US009993471B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 993 ,471 B2 Abelson et al. (45 ) Date of Patent : * Jun. 12 , 2018 ( 54 ) OPHTHALMIC FORMULATIONS OF ( 56 ) References Cited CETIRIZINE AND METHODS OF USE U . S . PATENT DOCUMENTS @(71 ) Applicant : Nicox Ophthalmics, Inc. , Fort Worth , 4 , 407 , 791 A 10 / 1983 Stark TX (US ) 4 ,525 , 358 A 6 / 1985 Baltes et al . 5 , 188 , 826 A 2 / 1993 Chandrasekaran et al. @(72 ) Inventors : Mark Barry Abelson , Andover , MA 5 , 419 , 898 A 5 / 1995 Ikejiri et al . (US ) ; Matthew J . Chapin , Amesbury , 5 ,698 , 558 A 12 / 1997 Gray 6 , 103 ,735 A 8 / 2000 Aslanian et al . MA (US ) ; Paul Gomes , Andover , MA 6 , 436 , 924 B2 8 /2002 Poppe et al. (US ) ; George Minno , Windham , NH 6 , 649 , 602 B1 . 11/ 2003 Yanni (US ) ; Jackie Nice , Medford , MA (US ) 6 , 827 , 946 B2 12 / 2004 Hirsh 2002 / 0037297 A1 3 /2002 Crespo et al. @( 73 ) Assignee : NICOX OPHTHALMICS , INC ., Fort 2004 /0198743 Al 10 /2004 Hey et al. 2004 / 0198828 A1 10 / 2004 Abelson et al. Worth , TX (US ) 2005 /0239745 Al 10 /2005 Abelson et al . 2006 / 0025391A 2 / 2006 Lulla et al. @( * ) Notice : Subject to any disclaimer , the term of this 2006 /0183698 A1 8 / 2006 Abelson patent is extended or adjusted under 35 2006 / 0216353 A1 9 /2006 Liversidge et al. U . S . C . 154 ( b ) by 0 days. days . 2006 / 0228306 AL 10 / 2006 Lane 2006 / 0263350 A1 11/ 2006 Lane This patent is subject to a terminal dis 2007 /0020330 AL 1 / 2007 Dang et al. claimer . 2007 / 0275974 A1 11/ 2007 Fanara et al . 2008 /0085922 A14 / 2008 Raja et al. (21 ) Appl. No. : 15/ 456 ,249 2008 /0254029 A1 10 / 2008 Yani et al. ( 22 ) Filed : Mar . 10 , 2017 FOREIGN PATENT DOCUMENTS FP 0433766 A1 6 / 1991 (65 ) Prior Publication Data EP 0920315 B1 . 6 / 1999 JP 6 - 239748 8 / 1994 US 2017 /0182035 A1 Jun . 29, 2017 JP 2009 -507009 2 / 2009 RU 2220740 C1 1 / 2004 Related U . S . Application Data WO WO 97 /46243 A112 / 1997 WO WO 98 / 06394 A1 2 / 1998 (63 ) Continuation of application No . 14 / 982 , 258 , filed on wo WO 99 / 15203 Al 4 / 1999 Dec . 29 , 2015 , now Pat . No. 9 ,750 ,684 , which is a wo WO 03 /049770 A1 6 / 2003 continuation of application No. 12 / 724 , 128 , filed on WO WO 04 / 066960 A2 8 /2004 Mar . 15 , 2010 , now Pat . No . 9 ,254 ,286 . WO WO 04 /069338 Al 8 / 2004 WO WO 05 /030331 Al 4 / 2005 (60 ) Provisional application No. 61 / 161, 006 , filed on Mar. WO WO 05 / 107711 A2 11 / 2005 17 , 2009, provisional application No. 61 / 174 ,850 , WO WO 06 / 102494 A2 9 /2006 WO WO 2007 /026151 A1 3 / 2007 filed on May 1 , 2009 . WO WO 07 / 117971 A2 10 /2007 (51 ) Int. CI. A61K 31/ 56 ( 2006 .01 ) OTHER PUBLICATIONS A61K 31/ 495 ( 2006 .01 ) Abelson et al. , “ A Randomized , Double - Blind , Parallel -Group A61K 31 /569 ( 2006 .01 ) Comparison of Olopatadine 0 . 1 % Ophthalmic Solution Versus A61K 31 /4965 ( 2006 .01 ) Placebo for Controlling the Signs and Symptoms of Seasonal A61K 9 / 00 ( 2006 .01 ) Allergic Conjuctivitis and Rhinoconjunctivitis ” , Clinical Therapeu A61K 9 / 08 ( 2006 .01 ) A61K 31/ 4174 ( 2006 .01 ) tics , 25 ( 3 ) : 931 -947 ( 2003 ) . A61K 47 / 10 ( 2017 . 01 ) (Continued ) A61K 47 / 18 ( 2017 .01 ) A61K 47/ 02 ( 2006 .01 ) Primary Examiner — Zohreh A Fay A61K 47 / 26 ( 2006 .01 ) ( 74 ) Attorney, Agent, or Firm — Arent Fox LLP A61K 47 /38 ( 2006 .01 ) ( 52 ) U . S . CI. (57 ) ABSTRACT CPC .. .. A61K 31 /495 (2013 . 01 ) ; A61K 9 /0048 ( 2013 .01 ) ; A61K 9 / 08 (2013 .01 ) ; A61K The present invention provides stable topical formulations 31/ 4174 ( 2013 . 01 ) ; A61K 31/ 4965 ( 2013 .01 ) ; of cetirizine that provide a comfortable formulation when A61K 31 / 56 ( 2013 .01 ) ; A61K 31 /569 instilled in the eye and is effective in the treatment of allergic ( 2013 . 01 ) ; A61K 47 /02 (2013 . 01 ) ; A61K 47 / 10 conjunctivitis and /or allergic conjunctivitis . The invention (2013 .01 ) ; A61K 47 / 183 ( 2013 .01 ) ; A61K further provides methods of treating allergic conjunctivitis 47 / 186 ( 2013 . 01 ) ; A61K 47 / 26 (2013 . 01) ; and /or allergic rhinoconjunctivitis in a subject in need of A61K 4738 ( 2013 . 01 ) such treatment by topical application of the cetirizine for (58 ) Field of Classification Search mulations of the invention directly to the eye . CPC combination set ( s ) only . See application file for complete search history . 6 Claims, 31 Drawing Sheets US 9 ,993 ,471 B2 Page 2 References Cited Berger et al . , “ Effects of adjuvant therapy with 0 . 1 % olopatadine ( 56 ) hydrochloride ophthalmic solution on quality of life in patients with allergic rhinitis using systemic or nasal therapy ” , Ann . Allergy Asthma Immunol, 95 ( 4 ) : 361 -37112005 ) . OTHER PUBLICATIONS Lanier et al. , Comparison of the Efficacy of Combined Fluticasone Crampton et al. , “ A Comparison of the Relative Clinical Efficacy of Propionate and Olopatadine Versus Combined Fluticasone Propionate and Fexofenadine for the treatment of Allergic a Single Dose of Ketotifen Fumarate 0 /025 % Ophthalmic Solution Rhinoconjunctivitis Induced by Conjunctival Allergen Challenge , Versus Placebo in Inhibiting the Signs and Symptoms of Allergic Clin . Ther ., 24 ( 7 ) : 1161 - 1174 ( 2002 ) . Rhinoconjunctivitis as Induced by the Conjunctival Allergen Chal Ousler et al ., “ An evaluation of the ocular drying effects of 2 lenge Model ” , Clinical Therapeutics , 24 ( 11 ) : 1800 - 1808 ( 2002 ) . systemic antihistamines : loratadine and cetirizine hydrochloride ” , Goodman and Gilman ' s the Pharmacological Basis of Therapeutics Ann . Allergy Asthma Immunol. , 93 ( 5 ) : 460 - 464 ( 2004 ) . ( Tenth Edition ) (2001 ) , McGraw Hill , Chapter 1 , pp . 3 - 29 . Spangler et al ., “ Randomized , Double -Masked Comparison of United States Pharmacopeia (http :/ /en .wikipedia . org /wiki / Olopatadine Ophthalmic Solution , Mometasone Furoate United States Pharmacopeia # Product_ quality. E2 . 80 . Monohydrate Nasal Spray, and Fexofenadine Hydrochloride Tablets 93standards _ and _ verification ) assessed from the internet on Oct . Using the Conjunctival and Nasal Allergen Challenge Models ” , 22 , 2012 Clin . Ther . , 25 ( 8 ) :2245 -2267 (2003 ) . U . S . Patent Jun . 12, 2018 Sheet 1 of 31 US 9 ,993 ,471 B2 * t VehicleN=16 w her ouse p *:Clinicallyandstatisticallysignificant(P<0.05)difference 35 Time(min)postCAC* * . * . * . * . * Post-Dose) *.Statisticallysignificant(P<005)difference RODRIOS Figure1A:AllergyHumanPOCStudy#1Results(OcularItching16Hoursw deparCetirizineN=15 WWWWWWWWWWWWWWWWWWWWWNanananananana . i News on 1 ) scale 4 - 0( Scores Itching Ocular Mean U . S . Patent Jun . 12, 2018 Sheet 2 of 31 US 9 ,993 ,471 B2 20 089929 1994 ogooc000990360og 15 9990000099/ Cetirizine0.1%N=15-Vehicle16 Time(min)post-CAC oogoo * gogsoo wwwwwwwwwwwwwwwwwwwwwwwWYNEwwwwwwwww7WWWWWWWWWWWW 7 S Figure1B:ConjunctivalRednessScoreswww hoor Baseline december u No svorite ) scale 4 - 0( Score RednessConjunctival Soooo goooo Mean U . S . Patent Jun . 12, 2018 Sheet 3 of 31 US 9 , 993, 471 B2 VehicleN=16+ AKKER 69692 XOO000000000000w annannnnnnnnnnnnnnnnn wwwwwwwww tion ! AnnaM wwwwwwwwwwwwwwwwwwwwwwwwcco wood Time(min)postinstillation! Figure2:AllergyHumanPOCStudy#1Results (DropComfort) CetirizineN=15atip *Statisticallysignificant(P<0.05)difference 000000 DOS songs99999000000 wwwwwwww 00000000000 wwwwwwwwwwwwwwwwwwwwwwwwwwwww Note:MostUncomfortableCommerciallyAvailableAllergyDrop=4K DOO L Senannnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 3:3A o voo ONWAO ) scale 10- 0 ( Scores Comfort* Drop Mean 9 ??Uncomfortable VeryComfortable U . S . Patent Jun . 12, 2018 Sheet 4 of 31 US 9 ,993 ,471 B2 BeginQDdosing X Visit2B(Day0) mm )CACAV2from(w ConfirmationCAC om w t=8hours Figure3A:StudyDesignScreening Redness,ChemosisLidSwellingWateryEyesRhinorrheaNasalPruritis&Earorpalate Onlysubjectswhoexperiencedascoreof>2forocularitching,conjunctivalrednessand nasalcongestionatVisit1andascoreof>2forocularitchingconjunctivalrednessin ourof3timepointand>2fornasalcongestioninatleastout4pointsVisit2B ConfirmationCAC t=0 Ocularallergicassessments:Itching3,5and7minutespost-CAC PeakNasalInspiratoryFlow:9and30minutespost-CAC Visit1(Day-),2A0 - - - Pruritis:7,15and20minutespost-CAC werescheduledforVisit3 t=0 1 t CACTitration U . S . Patent Jun . 12, 2018 Sheet 5 of 31 US 9 ,993 ,471 B2 Visit4B(Day7) CAC t=8hours(fromV4A StudyMedication) onogpogon CAC t=0 Visit4A(Day7) CACpostminutes-7Itching3,5andassessments:Ocularallergic Redness,ChemosisLidSwellingWateryEyesRhinorrheaNasalPruritis& Figure3B:StudyDesignEfficacy 4 Evaluation Study t=-15min PeakNasalInspiratoryFlow:9and30minutespost-CAC Medication CACpostminutes-and2015,palatePruritis:7Earor XXXXXXXXXXXXXXXXXXXXXXXXX* XXXXXXXXXXXXXX* X CAC two Visit3(Day6) StudyMedication t=-15min U . S . Patent Jun . 12 , 2018 Sheet 6 of 31 US 9, 993, 471 B2 Vehicle(N=15) * SelinaF10.01%(N=15) Figure4:PrimaryOcularItching(Visit4B) +F10.005%(N=16) willigaF10.001%(N=16) scalew ) 4- 0( cing Ith Ocularco - Mean o U . S . Patent Jun . 12 , 2018 Sheet 7 of 31 US 9 ,993 ,471 B2 seteVehicle(N=15) Cine 75 0.01%(N=15) Figure5:PrimaryConjunctivalRedness(Visit4B) +-0.005%(N=16) * * *P<0,05Futicasone.005%vsVehicle;Fluticasone01 laF10.001%(N=16) *P<0.05Futicasone005%vsVehicle * scaleetu ) 4 - 0 (w Redness6 N Conjunctivalc Mean U . S . Patent Jun . 12, 2018 Sheet 8 of 31 US 9 , 993, 471 B2 Figure6:PrimaryLidSwelling(Visit4B) +-F10.005%(N=16)meitena0115_*Vehicle alikanF10.001%(N=16) *:P<0.05Fluticasone001%vsVehicle om a 1.5 scale ) 3 - 0 ( Swelling Lid Mean& U . S . Patent Jun . 12, 2018 Sheet 9 of 31 US 9 , 993 , 471 B2 *Vehicle(N=15) 20 »F10.01%(N=15) Figure7:PrimaryNasalCongestion(Visit4B)