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(12) Patent Application Publication (10) Pub. No.: US 2012/0277199 A1 Ye Et Al US 20120277199A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0277199 A1 Ye et al. (43) Pub. Date: Nov. 1, 2012 (54) MODULATION OF GEL TEMPERATURE OF 61/255,783, filed on Oct. 28, 2009, provisional appli POLOXAMER-CONTAINING cation No. 61/255,780, filed on Oct. 28, 2009, provi FORMULATIONS sional application No. 61/297,170, filed on Jan. 21, 2010, provisional application No. 61/297,138, filed on (75) Inventors: Qiang Ye, San Diego, CA (US); Jan. 21, 2010, provisional application No. 61/364,288, Luis A. Dellamary, San Marcos, filed on Jul. 14, 2010, provisional application No. CA (US); Fabrice Piu, San Diego, 61/366,677, filed on Jul. 22, 2010. CA (US) Publication Classification Assignee: Otonomy, Inc., San Diego, CA (73) (51) Int. C. (US) A 6LX 3/573 (2006.01) A6IP35/00 (2006.01) (21) Appl. No.: 13/500,971 A6IP II/00 (2006.01) PCT Fled: Oct. 19, 2010 A6IP27/16 (2006.01) (22) A6IP37/06 (2006.01) (86) PCT NO.: PCT/US1 OAS3214 (52) U.S. Cl. ......................................... 514/171; 514/181 S371 (c)(1), (57) ABSTRACT (2), (4) Date: May 30, 2012 Disclosed herein are methods for modulation of gel tempera ture of poloxamer-containing formulations. Also described Related U.S. Application Data herein are Sustained release pharmaceutical formulations that (60) Provisional application No. 61/253.782, filed on Oct. gel upon contact with the body and are administered by direct 21, 2009, provisional application No. 61/255,379, application of these compositions and formulations onto or filed on Oct. 27, 2009, provisional application No. via perfusion into the targeted structure(s). Patent Application Publication Nov. 1, 2012 Sheet 1 of 28 US 2012/0277199 A1 Figure 1 1OOO -H Non-Sustained release 100--- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ^ -- Sustained release 10 s s -CH-BimOdal release Time (days) Patent Application Publication Nov. 1, 2012 Sheet 2 of 28 US 2012/0277199 A1 Figure 2 1OOO Active agent solution Active agent particulates suspension Active agent + thermoreversible gel Solution --- Cmin Active agent + thermoreversible gel suspension Time (days) Patent Application Publication Nov. 1, 2012 Sheet 3 of 28 US 2012/0277199 A1 Figure 3 ^s^ Y - ^s. N 8xissix 88& ^ ^s. s Patent Application Publication Nov. 1, 2012 Sheet 4 of 28 US 2012/0277199 A1 Figure 4 S$88.88 &S& sssssssssssssssssssssss SN 888&ss: Patent Application Publication Nov. 1, 2012 Sheet 5 of 28 US 2012/0277199 A1 Figure 5 High solubilty drug to Solution vehicle low Solubility drug Solution vehicle to gel vehicle to gel vehicle 50 40 30 High solubility drug to low solubility drug 10 Patent Application Publication Nov. 1, 2012 Sheet 6 of 28 US 2012/0277199 A1 Figure 6 1.2 Zole dronate MDTE 2h Brm 8. 1.0 s 0.8 0.6 0.4 Zole dronate-Ca complex MDT = 8h 0.2 Patent Application Publication Nov. 1, 2012 Sheet 7 of 28 US 2012/0277199 A1 Figure 7 Glucocorticoid DSP Glucocorticoid DA Glucocorticoid Methylprednisolone Glucocorticoid MPS Glucocorticoid Dextromethorphan NMDA antagonist Eliprodi NMDA antagonist L-701324 NMDA antagonist SP-6001.25 Amitriptyline Tricyclic Droperidol Antidopaminergic Meclizine Antihistamine Patent Application Publication Nov. 1, 2012 Sheet 8 of 28 US 2012/0277199 A1 Figure 8 DEX DSP DA 10,000 10,000 10,000 E s 5. g 2 E. c o d s 1,000 2E 1,000 2E 1,000 s s 3. O d . d e 100 100 100 wa3. w3. s : s 5 ? 10 10 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 910 0 1 2 3 4 5 6 7 8 9 10 Days post IT injection Days post IT injection Days post IT injection Patent Application Publication Nov. 1, 2012 Sheet 9 of 28 US 2012/0277199 A1 Figure 9 MP MPS 100,000 100,000 E E. E. 10,000 10,000 E S C 2 s 9 d 1,000 1,000 C C O O O O O 100 s 100 o o e e s s s s 10 10 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Days post IT injection Days post IT injection Patent Application Publication Nov. 1, 2012 Sheet 10 of 28 US 2012/0277199 A1 Figure 10 10,000 2 1,000 O E C 100 O V S y 10 O n 1 1 3 5 7 Days post IT injection L-701324 108.0 Patent Application Publication Nov. 1, 2012 Sheet 11 of 28 US 2012/0277199 A1 Figure 11 1,000 O E. 100 E 2n CD O . s 10 O O O 1 1 3 5 7 Days post IT injection SP6OO125 25.8 32 Patent Application Publication Nov. 1, 2012 Sheet 12 of 28 US 2012/0277199 A1 Figure 12 10,000 E 2 1,000 O E 2. 100 O O) N 10 5 CD d 1 1 3 5 7 Days post IT injection Meclizine 146.4 18 Patent Application Publication Nov. 1, 2012 Sheet 13 of 28 US 2012/0277199 A1 Figure 13 Cochlear Distribution of Dex from Gel Cochlear Distribution of Dex from Solution Salt and Plontke, Audiology & Neurotology (2009) Patent Application Publication Nov. 1, 2012 Sheet 14 of 28 US 2012/0277199 A1 Figure 14 20%. Dex 70 6%. Dex 60- 0.2%. Dex 2%. Dex ??-- ¿?No. ?? Days post IT injection Patent Application Publication Nov. 1, 2012 Sheet 15 of 28 US 2012/0277199 A1 Figure 15 3& & S$8&& Šs &SSSSSSS&SSS Š&s Sssss-SSSSSSSS s: 8, 88 is a 3&f S$8. Patent Application Publication Nov. 1, 2012 Sheet 16 of 28 US 2012/0277199 A1 Figure 16 S. S. g s S. S. s Sitese says: Sisse isssss Patent Application Publication Nov. 1, 2012 Sheet 17 of 28 US 2012/0277199 A1 Figure 17 (A) 15-18% P407+ water Ciprofloxacin Dexamethansone SY 2. x8x 2% 1000 0.5% rea 0.5% 1000 r: 0.2% s S. 100 ess r asS. 10 1 3 5. 7 9 11 13 1 3 5. 7 9 11 13 Time (days) Time (days) (B) 50% P407+ water-ethanol Ciprofloxacin Dexamethasone 1000 s. 2% 1000 Ys 2% 8 0.2% r8a. 0.2% 100 s &SS. 10 1 3 5. 7 9 11 13 1 3 5 7 9 11 13 Time (days) Time (days) Patent Application Publication Nov. 1, 2012 Sheet 18 of 28 US 2012/0277199 A1 Figure 18 (A) 15-18% P407+ water Ciprofloxacin Dexamethansone 1000 * 2% 1000 x&Y 2% o:8- 0.2% 1OO 10 ; ; ; , , , 1 3 5. 7 9 11 13 Time (days) Time (days) (B) 50% P407+ water-ethanol Ciprofloxacin DexamethaSone 1000 s. 2% 1000 sys 2% r: 0.2% m: 0.2% s 100 \sy 10 1 O 1 3 5. 7 9 11 13 1 3 5. 7 9 11 13 Time (days) Time (days) Patent Application Publication Nov. 1, 2012 Sheet 19 of 28 US 2012/0277199 A1 Figure 19 (A) 15-18% P407+ water Ciprofloxacin Dexamethansone 1000 & 2% 1000s. 2% w8- 0.2% 100 100 1 O 10 Time (days) Time (days) (B) 50% P407+ water-ethanol Ciprofloxacin Dexamethasone 10000 s. 2% 10000 r:o 0.2% 1000 1OOO 100 100 1 O 10 1 3 5 7 1 3 5 7 Time (days) Time (days) Patent Application Publication Nov. 1, 2012 Sheet 20 of 28 US 2012/0277199 A1 Figure 20 :S 38 SS 3. SS .3: Ss: 3; 3.38.8X SE 3.S. s: 3.SS s: is.& Sisk is SRs. 53.83 isiexistic SESS::::::: S-88 SS 2. s Patent Application Publication Nov. 1, 2012 Sheet 21 of 28 US 2012/0277199 A1 Figure 21 P407 - Water P407 water + ethanol Ciprodex Otic 120 120 100 100 an n S 80 S 80 O O s 60 8 60 40 1 40 C 20 20 O O O 1 3 5 7 O 1 3 5. 7 O 1 3 5. 7 Days post IT injection Days post IT injection Patent Application Publication Nov. 1, 2012 Sheet 22 of 28 US 2012/0277199 A1 Figure 22 Ciprofloxacin DexamethaSone 10 100 Eo so 3. 3. O 10 .9 w w 1 d CD d d C C O O O 1 O o o C ? ? 0.1 0.1 O 2 4 6 8 10 12 14 O 2 4 6 8 10 12 14 Time (days) Time (days) Patent Application Publication Nov. 1, 2012 Sheet 23 of 28 US 2012/0277199 A1 Figure 23 100 Ciprofloxacin 100 DexamethaSOne E s 3. S. 10 10 9 S. E E c O5 O5 o o ? ? O.1 0.1 O 5 10 15 20 25 30 O 5 10 15 20 25 30 Time (days) Time (days) Patent Application Publication Nov. 1, 2012 Sheet 24 of 28 US 2012/0277199 A1 Figure 24 Ciprofloxacin Dexamethasone 100 100 E s g S. 10 10 5J w O c 2 : 8 1 O 1 o 5o 0.1 0.1 O 5 10 15 20 25 30 0 5 10 15 20 25 30 Time (days) Time (days) Patent Application Publication Nov. 1, 2012 Sheet 25 of 28 US 2012/0277199 A1 Figure 25 800 600 o 400 200 S. 60 E D 52 40 O O) A 20 s O 1 3 7 14 21 28 1 3 7 14 21 28 Days post IT injection Patent Application Publication Nov. 1, 2012 Sheet 26 of 28 US 2012/0277199 A1 Figure 26 Ciprofloxacin Dexamethasone 100 10 So Eo 3.
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