US 20090312724A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0312724 A1 Pipkin et al. (43) Pub. Date: Dec. 17, 2009 (54) NASAL AND OPHTHALMIC DELIVERY OF tion-in-part of application No. PCT/US07/72387, filed AQUEOUS CORTICOSTEROID SOLUTIONS on Jun. 28, 2007, which is a continuation-in-part of application No. PCT/US07/72422, filed on Jun. 28, (75) Inventors: James D. Pipkin, Lenexa, KS (US); 2007. Rupert O. Zimmerer, Lenexa, KS (US); John M. Siebert, Lenexa, KS Publication Classification (US) (51) Int. Cl. Correspondence Address: A6M 37/00 (2006.01) SWANSON & BRATSCHUN, L.L.C. 38: 5. 308: 821 O SOUTHPARK TERRACE LITTLETON, CO 80120 (US) (52) U.S. Cl. ..................... 604/294; 514/171; 128/207.18 (73) Assignee: CYDEX PHARMACEUTICALS, (57) ABSTRACT INC., Lenexa, KS (US) The present invention is directed to methods of treating nasal and/or ophthalmic diseases, symptoms, or disorders that are (21) Appl. No.: 12/479,576 therapeutically responsive to corticosteroid therapy by deliv 1-1. ering aqueous solution formulations comprising a corticos (22) Filed: Jun. 5, 2009 teroid to nasal and ophthalmic tissues. The invention is also O O directed to methods, systems, devices, and compositions for Related U.S. Application Data delivering aqueous Solution formulations comprising a corti (63) Continuation-in-part of application No. PCT/US2008/ costeroid and an antihistamine to nasal and ophthalmic tis 068872, filed on Jun. 30, 2008, which is a continua SUS. Patent Application Publication Dec. 17, 2009 Sheet 1 of 40 US 2009/0312724 A1 Phase Solubility of Budesonide E O.OO7 M 30.006 | 9 0.005 - O 0.004 - 0.003 0.002 -- 2 O.OO1 -- Y - --SBE-7CD - O A D-o-o-e Water 3. O O. O.2 O.3 0.4 Molarity of Cyclodextrin FIG. 1A Patent Application Publication Dec. 17, 2009 Sheet 2 of 40 US 2009/0312724 A1 Budesonide Phase Solubility in Captisol and in SBEXGamma CD O.O.08 O.OOO O.OO O.O5 O.10 O.15 O.2O O.25 O.30 O.35 O.40 Cyclodextrin Concentration (M) 0 SBE (4.9)-gamma { SBE (5.2)-gamma -O SBE(6)-gamma -A-SBE (8.3)-gamma H Captisol Linear (SBE (4.9)-gamma) FIG. 1B Patent Application Publication Dec. 17, 2009 Sheet 3 of 40 US 2009/0312724 A1 Effect of CD Ring Size and DS on Solubility of Fluticas one Propionate O.OOO 0.020 0.040 O.O60 O.08O O. 1 OO O. 120 Cyclodextrin), M -- (SBE)6.7-beta -- (SPE)7-beta -- (SBE)5.2-gamma -- (SPE)5.4-gamma -H (SBE)7-alpha ->e- (SBE)6.1-gamma -O-(SBE)9.7-gamma -x- gamma FIG. 2 Patent Application Publication Dec. 17, 2009 Sheet 4 of 40 US 2009/0312724 A1 Effect of CD Ring Size and DS on Solubility of Mometasone Furoate OO 90 8O 7O 60 50 40 3O 2O O O O.O2 O.04 O.O6 O.O8 O. O. 12 Cyclodextrin), M -0-(SBE)6.7-beta -- (SPE)7-beta - (SBE)5.2-gamma -- (SPE)5.4-gamma -H (SBE)7-alpha bé (SBE)6.1-gamma -O-(SBE)9.7-gamma X-gamma FIG. 3 Patent Application Publication Dec. 17, 2009 Sheet 5 of 40 US 2009/0312724 A1 Solubilization of FluticasOne With or Without Ester by (SAE)5-6-gamma CD 1600 X is 1200 1. 1. 1000 1 1 SBE6.1 e A1 e 6 O O 400 200 --- O O.O2 O.04 0.06 0.08 0.1 O. 12 Cyclodextrin), M H Propionate (SBE)5.2-gamma -- Non-esterified (SBE)5.2-gamma - A - Propionate (SPE)5.4-gamma -A - Non-esterified (SPE)5.4-gamma --Propionate (SBE)6.1-gamma -0- Non-esterified (SBE)6.1-gamma FIG. 4 Patent Application Publication Dec. 17, 2009 Sheet 6 of 40 US 2009/0312724 A1 Solubility of Beclomethasone Dipropionate in 0.04MCD solutions (24hr equilibration) 500 go 450 400 350 3 O O SBE3.4g-CD SBE6.1 g-CD SBE7.5g-CD Captisol Gamma FIG. 5 Patent Application Publication Dec. 17, 2009 Sheet 7 of 40 US 2009/0312724 A1 -3 * P-value vs. Placebo <0.05 ** P-value vs. Rhinocort Aqua <0.05 O 1 2 3 4. 5 6 7 8 9 10 Time (hours) --CE-Budesonide --Rhinocort Aqua - o- Placebo F.G. 6A Patent Application Publication Dec. 17, 2009 Sheet 8 of 40 US 2009/0312724 A1 * P-value vs. Placebo <0.05 ** P-value vs. Rhinocort Aqua -0.05 O 1 2 3 4. 5 6 7 8 9 1 O Time (hours) --CE-Budesonide -- Rhinocort Aqua - o- Placebo FIG. 6B Patent Application Publication Dec. 17, 2009 Sheet 9 of 40 US 2009/0312724 A1 Total Ocular Symptom Score Change from Baseline -0.6 -08 -1.2 -1.4 .6 -8 O 2 4 6 8 1 O 12 Time (hours) --CE-Budesonide --Rhinocort Aqua A Placebo Patent Application Publication Dec. 17, 2009 Sheet 10 of 40 US 2009/0312724 A1 Itchy/Gritty Eyes Symptom Score Change From Baseline -O.8 O 2 4 6 8 O 12 Time (hours) FIG. 6D Patent Application Publication Dec. 17, 2009 Sheet 11 of 40 US 2009/0312724 A1 Tearing/Watering Eyes Symptom Score Change From Baseline --CE-Budesonide --Rhinocort Aqua - A- Placebo O 2 4. 6 8 1 O 12 Time (hours) F.G. 6E Patent Application Publication Dec. 17, 2009 Sheet 12 of 40 US 2009/0312724 A1 ise (hors O 2 4. 6 8 () 12 x Capiisoi-Enabied& Budescride -5 8x: rise Rhinocori. Aga3. xx -iaCe F.G. 6F Patent Application Publication Dec. 17, 2009 Sheet 13 of 40 US 2009/0312724 A1 AUC of total Nasal Symptom Stores NSS with Stadiarror 88:E-E:8esortige 8 Riatacort 8:38 to Faceb: F.G. 6G Patent Application Publication Dec. 17, 2009 Sheet 14 of 40 US 2009/0312724 A1 AC of Total Octia Syrpton Scores TOSS with Stascarci Error 8 E-E:8esori:e 8 Riacort 8:3a o Face: F.G. 6H Patent Application Publication Dec. 17, 2009 Sheet 15 of 40 US 2009/0312724 A1 -ja: ; S. late:is 2.83.38 FIG. 6 Patent Application Publication Dec. 17, 2009 Sheet 16 of 40 US 2009/0312724 A1 W1. W2a-d W3 W4a-b V5 V6a-b W7 DO 1-A D5 D20-21 22 D37.38 D39 Period Period 2 Period 3 FIG. 7 Patent Application Publication Dec. 17, 2009 Sheet 17 of 40 US 2009/0312724 A1 1. 5 CE-Budesonide Rhinocort Adua Placebo : 0.25 0.5 0.75 Time (Hours) Patent Application Publication Dec. 17, 2009 Sheet 18 of 40 US 2009/0312724 A1 TNSS change from baseline with onset of action during first three time points CE-BudeSonide Rhinocort Aqua Placebo O.25 O.5 0.75 Time (Hours) Patent Application Publication Dec. 17, 2009 Sheet 19 of 40 US 2009/0312724 A1 Mean Change from Baseline in EEC-RQOLQ for Captisol Enabled Budesonide Wersus Placebo for PCC PTSD 3 --Captisol-Enabled 2 ES EUSOil E --Fla.) 2. R -- RhiOCOrt, (Ua S. Time hous) FG. 9A Patent Application Publication Dec. 17, 2009 Sheet 20 of 40 US 2009/0312724 A1 Mean Change from Baseling in EEC-RQOLQ for Captisol Enabled Budesonicle wersus Placebo for Emotional Domain as g -HCaptisl-Enabled ESOFi --Fla.) is -- RhiOCOft A (a s Tire hous) FG. 9B Patent Application Publication Dec. 17, 2009 Sheet 21 of 40 US 2009/0312724 A1 Mean Change from Baseling in EEC-RQOLQ for Captisol Enabled Budesonide wersus Placebo for Non Nose/Eye Domain O. 5 3. a -HCaptis-Erald 3. EUSOfide r --Fla.) E -. 5 s -- RhiOCOft., (J3 E 5 Time (hours FG. 9C Patent Application Publication Dec. 17, 2009 Sheet 22 of 40 US 2009/0312724 A1 Azelastine pH Rate Profile Area 9% (25°C) 0.5mg/mLazelastine HCI in 3m M citrate G) pH 4, 5, & 6; with and without 1.75% Captisol Stored in 25°C Stability Chamber 99.7 99.65 99.6 99.55 99.5 O 20 40 60 8O OO 120 Time (days) FIG. 10A Patent Application Publication Dec. 17, 2009 Sheet 23 of 40 US 2009/0312724 A1 Azelastine pH Rate Profile Area % (40°C) 0.5mg/mL azelastine HCI in 3m M. citrate G pH 4, 5, & 6; with and without 1.75% Captisol Stored in 40°C Stability Chamber 99.75 99.7 99.85 99.6 99.55 99.5 I I s O 20 40 60 8O 1OO 2O Time (days) --pH4 az only --pH4 az?cap - ApH5az only --pH5azicap -e-pH6 az only -o-pH6 azcap FIG. 1 OB Patent Application Publication Dec. 17, 2009 Sheet 24 of 40 US 2009/0312724 A1 Azelastine pH Rate Profile Area 9% (60°C) 0.5mg/mLazelastine HCl in 3m M. citrate G) pH 4, 5, & 6; with and without 1.75% Captisol Stored in 60°C Stability Chamber 99.5 99 98.5 98 97.5 - 97 96.5 96 I I r O 20 40 60 80 OO 2O Time (days) FIG. 1 OC Patent Application Publication Dec. 17, 2009 Sheet 25 of 40 US 2009/0312724 A1 s S 1 .6 9 1.4 1.2 + S3 1.0 0.8 - O6 -a- MMMMMM MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMM O.4 MM O.2 | M woosuneouseumuse-20mM Captisol w AZ --30mM oute issue Captisol w AZ oute --40mM one Captisol usuruoso. w Az O 1 2 3 4. 5 6 7 8 Az Concentration (mM) FIG. 11A Patent Application Publication Dec.