US010166199B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 166 , 199 B2 Jones et al. ( 45 ) Date of Patent : Jan . 1 , 2019 ( 54 ) TRANSDERMAL PATCH COMPRISING A (58 ) Field of Classification Search ROPIVACAINE FORMULATION None (71 ) Applicant: BUZZZ PHARMACEUTICALS See application file for complete search history . LIMITED , Raheny , Dublin ( IE ) ( 56 ) References Cited ( 72 ) Inventors : Chris Jones , Cardiff GB( ) ; Darren U . S . PATENT DOCUMENTS Green , Cardiff (GB ) 4 , 956 , 171 A * 9 / 1990 Chang .. A61K 9 / 0014 ( 73 ) Assignee : Buzzz Pharmaceuticals Limited , 424 /448 Dublin (IE ) 9 , 295, 655 B2 * 3 / 2016 Choi .. .. .. .. .. .. A61K 9 / 7053 (Continued ) ( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U . S . C . 154 ( b ) by 0 days . EP 1661560 5 /2006 (21 ) Appl. No. : 15 /027 , 905 EP 1964552 9 / 2008 ( Continued ) ( 22 ) PCT Filed : Oct . 7 , 2014 ( 86 ) PCT No .: PCT/ EP2014 /071437 OTHER PUBLICATIONS $ 371 ( c ) ( 1 ) , Merriam Webster definition of oil ( obtained online May 25, 2017 ). * ( 2 ) Date : Apr. 7 , 2016 (Continued ) ( 87 ) PCT Pub . No . : W02015 / 052183 Primary Examiner — Robert A Wax PCT Pub. Date : Apr. 16 , 2015 Assistant Examiner — Melissa S Mercier (74 ) Attorney , Agent, or Firm - Barnes & Thornburg , (65 ) Prior Publication Data LLP US 2016 / 0235689 A1 Aug. 18 , 2016 (57 ) ABSTRACT (30 ) Foreign Application Priority Data The present invention relates to a transdermal patch com prising a pharmaceutical formulation , the formulation com Oct . 7 , 2013 ( EP ) .. .. .. .. .. .. .. .. .. .. .. 1317718 prising ropivacaine or an opioid , a pharmaceutically - accept able adhesive and optionally one or more excipients selected (51 ) Int. CI. from the group consisting of carrier oils , penetration enhanc A61K 9 / 70 ( 2006 .01 ) ers and hydrophilic materials . The present invention also A61K 47 / 10 ( 2017 .01 ) relates to methods of preparation of such a pharmaceutical (Continued ) formulation , as well as the use of such a transdermal patch (52 ) U . S . CI. in the treatment of pain ( e . g . nociceptive and / or neuropathic CPC . .. .. .. A61K 9 / 7061 ( 2013 . 01 ) ; A61K 31/ 445 pain ). ( 2013 .01 ) ; A61K 31/ 485 (2013 .01 ) ; ( Continued ) 19 Claims, 13 Drawing Sheets cremeriahan 1 ml saturated ropivacaine in pH5 . 5 wens 3 % Ropivacaine patch in 900A 5 % Ropivacaine patch in 2074 87 . 5 % Ropivacaine patch in 2074 V 10 % Ropivacaine patch in 2074 Ropivacainepermeated(ug/cm2) * 25% Ropivacaine patch in 2677 izatea. 7 . 5 % Ropivacaine patch in 2677 a halbmw 1 ml saturated ropivacaine in H20 12 24 36 48 Time ( h ) US 10 ,166 , 199 B2 Page 2 (51 ) Int . CI. WO WO2007070679 6 / 2007 A61K 31/ 445 ( 2006 .01 ) WO WO2007100910 9 / 2007 A61K 47 / 14 ( 2017 . 01 ) WO WO2011005853 1 / 2011 A61K 31/ 485 ( 2006 . 01 ) WO WO2011 / 121082 Al 10 / 2011 A61K 47 /22 ( 2006 .01 ) WO WO2016009063 AL 1 / 2016 (52 ) U . S . CI. CPC . .. .. .. A61K 47 / 10 (2013 . 01 ) ; A61K 47/ 14 OTHER PUBLICATIONS ( 2013. 01 ); A61K 47 / 22 ( 2013 .01 ) PCT Search Report and Written Opinion for PCT /EP2014 /071437 , completed Nov . 19 , 2014 . ( 56 ) References Cited GB Search Report for GB1317718 . 3 , completed Apr. 8 , 2014 . U . S . PATENT DOCUMENTS Power, I. , “ An Update on Analgesics; ” 2011 ; British Journal of Anaesthesia ; 107 , ( 1 ) ; pp . 19 - 24 . 2002 / 0197284 Al 12 / 2002 Luo et al . Cilurzo , F . , “ Adhesive properties: a critical issue in transdermal 2004 / 0096491 A1 5 / 2004 Tateishi et al. patch development, ” 2012 , Expert Opin . Drug Deliv . 9 ( 1 ) :33 - 45 . 2005 / 0087195 AL 4 / 2005 Huang Roy et al. “ Transdermal delivery of buprenorphine through cadaver 2005 /0276842 Al 12 / 2005 Zhang et al. skin ” Journal of Pharmaceutical Sciences , vol . 83 , No. 2 , 1994 , pp . 2007 / 0059351 A1 3 / 2007 Murrell et al. 126 - 130 . 2007 /0189978 A1 * 8 / 2007 Zhang . * * * * A61K 9 / 0014 424 /45 Taghizadeh et al. “ Preparation and In Vitro Evaluation of a New 2010 /0008991 A11 / 2010 Mantelle Fentanyl Patch Based on Acrylic /Silicone Pressure - Sensitive Adhe 2011/ 0104093 A1 * 5 / 2011 McLaughlin . .. .. .. A61K 8 /60 sive Blends” Drug Development and Industrial Pharmacy , vol. 35 , 424 / 70 . 11 No. 4 , 2009 , pp . 487 -498 . 2013 /0072884 Al * 3 / 2013 Hamlin . .. A61K 9 / 703 Liao et al. “ In Vitro Skin Permeation of Buprenorphine Transdermal 604 / 304 Patch ” Journal of Food and Drug Analysis , vol. 16 , No . 6 , 2008 , pp . 8 - 15 . Roy et al . “ Controlled transdermal delivery of fentanyl: Character FOREIGN PATENT DOCUMENTS izations of pressure - sensitive adhesives for matrix patch design ” EP 2177217 AL 4 / 2010 Journal of Pharmaceutical Sciences , vol . 85 , No . 5 , 1996 , pp . EP 2687205 1 / 2014 491 - 495 . EP 2759294 7 / 2014 WO WO2005123046 12 / 2005 * cited by examiner U . S . Patent Jan . 1 , 2019 Sheet 1 of 13 US 10 , 166 , 199 B2 70 T 1ml saturated ropivacaine in pH5 . 5 tamoyka3 % Ropivacaine patch in 900A + sanoin 5 % Ropivacaine patch in 2074 7 . 5 % Ropivacaine patch in 2074 secunoastem 10 % Ropivacaine patch in 2074 Ropivacainepermeated(ug/cm2) casamenwensen 5 % Ropivacaine patch in 2677 se 7 . 5 % Ropivacaine patch in 2677 BS 1ml saturated ropivacaine in H2O wwwMob 12 36 Time (h ) Figure 1 U . S . Patent Jan . 1 , 2019 Sheet 2 of 13 US 10 , 166 , 199 B2 1ml saturated ropivacaine in buffer pH 10 . 4 + strength 7 . 5 % ropivacaine in 2677 selen 7 . 5 % ropivacaine ( 5 % transcutol) in 2677 Ropivacainepermeated(ug/cm2) sono 4 % ropivacaine in 900A une inste 12 % Ropivacaine patch in 2074 TASYSHAKERS RIETAVAS O tePROP i 24 48 Time ( h ) Figure 2 U . S . Patent Jan . 1 , 2019 Sheet 3 of 13 US 10 , 166 , 199 B2 sucede 7 . 5 % ropivacaine , 15 % [30 /60 / 10 ] (PG /cap 90 /Brij 93 ) in 2677 1 + elektromos 7 . 5 % ropivacaine in 2677 Ropivacainepermeated(ug/cm2) + -+ -to + 24 36 48 Time ( h ) Figure 3 U . S . Patent Jan . 1 , 2019 Sheet 4 of 13 US 10 , 166 , 199 B2 and insenen 7 . 5 % ropivacaine , 15 % [ 25 /60 / 10 / 5 ] (PG / CAP 90 / Brij 93 / Tween 80 ) in 2677 ( b / n : 200213b ) H - - 7 . 5 % ropivacaine, 15 % [ 25 /60 / 10 / 5 ] ( PG / CAP 90 / Brij 93 /Cremphor EL) in 2677 ( b / n : 2002130 ) + men 7 . 5 % ropivacaine , 15 % [80 / 13. 3 / 6 . 7 ] (CAP 90 /Brij 93/ Tween 80 ) in 2677 ( b / n : - 200213e ) + - 7 . 5 % ropivacaine , 15 % [66 . 7 / 11. 1 /22 . 2 ] (CAP 90 /Brij 93 /Tween 80 ) in 2677 ( b / n - 200213h ) + - Ropivacainepermeated(ug/cm2) + - + - + - + - + - + - o 24 36 Time ( h ) Figure 4 atent Jan . 1 , 2019 Sheet 5 of 13 US 10 , 166 , 199 B2 6 . 5 % ropivacaine , 35 % [ 30 /60 / 10 ] ( PG / cap 90 / Brij 93 ) in 2677 ( b / n : 250313a ) esetleges 6 . 5 % ropivacaine , 5 % transcutol, 20 % [ 30 /60 / 10 ] (PG / cap 90 / Brij 93 ) in 2677 ( b / n : 0404130 ) + camerele 7 . 5 % ropivacaine, 15 % [ 30 /60 / 10 ] (PG / cap 90 / Brij 93 ) in Ropivacainepermeated(ug/cm2) 2677 ( b / n : 040213b ) 12 24 36 48 Time ( h ) Figure 5 U . S . Patent Jan . 1 , 2019 Sheet 6 of 13 US 10 , 166 , 199 B2 2000 1800 annelijamo lidocaine saturated H2O 1600 dhuropivacaine saturated H2O Amountpermeated(ug/cm2) 400 + - 200 + - ONES ANTERNER + SE X X A S SARAKSTS ARE MADERA EL MES LES FESTES CASESONGERASKANsamaa KESELAMATAS PERS mutassa . O 4 8 12 Time ( h. ) 1620 Figure 6 U . S . Patent Jan . 1 , 2019 Sheet 7 of 13 US 10 , 166 , 199 B2 S audio maa ropivacaine saturated H2O H 5- 7 . 5 % ropivacaine patch (bn : AH 011012 ) + XWENSIYADARE Ropivacainepermeated(ug/cm2) A + + - + - + - + - + O 4 8 12 16 20 24 28 32 36 40 44 48 Time ( h ) Figure 7 U . S . Patent Jan . 1 , 2019 Sheet 8 of 13 US 10 , 166 , 199 B2 condimm 4 % Ropivacaine in 900A ( b / n : 041212b ) ( n = 6 ) Ropivacainepermeated(ug/cm2) -to + 4 8 12 162024 Time ( h ) Figure 8 U . S . Patent Jan . 1 , 2019 Sheet 9 of 13 US 10 , 166 , 199 B2 Ropivacaineflux(ug/cm2h) and Ropivacaine in 900A ( b / n : 041212b ) ( n = 6 ) + 4 8 12 162024 Time ( h ) Figure 9 U . S . Patent Jan . 1 , 2019 Sheet 10 of 13 US 10 , 166 , 199 B2 se sasa 7 . 5 % Ropivacaine, 15 % [ 30 /60 / 10 ] ( PG /Capryol 90 / Brij 93 in 2677 ( b / n : 040213b ) ( n = 6 ) sunset 7 . 5 % ropivacaine in 2677 patch (bn : 011012 ) ( n = 6 ) Ropivacainepermeated(ug/cm2) EAA + 4812162024 Time ( h ) Figure 10 U . S . Patent Jan . 1 , 2019 Sheet 11 of 13 US 10 , 166 , 199 B2 4 . 5 , semuanythose 7 . 5 % Ropivacaine , 15 % [ 30 / 60 / 10 ] ( PG / Capryol 90 / Brij 93 in 2677 ( b / n : 040213b ) ( n = 6 ) HM Ropivacaineflux(ug/cm2h) ER + + o + 8 12 162024 Time ( h ) Figure 11 U . S . Patent Jan . 1 , 2019 Sheet 12 of 13 US 10 , 166 , 199 B2 140 Tsunadime 6 . 5 % ropivacaine , 35 % [ 30 /60 / 10 ] PG / Capryol 90 / Brij 93 in 2677 ( b / n : 250313a ) Sensations 6 . 5 % ropivacaine , 5 % menthol, 20 % [ 30 /60 / 10 ] PG / Capryol 90 / Brij 93 in 2677 ( b / n : 150413a - 1 ) englannen 5 % Lidocaine , Versatis ( b / n : 346D01 ) Ropivacainepermeated(ug/cm2) RISTA SENAW + 8 0 12 162024 Time ( h ) Figure 12 U .S . Patentatent Jan . 1 , 2019 Sheet 13 of 13 US 10 , 166 , 199 B2 x GURU SOSIS Ropivacaineflux(ug/cm2h) NISASI KERANA + - XXX + S - + ELEPAS conglom 6 . 5 % ropivacaine , 35 % [ 30 /60 / 10 ] PG / Capryol - 90 / Brij 93 in 2677 ( b / n : 250313a ) 6 . 5 % ropivacaine , 5 % menthol, 20 % [ 30 / 60 / 10 ] + PG /Capryol 90 / Brij 93 in 2677 ( b / n : 150413a - 1 ) - nam pasur 5 % Lidocaine, Versatis ( b / n : 346D01) + + o 4 12 2 16 20 24 Time ( h ) Figure 13 US 10 , 166 , 199 B2 TRANSDERMAL PATCH COMPRISING A In certain conditions , the pain may be caused by a ROPIVACAINE FORMULATION complex mixture of nociceptive and neuropathic factors .