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(12) United States Patent (10) Patent No.: US 9,687,445 B2 Li (45) Date of Patent: Jun

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(12) United States Patent (10) Patent No.: US 9,687,445 B2 Li (45) Date of Patent: Jun USOO9687445B2 (12) United States Patent (10) Patent No.: US 9,687,445 B2 Li (45) Date of Patent: Jun. 27, 2017 (54) ORAL FILM CONTAINING OPIATE (56) References Cited ENTERC-RELEASE BEADS U.S. PATENT DOCUMENTS (75) Inventor: Michael Hsin Chwen Li, Warren, NJ 7,871,645 B2 1/2011 Hall et al. (US) 2010/0285.130 A1* 11/2010 Sanghvi ........................ 424/484 2011 0033541 A1 2/2011 Myers et al. 2011/0195989 A1* 8, 2011 Rudnic et al. ................ 514,282 (73) Assignee: LTS Lohmann Therapie-Systeme AG, Andernach (DE) FOREIGN PATENT DOCUMENTS CN 101703,777 A 2, 2001 (*) Notice: Subject to any disclaimer, the term of this DE 10 2006 O27 796 A1 12/2007 patent is extended or adjusted under 35 WO WOOO,32255 A1 6, 2000 U.S.C. 154(b) by 338 days. WO WO O1/378O8 A1 5, 2001 WO WO 2007 144080 A2 12/2007 (21) Appl. No.: 13/445,716 (Continued) OTHER PUBLICATIONS (22) Filed: Apr. 12, 2012 Pharmaceutics, edited by Cui Fude, the fifth edition, People's Medical Publishing House, Feb. 29, 2004, pp. 156-157. (65) Prior Publication Data Primary Examiner — Bethany Barham US 2013/0273.162 A1 Oct. 17, 2013 Assistant Examiner — Barbara Frazier (74) Attorney, Agent, or Firm — ProPat, L.L.C. (51) Int. Cl. (57) ABSTRACT A6 IK 9/00 (2006.01) A control release and abuse-resistant opiate drug delivery A6 IK 47/38 (2006.01) oral wafer or edible oral film dosage to treat pain and A6 IK 47/32 (2006.01) substance abuse is provided. The drug delivery oral wafer or A6 IK 3/485 (2006.01) edible oral film dosage includes a controlled release layer A6 IK 45/06 (2006.01) containing enteric-release beads dispersed in a polymer matrix. The enteric-release beads are formed from a thera A6 IK 9/16 (2006.01) peutic amount of an opioid agonist and/or pharmaceutically (52) U.S. Cl. acceptable salt thereof and a sub-therapeutic amount of CPC ............ A61K 9/006 (2013.01); A61K 9/0056 opioid antagonist and/or pharmaceutically acceptable salt (2013.01); A61K 31/485 (2013.01); A61 K thereof coated or encapsulated in an enteric-release polymer. 45/06 (2013.01); A61K 47/32 (2013.01); A61 K The controlled release polymer matrix dissolves or disinte 47/38 (2013.01); A61 K 9/1635 (2013.01); grates following administration or consumption of the oral A61 K 9/1652 (2013.01) wafer or edible oral film, releasing the enteric-release beads (58) Field of Classification Search to be swallowed, with subsequent absorption of the active None ingredients within the patient's intestines. See application file for complete search history. 34 Claims, 1 Drawing Sheet US 9,687,445 B2 Page 2 (56) References Cited FOREIGN PATENT DOCUMENTS WO WO 2007 144081 A2 12/2007 WO WO 2007 144082 A2 12/2007 WO WO 2007 144083 A2 12/2007 WO WO 2007 144084 A2 12/2007 WO WO 2007 144085 A1 12/2007 * cited by examiner U.S. Patent Jun. 27, 2017 US 9,687,445 B2 US 9,687,445 B2 1. 2 ORAL FILMI CONTAINING OPIATE chronic pain. The inventive oral films dosages include at ENTERC-RELEASE BEADS least one layer formed from a controlled-release composi tion imparting intestinal release of a therapeutically effective FIELD OF THE INVENTION amount of an opioid agonist or pharmaceutically acceptable The present invention relates to films providing controlled salt thereof and a clinically effective amount of opioid enteric release of therapeutic actives. The present invention antagonist or pharmaceutically acceptable salt thereof. The more specifically relates to films providing a controlled controlled-release composition includes at least one con enteric release of an opioid agonist, present in therapeutic trolled-release matrix polymer and enteric-release beads amounts, and an opioid antagonist, present at a Sub-thera dispersed within the matrix polymer. The enteric-release peutic level. 10 beads are formed from an enteric-release-bead composition including at least one enteric-release polymer and an opioid BACKGROUND OF THE INVENTION agonist and an opioid antagonist and/or their respective salts encapsulated therein. The controlled-release composition The search for a safe, orally ingested opiate analgesic is further incorporates a pH adjuster in an amount effective to one of the oldest challenges known in medicinal chemistry. 15 adjust the composition to a pH of about 2.0 to 3.0 pH units Opiates are incredibly well known for the treatment of acute below the pKa of the opioid agonist, antagonist and their or chronic severe pain, and are arguably one of the oldest respective salts to bind the opioid to the enteric-release drugs known to man. The market for chronic pain treatment polymer. The oral film dosage or controlled-release compo is a substantial one, including the treatment of chronic pain sition or layer further optionally includes one or more associated with fibromyalgia, arthritis, sports injuries and additives selected from taste masking agents, emulsifiers, malignancies. Current pain management protocols have plasticizers, colorants, antioxidants, microbial preservatives resulted in a multi-billion dollar prescription market, with a pain management drug, hydrocodone/APAP, ranked number and permeation enhancers. one in prescription drug sales in 2010. In particularly advantageous embodiments, the edible oral Unfortunately, pain management drugs, particularly opi film dosages include buprenorphine as the opioid agonist ates, give rise to euphoria and other side effects when taken 25 along with naloxone as the opioid antagonist. by healthy individuals, and thus opiates are extremely addic Further inventive aspects include methods by which to tive. The diversion of prescription drugs for substance abuse form the inventive oral film dosages, as well as their is a Societal issue that cannot be ignored. Subsequent administration. SUBOXONE(R) is particularly well known prescription drug for treating narcotic addiction. Individuals addicted to 30 BRIEF DESCRIPTION OF THE DRAWINGS narcotics may suffer from a serious physical dependence, resulting in potentially dangerous withdrawal. One well FIG. 1 is a cross-sectional view of an exemplary mono known method by which to treat narcotic addiction is to layer inventive oral film dosage. provide a reduced amount of opiate, in an amount Sufficient to satisfy the addict's urge for the narcotic, but not in an 35 DETAILED DESCRIPTION OF amount Sufficient to induce euphoria, commonly referred to ADVANTAGEOUS EMBODIMENTS OF THE as a “high.” SUBOXONE(R) includes a particularly potent INVENTION opiate, buprenorphine, along with an antagonist, naloxone, providing both a reduced euphoric effect and potentially The present invention generally related to the treatment of avoiding opiate extraction (and Subsequent abuse) by 40 opioid dependence or chronic or acute pain in a patient using addicts. The narcotic antagonist binds to a receptor in the a dosage form that also hinders misuse of the narcotic. The brain to block the receptor, thus reducing the effect of the present invention provides a method of treating chronic/ opiate. SUBOXONER) was initially developed as an orally acute pain or narcotic dependence by administering an orally ingestible tablet. However, medicaments containing dissolvable film dosage (also referred to herein as an oral buprenorphine in tablet form have the potential for abuse, 45 wafer) providing a bioequivalent effect to the known opiate regardless of the presence of naloxone as an antagonist, tablets and films, particularly SUBOXONE(R) tablets and primarily due to the slow speed at which the tablet dissolved. films, but with enteric delivery of the active ingredients to SUBOXONER) films were subsequently developed having a provide a more prolonged efficacy. In particularly advanta far faster dissolution speed that provides direct buccal geous embodiments, the inventive film dosages preferably absorption of the buprenorphine in a form that could not be 50 provides buccal adhesion to the user's mouth, rendering it easily removed from the mouth once administered, thereby difficult to remove after administration further hindering retarding abuse. SUBOXONE(R) films are described in product misuse. United States Patent Application Publication No. 2011/ An exemplary mono-layered inventive oral film dosage is 0033541, hereby incorporated by reference herein. Unfor illustrated in FIG. 1. The inventive oral film dosage (1) tunately, the buccal absorption of opiate translates into a 55 generally include at least one controlled-release layer (2) shorter period of efficacy for the patient. imparting enteric release of a clinically effective, i.e. thera Thus there remains a need in the art for longer acting peutic, amount of an opioid agonist and a clinically effective, opiate drug forms for the treatment of addiction. There i.e. Subtherapeutic, amount of opioid antagonist. The com further exists a need in the art for opiates in film-form position used to form the controlled-release layer (i.e. the providing a more extended period of efficacy for the treat 60 controlled-release composition) generally includes at least ment of chronic or acute pain. one controlled-release matrix polymer (3) and enteric-re lease beads (4) dispersed therein, with the enteric-release SUMMARY OF ADVANTAGEOUS beads containing an opioid agonist (5) and an opioid antago EMBODIMENTS OF THE INVENTION nist (6) enveloped within an enteric-release polymer shell 65 (7). Although not wishing to be bound by theory, Applicants The present invention thus provides a longer acting opiate hypothesize that the enteric-release polymer shell (7) is drug forms for the treatment of addiction, acute pain and amorphous, hence there may be no visible, definite boundary US 9,687,445 B2 3 4 between the polymer shell (7) and controlled-release matrix Mich., BENECEL(R) from Ashland, Inc. of Covington, Ky. polymer (3), as illustrated within FIG. 1 by a dotted line. The and PHARMACOATR) from Shin-Etsu Chemical Col, Ltd.
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