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(12) United States Patent (10) Patent No.: US 7,771,707 B2 Hirsh Et Al

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(12) United States Patent (10) Patent No.: US 7,771,707 B2 Hirsh Et Al US00777 1707B2 (12) United States Patent (10) Patent No.: US 7,771,707 B2 Hirsh et al. (45) Date of Patent: *Aug. 10, 2010 (54) ABUSE-DETERRENT DRUG 6,156,764 A 12/2000 Asmussen et al. FORMULATIONS 6,162,467 A 12/2000 Miller et al. 6,261,599 B1 7/2001 Oshlack et al. (75) Inventors: Jane C. Hirsh, Wellesley, MA (US); 6,277.384 B1 8/2001 .N. Alison B. Fleming, North Attleboro, MA 4 (US); Roman V. Rariy, Allston, MA 6,294,195 B1 9, 2001 Oshlack et al. (US); Alexander M. Klibanov, Newton, 6,309.668 B1 10/2001 Bastin et al. MA (US) 6,310,072 B1 10/2001 Smith et al. 6,328,979 B1 12/2001 Yamashita et al. (73) Assignee: Collegium Pharmaceutical, Inc., 6,335,033 B2 1/2002 Oshlack et al. Cumberland, RI (US) 6,375,957 B1 4/2002 Kaiko et al. (*) Notice: Subject to any disclaimer, the term of this 6,475,494 B2 11/2002 KaikoakO etC. al. patent is extended or adjusted under 35 U.S.C. 154(b) by 1058 days. This patent is Subject to a terminal dis- (Continued) claimer. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 11/149,867 EP O 253 104 1, 1988 (22) Filed: Jun. 10, 2005 (65) Prior Publication Data (Continued) US 2005/0281748A1 Dec. 22, 2005 OTHER PUBLICATIONS Related U.S. Application Data Cortesi, et al., Sugar Cross-linked gelatin for controlled release: (60) Provisional application No. 60/579,191, filed on Jun microspheres and disksBiomaterials, 19:1641-1649 (1998). 12, 2004. (Continued) (51) Int. Cl. Primary Examiner Sreeni Padmanabhan A6 IK 49/00 (2006.01) Assistant Examiner—Renee Claytor A6 IK 3/44 (2006.01) (74) Attorney, Agent, or Firm Pabst Patent Group LLP (52) U.S. Cl. ...................................... 424/10.1; 514/282 (58) Field of Classification Search ................. 514/282; (57) ABSTRACT 424/10.1 See application file for complete search history. An abuse-deterrent pharmaceutical composition has been (56) References Cited developed to reduce the likelihood of improper administra tion of drugs, especially drugs such as opiods. In the preferred U.S. PATENT DOCUMENTS embodiment, the drug is modified to increase its lipophilicity 3,015,128 A 1/1962 Somerville by forming a salt between the drug and one or more fatty acids 3,336,200 A 8, 1967 Krause et al. wherein the concentration of the one or more fatty acids is one 3,773.955 A 11, 1973 Pachter et al. to 15 times the molar amount of the active agent, preferably 3,966,940 A 6, 1976 Pachter et al. two to ten times the molar amount of the active agent. In one 3,980,766 A 9, 1976 Shaw et al. 4,070,494 A 1/1978 Hoffmeister et al. embodiment the modified drug is homogeneously dispersed 4,457.933 A 7, 1984 Gordon et al. within microparticles composed of a material that is either 4,569,937 A 2f1986 Baker et al. slowly soluble or not soluble in water. In some embodiments 4,722,941 A 2f1988 Eckert et al. the drug containing microparticles or drug particles are 4,861,598 A 8, 1989 Oshlack ...................... 424/468 coated with one or more coating layers, where at least one 5, 190,947 A 3, 1993 Riess et al. coating is water insoluble and preferably organic solvent 5,508,042 A 4, 1996 OShlack et al. insoluble. The abuse-deterrent composition prevents the 5,756.483. A 5, 1998 Merkus immediate release of a Substantial portion of drug, even if the 5,849,240 A 12/1998 Miller et al. physical integrity of the formulation is compromised (for 5,891,471 A 4/1999 Miller et al. example, by chopping with a blade or crushing) and the 5,952,005 A 9, 1999 Olsson et al. resulting material is placed in water, Snorted, or Swallowed. 5,958,452 A 9, 1999 OShlack et al. However, when administered as directed, the drug is slowly 5,958.459 A 9, 1999 Chasin et al. released from the composition as the composition is broken 5,965,161 A 10, 1999 Oshlack et al. 5,965,163 A 10, 1999 Miller et al. down or dissolved gradually within the GI tract by a combi 5,968,551 A 10, 1999 Oshlack et al. nation of enzymatic degradation, Surfactant action of bile 6,048,736 A 4/2000 Kosak et al. acids, and mechanical erosion. 6,068,855 A 5, 2000 Leslie et al. 6,103,261 A 8, 2000 Chasin et al. 30 Claims, 2 Drawing Sheets US 7,771,707 B2 Page 2 U.S. PATENT DOCUMENTS WO WO97,14438 4f1997 WO WOOO, SOOO7 8, 2000 6,696,088 B2 2/2004 OShlack et al. WO WOO1,08661 2, 2001 6,706,281 B2 3, 2004 OShlack et al. WO WOO1, 58.447 8, 2001 6,723,343 B2 4/2004 Kugelmann WO WOO 1/72338 10, 2001 6,743,442 B2 6, 2004 OShlack et al. WO WO 2004/O75877 9, 2004 6,919,372 B1 7/2005 Yamashita et al. 7,261,529 B2 8/2007 Persyn et al. OTHER PUBLICATIONS 7,399,488 B2 7/2008 Hirsh, et al. 2002fOO81333 A1 6, 2002 Oshlack et al. Gennaro, ed., Remington. The Science and Practice of Pharmacol 2003, OO64099 A1 4/2003 Oshlack et al. Ogy, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, 2006/0104909 A1 5/2006 Vaghefi et al. p. 704–706 (2000). 2008/0260819 A1 10/2008 Fleming et al. Abuse and Mental Health Services Administration, "Results from the 2004 National Survey on Drug Use and Health: National Findings.” FOREIGN PATENT DOCUMENTS pp. 1-310 (2005). Nakmura, et al., “Development of an oral Sustained release drug EP O 647 448 4f1995 delivery system utilizing pH-dependent Swelling of carboxyvinyl GB 1513166 6, 1978 polymer, J. Control. Rel., 111:309-319 (2006). WO WO93/10765 6, 1993 WO WO95/20947 8, 1995 * cited by examiner U.S. Patent Aug. 10, 2010 Sheet 2 of 2 US 7,771,707 B2 Sorted by Decending Fatty Acid MW == KKNKKKNKKNKNNN No.,º.º.º.ae…:(--.: |ZZZZZZZZZZZZZZZZZ |ZZZZZZZZZZZZZZZZZDE!!!!!!!! NNNNNNNNNNNNNNNN ||[ZZZZZZZZ)Faeº.º.(…) ZZZZZZZZZZZZZZZZZZZZZZ 1:9‘OI’HVELS (NNNNNNNNNNNNNNNNNNNNNNN l:GI‘OILIWTwd 2:Gl'OILSIHAW 2 STEROTEx K BEESWAX N CAMAUBA O NO ADDITIONAL WAX A/6. 2 US 7,771,707 B2 1. 2 ABUSE-DETERRENT DRUG DEA's Office of Diversion Control reported 700 OxyCon FORMULATIONS tin. RTM thefts in the U.S. between January 2000 and June 2001. Some of these reported cases have been associated with CROSS-REFERENCE TO RELATED serious consequences including death. APPLICATIONS Oxycodone is a controlled substance in Schedule II of the Controlled Substances Act (CSA), which is administered by This application claims priority under 35 U.S.C. S 119 to the Drug Enforcement Administration (DEA). Despite the U.S. Provisional Application No. 60/579,191, filed Jun. 12. fact that Schedule II provides the maximum amount of con 2004 entitled “Abuse-Deterrent Drug Formulations'. trol possible under the CSA for approved drug products, in 10 practice, it is difficult for law enforcement agencies to control FIELD OF THE INVENTION the diversion or misuse of legitimate prescriptions. Although abuse, misuse, and diversion are potential problems for all The present invention is generally in the field of pharma opioids, including Oxycodone, opioids are a very important ceutical compositions, specifically compositions designed to part of the medical arsenal for the management of pain when reduce the potential for improper administration of drugs that 15 used appropriately under the careful supervision of a physi are subject to abuse. C1a. Currently available formulations for such drugs are BACKGROUND OF THE INVENTION designed for oral administration but do not include mecha nisms to prevent or retard improper methods of administra Oxycodone, morphine, and other opioid analgesics are tion such as chewing, injection and Snorting. This represents therapeutically useful and effective medications, e.g., as pain a serious problem given the large number of legitimate pre killers, when administered orally. Unfortunately, they also scriptions written in the U.S.; for example, the medical use of pose a severe threat for willful abuse due to their ability to opioids within the U.S. increased 400% from 1996 to 2000. alter mood and/or cause a sense of euphoria. Currently avail The problems with abuse are significant and longstanding. able sustained release formulations of such drugs, which con 25 and efforts to design new abuse-resistant or abuse-deterrent tain a relatively large amount of drug intended to be released formulations have been largely unsuccessful. U.S. Pat. Nos. from the formulation over an extended period of time, are 3,980,766, 4,070,494 and 6,309.668 describe formulations particularly attractive to abusers since the sustained release designed to prevent the injection of compositions meant for coating can be destroyed by crushing or grinding the formu oral administration. U.S. Pat. No. 3,980,766 describes the lation. The crushed material no longer controls the release of incorporation of an ingestible solid which causes a rapid drug. Depending on the drug, abusers can then (1) Snort the increase in viscosity upon concentration of an aqueous solu material, (2) swallow the material or (3) dissolve the material tion thereof. U.S. Pat. No. 4,070,494 describes the incorpo in water and subsequently inject it intravenously. The dose of ration of a non-toxic, water gelable material in an amount drug contained in the formulation is thus absorbed immedi sufficient to render the drug resistant to aqueous extraction.
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