19 .
Sarkar, N., “ ThermalGelation Properties ofMethyl and Hydroxypropyl Gould , “ Salt selection for basic drugs,” , Int J Pharma, 33 ( 1986 )
Methylcellulose,” Journal of Polymer Science, vol. 24 , No. 4 , Aug. 201-217 .
1979 , pp . 1073-1087. USP OfficialMonographs, “ Erythromycin Stearate ” and “ Erythro
Stafford , J.W., et al., “ Temperature dependence of the disintegration mycin Stearate Tablets,” 2000 , pp . 675 and 676 .
times of compressed tablets containing hydroxypropylcellulose as U.S. Appl. No. 10 /614,866 (U.S. Pat. No. 7,399,488 ).
binder,” Journal of Pharmacy and Pharmacology, vol. 30, No. 1, U.S. Appl. No. 11/ 149,867 ( U.S. Pat. No. 7,771,707).
Sep. 1978 , pp . 1-5 , John Wiley & Sons, New York , United States . U.S. Appl. No. 12 /473,073 (U.S. Pat. No. 8,557,291).
The 1997 Physician's Desk Reference (“ PDR ” ), 51s, edition , Nov. U.S. Appl. No. 12 / 823,628 (U.S. Pat. No. 8,449,909 ).
1996 , p . Nos. 955-957, 988-990 , 2163-2167, 2366-2367 , Medical U.S.Appl. No. 12/ 965,572 (U.S. Pat. No. 8,840,928 ).
Economics Company, Inc., Montvale, NJ, United States. U.S. Appl. No. 13/ 551,455 (U.S. Pat. No. 9,044,398 ).
Tough , Paul, “ The Alchemy of Oxycontin : From Pain Relief to Drug U.S. Appl. No. 13 /870,690 (U.S. Pat. No. 8,758,813 ).
Addiction," The New York Times, Jul. 29 , 2001, 11 pgs. U.S.Appl. No. 14 /054,513 (U.S. Pat. No. 9,248,195) .
U.S. Pharmacopeia & National Formulary 24/19 , The Standard of U.S. Appl. No. 14 /147,088 (U.S. Pat. No. 9,763,883 ).
Quality, United States Pharmacopeial Convention , Inc., 1999 , p . U.S. Appl. No. 14 /320,086 (U.S. Pat. No. 9,682,075 ).
Nos . 1233-1239 , 1372-1375 , 1941-1951 , 2002-2003, 2442-2443 , U.S.Appl. No. 14 / 946,275 (U.S. Pat. No. 9,592,200 ).
2493-2498 , National Publishing, Philadelphia, PA , United States. U.S. Appl. No. 15 / 255,859 (U.S. Pat. No. 9,737,530 ).
U.S. Pharmacopeia , p . 2205-2207 , 1995 . U.S. Appl. No. 15 /606,112 (U.S. Pat. No. 10,004,729 ).
Wilkins, Jeffrey , N., “ Pharmacotherapy of Schizophrenia Patients U.S. Appl. No. 15 /649,024 ( U.S. Pat. No. 9,968,598 ).
with Comorbid Substance Abuse," Schizophrenia Bulletin , vol. 23 , U.S. Appl. No. 15 /950,656 (U.S. Pat. No. 10,188,644 ).
No. 2 , 1997, pp . 215-228 . U.S. Appl. No. 15 /681,589 .
Woodburn, K.R., et al., “ Vascular Complications of Injecting Drug U.S. Appl. No. 15 / 725,818 .
Misuse,” British Journal of Surgery, 1996 , vol. 83 , pp . 1329-1334 . U.S. Appl. No. 16 /017,097 .
Yang , et al., “ Characterization of Compressibility and Compact U.S. Appl. No. 16 /017,099 .
ibility of Poly( ethylene oxide) Polymers for Modified Release U.S. Appl. No. 16 / 218,801 .
Application by Compaction Simulator,” Journal of Pharmaceutical U.S. Appl. No. 16 /413,242 .
Sciences, vol. 85 , No. 10 , Oct. 1996 , pp. 1085-1090 . U.S. Appl. No. 16 / 592,586 .
Zasypkin, et al., Multicomponent biopolymer gels , Food Hydrocol
loids, 1997, 11 (2 ): 159-170 . * cited by examiner
US 10,525,053 B2
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ABUSE -DETERRENT PHARMACEUTICAL circulation (for IV injection ). These abuse methods result in
COMPOSITIONS OF OPIOIDS AND OTHER the rapid bioavailability of relatively high doses of drug ,
DRUGS giving the abuser a “ high ” . Since relatively simple methods
( crushing , grinding , chewing and /or dissolution in water )
This application is a continuation of U.S. Ser. No. 15/457 , 5 can be used to transform such formulations into an abusable
153, filed Mar. 13 , 2017 , which is a continuation of U.S. Ser. form , they provide virtually no deterrent to a potential
No. 14 / 946,275 , now U.S. Pat. No. 9,592,200, filed Nov. 19 , abuser .
2015 , which is a continuation of U.S. Ser. No. 14 /054,513 , For example , the FDA recently strengthened the warnings
now U.S. Pat. No. 9,248,195 , filed Oct. 15 , 2013 , which is and precautions sections in the labeling of OxyContin®
a divisional of U.S. Ser. No. 12 /473,073 , now U.S. Pat. No. 10 (oxycodone HCl controlled -release) tablets, a narcotic drug
8,557,291, filed May 27, 2009, which is a continuation - in approved for the treatment of moderate to severe pain ,
part ofU.S. Ser. No. 12 / 112,993, filed Apr. 30 , 2008 , which because of continuing reports of abuse and diversion . Oxy
is a divisional of U.S. Ser. No. 10 /614,866 , now U.S. Pat. Contin® contains oxycodone HCl (available in 10 , 20 , 40
No. 7,399,488 , filed Jul. 7 , 2003 , which claims priority to and 80 mg strengths), an opioid agonist with an addiction
U.S. Ser. No.60 / 393,876 filed Jul. 5 , 2002 entitled “ Abuse- 15
potential similar to that of morphine . Opioid agonists are
Resistant Formulations of Oxycontin and Other Drugs ” by substances that act by attaching to specific proteins called
Alexander M.Klibanov, Stephen L. Buchwald , Timothy M. opioid receptors, which are found in the brain , spinal cord ,
Swager, and Whe - Yong Lo; U.S. Ser. No. 60/436,523 filed and gastrointestinal tract. When these drugs attach to certain
Dec. 23, 2002 by Alison B. Fleming , Roman V. Rariy , opioid receptors in the brain and spinal cord they can
Alexander M.Klibanov, Whe - Yong Lo , and Jane Hirsh ; U.S. 20 effectively block the transmission of pain messages to the
Ser. No.60 /443,226 filed Jan. 28 , 2003 by Jane Hirsh , Alison brain .
B. Fleming , Alexander M. Klibanov , and Whe - Yong Lo ; OxyContin® is supplied in a controlled -release dosage
U.S. Ser. No. 60 / 463,514 filed Apr. 15 , 2003 by Jane C. form and is intended to provide up to 12 hours of relief from
Hirsh , Alison B. Fleming, Roman V. Rariy, Stephen L. moderate to severe pain . The warning specifically states that
Buchwald , and Timothy M. Swager; and U.S. Ser. No. 25 the tablet must be taken whole and only by mouth . When the
60 /463,518 filed Apr. 15 , 2003 by Jane C. Hirsh , Alison B. tablet is chewed or crushed and its contents are swallowed ,
Fleming and Roman V. Rariy. snorted into the nostrils or dissolved and subsequently
U.S. Ser. No. 12 /473,073 is also a continuation -in -part of injected intravenously , the controlled release mechanism is
Ser. No. 12 / 112,937 , filed Apr. 30 , 2008 , which is a con destroyed and a potentially lethal dose of oxycodone
tinuation - in -part of U.S. Ser . No. 10 /614,866 , now U.S. Pat. 30 becomes bioavailable .
No. 7,399,488, filed Jul. 7 , 2003 , which claims priority to In recent years , there have been numerous reports of
U.S. Ser. No. 60 / 393,876 filed Jul. 5 , 2002; U.S. Ser. No. Oxycodone diversion and abuse in several states. For
60 /436,523 filed Dec. 23 , 2002; U.S. Ser. No. 60 /443,226 example , the DEA's Office of Diversion Control reported
filed Jan. 28 , 2003 ; U.S. Ser. No. 60 /463,514 filed Apr. 15 , 700 OxyContin® thefts in the United States between Janu
2003 ; and U.S. Ser. No. 60 / 463,518 filed Apr. 15 , 2003 and 35 beenary 2000 and June 2001. Some of these reported cases have
associated with serious consequences including death .
U.S. Ser. No. 12/473,073 is also a continuation -in -part of
U.S. Ser. No. 11 / 149,867,now U.S.Pat. No.7,771,707 , filed According to a report from the Abuse and Mental Health
Jun . 10 , 2005 , which claims priority to U.S. Ser. No. Services Administration , Results from the 2004 National
Survey on Drug Use and Health : National Findings (Rock
60 /579,191, filed Jun . 12 , 2004 .
40 ville ,Md.: US Dept. of Health and Human Services, Office
FIELD OF THE INVENTION of Applied Studies, 2005, p . 50 ), in 2004, the number of new
non -medical users of OxyContin® was 615,000 , with an
The present invention is generally in the field of pharma average age at first use of 24.5 years. Comparable data on
ceutical compositions, and specifically compositions that are past year Oxycontin® initiation are not available for prior
designed to reduce the potential for improper administration 45 years, but calendar year estimates of Oxycontin® initiation
of drugs, such as those subject to abuse. show a steady increase in the number of initiates from 1995 ,
the year this product was first available, through 2003
BACKGROUND OF THE INVENTION Oxycodone is a controlled substance in Schedule II of the
Controlled Substances Act (CSA ), which is administered by
Oxycodone, morphine, and other opioid analgesics are 50 the Drug Enforcement Administration (DEA ). Despite the
successful and therapeutically useful medications, e.g., as fact that Schedule IX provides the maximum amount of
pain killers , when administered orally. Unfortunately, they control possible under the CSA for approved drug products,
also pose a severe threat for willful abuse due to their ability in practice it is difficult for law enforcement agencies to
to alter mood and /or cause a sense of euphoria . Currently control the diversion or misuse of legitimate prescriptions .
available sustained release formulations of such drugs, 55 Although abuse , misuse , and diversion are potential prob
which contain a relatively large amount of drug meant to be lems for all opioids, including Oxycodone, opioids are a
released from the formulation over an extended time period, very important part of the medical armamentarium for the
are particularly attractive to abusers since the sustained management of pain when used appropriately under the
release action can be destroyed by crushing or grinding the careful supervision of a physician .
formulation . The resulting material ( i.e., the crushed formu- 60 Currently available formulations for such drugs are
lation ) can no longer control the release of drug . Depending designed for oral administration but are vulnerable to altera
on the drug, abusers can then (1 ) snort the material, (2 ) tions in their dissolution characteristics by physical manipu
swallow the material or (3 ) dissolve the material in water lation of the formulation as discussed above . Such formu
and subsequently inject it intravenously. The dose of drug lations are also vulnerable due to the inherently high water
contained in the formulation is absorbed immediately 65 solubility of the API contained therein . Because of their
through the nasal or GImucosa (for snorting or swallowing , nature, these formulations do not prevent or deter improper
respectively ) or is administered in a bolus to the systemic methods of administration such as chewing, injection and
US 10,525,053 B2
3 4
snorting . This represents a serious problem given the large oral administration . In a preferred embodiment, the drug is
number of legitimate prescriptions written in the US; for chemically modified to increase its lipophilicity and is
example , the medical use of opioids within the US increased formulated as microparticles. In other embodiments , the
400 % from 1996 to 2000. The problems with abuse are 5 formulation contains lipophilic or water-insoluble materials
significant and longstanding, and efforts to design new or is made using a process which increases the lipophilicity
abuse -resistant or abuse - deterrent formulations have been and /or water-insolubility of the composition . In some
largely unsuccessful. embodiments , the composition additionally contains one or
U.S. Pat. No. 3,980,766 to Shaw et al. (“ Shaw ” ), U.S. Pat. more antioxidants.
No. 4,070,494 to Hoffmeister et al. (“ Hoffmeister” ), and The abuse -deterrent composition retards the release of
U.S. Pat. No. 6,309,668 to Bastin et al. (“ Bastin " ) describe 10 drug, even if the physical integrity of the dosage form is
formulations designed to prevent the injection of composi compromised (for example , by chopping with a blade or
tions meant for oral administration . crushing ) and the resulting material is placed in water,
Shaw describes the incorporation of an ingestible solid snorted
which causes a rapid increase in viscosity upon concentra directed,, the or swallowed . However, when administered as
drug is released slowly ( typically over a period
tion of an aqueous solution thereof. 15
of 4-18 hours ) from the composition by diffusion as the
Hoffmeister describes the incorporation of a non -toxic , composition is broken down or dissolved gradually within
water gelable material in an amount sufficient to render the
drug resistant to aqueous extraction . the GI tract by a combination of surfactant action of bile
Bastin describes a tablet for oral administration contain acids, mechanical erosion and /or enzymatic degradation .
ing two ormore layers containing one or more drugs and one 20 In some embodiments , the individual drug -containing
or more gelling agents within separate layers of the tablet. microparticles or drug particles are coated With one or more
The resulting tablet forms a gel when combined with the independent coating layers . At least one of the coating
volume of water necessary to dissolve the drug allegedly materials is water-insoluble and/or organic solvent-in
reducing the extractability of the drug from the tablet. soluble , so that in vitro degradation of the formulation will
It should be noted that although these compositions 25 require more than one step. Thus, the drug is not easily
allegedly preclude abuse by injection , this approach fails to extractable from the formulations by conventional chemical
prohibit rapid dissolution of the drug once the dosage form means. In contrast , when administered to the gastrointestinal
is crushed into smaller particles or pieces . Thus, these tract via swallowing, the drug will gradually be released
formulations are vulnerable to abuse by crushing and swal from the coated microparticles as a consequence of diffu
lowing or snorting the formulation , which are commonly 30 sion , the gradual break down of the formulation via surfac
reported methods of abuse associated with OxyContin® . tant action of bile acids, mechanical erosion and /or enzy
U.S. Pat. Nos. 3,773,955 and 3,966,940 to Pachter et al. matic degradation .
describe formulations containing a combination of opioid The pharmaceutical composition , when administered
agonists and antagonists , in which the antagonist does not orally, results in a desired drug release profile. The release
block the therapeutic effect when the admixture is admin- 35 profile provides a therapeutic effect for an extended period
istered orally, butwhich does not produce analgesia , eupho of time, typically from 6 to 24 hours, preferably from 12 to
ria or physical dependence when administered parenterally 24 hours. Additional compositions are provided which
by an abuser. achieve a small immediate release dose that precedes the
U.S. Pat. No. 4,457,933 to Gordon et al, describes a sustained release of drug. The compositions disclosed herein
method for decreasing both the oral and parenteral abuse 40 may optionally contain a drug having no appreciable abuse
potential of strong analgetic agents by combining an anal potential.
gesic dose of the analgetic agent with an antagonist in
specific, relatively narrow ratios . DETAILED DESCRIPTION OF THE
U.S. Pat . Nos. 6,277,384, 6,375,957 and 6,475,494 to INVENTION
Kaiko et al. describe oral dosage forms including a combi- 45
nation of an orally active opioid agonist and an orally active Disclosed herein are an abuse - deterrent pharmaceutical
opioid antagonist in a ratio that, when delivered orally , is compositions and the method of making and using the
analgesically effective but that is aversive in a physically compositions.
dependent subject. While such a formulation may be suc I. Compositions
cessful in deterring abuse, it also has the potential to produce 50 As used herein , “ composition ” refers to the drug dosage
adverse effects in legitimate patients . unit for administration to a patient. “Composition ” may also
It is therefore an object of the present invention to provide be used in reference solely to the active ingredient, or to a
a pharmaceutical composition that significantly reduces the formulation containing the active ingredient.
potential for improper administration or use of drugs but The currently available sustained release dosage forms
which , when administered as directed, is capable of deliv- 55 containing narcotic analgesics and other drugs are subject to
ering a therapeutically effective dose . misuse , in part, because mechanical destruction of the
dosage form exposes the encapsulated drug and allows for
SUMMARY OF THE INVENTION immediate dissolution of the drug into aqueousmedia . Three
properties of the dosage form that contribute to this outcome
An abuse -deterrent pharmaceutical composition and 60 are, (1) the high water solubility of the drug salt form ; ( 2) the
methods of making and using thereof have been developed . lack of protection offered by the hydrophilic and /or water
The compositions can be used to reduce the likelihood of soluble excipients in the formulation ; and (3 ) the ease with
improper administration of drugs, especially drugs prone to which the surface area of the formulation is increased by
abuse such as oxycodone . The technology is useful for a simple chewing or crushing . Susceptibility to simple meth
number of other drugs where sustained release oral delivery 65 ods such as chewing or crushing is particularly problematic
is desired , and there is potential for abuse if the drug dose for monolithic controlled -release dosage forms. For mono
is made immediately available for nasal, intravenous (IV ) or lithic dosage forms, such as tablets, even splitting the unit
US 10,525,053 B2
5 6
into a few pieces (without completely crushing it ) can result herein , drugs prone to abuse refer to controlled substance
in a dramatic increase in the dissolution rate . specified as schedule II , III, IV and V drugs.
In the compositions disclosed herein , one ormore of these The terms“ drug” , “ active agent”, and “ pharmacologically
properties are altered in order to achieve an abuse - deterrent active agent” are used interchangeably herein to refer to a
composition . Specifically , in the one embodiment, the drug 5 chemical compound that induces a desired pharmacological,
is modified to increase its lipophilicity which reduces its physiological effect. The terms also encompass pharmaceu
water solubility . The modified drug is then homogeneously tically acceptable derivatives of those active agents specifi
dispersed within one ormore carrier materials that arc either cally mentioned herein , including , but not limited to , salts,
slowly soluble or not soluble in water. Dispersion within solvates, hydrates, complexes with one ormore molecules,
these materials further reduces the accessibility of the drug 10 prodrugs , active metabolites , analogs , and the like. When the
when crushed and exposed to an aqueous media . In some terms “ active agent” , “ pharmacologically active agent” and
embodiments, the drug may be partially or fully dispersed in " drug ” are used , or when a particular drug, such as oxyco
the carrier materials on a molecular level. The intimate done , is identified , it is to be understood as including the
mixture of modified drug and carrier materials is subse active agent per se as well as pharmaceutically acceptable
quently formulated into microparticles , producing a formu- 15 salts , solvates, hydrates , complexes with one ormore mol
lation whose surface area is minimally influenced by chew ecules, prodrugs, active metabolites, and analogs.
ing or crushing. Examples of preferred drugs include , 1-phenylcyclohex
The terms “ abuse -deterrent composition ” or “ abuse- de ylamine , 1-piperidinocyclohexanecarbonitrile , alfentanil,
terrent formulation ” are used interchangeably herein to refer alphacetylmethadol, alphaprodine, alprazolam , amobarbital,
to compositions that reduce the potential for improper 20 amphetamine, anileridine, apomorphine, aprobarbital, bar
administration of drugs but that deliver a therapeutically bital, barbituric acid derivative , bemidone , benzoylecgo
effective dose when administered as directed . Improper nine , benzphetamine , betacetylmethadol, betaprodine, bez
administration includes tampering with the dosage form itramide, bromazepam , buprenorphine , butabarbital,
and / or administering the drug by any route other than butalbital, butorphanol, camazepam , cathine , chloral,
instructed . For example , for a tablet or capsule, methods of 25 chlordiazepoxide, clobazam , clonazepam , clorazepate, clo
tampering with the dosage form may include, but are not tiazepam , cloxazolam , cocaine, codeine, chlorphentermine,
limited to , breaking, crushing , grinding , chewing and /or delorazepam , dexfenfluramine, dextromoramide, dextro
dissolving the tablet or the contents of the capsule. For oral propoxyphen , dezocine, diazepam , diethylpropion,
administration , improper administration includes adminis difenoxin , dihydrocodeine, dihydromorphine, dioxaphentyl
tering the drug by any route other than via swallowing . 30 butyrate, dipanone, diphenoxylate , diprenorphine , ecgonine,
The abuse deterrent compositions preferably contain a enadoline , eptazocine , estazolam , ethoheptazine , ethyl
drug modified to increase its lipophilicity . In some embodi loflazepate , ethylmorphine, etorphine , femproponex , fen
ments , the drug is homogenously dispersed within micropar camfamin , fenfluramine , fentanyl, fludiazepam , flunitraze
ticles composed of a material that is either slowly soluble in pam , flurazepam , glutethimide, halazepam , haloxazolam ,
water or water insoluble . The compositions maintain the 35 hexalgon , hydrocodone , hydromorphone , isomethadone ,
slow the release of drug if the dosage form is chopped or hydrocodone, ketamine , ketazolam , ketobemidone , leva
crushed and the resulting material is placed in water, none, levoalphacetylmethadol, levomethadone, levometh
snorted , or swallowed since most of the drug will remain adyl acetate , levomethorphan , levorphanol, lofentanil, lop
associated with or entrapped within portions of the core eramide, loprazolam , lorazepam , lormetazepam , lysergic
material of the microparticles . In other embodiments, the 40 acid, lysergic acid amide, mazindol, medazepam ,
drug containing microparticles or individual drug particles mefenorex , meperidine , meptazinol, metazocine , metha
are coated with one or more coating layers, where at least done , methamphetamine, methohexital, methotrimeprazine,
one coating is water insoluble and /or organic solvent niethyldihydromorphinone, methylphenidate,methylpheno
insoluble . The components of the resulting coated micropar barbital, metopon , morphine , nabilone , nalbuphine , nal
ticles are not mutually soluble in water or organic solvents , 45 bupine , nalorphine , narceine , nefopam , nicomorphine , nim
such that no one solvent or enzyme solution is capable of etazepam , nitrazepam , nordiazepam , normethadone,
dissolving the formulation in its entirety in vitro . Therefore , nonnorphine , oxazepam , oxazolam , oxycodone, oxymor
extraction of the drug from the formulation cannot be carried phone, pentazocine, pentobarbital, phenadoxone , phenazo
out in one step .However, when administered as directed , the cine, phencyclidine, phendimetrazine , phenrnetrazine , phen
drug is slowly released from the formulation via diffusion 50 eridine , piminodine, prodilidine , properidine ,
and erosion within the environment of the gastrointestinal propoxyphene , racemethorphan , racemorphan , racemor
tract . amide, remifentanil, secobarbital, sufentanil, talbutal, the
A. Drugs to be Formulated baine, thiamylal, thiopental, tramadol, trimeperidine, and
There are many drugs which can be delivered using the vinbarbital.
compositions described herein . The Controlled Substances 55 In addition to the compounds above, the following sched
Act ( CSA ), Title II of the Comprehensive Drug Abuse uled drugs may be incorporated into the composition ; allo
Prevention and Control Act of 1970 , places all substances barbitone, alprazolam , amylobarbitone, aprobarbital, barbi
that are regulated under existing federal law into one of five tal, barbitone , benzphetamine, brallobarbital, bromazepam ,
schedules based upon the substance's medicinal value , brotizolam , buspirone , butalbital, butobarbitone, butorpha
harmfulness , and potential for abuse or addiction . Drugs that 60 nol, camazepam , captodiame, carbromal, carfentanil,
are preferred include those classified as Schedule II, III , IV carpipratnine , cathine, chloral, chloral betaine, chloral
and V drugs. Drugs that are most preferable include those, hydrate , chloralose , chlordiazepoxide, chlorhexadol, chlo
like oxycodone, that are currently formulated as sustained or rmethiazole edisylate , chlormezanone , cinolazepam , cloba
controlled release compositions, where drug release is zam , potassium clorazepate , clotiazepam , cloxazolam ,
intended to occur over a prolonged period of time through 65 cyclobarbitone , delorazepam , dexfenfluramine , diazepam ,
the gastrointestinal tract, and immediate or burst release , for diethylpropion , difebarbamate , difenoxin , enciprazine , esta
example , by inhalation or injection , is undesirable . As used zolarn , ethyl loflazepate, etizolam , febarbamate, fencam
US 10,525,053 B2
7 8
famin , fenfluramine, fenproporex , fluanisone, fludiazepam , drug . Furthermore, if the drug is mademore lipophilic , it can
flunitraam , flunitrazepam , flurazepam , flutoprazepam , be solubilized in a molten fatty substance or wax like
gepirone , glutethimide , halazepain , haloxazolam , hexobar mixture, rather than physically dispersed in a particulate
bitone , ibomal, ipsapirone, ketazolam , loprazolam mesylate ; form . Solubilization of the drug enhances the abuse-deter
lorazepam , lormetazepain , mazindol, mebutamate , medaze- 5 rent properties of microparticles formulated from the mix
pam , mefenorex , mephobarbital, meprobamate , metaclaze ture as it is difficult to extract drug from an intimately
pam , methaqualone,methohexital, methylpentynol, methyl dispersed composition . Furthermore, such a composition is
phenobarbital, rnidazolam , milazolam , morphine, capable of controlling the release of drug , even when
nimetazepam , nitrazepam , nordiazepam , oxazepam , oxazo formulated into relatively small microparticles . Micropar
lam , paraldehyde, pemoline, pentabarbitone, pentazocine , 10 ticulate compositions, in contrast to monolithic composi
pentobarbital , phencyclidine, phenobarbital, phondimetra tions, are inherently less susceptible to tampering by mecha
zine , phennietrazine, phenprobamate , phentermine, phe nisms that are intended to increase the surface area and ,
nyacetone , pinazepam , pipradol, prazepam , proxibarbal, consequently , the release rate of drug ( such as chewing or
quazepam , quinalbaritone, secobarbital, secbutobarbitone , crushing ).
sibutramine , temazepam , tetrazepam , triazolam , triclofos , 15 The terms “ lipophilic derivative ” and “ lipophililic drug
zalepan , zaleplon, zolazepam , zolpidem , and zopiclone . derivative ”, as used herein , refer to derivatives of the drug
Certain compounds described herein may exist in particular that are less soluble or dissolve less rapidly in water than the
geometric or stereoisomeric forms. The composition dis most soluble salt of the drug ; the most soluble salt being
closed herein contemplates all such compounds, including selected from either base addition salts ( for acidic drugs) or
cis- and trans - isomers, R- and S - enantiomers,diastereomers,
20 acid addition salts (for basic drugs), such as by the addition
(D )-isomers , (L )-isomers, the racemic mixtures thereof,of inorganic acids. The examples of the latter include but are
compounds of different spacial conformations, and other not limited to hydrohalates, sulfates , and nitrates. Some of
mixtures thereof, as falling within the scope ofthe invention .
the methods that can be used to alter the drug's lipophilicity
Additional asymmetric carbon atoms may be present in a are outlined below . It is understood that two or more
substituent such as an alkyl group . All such isomers, as well
25 approaches can be combined to achieve a desired solubility
as mixtures thereof, are intended to be included in this profile .
invention . Methods for Increasing Lipophilicity
As used herein , “ pharmaceutically acceptable salts” refer In one embodiment, the drug is mademore lipophilic by
to derivatives of the disclosed compounds wherein the eliminating or reducing the overall charge of the drug
parent compound is modified by making acid or base salts 30 molecule. For example , for a basic drug , a water soluble salt
thereof. Examples of pharmaceutically acceptable salts (such as hydrochloride, sulfate, or maleate ) can be converted
include, but are not limited to , mineral or organic acid salts to a free base using techniques known in the art. In the case
of basic residues such as amities; alkali or organic salts of of an acidic drug, a water soluble salt (such as sodium ,
acidic residues such as carboxylic acids ; and the like . The potassium , or the like) can be converted to a free acid .
pharmaceutically acceptable salts include the conventional 35 In another embodiment, the drug's lipophilicity is
non -toxic salts or the quaternary ammonium salts of the increased by forming a salt between a drug molecule and a
parent compound formed , for example , from non -toxic charged lipophilic compound . In this case the lipophilicity of
inorganic or organic acids. For example, such conventional the resulting salt can be manipulated by varying the lipo
non -toxic salts include those derived from inorganic acids philicity of the counter -ion . In general, lipophilic acids or
such as hydrochloric , hydrobromic , sulfuric , sulfamic , phos- 40 amines with chain lengths between C5 -C30 are lipophilic
phoric , nitric and the like ; and the salts prepared from counter-ion candidates. Some specific examples include, but
organic acids such as acetic , propionic, succinic, glycolic, are not limited to , linoleic acid , octanoic acid , lauric acid ,
stearic ,myristic, palmitic , lactic ,malic, tartaric , citric , ascor stearic acid , palmitic acid , myristic acid , oleic acid , octyl
bic , pamoic ,maleic , hydroxymaleic , phenylacetic , glutamic , amine, lauryl amine, stearyl amine , pahnityl amine, linoleyl
benzoic, salicylic , sulfanilic , 2 -acetoxybenzoic , fumaric, 45 amine, and oleyl amine. Other salts which may increase
tolunesulfonic , methanesulfonic, ethane disulfonic, oxalic , lipophilicity and, hence , lipid solubility relative to the parent
and isethionic . drug compound include, but are not limited to , pectinate ,
The pharmaceutically acceptable salts of the compounds tannate , phytate , salicylate , saccharinate, acesulfamate, gal
can be synthesized from the parent compound , which con late , and terephthalate salts .
tains a basic or acidic moiety , by conventional chemical 50 In still a further embodiment, drug lipophilicity is
methods. Generally , such salts can be prepared by reacting increased via complexation with poorly water -soluble cyclo
the free acid or base forms of these compounds with a dextrin . For example , ethylated beta -cyclodextrin has been
stoichiometric amount of the appropriate base or acid in shown to decrease aqueous solubility of complexed drug
water or in an organic solvent, or in a mixture of the two ; molecules.
generally , non -aqueous media like ether, ethyl acetate, etha- 55 In another embodiment, a drug is covalently modified to
nol, isopropanol, or acetonitrile are preferred . Lists of suit increase its lipophilicity. For example, a lipophilic com
able salts are found in Remington's Pharmaceutical Sci pound can be covalently attached to a drug molecule via an
ences, 20th ed., Lippincott Williams & Wilkins, Baltimore , ester or amide linkage . Such drug derivatives are cleaved in
Md., 2000, p . 704 , the disclosure of which is hereby incor vivo , thus releasing the parent compound .
porated by reference . 60 C. Drug Containing Microparticles
Optionally , the composition described herein can further In some embodiments , the drug is formulated with a
include a drug having no appreciable abuse potential. carrier material to form microparticles. As used herein , the
B. Drug Solubility Modification term “microparticle” refers to a composition containing a
In some embodiments , the solubility characteristics of a drug dispersed within a carrier material and " coated
drug are altered. Modification of the drug to produce a more 65 microparticle” refers to a composition containing a drug
lipophilic derivative serves to reduce the water solubility of containing microparticle or a drug particle coated with one
the drug and thus reduce the aqueous extractability of the or more coating layers of material. Microparticles and
US 10,525,053 B2
9 10
coated microparticles have a size range of 10 to 3000 hydroxypropyl methylcellulose or polyethylene oxide may
microns in diameter , more preferably from 10 to 1000 also be suitable as carrier materials for drug containing
microns. microparticles.
Within microparticles , the drug is preferably homoge Encapsulation or incorporation of drug into carrier mate
neously dispersed in the form of fine particles within the 5 rials to produce drug containing microparticles can be
carrier material. More preferably, the drug is partially solu achieved through known pharmaceutical formulation tech
bilized in a molten carder material or partially dissolved niques. To create a composition that protects drug from
with the carrier material in a mutual solvent during the exposure upon mechanical disruption ( eg, grinding , chew
formulation of the microparticles. Most preferably, the drug ing, or chopping), the drug is intimately dispersed within the
is completely solubilized in the molten carrier material or 10 carrier material. In the case of formulation in fats , waxes or
completely dissolved with the carrier material in a co wax -like materials, the carrier material is heated above its
solvent during the formulation of themicroparticles. This is melting temperature and the drug is added to form a mixture
accomplished through the selection of materials and the containing drug particles suspended in the carrier material,
manner in which they are processed . drug dissolved in the carrier material, or a mixture thereof.
Carrier materials appropriate for the fabrication of drug 15 Microparticles can be subsequently formulated through sev
containing microparticles either dissolve slowly in water or eral methods including, but not limited to, congealing ,
are insoluble in water. As used herein , the term “ dissolves extrusion, spray chilling or aqueous dispersion . In a pre
slowly in water” refers to materials that are not completely ferred process, one or more carrier materials are heated
dissolved in water within a period of 30 minutes. Suitable above its melting temperature, the drug is added , and the
materials include fats, fatty substances, waxes, wax -like 20 molten carrier material-drug mixture is congealed to form
substances and mixtures thereof. Suitable fats and fatty solid , spherical particles via a spraying or spinning cylinder
substances include fatty alcohols (such as lauryl, myristyl or disk processes. Alternatively, the molten carrier material
stearyl, cetyl or cetostearyl alcohol), fatty acids and deriva drug mixture can be extruded and pelletized to form pellets
tives , including butnot limited , to fatty acid esters, fatty acid or beads. Detailed descriptions of these processes can be
glycerides (mono-, di- and tri- glycerides ), and hydrogenated 25 found in “ Remington — The science and practice of phar
fats . Specific examples include, but are not limited to macy ” , 20th Edition , Jennaro et. Al., (Phila , Lippencott ,
hydrogenated vegetable oil, hydrogenated cottonseed oil , Williams, and Wilkens, 2000 , Spinning disk processes are
hydrogenated castor oil , hydrogenated oils available under described in U.S. Pat. Nos. 3,015,128 and 7,261,529 .
the trade name Sterotex® , stearic acid , cocoa butter, glyceryl In a preferred process, spherical particles are produced .
behenate (available under the trade name COMPRITOL 30 Spherical particles may introduce an additional barrier to
888® ) , glyceryl dipalmitostearate (available under the trade deter tampering with the composition . Smaller , round par
name PRECIROL® ), and stearyl alcohol. Mixtures of ticles act as “ ball bearings ” that are more difficult to crush
mono-, di- and tri -glycerides and mono- and di-fatty acid or grind , and if crushed ,do not allow for significant decrease
esters ofpolyethylene glycol, available under the trade name in particle size or surface areas of the particles in order to
GELUCIRE® ) are also suitable fatty materials. Suitable 35 effect an increase in release rate .
waxes and wax - like materials include natural or synthetic For compositions containing salts composed of a phar
waxes, hydrocarbons, and normal waxes . Specific examples maceutically active agent and one or more fatty acids or
ofwaxes include beeswax , glycowax , castor wax , carnauba amines , the salt may be formed during the formulation
wax, paraffins and candelilla wax . As used herein , a wax -like process itself. To accomplish this , the one or more fatty acids
material is defined as any material which is normally solid 40 or amines are melted and mixed with the free base or acid
at room temperature and has a melting point of from about form of the active agent at a temperature above the melting
30 to 300 ° C. point(s ) of the fatty acid (s ) or amine(s ). Once a homoge
In some cases, itmay be desirable to alter the rate of water neous mixture is formed , one or more additional carrier
penetration into the hydrophobic drug containing micropar materials , such as fat, fatty substance (s ), wax or wax -like
ticles. To this end , rate-controlling (wicking ) agents may be 45 substance(s) can be added to the molten mixture to yield a
formulated along with the fats or waxes listed above . single phase composition . The molten solution is then solidi
Examples ofrate -controlling materials include certain starch fied into microparticles using one of the techniques
derivatives ( e.g., waxy maltodextrin and drum dried corn described above .
starch ), cellulose derivatives (e.g. , hydroxypropylmethylcel The molar concentration of fatty acid or amine may need
lulose, hydroxypropylcellulose , methylcellulose , and car- 50 to be higher than that of the drug in order to achieve a
boxymethylcellulose ), alginic acid , lactose and talc . Addi homogeneous single phase . For example, it has been found
tionally, a pharmaceutically acceptable surfactant ( for that, for oxycodone, a molar ratio in excess of about 7 :1
example, lecithin ) may be added to facilitate the degradation ( fatty acid to drug) results in a homogeneous melt using this
and/ or dissolution of the microparticles. technique. The molar ratio needed to obtain a homogeneous
Proteins which are water insoluble , such as zein , are 55 melt may depend on the type and quantity of additional
suitable carrier materials for the formation of drug contain carrier materials added . In one embodiment, the molar ratio
ing microparticles . Additionally , proteins , polysaccharides of fatty acid or fatty amine is from about 1 :1 to about 15 : 1 ,
and combinations thereof which are water soluble can be preferably from about 6 : 1 to about 15: 1. However, molar
formulated with drug into microparticles and subsequently ratios greater than 15 :1 , for example 15: 1 to 25 : 1, preferably
cross- linked to form an insoluble network. For example, 60 15:1-20 :1, may be required depending on the fatty acid or
cyclodextrins can be complexed with individual drug mol fatty amine , the drug to be formulated , and/or the carrier
ecules and subsequently cross - linked . material(s ).
Certain polymers may also be used as carrier materials in For some carrier materials it may be desirable to use a
the formulation of drug containing microparticles . Suitable solvent evaporation technique to produce drug containing
polymers include ethylcellulose and other natural or syn- 65 microparticles. In this case drug and carrier material are
thetic cellulose derivatives . Polymers which are slowly co - dissolved in a mutual solvent and microparticles can
soluble and form a gel in an aqueous environment, such as subsequently be produced by several techniques including ,
US 10,525,053 B2
11 12
but not limited to , forming an emulsion in water or other eryl monopalmitate and cetyl alcohol will also form films
appropriate media , spray drying or by evaporating off the that are dissolved slowly or broken down in the GI tract.
solvent from the bulk solution and milling the resulting Zein is an example of a naturally water-insoluble protein . It
material. can be coated onto drug containing microparticles or drug
In addition to modification of the drug itself, processing 5 particles by spray coating or by wet granulation techniques.
conditions can be used to influence the dispersion of the drug In addition to naturally water- insoluble materials, some
within water-insoluble or slowly water soluble materials . substrates of digestive enzymes can be treated with cross
For example , in the ease where the water in -soluble or linking procedures , resulting in the formation of non -soluble
slowly soluble material is melted and the drug is fully or networks. Many methods of cross- linking proteins, initiated
partially dissolved under stirring conditions, the tempera- 10 by both chemical and physical means, have been reported . In
ture , agitation rate and time of processing will influence the some embodiments, chemical cross-linking agents are used .
degree of dissolution achieved . More specifically , a more Examples of chemical cross- linking agents include alde
homogenous dispersion may be achieved with a higher hydes ( gluteraldehyde and formaldehyde ), epoxy com
temperature, faster stirring rate and/or longer processing pounds, carbodiimides , and genipin . In addition to these
time. Ultrasound can also be applied to the molten mixture 15 cross- linking agents, oxidized and native sugars have been
to increase the degree of dispersion and/ or the rate of used to cross- link gelatin (Cortesi, R., et al ., Biomaterials 19
dissolution of the drug . ( 1998 ) 1641-1649 ). Cross- linking can also be accomplished
In some embodiments , the drug in a particulate form is using enzymatic means; for example , transglutaminase has
homogeneously dispersed in a water -insoluble or slowly been approved as a GRAS substance for cross -linking
water soluble material. To minimize the size of the drug 20 seafood products . Finally, cross -linking can be initiated by
particles within the composition , the drug powder itself may physical means such as thermal treatment, UV irradiation
bemilled to generate fine particles prior to formulation . The and gamma irradiation.
process of jet milling, known in the pharmaceutical art , can To produce a coating layer of cross -linked protein sur
be used for this purpose . In some embodiments drug in a rounding drug containing microparticles or drug particles, a
particulate form is homogeneously dispersed in a wax or 25 water soluble protein can be spray coated onto themicropar
wax like substance by heating the wax or wax like substance ticles and subsequently cross-linked by one of themethods
above its melting point and adding the drug particles while described above . Alternatively, drug containing micropar
stirring the mixture . In this case a pharmaceutically accept ticles can be microencapsulated within protein by coacer
able surfactantmay be added to the mixture to facilitate the vation -phase separation ( for example , by the addition of
dispersion of the drug particles . 30 salts) and subsequently cross -linked . Some suitable proteins
D. Coated Drug Containing Microparticles for this purpose include gelatin , albumin , casein , and gluten .
In some embodiments , drug containing microparticles or Polysaccharides can also be cross- linked to form a water
drug particles are encapsulated . Drug containing micropar insoluble network . For many polysaccharides, this can be
ticles can be encapsulated in water insoluble materials , accomplished by reaction with calcium salts or multivalent
slowly water soluble materials, organic insoluble materials 35 cations which cross- link the main polymer chains . Pectin ,
and/or materials with pH dependent solubilities. alginate , dextran , amylose and guar gum are subject to
In general, any coating procedure which provides a con cross - linking in the presence of multivalent cations . Com
tiguous coating on each microparticle can be used . Coating plexes between oppositely charged polysaccharides can also
procedures known in the pharmaceutical arts include, but are be formed ; pectin and chitosan , for example, can be com
not limited to , fluid bed coating processes and microencap- 40 plexed via electrostatic interactions. Insoluble coatings can
sulation may be used to obtain appropriate coatings . be formed on particles in this fashion . It should be noted that
Detailed descriptions of these processes can be found in in many cases polysaccharides are broken down specifically
“ Remington — The science and practice of pharmacy” , 20th by enzymes produced by bacteria within the colon .
Edition , Jennaro et . Al., (Phila, Lippencott , Williams, and In some cases a water-insoluble but enzymatically
Wilkens, 2000 . 45 degradable coating including both a protein and a polysac
The water- insoluble coating materials may be selected charide can be produced if the components are oppositely
from natural or synthetic film - formers used singly, in admix charged polyelectrolytes. Under the proper temperature, pH ,
ture with each other, and in admixture with plasticizers , and concentrations, the two polymers can interact through
pigments and other substances to alter the characteristics of their opposite electrical charges and form a water - insoluble
the coating . A water -insoluble butwater-permeable diffusion 50 complex . If a core particle is present at the time the complex
barrier may contain ethyl cellulose, methyl cellulose and phase separates, it will be coated . For example , gelatin and
mixtures thereof. The water-permeable diffusion barrier may gum arabic can be coated onto a core particle utilizing this
also include ammonio methacrylate copolymers sold under process. Optionally, the complex can be made irreversibly
the trade name EUDRAGIT® (Rohm Pharma), such as insoluble by subsequent cross - linking induced by chemical
EUDRAGIT RS, EUDRAGIT RL , EUDRAGIT NE and 55 or physical means.
mixtures thereof. Other synthetic polymers , for example , Coating materials may also include a pH sensitive poly
polyvinyl acetate (available under the trade name KOLLI mer which is insoluble in the acid environment of the
COAT® ), can also be used to form water-insoluble but stomach , and soluble in the more basic environment of the
permeable coatings. GI tract. These coatings , referred to as enteric coatings,
The coating may also include a water- insoluble but enzy- 60 create a dosage form designed to prevent drug release in the
matically degradable material. In some instances the sub stomach . Preventing drug release in the stomach has the
strates of digestive enzymes are naturally water-insoluble advantage of reducing side effects associated with irritation
and can be utilized in the formulation without further of the gastric mucosa and / or of minimizing exposure of drug
processing . Solid esters of fatty acids, which are hydrolyzed to very low pH . Avoiding release within the stomach can be
by lipases , can be spray coated onto microparticles or drug 65 achieved using enteric coatings known in the art. The enteric
particles. Mixtures of waxes (beeswax , carnauba wax , etc.) coated formulation remains intact or substantially intact in
with glyceryl monostearate , stearic acid , palmitic acid , glyc the stomach , however, once the formulation reaches the
US 10,525,053 B2
13 14
small intestines, the enteric coating dissolves and exposes The concentration of the antioxidant is generally from
either drug -containing carrier particles or drug -containing about 0.001 % to about 1 % w / w , preferably from about
carrier particles coated with extended release coating . 0.01 % to about 0.5 % w /w . However, concentrations of less
Enteric coated particles can be prepared as described in than 0.001 % or greater than 0.5 % may be used , provided the
“ Pharmaceutical dosage form tablets” , eds. Liberman et. al. 5 concentration is sufficient to stabilize the formulation and is
(New York, Marcel Dekker , Inc., 1989), “ Remington — The nonF.-toxic .
Dosage Forms
science and practice of pharmacy” , 20th ed., Lippincott In one embodiment a drug is partially dissolved within a
Williams & Wilkins , Baltimore , Md., 2000 , and " Pharma
ceutical dosage forms and drug delivery systems”, 6th water- insoluble or slowly water soluble material during the
Edition , Ansel et. al., (Media , Pa.: Williams and Wilkins, 10 manufacturing process , forpoint
example
of the, bycarrier
mixingmaterial
at a ,tem
1995 ). Examples of suitable coating materials include, but perature the
above the
mixture is
melting
formulated into microparticles . In
and
another
are not limited to , cellulose polymers, such as cellulose embodiment a drug is fully dissolved within a water-in
acetate phthalate, hydroxypropyl cellulose, hydroxypropyl soluble or slowly water soluble material during the manu
methylcellulose phthalate and hydroxypropyl methylcellu- 15 facturing process, for example, by mixing at a temperature
lose acetate succinate; polyvinyl acetate phthalate, acrylic above the melting point of the carrier material, and the
acid polymers and copolymers, and certain methacrylic mixture is formulated into microparticles . In still a further
resins that are commercially available under the trade name embodiment, the drug containing microparticles , where the
EUDRAGIT (Rohm Pharma). Additionally the coating drug is homogeneously dispersed in a particulate form , or
material may contain conventional carriers such as plasti- 20 has been partially or fully dissolved within the carrier
cizers, pigments , colorants , glidants , stabilization agents, material during the manufacturing process, are coated with
and surfactants . one or more coatings to form coated microparticles. In a
In some cases itmay be desirable to coat the particles with further embodiment, drug particles are coated directly with
a coating which is soluble in aqueous solutions but insoluble one or more coatings to form coated microparticles.
in hydroalcoholic solutions . In this case the coatingmaterial 25 The microparticles , coated microparticles , or a mixture
may or may not have pH sensitive solubility in aqueous thereof are formed into a solid dosage form suitable for oral
solutions. administration . For example , microparticles or coated
In other cases it may be desirable to combine coating microparticles can be incorporated into hard shell capsules ,
materials to produce a tailored release of drug. For example , dispersed within a soft gelatin capsule, or combined with
combinations of insoluble polymers and pH dependent poly- 30 appropriate excipients such as magnesium stearate as lubri
mers can produce a pH dependent sustained release profile. cant, colloidal silicon dioxide as glidant, sodium starch
Combinations of insoluble polymers (eg , ethylcellulose ), glycolide, sodium croscarmellose or crospovidone as disin
water-soluble polymers (eg , HPMC or PEG ) and pH depen tegrant, sodium dodecyl sulfate or Polyoxyethylene (20 )
dent swellable polymers (eg , carboxyvinylpolymer ) have sorbitan rnonooleate , polyvinyl pyrrolidone or hydroxypro
also been reported to produce pH dependent sustained 35 pylmethylcellulose as crystallization inhibitor, and lactose
release profiles (See, for example , Journal of Controlled and microcrystalline cellulose as fillers , and tableted by
Release, 2006 , 111: 309-315 ). compression .
In one embodiment, the particles are coated with cellulose In some embodiments, the compositions are coated with
acetate phthalate . Cellulose acetate phthalate is typically an enteric coating . Enteric coatings known in the art are
used as an enteric coating. 40 applied directly to the abuse-deterrent microparticle or
E. Antioxidants coated microparticle compositions or are applied to the
In some embodiments , the composition includes one or surface of a capsule or tablet containing the abuse deterrent
more antioxidants . Suitable antioxidants include, but are microparticle and/or coated microparticle compositions .
not limited to , butylated hydroxytoluene (BHT); ascorbic Enteric coatings known in the art include , for example ,
acid , its salts and esters ; Vitamin E , tocopherol and its salts ; 45 acrylic polymers that are commercially available under the
sulfites such as sodium metabisulphite ; cysteine and its trade name EUDRAGIT® , cellulose acetate phthalate ,
derivatives; citric acid ; propyl gallate , and butylated hydroxypropylmethyl-cellulose phthalate , polyvinylacetate
hydroxyanisole ( BHA ). phthalate, shellac , hydroxypropylmethylcellulose succinate ,
Antioxidants may be necessary to preventoxidative deg cellulose acetate trimelliate or mixtures thereof. In one
radation of the active pharmaceutical ingredient and /or the 50 embodiment, the particles are coated with cellulose acetate
one or more inactive carrier materials in the composition . phthalate.
Oxidation of one or more components may occur during the Dosage forms can include one or more drugs. When the
formulation process itself or during the shelf - life of the dosage form includes two or more drugs they can be
composition . Oxidation may result from exposure to the Scheduled drugs or can be a combination of Scheduled and
oxygen content of air or, alternatively, may be related to 55 non -Scheduled drugs . The drugs can be incorporated into
impurities in the carrier materials . For example , highly separate microparticle compositions where the Scheduled
reactive species such as peroxides , superoxides , hypochlo drugs are incorporated into abuse deterrent microparticle
rites and formic acid may be present in carrier materials as compositions and the non -Scheduled drugs are incorporated
manufacturing - related impurities. Also , trace metal impuri into abuse deterrent microparticle compositions, sustained
ties in carrier materials, such as iron and copper , can catalyze 60 release compositions known in the art or immediate release
oxidation reactions. An antioxidant may be included in the compositions known in the art . The compositions containing
composition to mitigate the degradation of the drug in such the different drugs are formulated into a single solid dosage
cases. If the source of oxidation is a reactive manufacturing form suitable for oral administration , for example , they can
related impurity in one ormore of the carrier materials, the be incorporated into a gelatin capsule , or combined with
anti -oxidant can be co -melted with the carrier materials prior 65 appropriate excipients and compressed into a tablet form .
to the introduction of the drug into the formulation in order Examples of non -scheduled drugs that may be included in
to protect the drug from these reactive species . dosage forms described herein include , but are not limited
US 10,525,053 B2
15 16
to, aspirin , acetaminophen , non -steroidal anti- inflammatory
as starch , gelatin , sugars, natural and synthetic gums, poly
drugs, cyclooxygenase II inhibitors , N -methyl-D -aspartate
ethylene glycol, ethylcellulose , methylcellulose , hydroxy
receptor antagonists, glycine receptor antagonists , triptans,
propylmethylcellulose , carboxymethylcellulose, waxes and
dextromethorphan , promethazine , fiorinal, guaifenesin , polyvinyl pyrrolidone. Lubricants are used to facilitate tablet
butalbital, and caffeine . 5 manufacture ; examples of lubricants include talc , magne
An immediate release dose can be incorporated into the sium stearate , calcium stearate , hydrogenated vegetable oils
formulation in several ways. Immediate release micropar stearic acid , sodium stearyl fumarate , sodium benzoate ,
ticles can be made utilizing standard methodologies and sodium acetate , leucine, sodium oleate, sodium lauryl sul
formulated along with abuse -deterrent microparticle and /or fate, magnesium lauryl sulfate and polyethylene glycol.
coated microparticle compositions in a suitable oral dosage 10 Disintegrants can be added to pharmaceutical formulations
form . Alternatively , a coating containing drug which is in order to facilitate “ breakup ” or disintegration after admin
available for immediate release can be placed on a tablet istration . Materials used for this purpose include starches,
containing abuse-deterrent microparticle and/or coated clays , celluloses, aligns, gums, and cross-linked polymers . A
microparticle compositions plus appropriate excipients. plasticizer may be included in coating materials to alter their
Additionally, an immediate dose of drug can be granulated 15 mechanical properties. Examples of plasticizers include
or blended with rapidly dissolving excipients and subse benzyl benzoate, chlorobutanol, dibutyl sebacate , diethyl
quently compressed ( 1) as one layer of bi- layer tablets in phthalate , glycerin , mineral oil, polyethylene glycol, sorbi
which the abuse -deterrent microparticle and /or coated tol, triacetin, diethyl citrate, glycerol, etc. In addition to the
microparticle compositions are compressed as the other additives above, coloring and flavoring agents may also be
layer, or (2 ) as the outer layer of compression -coated tablets 20 incorporated into the composition .
in which the abuse -deterrent microparticle and /or coated II. Methods of Administration
microparticle compositions are compressed as the inner In addition to providing a deterrent to common methods
core , or (3 ) into tablets in which abuse -deterrent micropar of abuse/diversion , the formulation can provide a sustained
ticle and/or coated microparticle compositions are embed release of drug over an extended time period . This is a
ded . 25 natural consequence of the fact that, in the present formu
In some embodiments , the immediate release portion of lation , drug is slowly released from a predominantly water
the dosage form contains a lipophilic drug derivative . For insoluble , hydrophobic matrix as it passes through the GI
example , salt derivatives or complexes that are insoluble at tract. The barrier componentsmay be degraded as thematrix
a neutral pH but dissociate, thereby releasing the parent passes through the GI tract, for example, by enzymes, the
compound, at an acidic pH are ideal for immediate release 30 surfactant action of bile acids and mechanical erosion ,
within the stomach . In the case of oxycodone some salts that In some embodiments, an immediate release of drug is
may exhibit this property include, but are not limited to , the achieved within the stomach in order to provide rapid
tannate , phthalate , salicylate , gallate , pectinate, phytate , therapeutic onset .
saccharinate, asesulfamate and terephthalate salts. Com The pharmaceutical drug composition is administered
plexes of drug with one or more metal ions and , optionally , 35 orally. The appropriate dosage formulations can be obtained
one or more lipophilic counter-ions may also be used for by calculation of the pharmacokinetics of the formulation,
immediate drug release . Use of salts or complexes in the then adjusting using routine techniques to yield the appro
immediate release portion of the dosage form reduces the priate drug levels based on the approved dosage forms. Any
abuse potential of the immediate release dose if the formu suitable amountof drug containing microparticles or coated
lation is crushed and (1) snorted or (2 ) dissolved in water 40 microparticles can be included in the final formulation . The
since these salts will be poorly soluble under these condi selection of a suitable amount of drug containing micropar
tions . It is understood by the one of ordinary skill in the art ticles depends on the dosage desired and is readily deter
that such salts or complexes may also be used to formulate mined by those skilled in the art.
an immediate release dosage form without a sustained In addition to oral administration , some embodiments
release portion . 45 may also be administered by other routes, including, but not
Additional mechanisms to reduce the potential for abuse limited to , rectal and nasal administration . Some embodi
can also be incorporated during the process of formulating ments may also be suitable for formulation as oral liquids.
tablets. For example , ingredients can be added to deter The present composition and method ofmaking and using
chewing or snorting of the final formulation . For example , the composition will be further understood by reference to
an intensely bitter substance may deter chewing , while an 50 the following non - limiting examples.
intensely spicy ingredient, such as capsaicin , may deter
snorting. The addition of a colored dye , which would stain EXAMPLES
the skin and mucosal surface of the nose following snorting
may also serve to reduce this practice . Example 1 : Preparation of Drug Containing
Optional excipients present in the oral dosage form con- 55 Microparticles
taining abuse deterrent microparticles or coated micropar
ticles include , but are not limited to diluents, binders ,
lubricants, disintigrants , colorants , plasticizers and the like . TABLE 1
Diluents, also termed " fillers,” are typically necessary to Compositions
increase the bulk of a solid dosage form so that a practical 60
size is provided for compression of tablets . Examples of Composition Composition Composition Composition
diluents include cellulose , dry starch , microcrystalline cel of of of of
lulose, dicalcium phosphate, calcium sulfate, sodium chlo Ingredient Formulation Formulation Formulation Formulation
A B ? D
ride confectioner's sugar , compressible sugar, dextrates ,
dextrin , dextrose , sucrose, mannitol, powdered cellulose , 65 Oxycodone 5 g 5 g 10 g 5 g
sorbitol, and lactose . Binders are used to impart cohesive Base
qualities powdered materials and can include materials such
US 10,525,053 B2
17 18
TABLE 1 - continued TABLE 2 - continued
Compositions Drug Release from Crushed Compositions
Composition Composition Composition Composition % Released in 15
of of of of 5 minutes in 0.1N HCI
Formulation Formulation Formulation Formulation Sample (n = 3)
Ingredient A B ? D
Formulation C 14.8 +/- 1.1
Myristic Acid 50 g 30 g (microparticles containing 20 mgoxycodone
Stearic Acid 34 g 34 g HCl equivalent)
Yellow 10 g 10 g 10 g 10 Formulation D 18.2 +/- 1.6
Beeswax (microparticles containing 20 mg oxycodone
Carnauba wax 5g 10 g 20 g 10 g HCl equivalent)
Procedure : As illustrated in the table above, the microparticle com

1. Fatty acid (myristic or stearic acid ) was melted in an 15 positions of Example 1 release only a fractionate total drug
erlenmeyer flask in a silicone oil bath at 100 ° C. The load in simulated stomach conditions when crushed . In
mixture was stirred and kept, under an argon blanket for contrast, a currently marketed sustained release composi
this and all subsequent steps. tion , OxyContin® , releases approximately 96 % of the drug
2. Oxycodone base was introduced into themolten fatty acid load when crushed and exposed to identical conditions.
and the melt was stirred until the oxycodone base was 20
completely dissolved and a clear liquid was formed . Example 3: Preparation of Oxycodone Containing
3. Yellow beeswax was added and dissolved under constant Microparticles Using a Spinning Disk Atomization
stirring Process
4. Carnauba wax was added and dissolved under constant
stirring . 25
Batch size : 1000 g
5. The resulting homogeneous molten solution was poured
onto aluminum foil and allowed to solidify at room
temperature . Component Quantity (g )/Batch
6. The bulk material obtained was combined with small
quantities of dry ice and subjected to size reduction in a 30 Oxycodone base 91
Myristic acid 545
mortar and pestle . Beeswax 182
7. The dry ice was allowed to dissipate and the particles were Carnauba Wax 182
sieved to obtain various size ranges. Particles 20-40 mesh Total 1000.0
in size (400-841 micron ) were subjected to testing . 35
Example 2. Release of Drug from Crushed Procedure :
Microparticles 1.Myristic acid was melted at 85 ° C. in a silicone oil bath
while constantly flowing argon above the surface of the
In vitro testing was conducted in order to assess the solution .
influence of crushing of the microparticles produced
Example 1 on the release in simulated stomach conditions .
in 40 2. Beeswax was added to the molten fatty acid and mixed
A currently marketed sustained release formulation of oxy until a clear, homogeneous solution was obtained .
codone, OxyContin® , was also subjected to crushing and 3.mixed Carnauba wax was added to the molten solution and
until a clear, homogeneous solution was obtained .
dissolution for comparison purposes .
Microparticles (Formulations A , B , C or D , all 20-40 45 4.mixed Oxycodone base was added to the molten solution and
until a clear, homogeneous solution was obtained .
mesh in starting particle size ) or tablets were crushed using
a glass mortar & pestle . The resulting crushed material was 5.kettle The resulting molten solution was transferred to a feed
and continuously metered onto a spinning disk
placed in a dissolution vessel equipped with paddles (USP atomizer in order to form solid , spherical microparticles .
Apparatus II). 900 mL of 0.1N HCl pre -warmed to 37 ° C.
was added to the vessels and stirred for 15 minutes. After 15 50
minutes the amount of oxycodone released was determined . Example 4: Preparation of Coated Drug Containing
The results are shown in Table 2 . Microparticles
TABLE 2 The drug -containing particles from Example 3 can be
Drug Release from Crushed Compositions
55 spray coated with cellulose acetate phthalate
% Released in 15 Example 5 : Preparation of Oxymorphone
minutes in 0.1N HCI Containing Microparticles
Sample (n = 3)
Oxycontin ® 95.6 +/- 2.7 60 Batch size : 630.6 g
(40 mg Tablet )
Formulation A 31.6 +/- 2.6
(microparticles containing 40 mg oxycodone Component Quantity ( g )/Batch
HCl equivalent)
Formulation B 19.7 +/- 1.4 Oxymorphone base 60
(microparticles containing 40 mgoxycodone 65 Stearic Acid 420
HCl equivalent) Beeswax 30
US 10,525,053 B2
19 20
-continued ( a ) oxycodone;
(b ) myristic acid ; and
Component Quantity (g )/Batch (c) one or more carrier materials ;
Carnauba Wax NF 120
wherein the weight ratio ofmyristic acid to oxycodone is
Butylated Hydroxyanisole 0.6 5 about 5 : 1 to about 8 : 1 and the oxycodone is in the form
of a myristic acid salt.
Total 630.6 2. The oral dosage form of claim 1, wherein the one or
more carrier materials comprise fats, fatty substances,
Procedure : waxes, wax - like substances or mixtures thereof.
1. Stearic acid was melted in an erlenmeyer flask in a more 10 3. The oral dosage form of claim 2 , wherein the one or
silicone oil bath at 100 ° C. Note the composition was mixtures carriermaterials comprise beeswax , carnauba wax, or
subjected to stirring and was kept under an argon blanket thereof.
for this and all subsequent steps. 4. The oral dosage form of claim 2 , wherein the one or
more carrier materials comprise beeswax , carnauba wax ,
2. Butylated hydroxyanisole was added to the molten stearic 15 mixtures
acid while mixing. of mono-, di- and tri- glycerides and mono- and
3. Oxymorphone base was introduced into the molten fatty thereof. di- fatty acid esters of polyethylene glycol, or mixtures
acid and themelt was stirred until all oxymorphone base 5. The oral dosage form of claim 1 , wherein the oral
dissolved and a clear liquid was formed .
4. Beeswax was added and dissolved under constant stirring. 20 dosage form is a capsule or a tablet.
5. Carnauba wax was added and dissolved under constant dosage formoralis dosage
6. The form of claim 5 , wherein the oral
a capsule .
stirring
6. The resulting homogeneous molten solution was poured dosage 7. The oral dosage form of claim 1 , wherein the oral
onto aluminum , foil and allowed to solidify at room form further comprises an antioxidant.
temperature . 8. The oral dosage form of claim 7, wherein the antioxi
7. The bulk wax obtained was combined with dry ice and 25 acid dant, comprises butylated hydroxy toluene (BHT); ascorbic
its salts and esters; Vitamin E , tocopherol and its salts ;
subjected to size reduction in a mortar and pestle . sodium metabisulphite ; cysteine ; citric acid ; propyl gallate ;
8. The dry ice was allowed to dissipate and the particles were butylated hydroxyanisole (BHA ); or combinations thereof.
sieved to obtain particles in the 40-80 mesh size range . 9. The oral dosage form of claim 1, wherein the oral
Example 6 : Preparation of Capsules for Oral 30 dosage form is a controlled -release oral dosage form .
Administration 10. The oral dosage form of claim 1, wherein each
microparticle further comprises a pharmaceutically accept
The drug containing microparticles from Examples 1 , 3 , able surfactant.
4 , or 5 can be blended with a lubricant and incorporated into 35 the11. The oral dosage form of any of claims 1-10 , wherein
microparticles are spherical.
standard hard gelatin capsules
We claim : 12. The oral dosage form of claim 1, wherein the weight
1. An oral dosage form comprising a plurality of and ratio ofmyristic acid to oxycodone is about 6 : 1 to about 8 :1
microparticles, wherein each microparticle comprises a the oxycodone is in the form of a myristic acid salt.
homogenous single phase comprising:

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US010525053B2

United States Patent ( 10 ) Patent No.: US 10,525,053 B2

Related U.S. Application Data 4,765,989 A 8/1988 Wonq et al .

( 56 ) References Cited 6,419,954 B1 7/2002 Chu

( 56 ) References Cited 2006/0251721

( 56 ) References Cited WO WO 2004/026283 4/2004

( 56 ) References Cited Handbook of Pharmaceutical Excipients, ( Ainley Wade & Paul J.

( 56 ) References Cited Exhibit 1025 of IPR2016-01027 and IPR2016-01028 , dated May

Procedure : As illustrated in the table above, the microparticle com

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