US 20090203722A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0203722 A1 Sherman et al. (43) Pub. Date: Aug. 13, 2009 (54) NOVEL COMPOSITIONS AND METHODS tion of application No. 10/047.367, filed on Jan. 14, FOR ENHANCING POTENCY OR REDUCING 2002, now abandoned, which is a continuation of ADVERSE SIDE EFFECTS OF OPOLD application No. 09/849,721, filed on May 4, 2001, now AGONSTS abandoned, which is a continuation of application No. 09/756,331, filed on Jan. 8, 2001, now abandoned, (75) Inventors: Barry M. Sherman, Hillsborough, which is a continuation of application No. 09/566,071, CA (US); Mary M. Remien, San filed on May 5, 2000, now abandoned, Continuation of Francisco, CA (US); Remi Barbier, application No. PCT/US00/12493, filed on May 5, San Francisco, CA (US); Kathleen 2OOO. Dumas, Cupertino, CA (US); Grant L. Schoenhard, San Carlos, Publication Classification CA (US) (51) Int. Cl. Correspondence Address: A63L/485 (2006.01) BELL, BOYD & LLOYD, LLP A63L/35 (2006.01) P.O. Box 1135 A6IP 25/00 (2006.01) CHICAGO, IL 60690 (US) (52) U.S. Cl. ......................................... 514/282; 514/646 (73) Assignee: PAIN THERAPEUTICS, INC., (57) ABSTRACT South San Francisco, CA (US) The invention generally relates to novel compositions and methods with an opioid agonist and an opioid antagonist to (21) Appl. No.: 11/456,079 differentially dose a human Subject so as to either enhance analgesic potency without attenuating an adverse side effect (22) Filed: Jul. 6, 2006 of the agonist, or alternatively maintain the analgesic potency of the agonist while attenuating an adverse side effect of the Related U.S. Application Data agonist. The invention additionally relates to novel opioid (63) Continuation of application No. 10/228,835, filed on compositions and methods for the gender-based dosing of Aug. 26, 2002, now abandoned, which is a continua men and women. Patent Application Publication Aug. 13, 2009 Sheet 1 of 73 US 2009/0203722 A1 g se s | Patent Application Publication Aug. 13, 2009 Sheet 2 of 73 US 2009/0203722 A1 s aS Patent Application Publication Aug. 13, 2009 Sheet 3 of 73 US 2009/0203722 A1 Patent Application Publication Aug. 13, 2009 Sheet 4 of 73 US 2009/0203722 A1 60| 9,0- TWAIA?OS Patent Application Publication US 2009/0203722 A1 EWILHEAOSEHOOS(Hd)HEITENNIWA SINEIlydTiv'NOIVT^?OdIVER1-01-INHINI Patent Application Publication Aug. 13, 2009 Sheet 7 of 73 US 2009/0203722 A1 BW||H?AOSE800S(Qld)BONEHEHHIGÅLISNEININIWASINHLydTiv'NQIYmdod?aeiforniini (SH6OH)3WILINAWSSESSY 8!99Þ8.?|0 Patent Application Publication US 2009/0203722 A1 8ET??10IJ SLO?IJ?QIGIOTISQISNIGLACIV Patent Application Publication US 2009/0203722 A1 'yºOldS HEGN30CNYd?080INGWIYEHIAGV6'9|- Patent Application Publication US 2009/0203722 A1 Patent Application Publication Aug. 13, 2009 Sheet 11 of 73 US 2009/0203722 A1 SET\/WU 0"|XINIM-XIN/MÅ50W09SW:?M|0'0!'0XIN 'y-OldSH3CN?0QNWdnogÐINAWIWAHIAG 0 Patent Application Publication Aug. 13, 2009 Sheet 12 of 73 US 2009/0203722 A1 (SºnOH)BWIL 98100YIN/OW09S}-b,-o-p-||·BWl'OXINER03SW-v~~ ~ ||89 -6'0 -S’O Patent Application Publication US 2009/0203722 A1 d C Patent Application Publication Aug. 13, 2009 Sheet 14 of 73 US 2009/0203722 A1 Patent Application Publication Aug. 13, 2009 Sheet 15 of 73 US 2009/0203722 A1 Patent Application Publication Patent Application Publication Aug. 13, 2009 Sheet 18 of 73 US 2009/0203722 A1 98iXINER09SW-º-º-º- BW||HBAOSE800S(Hd)BEITENNIYA SINH|1\d|BTWW33}NOLIWTndOd1\381-04-1NJANI $#{? (S800H)BW||LINEWSSESSY Patent Application Publication Aug. 13, 2009 Sheet 19 of 73 US 2009/0203722 A1 9?»8.?10! (SunOH)3W|LINEWSSESSW Patent Application Publication Aug. 13, 2009 Sheet 20 of 73 US 2009/0203722 A1 BWLIHRÁ0SB800S(Old)BONBHEJJIGAJISNEININIYA ndodIwa?i1:01:1NHINI•SINGLIWdBTWW33‘NOLIWT Ç (SH?OH)3WILINEWSSESSY 3800SGldNW3W Patent Application Publication Aug. 13, 2009 Sheet 21 of 73 US 2009/0203722 A1 BÈJOOS,QildNÝBW Patent Application Publication US 2009/0203722 A1 89IST?[19][H SLO?IJ?TITICIISSISI??AQy S9?uJN Patent Application Publication HEITEHNIWdTf149NINWHWO1EW|| SINHIYETW'NOITTAGETOEROETEN Patent Application Publication '0|-'1], LEWI?OBSNO|HOWIS30TWNW ??EGETEINT Tiv'NOlivinaeSINHLyd O'I* Patent Application Publication NO||WO||G|E|WED}}OLBW||1 SINEILWdTTW'NOIVT^dOdIVBHL-OL·LNEJNI (SunOH8-0)GORJEdNOIVAHESGOKOVOHHH! Patent Application Publication Aug. 13, 2009 Sheet 27 of 73 US 2009/0203722 A1 Patent Application Publication Aug. 13, 2009 Sheet 28 of 73 US 2009/0203722 A1 NIWEHEITE8(Nd)SB800S83A0BW|| ???Jrori?iniSINH|1\dTiv''NOLIV?ndod NWBWNI?d 3BITBA(dd) 3800S Patent Application Publication Aug. 13, 2009 Sheet 30 of 73 US 2009/0203722 A1 ZZSTRIQ9ISI SJLO?I,IJIQIQIQUISQISNIQ?AQTY posrtvAN 33ua?ouuos (uoffpa?) Patent Application Publication Aug. 13, 2009 Sheet 31 of 73 US 2009/0203722 A1 |- INEWIWB8||y,NYEWdn080 Patent Application Publication Aug. 13, 2009 Sheet 32 of 73 US 2009/0203722 A1 SEITWW3)DZI |al |0'0XIN 'y-OldS|-HaGNESGNVd?089INGWIYEHIAG82Z'9|+ Patent Application Publication US 2009/0203722 A1 Patent Application Publication Aug. 13, 2009 Sheet 34 of 73 US 2009/0203722 A1 BWII(SunOH. Patent Application Publication Aug. 13, 2009 Sheet 35 of 73 US 2009/0203722 A1 Patent Application Publication -60 Patent Application Publication Aug. 13, 2009 Sheet 38 of 73 US 2009/0203722 A1 -0"| -30 Patent Application Publication Aug. 13, 2009 Sheet 39 of 73 -D•--•-*•- |60 |80 #-CO Patent Application Publication Aug. 13, 2009 Sheet 40 of 73 US 2009/0203722 A1 HEITHANIYABW||18BA0SB800S(?jd)17381-04-1NBIN? SINH|1\d|3TWW33'NOLIWTmdOd #20 Patent Application Publication Aug. 13, 2009 Sheet 41 of 73 US 2009/0203722 A1 GAZ'914 3WL18BA0SB800S(Hd]BEITENNIYA SINBIYAHYW'NOIIV?nd0d17'381-01-INHINI Patent Application Publication Aug. 13, 2009 Sheet 42 of 73 US 2009/0203722 A1 EWL188A0SB800S(Qld)BON3H3+3|0ÁLISN3ININIYAsi?ällydawyBº'Noli?indodlyawl-ol-l'EINI (SunOH.BWIIINEWSsassy Patent Application Publication Aug. 13 9 2009 Sheet 44 of 73 US 2009/0203722 A1 Patent Application Publication Aug. 13, 2009 Sheet 45 of 73 US 2009/0203722 A1 %0,1| pºsitUN Patent Application Publication Aug. 13, 2009 Sheet 47 of 73 US 2009/0203722 A1 S3800SBONB8.Bd410Å1||SNELNINIWdGEWWmsNWEN SLNE||WdÅ133|WS OldsNyaw Patent Application Publication US 2009/0203722 A1 .z8{99}£|0 [5800H)WIS30TYNYHO13SNOOIHWII Patent Application Publication Aug. 13, 2009 Sheet 51 of 73 US 2009/0203722 A1 Patent Application Publication Aug. 13, 2009 Sheet 52 of 73 US 2009/0203722 A1 J-10100'0XLNIM= |+90NIWENYEW 70AISNEINI Patent Application Publication Aug. 13, 2009 Sheet 53 of 73 US 2009/0203722 A1 dydV/OHdVdV/OH| R[[]{DI?I?º TISTI?IA?yTICIISSLO?IJ? XLNXLN vasiiv.N. Patent Application Publication Aug. 13, 2009 Sheet 54 of 73 US 2009/0203722 A1 01XINM-10XINIM?0'0XIN/MdWdWISHXIN/M300'0 -?) >0 INBWIW38||-ogNy3Wdno80 Patent Application Publication Aug. 13, 2009 Sheet 55 of 73 US 2009/0203722 A1 HEQN30QNWdno801NHWIYEHIAG 'yºOldS880'0|+ ·0';· D|-0,S3TWW3) Patent Application Publication Aug. 13, 2009 Sheet 56 of 73 US 2009/0203722 A1 Patent Application Publication Aug. 13 , 2009 Sheet 59 of 73 US 2009/0203722 A1 dyqy?oHNo.Hidydydydy'0H|dydVIOH?| TInÐIRWOW QISNICIACIVQIQISSJLO?IJIIQI Sº?Blu3J. ORTOVT?|dv?VOH_XIN_|!X?N),XLN Patent Application Publication Aug. 13 9 2009 Sheet 60 of 73 US 2009/0203722 A1 ..Ssal?zziq pºsitUN 29uayoutuos pa?),(to?it Patent Application Publication Aug. 13, 2009 Sheet 61 of 73 US 2009/0203722 A1 Patent Application Publication Aug. 13, 2009 Sheet 62 of 73 US 2009/0203722 A1 d[1089LNHWIWEHLÅ8‘y-OldSNYEWN0||Vind0dÅOWOHHHAHVWIN3 Patent Application Publication Aug. 13, 2009 Sheet 63 of 73 US 2009/0203722 A1 d0Å1|T|8,7808d. 30LESNO VISESTYNy Patent Application Publication 77'9||-|| HWILHEA0N0|IW0|0|EN-BÀIHOALÍTIGWGONG NOIVT^d0dADWOHHBAHVWHa ÅLITI8W808.g. 30 °38|- NOHLWOICEW Patent Application Publication Aug. 13, 2009 Sheet 65 of 73 US 2009/0203722 A1 G7'9||-|| BW|l}{3^0ERHOOSBEITENNIWEN0||Vind0dADWOHHHAHWINIHA 3800S(Hd} Patent Application Publication US 2009/0203722 A1 HWILHEAO(TVORO?EJV0]3800SBONEHEHAIGÅl?SNELNINIwd N0||Wißd0dÅOW0I++3ÅHWW|\ld Patent Application Publication Aug. 13, 2009 Sheet 67 of 73 US 2009/0203722 A1 o -- 2 P so 2 CD - six ESS 3s H.r Nx&SRSS383, 52 a. 2. N 8SSESEEEEEESSR, edO is 2 C c waxis is a KXXXXX& issus SS E Oa - & S h- & 0- - e t O O g S3 N 2 r t S. 2.O N: upg S2cit a iscs N: s - - 8 S. Hi SS & is g CESX 2 O O-a XX8&888 a - Y - -- ce ERS on a O 2 st ch S&3SE CD KCKCXXCXSSSSSSS ESSESSEES3 5 2. V) SXSX2S&SRS& 8ESSEE - C2 2 - mm.1 g He g S O a - ce a do es e es as a Lust 2SE s 22 a , O -a O . a2 5 p. is a 2 to 9 l5u d Patent Application Publication Aug. 13, 2009 Sheet 69 of 73 US 2009/0203722 A1 o E. 2 a r 29 d l 2 g HeCo- un Se s S t C2 - : d 3 2 - c 25r s 3 2 -3 l e Patent Application Publication Aug. 13, 2009 Sheet 70 of 73 US 2009/0203722 A1 o s 5 Patent Application Publication Aug. 13, 2009 Sheet 71 of 73 US 2009/0203722 A1 ?9'9||-|| LNHWSSESSWTWROT9XT|WQNWEW US 2009/0203722 A1 Aug. 13, 2009 NOVELCOMPOSITIONS AND METHODS than its N-allyl cogener, naloxone, and is active when given FOR ENHANCING POTENCY OR REDUCING orally. For example, 50 mg dosage forms of naltrexone, are ADVERSE SIDE EFFECTS OF OPOLD marketed as ReVia(R) in the United States or Trexan in other AGONSTS countries. Nalmefene (6-methylene-6-desoxy-N-cyclopro pyl-methyl-14-hydroxydihydroxydihydronor-morphine) CROSS-REFERENCE TO RELATED was also developed as a long acting, orally available, potent APPLICATIONS opioid antagonist, and has also been characterized as a pure 0001.