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(12) United States Patent (10) Patent No.: US 7,201.920 B2 Kumar Et Al

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(12) United States Patent (10) Patent No.: US 7,201.920 B2 Kumar Et Al US007201920B2 (12) United States Patent (10) Patent No.: US 7,201.920 B2 Kumar et al. (45) Date of Patent: Apr. 10, 2007 (54) METHODS AND COMPOSITIONS FOR 6,153,621 A 11/2000 Hamann DETERRING ABUSE OF OPOD 6,228,863 B1 5, 2001 Palermo et al. CONTAINING DOSAGE FORMS 6,309.668 B1 10/2001 Bastin et al. 6,352,721 B1 3/2002 Faour (75) Inventors: Vijai Kumar, Morris Plains, NJ (US); 6,375,957 B1 4/2002 Kaiko et al. David Dixon, Woodside, NY (US); 6,491,949 B2 12/2002 Faour et al. s ina: 6,559,159 B2 5/2003 Carroll et al. Divya Tewari, Suffern, NY (US); Dilip 6,572,885 B2 6/2003 Oshlack et al. B. Wadgaonkar, Suffern, NY (US) 6.593,367 B1 7/2003 Dewey et al. 2003/OOO4177 A1 1/2003 Kao et al. (73) Assignee: Acura Pharmaceuticals, Inc., Palatine, 2003, OO64099 A1 4/2003 Oshlack et al. IL (US) 2003, OO64122 A1 4/2003 Goldberg et al. 2003, OO68276 A1 4/2003 Hughes et al. (*) Notice: Subject to any disclaimer, the term of this 2003-0068370 A 42003 Sackler patent is extended or adjusted under 35 2003/0068375 A1 4/2003 Wright et al. U.S.C. 154(b) by 476 days. 2003.0068392 A1 4/2003 Sackler et al. 2003/O124061 A1 7/2003 Roberts 2003/O1241.85 A1 7/2003 Oshlack et al. (21) Appl. No.: 10/723,654 2003/O125347 A1 7/2003 Anderson et al. 1-1. 2003/0170181 A1 9, 2003 Midha (22) Filed: Nov. 26, 2003 2003/0232081 A1 12/2003 Doshi et al. O O 2004/O131552 A1 7/2004 Boehm (65) Prior Publication Data 2004/0151791 A1 8/2004 Mayo-Alvarez US 2005/O112O67 A1 May 26, 2005 2004/0228802 Al 11/2004 Chang et al. s 2005.0020613 A1 1/2005 Boehm et al. 2005, OO63909 A1 3/2005 Wright et al. (51) Int. Cl. 2005/0106249 A1 5/2005 Hwang9. et al. 3. 32. 3.08: 2006, OO18837 A1 1/2006 Preston et al. A6 IK3I/35 (2006.01) FOREIGN PATENT DOCUMENTS A6 IK 3/485 (2006.01) WO WO 2003 O26743 A2 4, 2003 A6 IK 3/4468 (2006.01) WO WO 2004/O26256 A2 1/2004 AOIN 43/647 (2006.01) WO WO 2004/O26283 4/2004 AOIN 43/40 (2006.01) WO WO 2004/037259 A1 5, 2004 AOIN 43/46 (2006.01) OTHER PUBLICATIONS (52) U.S. Cl. ...................... 424/454: 514/282: 514/242: 514/333; 514/277: 514/766: 514/214.03; Wells, Mickey L. and, Eugene L. Parrott. “Effect of Anionic 514/740, 514/747: 514/764 Surfactants on the Release of Chlorpheniramine Maleate From an (58) Field of Classification Search ................ 424/451. Inert, Heterogeneous Matrix.” Drug Development and Industrial s Pharmacy 18(2) (1992): 175-186. 424/408, 454; $14,282 .....' Rao, B. Sreenivasa and K.V. Ramana Murthy. “Effect of Sodium lication file f 1 h hi s Lauryl Sulfate on the Release of Rifampicin from Guar Gum See application file for complete search history. Matrix.” Indian Journal of Pharmaceutical Science (2000): 404 (56) References Cited 406. Matschiner et al., “Characterization of Ion Pair Formation Between U.S. PATENT DOCUMENTS Erythromycin and Lipophilic Counter Ions.” Pharmazie 50 (1995): 462-464. 3,065,143 A 11, 1962 Christenson et al. 3.260,646 A 7, 1966 Paulsen et al. Primary Examiner Johann R. Richter 4,070,494 A 1/1978 Hoffmeister et al. Assistant Examiner James H. Alstrum-Acevedo 4,175,119 A 11, 1979 Porter (74) Attorney, Agent, or Firm Morgan Lewis & Bockius 4.389,393 A 6, 1983 Schor et al. LLP 4,457.933 A 7, 1984 Gordon et al. 4.459.278 A 7, 1984 Porter (57) ABSTRACT 4,599,342 A 7, 1986 LaHann 4,610,870 A 9, 1986 Jain et al. This invention relates to an abuse deterrent dosage form of 4,666,705 A 5, 1987 DeCrosta et al. opioid analgesics, wherein an analgesically effective amount 5,059,600 A 10, 1991 Gawin et al. 5,114,942 A 5, 1992 Gawin et al. of opioid analgesic is combined with a polymer to form a 5.330,766 A 7, 1994 Morella et al. matrix. 5,741,524 A 4, 1998 Staniforth et al. 5,968,551 A 10, 1999 Oshlack et al. 54 Claims, 9 Drawing Sheets U.S. Patent Apr. 10, 2007 Sheet 1 of 9 US 7,201.920 B2 Extractin f Opioids from immediatel controlled release formulations t O O w E wd Od O O s U d x c C u O SS Oxycodone Hydrocodone Oxycontins" Hydrochloride Bitaritrate (Controlled release) (lmmediate release) (immediate release) Fig. 1 U.S. Patent Apr. 10, 2007 Sheet 2 of 9 US 7,201.920 B2 Extraction f Opioids from anti-abuse formulation 100 80 60 40 20 O Oxycodone Hydrocodone Morphine Hydrochloride Bitatrate Sulfate (Immediate release) (Immediate release) (Immediate release) Fig. 2 * Extraction process of opioids for anti-abuse properties is the same for figure 1 and figure 2. ** Marketed Oxycodone formulation from Purdue Pharma. U.S. Patent Apr. 10, 2007 Sheet 3 of 9 US 7.201.920 B2 ºu?sºI,9SnqVJOS?InsòYI suopelnuuJOJI3?IS9u0p000.IpÁH peoeux find 9/ U.S. Patent Apr. 10, 2007 Sheet 4 of 9 US 7,201.920 B2 SnO?IBAJOSÐI?OJAUIO!]n[OSSICI s????pmorsmopošo oQ!06080/09090,708OZ01 (sº)nu?uu)au?L 00! pe NIOSSIO find % U.S. Patent Apr. 10, 2007 Sheet 5 Of 9 US 7,201.920 B2 Figure 5a U.S. Patent Apr. 10, 2007 Sheet 6 of 9 US 7,201.920 B2 Figure 5b U.S. Patent Apr. 10, 2007 Sheet 7 Of 9 US 7,201.920 B2 Figure 5c U.S. Patent Apr. 10, 2007 Sheet 8 of 9 US 7,201.920 B2 Step 3 Figure 6: Process Flow Chart U.S. Patent Apr. 10, 2007 Sheet 9 of 9 US 7.201.920 B2 18OH‘H siº?quimisiohjoisenyo,nonnossia p0AOSSC 24, US 7,201.920 B2 1. 2 METHODS AND COMPOSITIONS FOR dosage form with a Suitable solvent (e.g., water), and then DETERRING ABUSE OF OPOD Subsequently extracting the opioid component from the CONTAINING DOSAGE FORMS mixture for use in a solution Suitable for intravenous injec tion of the opioid to achieve a “high.” FIELD OF INVENTION 5 Attempts have been made to diminish abuse of orally This invention pertains to abuse deterrent compositions administered opioid drugs. These attempts generally cen containing a drug (e.g., an analgesic opioid). Additionally, tered on the inclusion in the oral dosage form of an opioid antagonist which is not orally active but which will sub the invention relates to a method of administering a dose of stantially block the analgesic effects of the opioid if one an analgesic from a dosage form, which is abuse deterrent. 10 attempts to dissolve the opioid and administer it parenterally. BACKGROUND OF THE INVENTION For example, commercially available Talwin RNX tablets from Sanofi-Winthrop contain a combination of pentazocine The class of drugs exhibiting opium or morphine-like and naloxone. Pentazocine is a partial agonist of LL receptors properties are referred to as opioids, or opioid agonists. 15 and also has affinity for K receptors, whereas, naloxone is an Certain opioids act as agonists, interacting with stereo antagonist of LL receptors. Talwin RNX contains pentazocine specific and Saturable binding sites in the brain and other hydrochloride equivalent to 50 mg base and naloxone hydro tissues. Endogenous opioid-like peptides are present in areas chloride equivalent to 0.5 mg base. Talwin RNx is indicated of the central nervous system that are presumed to be related for the relief of moderate to severe pain. The amount of to the perception of pain; to movement, mood and behavior, 20 naloxone present in this combination has no action when and to the regulation of neuroendocrinological functions. taken orally, and will not interfere with the pharmacologic Three classical opioid receptor types, mu (LL), delta (Ö), and action of pentazocine. However, this amount of naloxone kappa (K), have been studied extensively. Each of these given by injection has profoundantagonistic action to opioid receptors has a unique anatomical distribution in the brain, analgesics. Thus, the inclusion of naloxone is intended to spinal cord, and the periphery. Most of the clinically used 25 curb a form of misuse of oral pentazocine, which occurs opioids are relatively selective for u receptors, reflecting when the dosage form is solubilized and injected. Therefore, their similarity to morphine. However, it is important to note this dosage has lower potential for parenteral misuse than that opioid containing drugs that are relatively selective at previous oral pentazocine formulations. standard doses will often interact with additional receptor U.S. Pat. No. 6,559,159 (Carroll et al.) describes the use Subtypes when given at Sufficiently high doses, leading to 30 of kappa receptors antagonist for the treatment of opioid possible changes in their pharmacological effect. This is related addictions. One Such compound is naltrexone, which especially true as opioid doses are escalated to overcome is commercially available in the tablet form Revia(R) for the tolerance. treatment of alcohol dependence and for the blockade of The potential for the development of tolerance, physical exogenously administered opioids. (Physicians Desk Refer and/or psychological, dependence (i.e., addiction) with 35 ence 57" ed., Montvale, N.J.) repeated opioid use is a characteristic feature of most opioid U.S. Pat. No. 6,375,957 (Kaiko et al.) describes in detail containing drugs. The possibility of developing addiction is the combination of opioid agonist, NSAID, and an orally one of the major concerns in the use of opioids for the active opioid antagonist.
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