USO10946009B2 ( 12 ) United States Patent ( 10 ) Patent No .: US 10,946,009 B2 Li et al . ( 45 ) Date of Patent : Mar. 16 , 2021 ( 54 ) COMBINATION DOSAGE FORM OF A MU 7,951,400 B2 5/2011 Desai et al . OPIOID RECEPTOR ANTAGONIST AND AN 8,246,986 B2 8/2012 Cruz et al . 8,247,555 B2 8/2012 Dalziel et al . OPIOID AGENT 8,247,559 B2 8/2012 Colson et al . 8,263,618 B2 9/2012 Long et al . ( 71 ) Applicant: THERAVANCE BIOPHARMA R & D 8,476,440 B2 7/2013 Colson et al . IP , LLC , South San Francisco , CA 8,536,335 B2 9/2013 Dalziel et al . ( US ) 8,580,310 B2 11/2013 Krishnamurthy et al . 8,664,242 B2 3/2014 Long et al . 8,685,450 B2 4/2014 Lim et al. ( 72 ) Inventors : Shaoling Li , Sunnyvale, CA ( US ); 8,816,091 B2 8/2014 Dalziel et al . Manshiu Leung , Daly City, CA ( US ) ; 8,927,573 B2 1/2015 Long et al . Hao Zhang , Foster City, CA ( US ) ; 9,206,172 B2 12/2015 Long et al . Venkat R. Thalladi , Foster City, CA 9,290,491 B2 3/2016 Dalziel et al . 9,663,509 B2 5/2017 Long et al . ( US ) ; Yun Mo , Foster City, CA (US ) 9,949,963 B2 4/2018 Dalziel et al . 10,081,626 B2 9/2018 Long et al. ( 73 ) Assignee : Theravance Biopharma R & D IP , 2006/0199839 A1 9/2006 Goldblum et al . LLC , South San Francisco , CA ( US ) 2007/0219278 Al 9/2007 Long et al . 2008/0207676 Al 8/2008 Dalziel et al . Subject to any disclaimer , the term of this 2008/0269198 Al 10/2008 Benjamin et al . ( * ) Notice : 2010/0291183 Al 11/2010 Farrell et al . patent is extended or adjusted under 35 2011/0287093 Al 11/2011 Schoenhard U.S.C. 154 ( b ) by 74 days. 2012/0009227 A1 1/2012 Humar et al . 2013/0164384 A1 6/2013 Johnson et al . ( 21 ) Appl . No .: 16 / 454,353 2014/0079778 Al 3/2014 Narang et al . 2014/0271862 Al 9/2014 Jacob et al . 2018/0050028 A1 2/2018 Li et al . ( 22 ) Filed : Jun . 27 , 2019 2018/0200246 A1 7/2018 Dalziel et al . ( 65 ) Prior Publication Data 2019/0119267 A1 4/2019 Long et al . US 2019/0321350 A1 Oct. 24 , 2019 FOREIGN PATENT DOCUMENTS CN 101500542 A 8/2009 Related U.S. Application Data CN 102858324 A 1/2013 ( 62 ) Division of application No. 15 / 798,647 , filed on Oct. JP 2009-185046 A 8/2009 31 , 2017 , now Pat . No. 10,369,142 , which is a JP 2013-538814 A 10/2013 division of application No. 15 / 086,816 , filed on Mar. 31 , 2016 , now abandoned . OTHER PUBLICATIONS ( 60 ) Provisional application No. 62 / 141,981 , filed on Apr. Yao , Jing , “ Application directory of pharmaceutical excipients ” , 2 , 2015 . China Medical Science and Technology Press , pp . 37-39 ( 2011 ) . Yao , Risheng, “ Pharmaceutical polymer materials ” , Chemical Indus ( 51 ) Int . Cl . try Press, pp . 166-167 ( 2003 ). A61K 31/46 ( 2006.01 ) International Search Report for PCT / US2016 / 025176 dated Jun . 24 , A61K 31/439 ( 2006.01 ) 2016 . A61K 9/24 Koo et al . , “ Investigation into Stability of Poly ( Vinyl Alcohol ) ( 2006.01 ) Based Opadry II Films” , AAPS PharmSci Tech , 2011 , vol . 12 , No. A61K 31/485 ( 2006.01 ) 2 , pp . 746-754. A61K 9/28 ( 2006.01 ) Poster Presentation , Abstract 0520 , PAINWeek 2015 , Sep. 8-12 , ( 52 ) U.S. CI . 2015 , Las Vegas , NV . CPC A61K 31/46 ( 2013.01 ) ; A61K 9/209 Theravance Biopharma, Inc. , Investor and Analyst' Day Presenta ( 2013.01 ) ; A61K 9/282 ( 2013.01 ) ; A61K 9/284 tion , New York , NY ( Dec. 12 , 2014 ) . ( 2013.01 ) ; A61K 9/2853 ( 2013.01 ) ; A61K 9/2893 ( 2013.01 ) ; A61K 31/439 ( 2013.01 ) ; A61K 31/485 ( 2013.01 ) Primary Examiner Mina Haghighatian ( 58 ) Field of Classification Search ( 74 ) Attorney, Agent, or Firm — Jeffrey A. Hagenah ; CPC ...... A61K 31/46 ; A61K 31/439 ; A61K 9/209 ; Florence Jovic A61K 9/2893 ; A61K 9/282 ; A61K 9/2853 ; A61K 9/284 ( 57 ) ABSTRACT See application file for complete search history . The invention provides a solid composition of the peripheral ( 56 ) References Cited mu opioid antagonist axelopran and a combination dosage form of the mu opioid antagonist axelopran sulfate in an U.S. PATENT DOCUMENTS immediate release form and an opioid analgesic agent which 6,277,384 B1 8/2001 Kaiko et al . may be in an extended release , sustained release , modified 6,451,806 B2 9/2002 Farrar release, or controlled release form and methods of preparing 7,622,508 B2 11/2009 Long et al . such a combination dosage form . 7,842,307 B2 11/2010 Oshlack et al . 7,932,402 B2 4/2011 Colson et al . 7,943,772 B2 5/2011 Dalziel et al . 14 Claims , 6 Drawing Sheets U.S. Patent Mar. 16 , 2021 Sheet 1 of 6 US 10,946,009 B2 120 80 %LABELCLAIM 60 AXELOPRAN 20 -- OXYCODONE 0 0 2 4 6 8 10 12 TIME (HR ) FIG . 1A 140 120 %LABELCLAIM AXELOPRAN 40 met een OXYCODONE 20 0 0 2 4 6 8 10 12 TIME (HR ) FIG . 1B U.S. Patent Mar. 16 , 2021 Sheet 2 of 6 US 10,946,009 B2 120 100 wwwxxx 80 %LABELCLAIM 60 ook om AXELOPRAN 40 mento forma OXYMORPHONE 20 0 0 5 15 TIME (HR ) FIG . 2A 120 100 %LABELCLAIM YYYY AXELOPRAN 40 met OXYMORPHONE 20 0 0 65 10 15 TIME (HR ) FIG . 2B U.S. Patent Mar. 16 , 2021 Sheet 3 of 6 US 10,946,009 B2 1000 Chan OXYCODONE ALONE - AXELOPRANOXYCODONE COMBINATION DOSAGE FORM PLASMACONCENTRATION(ng/mL) A AXELOPRAN + OXYCODONE OXYCODONE 10 ???? 0 20 60 80 TIME (HR ) FIG . 3A O. AXELOPRAN ALONE med 100 mem AXELOPRAN /OXYCODONE COMBINATION DOSAGE FORM PLASMACONCENTRATION(ng/mL) AXELOPRAN + OXYCODONE AXELOPRAN 10 humillaBununla * 20 40 60 TIME (HR ) FIG . 3B U.S. Patent Mar. 16 , 2021 Sheet 4 of 6 US 10,946,009 B2 10 gagangan - OXYMORPHONE ALONE - AXELOPRAN + OXYMORPHONE *** OXYMORPHONEPLASMACONCENTRATION (ng/mL) w AXELOPRANOXYMORPHONE COMBINATION DOSAGE FORM T 0 20 40 80 TIME (HR ) FIG . 4A 1000 33 -C AXELOPRAN ALONE - AXELOPRANOXYMORPHONE COMBINATION DOSAGE FORM PLASMACONCENTRATION(ng/mL) 4 AXELOPRAN + OXYMORPHONE AXELOPRAN 10 0.1 I 0.01 0 20 TIME (HR ) FIG . 4B U.S. Patent Mar. 16 , 2021 Sheet 5 of 6 US 10,946,009 B2 mua meAXELOPRANOXYCODONE COMBINATION DOSAGE FORM w we fuerans AXELOPRAN + OXYCODONE OXYCODONECONCENTRATION(ng/ml) - OXYCODONE ALONE 0 . Www 6 12 18 24 30 36 42 54 60 66 72 TIME AFTER DOSE (HR ) FIG . 5 mmmm AXELOPRAN OXYCODONE COMBINATION DOSAGE FORM 20 vef Funes AXELOPRAN + OXYCODONE - AXELOPRAN ALONE AXELOPRANCONCENTRATION(ng/mL) ??? w 0.01 0 6 12 18 24 30 36 42 48 54 60 66 72 TIME AFTER DOSE (HR ) FIG . 6 U.S. Patent Mar. 16 , 2021 Sheet 6 of 6 US 10,946,009 B2 RELATIVEINTENSITY(%) Warhammer WhenAman 0 5 ????????10 15 20 25 30 20 (DEGREES ) FIG . 7 10 8 WEIGHTCHANGE(%) 4 2 -2 8 16 24 32 ELAPSED TIME ( HR ) FIG . 8 US 10,946,009 B2 1 2 COMBINATION DOSAGE FORM OF A MU (U.S. Pat . Nos . 7,622,508 and 7,943,772 ) has been demon OPIOID RECEPTOR ANTAGONIST AND AN strated clinically to ameliorate the symptoms of OIC in OPIOID AGENT non - cancer pain patients on a stable opioid regimen without compromising analgesia . ( Vickery et al . Pain Week 2012 , CROSS - REFERENCE TO RELATED 5 Las Vegas, Nev . ( P - 87 ) . APPLICATIONS Patients taking opioid analgesics for pain management may find it useful to also take a peripheral opioid antagonist This application is a divisional of U.S. Ser. No. 15/798 , to manage adverse side effects of their pain medication . 647 , filed on Oct. 31 , 2017 , now allowed ; which is a Such patients, who may be suffering from a variety of divisional application of U.S. Ser. No. 15 / 086,816 , filed on 10 serious conditions, frequently are also prescribed additional Mar. 31 , 2016 , now abandoned ; which application claims drugs and thus are burdened with managing a complicated the benefit of U.S. Provisional Application No. 62 / 141,981 , pharmaceutical regimen . Therefore, it may be desirable to filed on Apr. 2 , 2015 the disclosure ofwhich is incorporated combine multiple drugs in a combination dosage form for herein by reference in its entirety . ease of administration and improved therapeutic compli BACKGROUND OF THE INVENTION 15 ance . In particular, use of a combination of a peripheral opioid antagonist, such as axelopran , and an opioid agonist Field of the Invention may address concerns of OIC before they develop . Depending on the clinical need , opioid analgesics can be The invention is directed to a solid composition of a administered through oral, transdermal and parenteral routes peripheral mu opioid receptor antagonist and to a combina- 20 for either chronic or acute use , of which oral administration tion of the mu opioid receptor antagonist composition and an is commonly preferred . While immediate release opioids opioid analgesic agent . In particular, the invention is directed to a unit dosage form in which the mu opioid provide efficacious pain management, especially for acute receptor antagonist is in an immediate release form and the and break - through pain , controlled or extended release opi opioid analgesic agent may be in an extended release, 25 theoids prophylactic have demonstrated effect of significant a peripheral clinical opioid value antagonist . However is, sustained release , modified release , or controlled release typically achieved by immediate release of the antagonist form and to methods of preparing such a unit dosage form.