US009566311B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 566 ,311 B2 Siekmann et al. (45 ) Date of Patent: Feb . 14 , 2017 ( 54 ) PHARMACEUTICAL COMPOSITION ( 56 ) References Cited (75 ) Inventors : Britta Siekmann , Lomma ( SE ) ; U . S . PATENT DOCUMENTS Mattias Malm , Copenhagen (DK ) ; 7 ,635 ,473 B2 * 12 /2009 Warne et al. .. .. .. .. 424 / 133 . 1 Anders Nilsson , Copenhagen (DK ) ; 2001/ 0027177 Al 10 / 2001 Woodrow Kazimierz Wisniewski, Copenhagen 2003 /0119728 A1 6 / 2003 Scheidl et al . 2003/ 0138417 A1 7 / 2003 Kaisheva et al. (DK ) 2004/ 0235956 A1 * 11/ 2004 Quay .. .. .. .. .. .. .. 514 /573 ( 73 ) Assignee : Ferring B . V ., Hoofddorp (NL ) FOREIGN PATENT DOCUMENTS ( * ) Notice : Subject to any disclaimer, the term of this EP 0916347 A15 / 1999 patent is extended or adjusted under 35 EP 2174652 A2 4 / 2010 U . S . C . 154 (b ) by 0 days . WO W09501185 * 1 / 1995 A61K 38 / 11 WO W09501185 A11 / 1995 WO 2004062689 AL 7 /2004 ( 21 ) Appl. No. : 13 /824 , 132 WO WO2008042452 A 4 / 2008 WO WO 2008150305 A1 * 12 /2008 A61K 9 /08 ( 22 ) PCT Filed : Sep . 29 , 2011 WO WO2008150305 Al 12 /2008 WO WO2009122285 * 10 / 2009 .. .. CO7K 7 / 16 ( 86 ) PCT No. : PCT/ IB2011 / 002394 WO WO2009122285 A8 12 / 2009 $ 371 ( c ) ( 1 ), OTHER PUBLICATIONS ( 2 ) , ( 4 ) Date : May 3 , 2013 Remington : The Science and Practice of Pharmacy , Alfonso R . (87 ) PCT Pub. No. : W02012 /042371 Gennaro , Ed ., 20th Edition , 2000 , (only pp . 245, 1690 provided herewith ) . * PCT Pub . Date : Apr. 5 , 2012 Product Monograph Duratocin , Ferring Inc . Mar. 29 , 2006 revi sion. * (65 ) Prior Publication Data Hawe et al . , Towards Heat - stable Oxytocin Formulations : Analysis of Degradation Kinetics and Identification of Degradation Products , US 2013 / 0210746 A1 Aug. 15 , 2013 Pharm . Res , vol. 26 , No . 7 , Jul . 2009. * Rath et al. ; “ Prevention of postpartum haemorrhage with the ( 30 ) Foreign Application Priority Data oxytocin analogue carbetocin ” ; European Journal of Obstetrics & Gynecology and Reproductive Biology ; vol . 147 , No . 1 , pp . 15 - 20 Sep . 30 , 2010 (EP ) .. .. .. .. .. .. .. 10251690 ( 2009 ) . International Search Report mailed Feb . 1 , 2013 , which issued in corresponding International Application No. PCT/ IB2011 / 002394 . (51 ) Int. Cl. Office Action issued on May 26 , 2015 in corresponding Japanese A61K 38 / 12 (2006 . 01) Application No. 2013 - 530810 , and English translation thereof, 6 A61K 9 / 00 ( 2006 .01 ) pages. A61K 38 / 11 ( 2006 .01 ) A61K 47 / 12 ( 2006 .01 ) * cited by examiner A61K 47 / 18 ( 2006 .01 ) (52 ) U .S . Ci. Primary Examiner — Lianko Garyu CPC .. A61K 38 / 12 (2013 . 01 ) ; A61K 9 /0019 Assistant Examiner — Joseph Fischer (2013 .01 ) ; A61K 9 /0043 ( 2013 .01 ) ; A61K ( 74 ) Attorney , Agent, or Firm — Fish & Richardson P . C . 38 / 11 (2013 .01 ) ; A61K 47/ 12 (2013 .01 ) ; A61K 47 / 183 (2013 . 01) (57 ) ABSTRACT (58 ) Field of Classification Search The present invention relates to pharmaceutical composi CPC . .. A61K 9 / 0019 ; A61K 9 / 0043 ; A61K 38 / 11 ; tions having improved stability . A61K 47 / 12 ; A61K 47 / 183 ; A61K 38 / 12 See application file for complete search history . 17 Claims, 8 Drawing Sheets U . S . Patent Feb . 14 , 2017 Sheet 1 of 8 US 9 ,566 , 311 B2 Chromatogram of an impurity mix of carbetocin and degradation products L 24.00 22.00 20.00 517, 19 - ] DAsn5( 751 , 17 - carbetocin 18.00 0016. 405, 14 - ] DCys6[ = ILLLLLLLLLL14. 00 FIG.1 556, 11 - ] BetaAsp5( 12.00 Minutes 885, 10 - ] Glu4( 10.00 244, 9 - || sulfoxide 531, 8 - ) Asp5[ S 553, 7 -) Gly90H[ – 8.00 808 , 6 - I sulfoxide - 6.00 4.00 ????????????????? 2.00 manyomy70000 0.00 .0100 .0080 .0060 F1000 .0020 .002-0 AU U . S . Patent Feb . 14 , 2017 Sheet 2 of 8 US 9 ,566 ,311 B2 Carbetocin : 1 2 3 4 5 6 7 8 9 CH2 - CO - Tyr (Me ) -le - Gin - Asn - HN - CH - CO - Pro - Leu - Gly - NH2 CH2CH2 — 5 — CH2 (Gly90H ]carbetocin : 2 3 4 5 7 8 9 CH2 - CO - Tyr( Me ) - le - Gln - Asn - HN - CH - CO - Pro - Leu - Gly - OH CH2 CH2 — 5 — CH2 (Glu4 ]carbetocin : 1 2 3 4 5 6 7 8 9 CH2 - CO - Tyr( Me ) - Ile - Glu - Asn - HN - CH - CO - Pro - Leu - Gly - NH2 CH2CH25 - CH2 (Asp5 ]carbetocin : 1 2 3 4 5 6 7 8 9 CH2- CO - Tyr( Me ) - Ile -Gin -Asp -HN - CH -CO - Pro -Leu -Gly - NH2 CH2 - CH2 - S - CH2 [betaAsp5 ] carbetocin : 1 2 3 4 5 6 7 8 9 CH2 - CO - Tyr (Me ) - Ile - Gin - betaAsp - HN - CH - CO - Pro - Leu - Gly - NH2 CH2 - CH2 - S - CH2 [ DAsn5 ]carbetocin : 1 2 3 4 5 6 7 8 9 CH2 - CO - Tyr (Me ) - Ile - Gln - DAsn -HN - CH - CO - Pro - Leu - Gly - NH2 CH2 – CH2 - CH2 sulfoxide 1+ 11 carbetocin ( two structural isomers ) CH2 - CO - Tyr( Me ) - Ile - Gln - DAsn - HN - CH - CO - Pro -Leu -Gly - NH2 CH2- - - - - - - - CH2 - - - - - - - SO - - - - - - - - - - - CH2 sulfoxide l has the R - configuration on the sulphur atom , sulfoxide II has the S - configuration ). FIG . 1a U . S . Patent Feb . 14 , 2017 Sheet 3 of 8 US 9 , 566 ,311 B2 Content of (Gly® OH ] carbetocin in the antioxidant study samples ( constant pH ) 5%EDTA+0.1pH2 Currentformulation pH5.2noadditives pH5.2+01%EDTA pH5.2+0%methionine methionine Specification + + * *- - - — - - - — - - — - - - - - - — - - - - — - - - - — - - - - — - - - — - - - - — - - - - - - — - - — - 30 - - - - — - - - - - — - - - - — - - - — - - - - - - - — - - - - - - - - - - - - - — * - - - - - - - - - - - - - - * - - - - - - They - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - — - - - - - - - — - - - - - - - - — - — - - - - - = - — - - - — 20 = — - - - — - - = - — - — - - Time(weeksat40°C). - — - - - = — - - - = — - — - - = FIG.2 - - — - - — - - - — - - — - - - - — - — - - - - — - - — - - — - - - - — - - - — - - - - [Gly9OH]carbetocin — - - - - — - - - = - — - - - - - - - - - - - - — - - - = - - — = - - - — - - - - = - - - - — - - - - = - = - - — - - - - — = = - - - - - - — - = = - - — - - - - - = - - - — - - - - - = - - — - - = - — - = - - - - - 10 - — - - = - - - - - - — - - - - - — - - - - - - - — - - = - - - - - — - - - - - - - - - - - — - - - - - - - - — - - - - - - - - — - - - - - - - - - - - - - — - - - - - — - - - - - - - - - - — - - - — - - — - — - - - - - - - — - - - - - - - - — - — - - - - — - - - - - - — - - — - - - — — - 5.0%+- 2.5%+- 4.5%+ 4.0%+ 3.0%+ +%0 Nowi7.0% 6.5% 6.0% 5.% w i og om na2.0% 1.5% 1.0% 0.5% impurity % atent Feb . 14 , 2017 Sheet 4 of 8 US 9, 566, 311 B2 Content of sulfoxide II carbetocin in the antioxidant study samples ( constant pH ) pH5.2+01%EDTA Currentformulation pH5.2noadditives pH5.2+01%EDTA pH5.2+0%methionine methionine Specification + * - * - - - - - - - - - 4 + - - - - * * - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 2 - 30 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 20 - - - - - - - - - - - - - - - - - - - - - - - FIG.3 - - - - Time(weeksat40°C) - - - - - - - - - - - - - - - - - - - - - - - - - - - sulfoxideIlcarbetocin - - - - - - - - - - - - - - - - C - - - - - - - - - - - - - - - - - - - - .- - - - - - - - - - - - .- - - - - - 10 - - - - - - - - - - - - - - - - . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1.0%T 0.9%+ 0.%+ 0.8% 0.7% 0.3% 0.2% 0.1% impurity % U . S . Patent Feb . 14 , 2017 Sheet 5 of 8 US 9 ,566 ,311 B2 individual degradation products at different pH (pH study , constant antioxidant) (tR2.0min)Unknown Gly9OH 1*Sulfoxide Il*Sulfoxide +Asp5 AGlu4 BetaAsp5- +DAsn5 2 - - - - - - - - - - - - - - - - - - - - - - - - - 6.0 - - - - = - - = - = - - - = - - = - - - = - - - = - - - - - - 5. pH FIG.4 - - - - - - - - - - - - - - - - - - - - - - - - - 5.0 - - - - - - - - - Vw - - - - - - - 4.5 - - - - - - - - - -- 4.0 0.40+- 80.0 *00'0 1.40 1.20 1.00 0.60 0.20 impurity % atent Feb . 14 , 2017 Sheet 6 of 8 US 9 , 566 ,311 B2 shows the sum of degradation products at different pH (pH study, constant antioxidant ) wns - - - A - = - - - - - - - - 02 = - - - - - - - - - = - - - = - - - - - - - - - - = - - - - - - = - - - = - - - - - - - - - - - - - - - - = - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - S9 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 0'9 - - - - - - - - - - - - - - - - - - - - - - = - - - - - - - - - - - = - - - - - - - - - = - - - - - - = - - - - - - - - - - - - - - - - - - - - = - - - - - = - - - - = - - - - = - - - - - - - = - - - - - = - - - - - - - - - - - - Hd - = - - = wns - - - - - - - - - - - - - - - - - - = - - - - = - - - - - = - - - - - = - - - - - = - - - - - - SOS = - - - - - - = - - - - - - - - = - - - - - - - - - - - - - - - 990'S - - - - - = - - - - - - ??? = - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - * - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - $t - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 0't +00't ztog +00'1 togo +00'0 OS't OSE 00€ tost products degradation of Sum atent Feb . 14 , 2017 Sheet 7 of 8 US 9 ,566 ,311 B2 CP50 +CP55 +CP60 CT50 *CT55 CT60 * - - - - - - 180 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 150 -